Non‐clotting factor therapies for preventing bleeds in people with congenital hemophilia A or B

Omotola O Olasupo; Noella Noronha; Megan S Lowe; Derek Ansel; Mihir Bhatt; Davide Matino

doi:10.1002/14651858.CD014544.pub2

. 2024 Feb 27;2024(2):CD014544. doi: 10.1002/14651858.CD014544.pub2

Non‐clotting factor therapies for preventing bleeds in people with congenital hemophilia A or B

Omotola O Olasupo ¹, Noella Noronha ¹, Megan S Lowe ², Derek Ansel ³, Mihir Bhatt ⁴, Davide Matino ^5,^✉

Editor: Cochrane Cystic Fibrosis and Genetic Disorders Group

PMCID: PMC10897951 PMID: 38411279

Abstract

Background

Management of congenital hemophilia A and B is by prophylactic or on‐demand replacement therapy with clotting factor concentrates. The effects of newer non‐clotting factor therapies such as emicizumab, concizumab, marstacimab, and fitusiran compared with existing standards of care are yet to be systematically reviewed.

Objectives

To assess the effects (clinical, economic, patient‐reported, and adverse outcomes) of non‐clotting factor therapies for preventing bleeding and bleeding‐related complications in people with congenital hemophilia A or B compared with prophylaxis with clotting factor therapies, bypassing agents, placebo, or no prophylaxis.

Search methods

We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Coagulopathies Trials Register, electronic databases, conference proceedings, and reference lists of relevant articles and reviews. The date of the last search was 16 August 2023.

Selection criteria

Randomized controlled trials (RCTs) evaluating people with congenital hemophilia A or B with and without inhibitors, who were treated with non‐clotting factor therapies to prevent bleeds.

Data collection and analysis

Two review authors independently reviewed studies for eligibility, assessed risk of bias, and extracted data for the primary outcomes (bleeding rates, health‐related quality of life (HRQoL), adverse events) and secondary outcomes (joint health, pain scores, and economic outcomes). We assessed the mean difference (MD), risk ratio (RR), 95% confidence interval (CI) of effect estimates, and evaluated the certainty of the evidence using GRADE.

Main results

Six RCTs (including 397 males aged 12 to 75 years) were eligible for inclusion.

Prophylaxis versus on‐demand therapy in people with inhibitors

Four trials (189 participants) compared emicizumab, fitusiran, and concizumab with on‐demand therapy in people with inhibitors.

Prophylaxis using emicizumab likely reduced annualized bleeding rates (ABR) for all bleeds (MD −22.80, 95% CI −37.39 to −8.21), treated bleeds (MD −20.40, 95% CI −35.19 to −5.61), and annualized spontaneous bleeds (MD −15.50, 95% CI −24.06 to −6.94), but did not significantly reduce annualized joint and target joint bleeding rates (AjBR and AtjBR) (1 trial; 53 participants; moderate‐certainty evidence).

Fitusiran also likely reduced ABR for all bleeds (MD −28.80, 95% CI −40.07 to −17.53), treated bleeds (MD −16.80, 95% CI −25.80 to −7.80), joint bleeds (MD −12.50, 95% CI −19.91 to −5.09), and spontaneous bleeds (MD −14.80, 95% CI −24.90 to −4.71; 1 trial; 57 participants; moderate‐certainty evidence). No evidence was available on the effect of bleed prophylaxis using fitusiran versus on‐demand therapy on AtjBR.

Concizumab may reduce ABR for all bleeds (MD −12.31, 95% CI −19.17 to −5.45), treated bleeds (MD −10.10, 95% CI −17.74 to −2.46), joint bleeds (MD −9.55, 95% CI −13.55 to −5.55), and spontaneous bleeds (MD −11.96, 95% CI −19.89 to −4.03; 2 trials; 78 participants; very low‐certainty evidence), but not target joint bleeds (MD −1.00, 95% CI −3.26 to 1.26).

Emicizumab prophylaxis resulted in an 11.31‐fold increase, fitusiran in a 12.5‐fold increase, and concizumab in a 1.59‐fold increase in the proportion of participants with no bleeds.

HRQoL measured using the Haemophilia Quality of Life Questionnaire for Adults (Haem‐A‐QoL) physical and total health scores was improved with emicizumab, fitusiran, and concizumab prophylaxis (low‐certainty evidence).

Non‐serious adverse events were higher with non‐clotting factor therapies versus on‐demand therapy, with injection site reactions being the most frequently reported adverse events. Transient antidrug antibodies were reported for fitusiran and concizumab.

Prophylaxis versus on‐demand therapy in people without inhibitors

Two trials (208 participants) compared emicizumab and fitusiran with on‐demand therapy in people without inhibitors. One trial assessed two doses of emicizumab (1.5 mg/kg weekly and 3.0 mg/kg bi‐weekly).

Fitusiran 80 mg monthly, emicizumab 1.5 mg/kg/week, and emicizumab 3.0 mg/kg bi‐weekly all likely resulted in a large reduction in ABR for all bleeds, all treated bleeds, and joint bleeds. AtjBR was not reduced with either of the emicizumab dosing regimens. The effect of fitusiran prophylaxis on target joint bleeds was not assessed. Spontaneous bleeds were likely reduced with fitusiran (MD −20.21, 95% CI –32.12 to −8.30) and emicizumab 3.0 mg/kg bi‐weekly (MD −15.30, 95% CI −30.46 to −0.14), but not with emicizumab 1.5 mg/kg/week (MD –14.60, 95% CI –29.78 to 0.58).

The percentage of participants with zero bleeds was higher following emicizumab 1.5 mg/kg/week (50% versus 0%), emicizumab 3.0 mg/kg bi‐weekly (40% versus 0%), and fitusiran prophylaxis (40% versus 5%) compared with on‐demand therapy.

Emicizumab 1.5 mg/kg/week did not improve Haem‐A‐QoL physical and total health scores, EQ‐5D‐5L VAS, or utility index scores (low‐certainty evidence) when compared with on‐demand therapy at 25 weeks. Emicizumab 3.0 mg/kg bi‐weekly may improve HRQoL measured by the Haem‐A‐QoL physical health score (MD –15.97, 95% CI −29.14 to –2.80) and EQ‐5D‐5L VAS (MD 9.15, 95% CI 2.05 to 16.25; 1 trial; 43 participants; low‐certainty evidence). Fitusiran may result in improved HRQoL shown as a reduction in Haem‐A‐QoL total score (MD –7.06, 95% CI −11.50 to –2.62) and physical health score (MD –19.75, 95% CI −25.76 to −11.94; 1 trial; 103 participants; low‐certainty evidence).

The risk of serious adverse events in participants without inhibitors also likely did not differ following prophylaxis with either emicizumab or fitusiran versus on‐demand therapy (moderate‐certainty evidence). Transient antidrug antibodies were reported in 4% (3/80) participants to fitusiran, with no observed effect on antithrombin lowering.

A comparison of the different dosing regimens of emicizumab identified no differences in bleeding, safety, or patient‐reported outcomes.

No case of treatment‐related cancer or mortality was reported in any study group. None of the included studies assessed our secondary outcomes of joint health, clinical joint function, and economic outcomes.

None of the included studies evaluated marstacimab.

Authors' conclusions

Evidence from RCTs shows that prophylaxis using non‐clotting factor therapies compared with on‐demand treatment may reduce bleeding events, increase the percentage of individuals with zero bleeds, increase the incidence of non‐serious adverse events, and improve HRQoL. Comparative assessments with other prophylaxis regimens, assessment of long‐term joint outcomes, and assessment of economic outcomes will improve evidence‐based decision‐making for the use of these therapies in bleed prevention.

Keywords: Adult, Humans, Male, Blood Coagulation Factors, Blood Coagulation Factors/therapeutic use, Hemarthrosis, Hemarthrosis/etiology, Hemarthrosis/prevention & control, Heme, Heme/therapeutic use, Hemophilia A, Hemophilia A/complications, Hemophilia A/drug therapy, Hemorrhage, Hemorrhage/chemically induced, Hemorrhage/prevention & control

Plain language summary

What are the benefits and risks of newer non‐clotting factor therapies for the prevention of bleeds in people with hemophilia A or B?

Key messages

‐ In people living with hemophilia A or B with or without inhibitors, non‐clotting factor therapies for preventing bleeds reduced the annual bleeding rates for all bleeds, joint bleeds, and spontaneous bleeds compared with no bleed prevention. There was a significant increase in the percentage of people with zero bleeds. An improvement in well‐being was also reported with non‐clotting factor therapies. None of the included studies assessed our secondary outcomes of joint health, clinical joint function, and economic outcomes.

‐ Overall unwanted events were increased, although severe events were comparable between non‐clotting factor prophylaxis and no prophylaxis.

‐ Further studies are needed to establish the long‐term effects of each of the non‐clotting factor therapies.

What are the non‐clotting factor therapies used to prevent bleeds in people with hemophilia A or B?

Uncontrolled and spontaneous bleeding is a major problem in hemophilia A and B. Bleeding is typically prevented and treated with clotting factor concentrates. Non‐clotting factor therapies emicizumab, fitusiran, concizumab, and marstacimab are new options in hemophilia care.

What did we want to find out?

We wanted to find out if using non‐clotting factor therapies to prevent bleeding was better than standard clotting factors, bypassing agents, or no bleed prevention to improve bleeding and well‐being.

We also wanted to find out if these therapies were associated with any unwanted events.

What did we do?

We searched for studies that used non‐clotting factor therapies to prevent bleeding compared with clotting factors, bypassing agents, or no bleed prevention in people with hemophilia A or B.

We compared and summarized the results of the studies and rated our confidence in the evidence based on factors such as study methods and sizes.

What did we find?

We found six studies involving a total of 397 males with hemophilia, aged between 12 and 75 years, most of whom (> 90%) had severe disease. The largest study was in 120 people, and the smallest study was in 26 people.

The studies were conducted in 38 countries around the world. Three studies lasted for six months; two studies lasted for nine months; and one study lasted for eight months.

Four trials were in people with inhibitors, and two trials were in people without inhibitors. Inhibitors are antibodies that neutralize clotting factor therapies, making them ineffective. Two studies each examined non‐clotting factor therapies emicizumab, fitusiran, and concizumab. All of the studies were industry‐sponsored and compared non‐clotting factor therapies with no bleed prevention. In one of the studies, two dosing schedules of the same therapy were compared with no bleed prevention.

Main results

Compared with no bleed prevention, non‐clotting factor therapies reduced annual bleeding rates for all bleeds (either treated or untreated bleeds), treated bleeds, and spontaneous bleeds (6 studies in 397 people), but not target joint bleeds (3 studies in 192 people), which are painful joints where repeated joint bleeds have taken place. Non‐clotting factor therapies increased the percentage of people with zero bleeds (5 studies in 371 people), improved well‐being (6 studies in 358 people), and increased overall unwanted events, but not severe unwanted events (6 studies in 397 people).

What are the limitations of the evidence?

We are moderately confident in the evidence; our confidence in the evidence was lowered because in all the studies people knew which treatment they were receiving (open‐label studies), which could have affected the results.

Our confidence was also lowered for well‐being outcomes due to some outcome data being missing.

None of the included studies assessed our secondary outcomes of joint health, clinical joint function, and economic outcomes.

More studies are needed on the effect of these therapies in preventing joint and target joint bleeds, and to establish the long‐term effects of each of the non‐clotting factor therapies.

How up‐to‐date is this evidence?

The evidence is current to August 2023.

Summary of findings

Summary of findings 1. Summary of findings table ‐ Emicizumab prophylaxis compared to on‐demand therapy in people with inhibitors.

Emicizumab prophylaxis compared to on‐demand therapy in people with inhibitors
Patient or population: people with inhibitors Setting: outpatient (multicenter trial in 14 countries: HAVEN 1 trial) Intervention: Emicizumab prophylaxis Comparison: on‐demand therapy
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
Outcomes	Risk with on‐demand therapy	Risk with Emicizumab prophylaxis	Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
Annualized Bleeding Rate (ABR) ‐ All treated bleeds follow‐up: 12 months	The mean annualized Bleeding Rate (ABR) ‐ All treated bleeds was 28.3	MD 20.4 lower (35.19 lower to 5.16 lower)	‐	53 (1 RCT)	⊕⊕⊕⊝ Moderate^a
Annualized spontaneous Bleeding Rate (AsBR) follow‐up: 12 months	The mean annualized spontaneous Bleeding Rate (AsBR) was 16.8	MD 15.5 lower (24.06 lower to 6.94 lower)	‐	53 (1 RCT)	⊕⊕⊕⊝ Moderate^a
Annualized joint Bleeding Rate (AjBR) follow‐up: 12 months	The mean annualized joint Bleeding Rate (AjBR) was 6.7	MD 5.9 lower (15.42 lower to 3.62 higher)	‐	53 (1 RCT)	⊕⊕⊕⊝ Moderate^a
Proportion with zero bleeds  follow‐up: 12 months	56 per 1000	628 per 1000 (92 to 1000)	RR 11.31 (1.66 to 77.30)	53 (1 RCT)	⊕⊕⊕⊝ Moderate^a
Change from baseline in total score ‐ Haem‐A‐QoL  Scale from: 0 (better) to 100 follow‐up: 25 weeks	The mean change from baseline in total score ‐ Haem‐A‐QoL was 2.5	MD 13.2 lower (20.84 lower to 5.56 lower)	‐	40 (1 RCT)	⊕⊕⊝⊝ Low^b
All adverse events	500 per 1000	985 per 1000 (630 to 1000)	RR 1.97 (1.26 to 3.10)	52 (1 RCT)	⊕⊕⊕⊝ Moderate^a
Serious adverse events	222 per 1000	293 per 1000 (107 to 807)	RR 1.32 (0.48 to 3.63)	52 (1 RCT)	⊕⊕⊕⊝ Moderate^a
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).  CI: confidence interval; MD: mean difference; RR: risk ratio
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.
See interactive version of this table: https://gdt.gradepro.org/presentations/#/isof/isof_question_revman_web_444686035257674561.

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^a Downgraded once due to high risk of bias from lack of blinding. ^b Downgraded twice due to high risk of bias from lack of blinding and incomplete outcome data.

Summary of findings 2. Summary of findings table ‐ Fitusiran prophylaxis compared to on‐demand therapy in people with inhibitors.

Fitusiran prophylaxis compared to on‐demand therapy in people with inhibitors
Patient or population: people with inhibitors Setting: outpatient (multicenter trial in 12 countries: ATLAS‐INH trial) Intervention: Fitusiran prophylaxis Comparison: on‐demand therapy
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
Outcomes	Risk with on‐demand therapy	Risk with Fitusiran prophylaxis	Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
Annualized Bleeding Rate (ABR) ‐ All treated bleeds follow‐up: 12 months	The mean annualized Bleeding Rate (ABR) ‐ All treated bleeds was 18.8	MD 16.8 lower (25.8 lower to 7.8 lower)	‐	57 (1 RCT)	⊕⊕⊕⊝ Moderate^a
Annualized spontaneous Bleeding Rate (AsBR) follow‐up: 12 months	The mean annualized spontaneous Bleeding Rate (AsBR) was 15.7	MD 14.8 lower (24.9 lower to 4.71 lower)	‐	57 (1 RCT)	⊕⊕⊕⊝ Moderate^a
Annualized joint Bleeding Rate (AjBR) follow‐up: 12 months	The mean annualized joint Bleeding Rate (AjBR) was 13.8	MD 12.5 lower (19.91 lower to 5.09 lower)	‐	57 (1 RCT)	⊕⊕⊕⊝ Moderate^a
Change from baseline in total health score, Haem‐A‐QoL Scale from: 0 (better) to 100 follow‐up: 9 months	The mean change from baseline in total health score, Haem‐A‐QoL was ‐0.42	MD 14.85 lower (21.04 lower to 8.66 lower)	‐	48 (1 RCT)	⊕⊕⊝⊝ Low^b
Proportion with zero bleeds  follow‐up: 12 months	5 per 100	66 per 100 (10 to 100)	RR 12.50 (1.83 to 85.38)	57 (1 RCT)	⊕⊕⊕⊝ Moderate^a
All adverse events	58 per 100	93 per 100 (63 to 100)	RR 1.60 (1.08 to 2.37)	60 (1 RCT)	⊕⊕⊕⊝ Moderate^a
Serious adverse events	26 per 100	17 per 100 (6 to 47)	RR 0.65 (0.24 to 1.78)	60 (1 RCT)	⊕⊕⊕⊝ Moderate^a
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).  CI: confidence interval; MD: mean difference; RR: risk ratio
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.
See interactive version of this table: https://gdt.gradepro.org/presentations/#/isof/isof_question_revman_web_444620479214578781.

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^a Downgraded once due to high risk of bias from lack of blinding. ^b Downgraded twice due to high risk of bias from lack of blinding and incomplete outcome data.

Summary of findings 3. Summary of findings table ‐ Concizumab prophylaxis compared to on‐demand therapy in people with inhibitors.

Concizumab prophylaxis compared to on‐demand therapy in people with inhibitors
Patient or population: people with inhibitors Setting: outpatient (2 multicenter trials in 29 countries: EXPLORER 4 and EXPLORER 7)  Intervention: Concizumab prophylaxis Comparison: on‐demand therapy
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
Outcomes	Risk with on‐demand therapy	Risk with Concizumab prophylaxis	Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
Annualized Bleeding Rate (ABR), All bleeds follow‐up: 12 months	The mean annualized Bleeding Rate (ABR), All bleeds ranged from 13.3 to 20.4	MD 12.31 lower (19.17 lower to 5.45 lower)	‐	68 (2 RCTs)	⊕⊕⊝⊝ Low^a
Annualized spontaneous Bleeding Rate (AsBR)  follow‐up: 12 months	The mean annualized spontaneous Bleeding Rate (AsBR) ranged from 9.4 to 18.5	MD 11.96 lower (19.89 lower to 4.03 lower)	‐	78 (2 RCTs)	⊕⊝⊝⊝ Very low^a,^b
Annualized joint Bleeding Rate (AjBR) follow‐up: 12 months	The mean annualized joint Bleeding Rate (AjBR) was 9.1 to 15	MD 9.55 lower (13.55 lower to 5.55 lower)	‐	78 (2 RCTs)	⊕⊕⊝⊝ Low^a
Proportion with zero bleeds  follow‐up: 12 months	105 per 1000	637 per 1000 (167 to 1000)	RR 6.05 (1.59 to 23.00)	52 (1 RCT)	⊕⊕⊝⊝ Low^a
Change from baseline in SF‐36v2 ‐ mental component score Scale from: 0 to 100 (better) follow‐up: 9 months	The mean change from baseline in SF‐36v2 ‐ mental component score was 0.4	MD 0.4 higher (4.45 lower to 5.25 higher)	‐	26 (1 RCT)	⊕⊝⊝⊝ Very low^c,^d
Adverse events ‐ All adverse events	536 per 1000	611 per 1000 (407 to 911)	RR 1.14 (0.76 to 1.70)	78 (2 RCTs)	⊕⊕⊝⊝ Low^a
Adverse events ‐ Serious adverse events	321 per 1000	145 per 1000 (19 to 1000)	RR 0.45 (0.06 to 3.38)	78 (2 RCTs)	⊕⊕⊝⊝ Low^a
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).  CI: confidence interval; MD: mean difference; RR: risk ratio
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.
See interactive version of this table: https://gdt.gradepro.org/presentations/#/isof/isof_question_revman_web_444621089087876372.

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^a Downgraded twice due to high risk of bias for lack of blinding, incomplete outcome data, and unclear risk of other sources of bias.  ^b Downgraded once due to high heterogeneity. ^c Downgraded twice due to high risk of bias for lack of blinding and unclear risk of bias for incomplete outcome data. ^d Downloaded once due to small sample size.

Summary of findings 4. Summary of findings table ‐ Emicuzimab 1.5 mg/kg weekly prophylaxis compared to on‐demand therapy in people without inhibitors.

Emicuzimab 1.5 mg/kg weekly prophylaxis compared to on‐demand therapy in people without inhibitors
Patient or population: people without inhibitors  Setting: outpatient (multicenter trial in 14 countries: HAVEN 3 trial) Intervention: Emicuzimab 1.5 mg/kg weekly prophylaxis Comparison: on‐demand therapy
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
Outcomes	Risk with on‐demand therapy	Risk with Emicuzimab 1.5 mg/kg weekly prophylaxis	Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
Annualized Bleeding Rate (ABR) ‐ All treated bleeds follow‐up: 12 months	The mean annualized Bleeding Rate (ABR) ‐ All treated bleeds was 38.2	MD 36.7 lower (60.53 lower to 12.87 lower)	‐	54 (1 RCT)	⊕⊕⊕⊝ Moderate^a
Annualized joint Bleeding Rate (AjBR) follow‐up: 12 months	The mean annualized joint Bleeding Rate (AjBR) was 26.5	MD 25.4 lower (45.23 lower to 5.57 lower)	‐	54 (1 RCT)	⊕⊕⊕⊝ Moderate^a
Annualized spontaneous Bleeding Rate (AsBR) follow‐up: 12 months	The mean annualized spontaneous Bleeding Rate (AsBR) was 15.6	MD 14.6 lower (29.78 lower to 0.58 higher)	‐	54 (1 RCT)	⊕⊕⊕⊝ Moderate^a
Proportion of participants with zero bleeds	0 per 1000	0 per 1000 (0 to 0)	RR 19.00 (1.21 to 298.40)	54 (1 RCT)	⊕⊕⊝⊝ Low^a,^b
Change in Haem‐A‐QoL total score  Scale from: 0 (better) to 100 follow‐up: 25 weeks	The mean change in Haem‐A‐QoL total score was 13.56	MD 5.91 lower (14.89 lower to 3.07 higher)	‐	47 (1 RCT)	⊕⊕⊝⊝ Low^d
All adverse events follow‐up: 6 months	333 per 1000	943 per 1000 (490 to 1000)	RR 2.83 (1.47 to 5.47)	54 (1 RCT)	⊕⊕⊕⊝ Moderate^a
Serious adverse events follow‐up: 6 months	56 per 1000	28 per 1000 (2 to 419)	RR 0.50 (0.03 to 7.54)	54 (1 RCT)	⊕⊕⊕⊝ Moderate^a
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).  CI: confidence interval; MD: mean difference; RR: risk ratio
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.
See interactive version of this table: https://gdt.gradepro.org/presentations/#/isof/isof_question_revman_web_444621655726813647.

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^a Downgraded once due to high risk of bias from lack of blinding. ^b Downgraded once due to wide confidence intervals. ^d Downgraded twice due to high risk of bias from lack of blinding and incomplete outcome data.

Summary of findings 5. Summary of findings table ‐ Emicuzimab 3.0 mg/kg bi‐weekly prophylaxis compared to on‐demand therapy in people without inhibitors.

Emicuzimab 3.0 mg/kg bi‐weekly prophylaxis compared to on‐demand therapy in people without inhibitors
Patient or population: people without inhibitors Setting: outpatient (multicenter trial in 14 countries: HAVEN 3 trial) Intervention: Emicuzimab 3.0 mg/kg bi‐weekly prophylaxis Comparison: on‐demand therapy
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
Outcomes	Risk with on‐demand therapy	Risk with Emicuzimab 3.0 mg/kg bi‐weekly prophylaxis	Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
Annualized Bleeding Rate (ABR) ‐ All treated bleeds follow‐up: 12 months	The mean annualized Bleeding Rate (ABR) ‐ All treated bleeds was 51.4	MD 36.9 lower (60.67 lower to 13.13 lower)	‐	53 (1 RCT)	⊕⊕⊕⊝ Moderate^a
Annualized joint Bleeding Rate (AjBR) follow‐up: 12 months	The mean annualized joint Bleeding Rate (AjBR) was 26.5	MD 25.6 lower (45.4 lower to 5.8 lower)	‐	53 (1 RCT)	⊕⊕⊕⊝ Moderate^a
Annualized spontaneous Bleeding Rate (AsBR) follow‐up: 12 months	The mean annualized spontaneous Bleeding Rate (AsBR) was 15.6	MD 15.3 lower (30.46 lower to 0.14 lower)	‐	53 (1 RCT)	⊕⊕⊕⊝ Moderate^a
Proportion of participants with zero bleeds follow‐up: 12 months	0 per 1000	0 per 1000 (0 to 0)	RR 15.31 (0.96 to 242.76)	53 (1 RCT)	⊕⊕⊝⊝ Low^a,^b
Change in total score, Haem‐A‐QoL Scale from: 0 (better) to 100 follow‐up: 25 weeks	The mean change in total score, Haem‐A‐QoL was 13.6	MD 8.56 lower (17.25 lower to 0.13 higher)	‐	53 (1 RCT)	⊕⊕⊝⊝ Low^c
All adverse events	500 per 1000	855 per 1000 (530 to 1000)	RR 1.71 (1.06 to 2.77)	53 (1 RCT)	⊕⊕⊕⊝ Moderate^a
Serious adverse events	56 per 1000	86 per 1000 (9 to 766)	RR 1.54 (0.17 to 13.79)	53 (1 RCT)	⊕⊕⊕⊝ Moderate^a
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).  CI: confidence interval; MD: mean difference; RR: risk ratio
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.
See interactive version of this table: https://gdt.gradepro.org/presentations/#/isof/isof_question_revman_web_444626384990963572.

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^a Downgraded once due to high risk of bias from lack of blinding. ^b Downgraded once due to wide confidence intervals. ^c Downgraded twice due to high risk of bias from lack of blinding and incomplete outcome data.

Summary of findings 6. Summary of findings table ‐ Emicizumab 1.5 mg/kg once weekly compared to emicizumab 3.0 mg/kg every 2 weeks in people without inhibitors.

Emicizumab 1.5 mg/kg once weekly compared to emicizumab 3.0 mg/kg every 2 weeks in people without inhibitors
Patient or population: people without inhibitors Setting: outpatient (multicenter trial in 14 countries: HAVEN 3 trial) Intervention: Emicizumab 1.5 mg/kg once weekly Comparison: emicizumab 3.0 mg/kg every 2 weeks
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
Outcomes	Risk with emicizumab 3.0 mg/kg every 2 weeks	Risk with Emicizumab 1.5 mg/kg once weekly	Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
Annualized Bleeding Rate (ABR) ‐ All treated bleeds follow‐up: 12 weeks	The mean annualized Bleeding Rate (ABR) ‐ All treated bleeds was 1.3	MD 0.2 higher (2.01 lower to 2.41 higher)	‐	71 (1 RCT)	⊕⊕⊕⊝ Moderate^a
Annualized joint Bleeding Rate (AjBR) follow‐up: 12 months	The mean annualized joint Bleeding Rate (AjBR) was 0.2	MD 0.2 higher (1.32 lower to 1.72 higher)	‐	71 (1 RCT)	⊕⊕⊕⊝ Moderate^a
Annualized spontaneous Bleeding Rate (AsBR) follow‐up: 12 months	The mean annualized spontaneous Bleeding Rate (AsBR) was 0.3	MD 0.7 higher (0.26 lower to 1.66 higher)	‐	71 (1 RCT)	⊕⊕⊕⊝ Moderate^a
Proportion of participants with zero bleeds follow‐up: 12 months	400 per 1000	500 per 1000 (296 to 840)	RR 1.25 (0.74 to 2.10)	71 (1 RCT)	⊕⊕⊕⊝ Moderate^a
Change in total score, Haem‐A‐QoL  Scale from: 0 (better) to 100 follow‐up: 25 weeks	The mean change in total score, Haem‐A‐QoL was 21.4	MD 2.65 more (4.24 fewer to 9.54 more)	‐	63 (1 RCT)	⊕⊕⊝⊝ Low^b
All adverse events follow‐up: 6 months	857 per 1000	943 per 1000 (34 to 1000)	RR 1.10 (0.04 to 2.97)	71 (1 RCT)	⊕⊕⊕⊝ Moderate^a
Serious adverse events follow‐up: 6 months	86 per 1000	27 per 1000 (3 to 255)	RR 0.32 (0.04 to 2.97)	71 (1 RCT)	⊕⊕⊕⊝ Moderate^a
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).  CI: confidence interval; MD: mean difference; RR: risk ratio
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.
See interactive version of this table: https://gdt.gradepro.org/presentations/#/isof/isof_question_revman_web_444600347094067529.

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^a Downgraded once due to high risk of bias from lack of blinding. ^b Downgraded twice due to high risk of bias from lack of blinding and incomplete outcome data.

Summary of findings 7. Summary of findings table ‐ Fitusiran prophylaxis compared to on‐demand therapy in people without inhibitors.

Fitusiran prophylaxis compared to on‐demand therapy in people without inhibitors
Patient or population: people without inhibitors  Setting: outpatient (multicenter trial in 17 countries: ATLAS‐A/B trial) Intervention: Fitusiran prophylaxis Comparison: on‐demand therapy
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
Outcomes	Risk with on‐demand therapy	Risk with Fitusiran prophylaxis	Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
Annualized Bleeding Rate (ABR) ‐ All treated bleeds follow‐up: 12 months	The mean annualized Bleeding Rate (ABR) ‐ All treated bleeds was 31.0	MD 27.86 lower (41.95 lower to 13.76 lower)	‐	119 (1 RCT)	⊕⊕⊕⊝ Moderate^a
Annualized joint Bleeding Rate (AjBR) follow‐up: 12 months	The mean annualized joint Bleeding Rate (AjBR) was 38.4	MD 21.13 lower (33.06 lower to 9.2 lower)	‐	119 (1 RCT)	⊕⊕⊕⊝ Moderate^a
Annualized spontaneous Bleeding Rate (AsBR) follow‐up: 12 months	The mean annualized spontaneous Bleeding Rate (AsBR) was 38.3	MD 20.21 lower (32.12 lower to 8.3 lower)	‐	119 (1 RCT)	⊕⊕⊕⊝ Moderate^a
Proportion with zero bleeds  follow‐up: 9 months	50 per 1000	405 per 1000 (102 to 1000)	RR 8.10 (2.04 to 32.11)	119 (1 RCT)	⊕⊕⊕⊝ Moderate^a
Change in total scores, Haem‐A‐QoL  Scale from: 0 (better) to 100 follow‐up: 9 months	The mean change in total scores, Haem‐A‐QoL was ‐2.62	MD 7.06 lower (11.5 lower to 2.62 lower)	‐	103 (1 RCT)	⊕⊕⊝⊝ Low^b
All adverse events	450 per 1000	783 per 1000 (545 to 1000)	RR 1.74 (1.21 to 2.50)	119 (1 RCT)	⊕⊕⊕⊝ Moderate^a
Adverse events ‐ Serious adverse events	450 per 1000	225 per 1000 (68 to 733)	RR 0.50 (0.15 to 1.63)	120 (1 RCT)	⊕⊕⊕⊝ Moderate^a
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).  CI: confidence interval; MD: mean difference; RR: risk ratio
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.
See interactive version of this table: https://gdt.gradepro.org/presentations/#/isof/isof_question_revman_web_444690793457516636.

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^a Downloaded once due to high risk of bas from lack of blinding. ^b Downloaded twice due to high risk of bias from lack of blinding and incomplete outcome data.

Background

Description of the condition

Congenital hemophilia is a rare X‐linked bleeding disorder resulting from a deficiency in clotting factor VIII (for hemophilia A) or factor IX (for hemophilia B). Prevalence at birth is estimated to be 24.6 cases per 100,000 (1 in 4000) live male births for hemophilia A and 5.0 cases per 100,000 (1 in 20,000) live male births for hemophilia B, with an overall population of 1,125,000 people affected by hemophilia A and B globally (Iorio 2019). Disease severity may be severe, moderate, or mild, with baseline coagulation factor level less than 1% in severe disease, 1% to 5% in moderate, and greater than 5% of normal levels in mild disease (Mannucci 2001; Srivastava 2020).

People with moderate and mild hemophilia rarely bleed, and often only after trauma or in association with surgery and invasive procedures. In severe cases, in addition to excessive and prolonged bleeding after injuries, there is an increased risk of spontaneous bleeding into joints, muscles, and soft tissues, even without a hemostatic challenge (Wight 2003). Recurrent joint bleeding leads to the development of different degrees of hemophilic arthropathy.

Treatment of hemophilia is by prophylactic and on‐demand therapy with deficient clotting factors, which can be plasma‐derived or recombinant concentrates (Mannucci 2001). Compared with on‐demand therapy, primary and secondary bleed prevention have been shown to improve clinical and patient‐reported outcomes, including reduction in bleeds, joint damage, health resource utilization, and overall health‐related quality of life (HRQoL) (Nugent 2018; Srivastava 2020). However, neutralizing antibodies (or inhibitors) to clotting factors develop in 30% to 50% of individuals, making replacement therapy ineffective (Wight 2003; Witmer 2013).

Inhibitors can be eradicated by immune tolerance induction (ITI), a process where very high doses of clotting factors are administered followed by continually high doses for several months and up to a year. The overall success rate of ITI is approximately 74% to 85%, with hemostasis achieved by regular clotting factor therapy afterward (Rocino 2016). Rituximab, an anti‐CD20 agent, is also used as a second‐line therapy to eradicate inhibitors resistant to ITI, with a response rate of up to 63% (Borker 2011; Jiang 2017). In individuals where inhibitors remain, therapy involves the use of bypassing agents: activated prothrombin complex concentrate (aPCC) and recombinant activated factor VII (rFVIIa) for both preventing and treating bleeds (Rocino 2016; Wight 2003).

Description of the intervention

Recent therapeutic advancements have led to the introduction of agents that not only bypass factors VIII or IX in the clotting cascade but are also non‐clotting factors (Franchini 2018; Nogami 2019). The first of these is emicizumab, a bispecific monoclonal antibody approved in 2017 for treating severe hemophilia A in people with inhibitors (USA FDA Approval). More recently, it was approved for use in people without inhibitors, causing a paradigm shift in hemophilia treatment, such that treatment decisions can be made regardless of inhibitor status (Azvedo 2018; Mahlangu 2018).

Other non‐clotting factor therapies include humanized monoclonal antibodies concizumab and marstacimab and the RNA interference (RNAi) therapy fitusiran, which are indicated for preventing and treating bleeds, not only in hemophilia A, but also in hemophilia B, with or without inhibitors (Chowdary 2018; Machin 2018; Patel‐Hett 2019). However, concizumab, marstacimab, and fitusiran are currently at different developmental and drug approval stages.

With the intravenous route of administration required for clotting factor therapies, problems with venous access, difficulty with self‐administration, and sometimes regular support at a hemophilia center, are potential issues addressed by the subcutaneous route of administration of non‐clotting factor therapies (Nogami 2019).

How the intervention might work

Non‐clotting factor therapies produce the desired hemostatic effect through different mechanisms. Emicizumab, an FVIII mimetic, exerts its action by bridging and activating factor IXa and X, thereby mimicking the action of factor VIII (Shima 2016). Concizumab and marstacimab inhibit an anticoagulant protein, tissue factor pathway inhibitor (TFPI), which prevents the initiation of the coagulation response (Mast 2015). This results in the generation of clotting factor Xa, leading to thrombin production and hemostasis (Chowdary 2018; Mast 2015; Patel‐Hett 2019). Fitusiran exerts its hemostatic effect by inhibiting hepatic production of antithrombin, leading to enhanced thrombin generation (Machin 2018). Concizumab, marstacimab, and fitusitran are referred to as rebalancing therapies, as they restore the imbalance between clotting factors and anticoagulation factors in the coagulation cascade (Ellsworth 2021).

Why it is important to do this review

Due to the recent development of these novel non‐clotting factor drug therapies, no systematic review has as yet been conducted examining their effects compared with existing standards of care. Previous systematic reviews on prophylaxis in hemophilia include reviews of clotting factor prophylaxis compared with on‐demand therapy (Iorio 2011; Olasupo 2021), and prophylaxis using bypassing agents in people with inhibitors (Chai‐Adisaksopha 2017). A review has also been conducted on the effect of emicizumab in people with hemophilia A and inhibitors (Rind 2018); however, when this was conducted, emicizumab had not yet been expanded for use in people without inhibitors. Furthermore, no other non‐clotting factor therapies were assessed, and insufficient evidence was available for meta‐analysis.

Objectives

Methods

Criteria for considering studies for this review

Types of studies

Randomized controlled trials (RCTs), including unpublished or published trials as articles, abstracts, or conference proceedings, were eligible for inclusion. Quasi‐RCTs in which other methods of treatment allocation were used to assign participants to study groups (e.g. covariate‐based minimization, response‐adaptive allocation, or block randomization) were also eligible for inclusion. We excluded narrative reviews, correspondence, expert reviews, guidance, terminated trials with no results, as well as phase 1 and phase 1/2 extension studies with no comparative study arms.

Types of participants

We included studies assessing individuals with congenital hemophilia A or B. We did not exclude studies based on participant age, disease severity, type of previous treatment (if any), inhibitor status, or the presence or absence of joint damage. We excluded studies of people with other bleeding disorders, including acquired hemophilia.

Types of interventions

We included all studies where prophylactic non‐clotting factor therapies were given in any dosage, component, route of administration, frequency, duration, or timing. Prophylaxis with non‐clotting factors therapies may have been compared with prophylaxis with clotting factors therapies, bypassing agents, placebo, or with one or more different prophylaxis regimens. We excluded studies involving desmopressin, tranexamic acid, gene therapies, and non‐pharmacological interventions such as exercise. The treatment exposure should have been greater than a single dose, and at least one of the treatment arms must have been a non‐clotting factor therapy.

The comparison groups were as follows:

non‐factor prophylaxis versus clotting factor prophylaxis;
non‐factor prophylaxis versus bypassing agents prophylaxis;
non‐factor prophylaxis versus any other alternative prophylaxis;
non‐factor prophylaxis versus no prophylaxis, on‐demand therapy, or placebo.

Types of outcome measures

We assessed the following primary and secondary outcomes. We intended to report the listed outcomes at one week, one month, three months, six months, up to one year, and then annually thereafter in the case of sufficient data. We preferred to report annual bleed rates for analysis in the review.

Primary outcomes

Bleeding rates (Chai‐Adisaksopha 2015; Konkle 2019):
1. total annualized bleeding rates (ABR), annualized spontaneous bleeding rates (AsBR), annualized joint bleeding rates (AjBR), annualized target joint bleeding rates (AtjBR);
2. total bleeding frequency (during the study period);
3. proportion with zero bleeds;
4. other.
Health‐related quality of life (HRQoL):
1. using validated disease‐specific instruments, e.g. Haemophilia Quality of Life Index for Adults (Haem‐A‐QoL);
2. generic instruments, e.g. EQ‐5D;
3. other dimensions or measures of HRQoL and patient‐reported outcomes including missed days of school or employment, integration into society, length of inpatient stay, physical functioning, feelings of well‐being and global functioning reported using unvalidated instruments or as reported by study authors.
Adverse events:
1. all European Haemophilia Safety Surveillance (EUHASS) reportable events, e.g. inhibitor development, thromboembolic events, thrombotic microangiopathy, infection, cancer, mortality (Fischer 2012; Makris 2011);
2. serious adverse events defined as an event that results in death, is life‐threatening, requires inpatient hospitalization or extends a current hospital stay, results in an ongoing or significant incapacity, or interferes substantially with normal life functions, or causes a congenital anomaly or birth defect (European Medicines Agency; Wallace 2016).

Secondary outcomes

Joint health (Ribeiro 2019):
1. hemophilia joint health score (HJHS);
2. proportion of participants with target joints;
3. radiologic scores;
4. clinical joint function;
5. other.
Pain score (as reported by study authors)
Economic outcomes:
1. cost‐effectiveness;
2. cost benefit;
3. cost utilization;
4. cost minimization;
5. budget impact.

Search methods for identification of studies

We searched for relevant published and unpublished trials without restrictions on language, year, or publication status.

Electronic searches

The Cochrane Cystic Fibrosis and Genetic Disorders Group's Information Specialist conducted a search of the Group's Coagulopathies Trials Register for relevant trials using the terms: (haemophilia*:KW) AND (Non‐factor Replacement:KW).

The Coagulopathies Trials Register is compiled from electronic searches of the Cochrane Central Register of Controlled Trials (CENTRAL) (updated each new issue of the Cochrane Library) and weekly searches of MEDLINE and the prospective handsearching of one journal, Haemophilia. Unpublished work is identified by searching the abstract books of major conferences: the European Haematology Association conference; the American Society of Hematology conference; the British Society for Haematology Annual Scientific Meeting; the Congress of the World Federation of Hemophilia; the European Association for Haemophilia and Allied Disorders; the American Society of Gene and Cell Therapy; and the International Society on Thrombosis and Haemostasis. For full details of all search activities for the register, please see the relevant section of the Cochrane Cystic Fibrosis and Genetic Disorders Group's website.

Date of latest search: 16 August 2023.

We conducted a search of the following databases and trial registries for relevant articles:

MEDLINE Ovid (Epub Ahead of Print, In‐Process & Other Non‐Indexed Citations, MEDLINE(R) Daily and MEDLINE(R) from 1946 to 16 August 2023);
Embase Ovid (1996 to 16 August 2023);
World Health Organization International Clinical Trials Registry Platform (www.who.int/trialsearch) (to 16 August 2023);
ClinicalTrials.gov (www.clinicaltrials.gov) (to 16 August 2023).

In the MEDLINE search, in addition to search terms for the population and interventions, we used the Cochrane Highly Sensitive Search Strategy: sensitivity‐maximizing version (2008 revision) to identify randomized trials (Lefebvre 2020).

We explored the grey literature, including the websites of organizations such as the World Federation of Hemophilia (WFH) (www.wfh.org) and the National Hemophilia Foundation (NHF) (www.hemophilia.org). We also assessed the publications and websites of regulatory agencies such as the US Food and Drug Administration (FDA), the Canadian Agency for Drugs and Technologies in Health (CADTH), and the National Institute for Health and Care Excellence (NICE).

For details of our search strategies, please see Appendix 1.

Searching other resources

We checked the bibliographies of the included studies and any relevant systematic reviews identified for further references to relevant studies. We assessed the reference lists of relevant articles and other systematic reviews for additional reports of clinical trials.

We handsearched the conference proceedings of the International Society for Thrombosis and Haemostasis (ISTH) and the European Association for Haemophilia and Allied Disorders (EAHAD) for the years 2010 to 2023.

Data collection and analysis

We conducted all data collection and analysis according to the guidance provided in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2020).

Selection of studies

Two review authors independently screened the titles and abstracts of retrieved articles for potentially relevant studies. We obtained the full‐text reports of studies deemed potentially relevant, and two review authors screened the full texts for inclusion in the review based on the previously defined inclusion criteria. We resolved any disagreements by discussion or by consulting a third review author if necessary.

Data extraction and management

Two review authors extracted data independently and compared the results. We resolved any differences by consensus, referral to the original paper, and review by a third review author. We extracted the following information from the included studies to a structured data extraction template within Covidence, an online systematic review software (Covidence):

study characteristics (authors, study date, design, location);
participant characteristics (inclusion criteria of the trial, age, demographics, inhibitor history, sample size);
study intervention and co‐interventions (including dosing, frequency, route of administration);
study outcomes (including primary and secondary outcome measures and description);
information regarding limitations and biases (or both).

Assessment of risk of bias in included studies

Two review authors independently assessed the risk of bias using the risk of bias tool in RevMan (Review Manager 2020; RevMan 2024), based on guidance provided in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2017). We resolved any disagreements by discussion or in consultation with a third review author.

We assessed the following domains as having either a low, high, or unclear risk of bias:

random sequence generation;
allocation concealment;
blinding of participants and personnel;
blinding of outcome assessment;
incomplete outcome data;
selective outcome reporting;
other sources of bias.

The results of the risk of bias assessment are presented in the risk of bias tables in the Characteristics of included studies tables.

Measures of treatment effect

We anticipated that bleeding outcomes would be measured and reported as rates (i.e. frequency of events over a period, e.g. ABR). For all bleeding outcomes reported as rates, we used the rate difference as a measure of treatment effect.

We expected HRQoL, joint health scores, and other secondary outcomes to be reported as continuous outcomes with a mean and standard deviation (SD), or a median and interquartile range (IQR). We also anticipated some outcomes to be measured as binary outcomes, reported as the frequency of each option.

We expressed effect measures for continuous outcomes as mean differences (MDs) and binary outcomes as risk ratios (RRs). We reported the 95% confidence interval (CI) of each measure of treatment effect (Deeks 2021).

Unit of analysis issues

The unit of analysis in the included studies was the individual participant. We assessed the intention‐to‐treat (ITT) population in all analyses. Given the chronic nature of hemophilia A and B, we anticipated that some studies would be cross‐over in design. We did not include any cross‐over RCTs in the current review. If we do so in a future update of this review, we will assess each study individually for the possibility of carry‐over and period effects. Where these effects cannot be ruled out, we will analyze data for the first period only and analyze the data as for parallel studies, based on the appropriateness of the cross‐over design. We will use the generic inverse variance method to include cross‐over RCTs in meta‐analysis, as recommended in Chapter 23 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2021).

Dealing with missing data

We investigated missing data and considered approaches to address this. We planned to contact study authors for any missing data as needed.

Assessment of heterogeneity

We assessed heterogeneity by the Chi² test with a P value of < 0.1 set to indicate statistical significance. We used the I² statistic to quantify the variability between studies, applying the following thresholds (Deeks 2021; Guyatt 2011):

0% to 40%: might not be important;
30% to 60%: may represent moderate heterogeneity;
50% to 90%: may represent substantial heterogeneity;
70% to 100%: represents considerable heterogeneity.

Assessment of reporting biases

We assessed potential publication bias by conducting a comprehensive search of the literature including checking open trial registries (www.clinicaltrials.gov and www.who.int/trialsearch).

As there were fewer than 10 studies in our review and meta‐analysis, we did not construct a funnel plot to check for non‐reporting bias. However, we checked for outcome reporting bias by identifying differences between study protocols and any relevant unreported outcome data (Page 2021).

Data synthesis

To pool effect estimates, we used a random‐effects model to account for possible statistical heterogeneity and generic inverse variance weighting in each meta‐analysis undertaken. In the current review, we meta‐analyzed only studies assessing concizumab prophylaxis in people with hemophilia with inhibitors. We did not pool studies assessing emicizumab and fitusiran, as only one trial was available for each of these therapies in the population with and without inhibitors.

Subgroup analysis and investigation of heterogeneity

Based on the number and types of studies identified, we explored subgroups based on the presence or absence of inhibitors, and the non‐clotting factor therapy of interest. Treatment modalities and responses are different for people with inhibitors compared with those without inhibitors, with inhibitors being associated with higher bleeding rates and poorer treatment outcomes overall (Olasupo 2023). We therefore presented separate comparisons based on the presence or absence of inhibitors. We assessed heterogeneity as previously described (Deeks 2021).

Sensitivity analysis

We planned to conduct sensitivity analyses to investigate the robustness of any meta‐analysis by varying different study assumptions and parameters, such as the use of fixed‐effect versus random‐effects model in meta‐analyses.

Limited data precluded sensitivity analysis as planned. However, we checked the robustness of the meta‐analyses by using both fixed‐effect and random‐effects models, and the results did not change.

Summary of findings and assessment of the certainty of the evidence

We assessed the certainty of the evidence using the GRADE approach. We generated a summary of findings table for each comparison as recommended in the Cochrane Handbook for Systematic Reviews of Interventions (Schünemann 2020), presenting the following outcomes in each table:

total ABR, AsBR, AjBR;
the proportion of participants with zero bleeds;
HRQoL on any validated hemophilia‐specific scale;
any reported drug‐related adverse effects or toxicity.

We rated the certainty of the evidence as high, moderate, low, or very low based on the five GRADE domains:

risk of bias (serious or very serious);
inconsistency (serious or very serious);
indirectness (serious or very serious);
imprecision (serious or very serious);
publication bias (likely or very likely).

We downgraded the certainty of the evidence by one level for serious limitation and two levels for very serious limitation (Schünemann 2020). We used GRADEpro GDT software to create summary of findings tables for the reported outcomes (GRADEPro GDT).

Based on consultation with clinicians in hemophilia and thrombosis care, we considered an absolute reduction of one spontaneous bleed per person per year as a minimum clinically important difference. We also deemed a 10% reduction in the proportion of individuals with zero bleeds per annum as clinically important. Based on responder definition (RDs) thresholds most indicative of HRQoL benefit, we considered a 10‐point reduction in ‘Physical Health’ and ‘Sports & Leisure,’ and a 7‐point reduction in ‘Total Score’ of the Haem‐A‐QoL (Wyrwich 2015), to be clinically meaningful.

Results

Description of studies

Description of studies and results of the search are described below.

Results of the search

We identified 1607 references from our electronic database search and 281 additional references from other sources. After removal of duplicates by automation, we reviewed titles and abstracts for 860 references and screened 193 full texts against the specified eligibility criteria.

Six RCTs (80 references) were eligible for inclusion after full‐text screening (ATLAS ‐ A/B; ATLAS ‐ INH; EXPLORER 4; EXPLORER 7; HAVEN 1; HAVEN 3).

We excluded 81 studies (n = 109 references) based on population, intervention, comparison, outcomes, and study design criteria. Three trials (n = 4 references) are ongoing (EXPLORER 8; HAVEN 5; NCT05053139). A study flow diagram is shown in Figure 1.

Included studies

We included six RCTs (397 participants) in the review: ATLAS ‐ A/B (120 participants); ATLAS ‐ INH (57 participants); EXPLORER 4 (26 participants); EXPLORER 7 (52 participants); HAVEN 1 (53 participants); and HAVEN 3 (89 participants). For details, see Characteristics of included studies.

Methods

All six studies were open‐label, parallel, multicenter RCTs. The studies were conducted in 12 (EXPLORER 4) to 28 countries (EXPLORER 7) and span a total of 38 countries including Algeria, Austria, Australia, Bulgaria, Canada, China, Croatia, the Czech Republic, Costa Rica, Denmark, France, Germany, Greece, Hungary, India, Ireland, Israel, Italy, Japan, Malaysia, Mexico, New Zealand, Norway, Poland, Portugal, Republic of Korea, Russia, Serbia, Slovakia, South Africa, Spain, Sweden, Taiwan, Thailand, Turkey, Ukraine, the UK, and the USA.

One trial was a phase 2 trial (ATLAS ‐ A/B), and five studies were phase 3 trials (ATLAS ‐ INH; EXPLORER 4; EXPLORER 7; HAVEN 1; HAVEN 3). Five studies were two‐armed trials with a single active intervention arm compared to a control arm, while one trial was a three‐armed trial with two active intervention arms (different dose schedules of the same drug) (HAVEN 3). Three studies included participants who were not randomized. We did not include non‐randomized arms in this review (EXPLORER 7; HAVEN 1; HAVEN 3). All six studies were industry‐sponsored.

Four studies were conducted with extension phases (EXPLORER 4; EXPLORER 7; HAVEN 1; HAVEN 3). We did not include data from the extension phases in this review. In the two emicizumab studies (HAVEN 1; HAVEN 3), the on‐demand therapy or no prophylaxis arms were switched to emicizumab prophylaxis after completion of the initial 24‐week study period. One participant in HAVEN 3 who was randomized to no prophylaxis switched to emicizumab before the completion of the first 24 weeks of the study period (at 23.5 weeks).

Participants

The six studies included 397 males, aged 12 to 75 years. Although women were eligible for the emicizumab studies, no participants in the randomized arms were female (HAVEN 1; HAVEN 3).

Sample sizes ranged from 26 participants (EXPLORER 4) to 120 participants (ATLAS ‐ A/B).

The two studies investigating emicizumab randomized 142 men with hemophilia A only (HAVEN 1; HAVEN 3), while the trials exploring fitusiran and concizumab randomized a total of 255 participants with either hemophilia A or hemophilia B (ATLAS ‐ A/B; ATLAS ‐ INH; EXPLORER 4; EXPLORER 7).

Three studies only enrolled people with severe hemophilia (ATLAS ‐ A/B; ATLAS ‐ INH; HAVEN 3). Of the three studies with no restrictions on disease severity, one trial comprised 92.5% (49/53) with severe disease (HAVEN 1), while the distribution of hemophilia severity was not reported in EXPLORER 4 and EXPLORER 7.

Four studies (189 participants) were conducted in people with inhibitors (ATLAS ‐ INH; EXPLORER 4; EXPLORER 7; HAVEN 1), while two studies (208 participants) were conducted in people without inhibitors (ATLAS ‐ A/B; HAVEN 3).

Interventions

Two studies each assessed the factor mimetic therapy emicizumab (HAVEN 1; HAVEN 3), fitusiran (ATLAS ‐ A/B; ATLAS ‐ INH), and concizumab (EXPLORER 4; EXPLORER 7). No RCT evaluating marstacimab met the inclusion criteria.

Both emicizumab studies administered emicizumab at a dose of 3 mg/kg weekly for four weeks, followed by 1.5 mg/kg/week maintenance thereafter, compared to a group receiving only on‐demand treatment for six months (HAVEN 1; HAVEN 3); the HAVEN 3 trial had an additional study arm that received a maintenance dose of 3 mg/kg bi‐weekly (HAVEN 3).

The two studies assessing subcutaneous (SC) fitusiran employed a dose of 80 mg once monthly from Day 1 up to a total of nine months compared to on‐demand factor concentrates for episodic bleeding episodes (ATLAS ‐ A/B; ATLAS ‐ INH). In the fitusiran prophylaxis groups, participants received on‐demand factor concentrates (per the investigator's discretion and within bleeding dosing guidelines) to treat breakthrough bleeds.

The EXPLORER 4 trial compared prophylactic SC concizumab once daily to on‐demand therapy with recombinant factor VIIa (rFVIIa) for 24 weeks. In the intervention group, an initial loading dose of 0.15 mg/kg concizumab was administered, which was escalated to 0.20 and 0.25 mg/kg based on the number of spontaneous bleeding episodes. A single injection of 90 μg/kg rFVIIa was administered in a non‐bleeding state one week after the dosing with concizumab had been initiated. In EXPLORER 7, concizumab prophylaxis for 32 weeks or more was compared to on‐demand treatment for 24 weeks or more. Due to a non‐fatal thromboembolic event (renal infarct) in one study participant, concizumab treatment was paused by the safety monitoring committee. Treatment was restarted with updated guidance on the management of breakthrough bleeds and a new dosing regimen (1 mg/kg loading dose, followed by an initial lower daily dose of 0.2 mg/kg instead of 0.25 mg/kg). Dose adjustments could be considered at five to eight weeks to 0.2 mg/kg or 0.15 mg/kg based on concizumab plasma concentrations.

Outcome measures

All studies assessed ABR for all bleeds, AjBR, and AsBR (ATLAS ‐ A/B; ATLAS ‐ INH; EXPLORER 4; EXPLORER 7; HAVEN 1; HAVEN 3). Five studies assessed ABR for treated bleeds (ATLAS ‐ A/B; ATLAS ‐ INH; EXPLORER 7; HAVEN 1; HAVEN 3). Three studies reported on AtjBR (EXPLORER 7; HAVEN 1; HAVEN 3), and five studies reported on the proportion of participants with zero bleeds (ATLAS ‐ A/B; ATLAS ‐ INH; EXPLORER 7; HAVEN 1; HAVEN 3)

Changes in HRQoL were examined in five studies using the Haem‐A‐QoL (ATLAS ‐ A/B; ATLAS ‐ INH; EXPLORER 7; HAVEN 1; HAVEN 3), two studies using the EQ‐5D‐5L (HAVEN 1; HAVEN 3), and two studies using the SF‐36v2 (EXPLORER 4; EXPLORER 7).

All six studies assessed adverse events including injection‐site reactions, serious adverse events, thromboembolic events, abnormal laboratory values, and antidrug antibodies.

Excluded studies

Descriptions of the excluded studies along with reasons for their exclusion are provided in Characteristics of excluded studies.

We excluded 81 studies (109 references) at the full‐text screening stage due to study design not being an RCT (n = 54); phase I/II dose escalation study (n = 17); population including healthy participants or non‐human population (n = 4); intervention not of interest (n = 6); outcomes not of interest (n = 4); studies terminated with no results available (n = 4). We also excluded article types including narrative reviews (n = 5), correspondence or letters to the editor (n = 7), expert reviews (n = 4), consensus documents (n = 1), and commentaries (n = 3).

Ongoing studies

Three studies are listed as ongoing (EXPLORER 8; HAVEN 5; NCT05053139).

All three studies are open‐label, parallel, multicenter, phase 3 studies conducted in four, HAVEN 5, to 34 countries, EXPLORER 8, and span 44 countries: Algeria, Austria, Australia, Belgium, Bosnia and Herzegovina, Bulgaria, Canada, China, Croatia, the Czech Republic, Denmark, Estonia, France, Germany, Hong Kong, Hungary, India, Ireland, Israel, Italy, Japan, Latvia, Lithuania, Malaysia, Mexico, the Netherlands, Poland, Portugal, Republic of Korea, Romania, Russian Federation, Saudi Arabia, Serbia, Slovakia, South Africa, Spain, Sweden, Switzerland, Taiwan, Thailand, Turkey, Ukraine, the UK, and the USA. All three studies are industry‐sponsored.

Sample sizes range from 85 participants, HAVEN 5, to 267 participants, NCT05053139.

EXPLORER 8 aims to assess the effects of concizumab prophylaxis in people 12 years or older with severe hemophilia A or B without inhibitors. HAVEN 5 examines emicizumab in people with hemophilia A regardless of factor VIII (FVIII) inhibitor status, and NCT05053139 assesses prophylaxis using Mim8 in adults and adolescents with hemophilia A with or without inhibitors.

Two ongoing trials have no results reported yet (EXPLORER 8; NCT05053139), while some results are reported in an abstract for HAVEN 5, but with insufficient information to be included in this review (trial is described as "active, not recruiting" on the trials registry).

For details, see Characteristics of ongoing studies.

Risk of bias in included studies

Risk of bias summaries are shown in Figure 2 and Figure 3.

Risk of bias graph: review authors' judgments about each risk of bias item presented as percentages across all included studies.

Risk of bias summary: review authors' judgments about each risk of bias item for each included study.

Allocation

Random sequence generation

We assessed all six trials as at low risk of bias for random sequence generation. Techniques used for random sequence generation included a combination of permuted blocks, stratification, and an interactive voice/web response system (HAVEN 1), stratified randomization (ATLAS ‐ A/B; ATLAS ‐ INH), and interactive voice/web response system (EXPLORER 4; EXPLORER 7; HAVEN 3). The two‐armed trials were randomized in a 2:1 intervention to control ratio, while the three‐armed trial was randomized in a 2:2:1 ratio (HAVEN 3).

Allocation concealment

We assessed all six trials as at low risk of bias for allocation concealment as they all used an interactive voice/web response system, which ensures that investigators are unaware of the allocation groups.

Blinding

All six studies had an open‐label design and were therefore judged to be at high risk of performance and detection bias (ATLAS ‐ A/B; ATLAS ‐ INH; EXPLORER 4; EXPLORER 7; HAVEN 1; HAVEN 3).

Incomplete outcome data

Four studies had little to no attrition or missing data for reporting of bleeding outcomes (ATLAS ‐ A/B; ATLAS ‐ INH; HAVEN 1; HAVEN 3). In cases where there were losses to follow‐up, these were explained and balanced across treatment arms. We therefore judged these four trials to be at low risk of attrition bias. Results for bleeding outcomes from the EXPLORER 4 trial were combined with results from the excluded Explorer 5 trial in the articles included in this review. We believe there is a chance of overlap and missing outcome data in the reporting, therefore we judged this trial to be at an unclear risk of bias for incomplete outcome data (EXPLORER 4). In EXPLORER 7, both study arms recorded attrition, with more participants not completing treatment in the on‐demand versus the prophylaxis group (15% versus 26.3%). We therefore judged this study as at high risk of attrition bias.

Regarding HRQoL outcomes, we assessed five trials to be at high risk of bias due to incomplete HRQoL outcome data (ATLAS ‐ A/B; ATLAS ‐ INH; EXPLORER 7; HAVEN 1; HAVEN 3). We rated EXPLORER 4 as at low risk of bias for incomplete HRQoL outcome data, as one out of the nine participants in the control group and none of the 17 participants in the concizumab group had missing data for HRQoL assessment using SF‐36v2.

Selective reporting

We judged five studies to be at low risk of reporting bias (ATLAS ‐ A/B; ATLAS ‐ INH; EXPLORER 7; HAVEN 1; HAVEN 3). Protocols were available for all six trials, and all expected outcomes were reported; however, in one trial reporting for bleeding and safety outcomes was unclear (EXPLORER 4). There were overlaps and switches across the different doses of concizumab used, resulting in insufficient information on the number of participants with safety and bleeding outcomes. We therefore judged this trial to be at an unclear risk of reporting bias.

Other potential sources of bias

We identified no other potential sources of bias in five studies (ATLAS ‐ A/B; ATLAS ‐ INH; EXPLORER 4; HAVEN 1; HAVEN 3). The EXPLORER 7 study was paused and restarted, with changes made to the initial study protocol; we judged the effect of this on study results to be unclear.

Effects of interventions

See: Table 1; Table 2; Table 3; Table 4; Table 5; Table 6; Table 7

Non‐clotting factor prophylaxis versus on‐demand therapy in people with inhibitors

See Table 1; Table 2; Table 3.

We included four trials (189 participants) in this comparison (ATLAS ‐ INH; EXPLORER 4; EXPLORER 7; HAVEN 1). Bleed prophylaxis was assessed in one trial with emicizumab (HAVEN 1), one trial with fitusiran (ATLAS ‐ INH), and two trials with concizumab (EXPLORER 4; EXPLORER 7). The comparator group in all four trials was on‐demand therapy.

Primary outcomes

1. Bleeding rates

a. Annualized Bleeding Rates (ABR)—all bleeds and treated bleeds

Comparing emicizumab prophylaxis 3 mg/kg/week for four weeks, followed by a maintenance dose of 1.5 mg/kg/week, versus on‐demand treatment in the HAVEN 1 trial, emicizumab prophylaxis likely results in a lower annualized bleeding rate for all bleeds (mean difference (MD) −22.80, 95% confidence interval (CI) −37.39 to −8.21), and lower annualized bleeding rates for treated bleeds (MD −20.40, 95% CI −35.19 to −5.61; 1 trial; 53 participants; moderate‐certainty evidence; Analysis 1.1).

1.1 — Comparison 1: Emicizumab prophylaxis versus on‐demand therapy in people with inhibitors, Outcome 1: Annualized Bleeding Rates (ABR)

Once‐monthly 80 mg fitusiran for nine months compared with on‐demand therapy in the ATLAS ‐ INH trial also likely resulted in reduced ABR for all bleeds (MD −28.80, 95% CI −40.07 to −17.53; 1 trial; 57 participants) and reduced ABR for all treated bleeds (MD −16.80, 95% CI −25.80 to −7.80; 1 trial; 57 participants; moderate‐certainty evidence; Analysis 2.1)

2.1 — Comparison 2: Fitusiran prophylaxis versus on‐demand therapy in people with inhibitors, Outcome 1: Bleeding rates

Concizumab, administered at a dose of 0.15 mg/kg followed by 0.20 or 0.25 mg/kg, versus on‐demand therapy (EXPLORER 4; EXPLORER 7), may reduce ABR for all bleeds (MD −12.31, 95% CI −19.17 to −5.45; 2 trials, 68 participants; low‐certainty evidence; Analysis 3.1) and ABR for treated bleeds (MD −10.10, 95% CI −17.74 to −2.46; 1 trial; 52 participants; low‐certainty evidence; Analysis 3.1; EXPLORER 7).

3.1 — Comparison 3: Concizumab prophylaxis versus on‐demand therapy in people with inhibitors, Outcome 1: Bleeding rates

b. Annualized joint Bleeding Rates (AjBR)

Emicizumab prophylaxis compared to on‐demand therapy did not result in significantly different bleeding rates for annualized joint bleeds (MD −5.90, 95% CI −15.42 to 3.62; 1 trial; 53 participants; moderate‐certainty evidence; Analysis 1.1).

Fitusiran prophylaxis likely reduced AjBR (MD −12.50, 95% CI −19.91 to −5.09; 1 trial; 57 participants; moderate‐certainty evidence; Analysis 2.1).

Concizumab prophylaxis may reduce AjBR compared to on‐demand therapy (MD −9.55, 95% CI −13.55 to −5.55; 2 trials; 78 participants; low‐certainty evidence; Analysis 3.1).

c. Annualized target joint Bleeding Rates (AtjBR)

Compared to on‐demand therapy, emicizumab prophylaxis did not significantly reduce AtjBR (MD −2.90, 95% CI −8.61 to 2.81; 1 trial; 53 participants; moderate‐certainty evidence; Analysis 1.1). Prophylaxis with concizumab did not significantly reduce AtjBR (MD −1.00, 95% CI −3.26 to 1.26; 1 trial; 38 participants; low‐certainty evidence; Analysis 3.1). AtjBR was not assessed for fitusiran prophylaxis versus on‐demand therapy in ATLAS ‐ INH.

d. Annualized spontaneous bleeding rates (AsBR)

Emicizumab prophylaxis likely results in lower AsBR compared to on‐demand therapy (MD −15.50, 95% CI −24.06 to −6.94; 1 trial; 53 participants; moderate‐certainty evidence; Analysis 1.1). This was consistent with results obtained for fitusiran prophylaxis (MD −14.80, 95% CI −24.90 to −4.71; 1 trial; 57 participants; moderate‐certainty evidence; Analysis 2.1) and concizumab prophylaxis (MD −11.96, 95% CI −19.89 to −4.03; 2 trials; 78 participants; very low‐certainty evidence; Analysis 3.1).

2. Proportion with zero bleeds

At 24‐week follow‐up, emicizumab prophylaxis resulted in an 11.31‐fold increase in the proportion of participants with no bleeds compared with on‐demand therapy (62.9% versus 5.6%; risk ratio (RR) 11.31, 95% CI 1.66 to 77.30; 1 trial; 53 participants; moderate‐certainty evidence; Analysis 1.2).

1.2 — Comparison 1: Emicizumab prophylaxis versus on‐demand therapy in people with inhibitors, Outcome 2: Proportion with zero bleeds (risk ratio)

There was a 12.5‐fold increase in the proportion of participants with no bleeds on fitusiran prophylaxis compared with on‐demand therapy (66% versus 5%; RR 12.50, 95% CI 1.83 to 85.38; 1 trial; 57 participants; moderate‐certainty evidence; Analysis 2.2).

2.2 — Comparison 2: Fitusiran prophylaxis versus on‐demand therapy in people with inhibitors, Outcome 2: Proportion with zero bleeds (risk ratio)

Concizumab prophylaxis resulted in more participants having zero bleeds compared to on‐demand therapy (64% versus 11%; RR 6.05, 95% CI 1.59 to 23.00; 1 trial; 52 participants; low‐certainty evidence; Analysis 3.2).

3.2 — Comparison 3: Concizumab prophylaxis versus on‐demand therapy in people with inhibitors, Outcome 2: Proportion with zero bleeds (risk ratio)

3. HRQoL

Three studies reported on HRQoL using the Haem‐A‐QoL (ATLAS ‐ INH; EXPLORER 7; HAVEN 1). The HAVEN 1 trial also reported HRQoL using the EQ‐5D‐5L (Herdman 2011). The two studies assessing concizumab, EXPLORER 4 and EXPLORER 7, reported HRQoL using the SF‐36v2 (Maruish 2011).

a. Haem‐A‐QoL

Scores on the Haem‐A‐QoL range from 0 to 100, with lower scores representing an improvement in quality of life; a change of seven points is estimated to be clinically meaningful.

At 25 weeks, a greater reduction was observed from baseline in the Haem‐A‐QoL total score with emicizumab compared with no prophylaxis (MD −13.20, 95% CI −20.84 to −5.56; 1 trial; 40 participants). Emicizumab prophylaxis reduced the Haem‐A‐QoL physical health score by 20.20 points (MD −20.20, 95% CI −32.38 to −8.02; 1 trial; 40 participants; low‐certainty evidence; Analysis 1.3).

1.3 — Comparison 1: Emicizumab prophylaxis versus on‐demand therapy in people with inhibitors, Outcome 3: HRQoL—Haem‐A‐QoL

The nine‐month ATLAS ‐ INH trial comparing fitusiran with on‐demand treatment also showed a greater reduction in Haem‐A‐QoL total score in the prophylactic group (MD −14.85, 95% CI −21.04 to −8.66; 1 trial; 48 participants; low‐certainty evidence; Analysis 2.3). Fitusitan prophylaxis reduced the Haem‐A‐QoL physical health score by 20.20 points (MD −28.73, 95% CI −38.52 to −18.94; 1 trial; 49 participants; low‐certainty evidence; Analysis 2.3).

2.3 — Comparison 2: Fitusiran prophylaxis versus on‐demand therapy in people with inhibitors, Outcome 3: HRQoL—Haem‐A‐QoL

Evidence from EXPLORER 7 also suggests that concizumab prophylaxis improves HRQoL, with a reduction in Haem‐A‐QoL scores by −22.60 points (95% CI −42.5 to −2.7; 1 trial; 17 participants; very low‐certainty evidence).

b. SF‐36v2

In this survey, mental component scores (MCS) and physical component scores (PCS) range from 0 to 100, with higher scores indicating better HRQoL.

Results from EXPLORER 4 showed no difference between concizumab prophylaxis and on‐demand therapy in either MCS (MD 0.40, 95% CI −4.45 to 5.25; 1 trial; 26 participants) or PCS (MD 4.20, 95% CI −0.50 to 8.90; 1 trial; 25 participants; very low‐certainty evidence; Analysis 3.3).

3.3 — Comparison 3: Concizumab prophylaxis versus on‐demand therapy in people with inhibitors, Outcome 3: HRQoL—SF‐36v2

In EXPLORER 7, concizumab prophylaxis also resulted in no difference in PCS compared to on‐demand therapy (MD 2.34, 95% CI −3.81 to 8.48; 1 trial; 32 participants; very low‐certainty evidence). However, MCS was higher with concizumab compared to on‐demand therapy (MD 8.65, 95% CI 1.07 to 16.22; 1 trial; 32 participants; very low‐certainty evidence). We did not pool findings from these two studies (EXPLORER 4; EXPLORER 7), as the results from EXPLORER 7 are currently presented in a conference presentation (Linari 2023), with more data needed for meta‐analysis.

c. EQ‐5D‐5L

The EQ‐5D‐5L measures HRQoL in two components: the EQ‐5D‐5L health state profile (descriptive system) and the EQ‐5D‐5L Visual Analog Scale (VAS). The descriptive system records the participant's current health state in five domains: mobility, self‐care, usual activities, pain/discomfort, and anxiety/depression. Responses from the five domains are used to calculate a single utility index value ranging from 1 to 5, where 1 indicates a better health state (no problems) and 5 indicates a poor health state (confined to bed). The VAS records self‐rated health on a scale of 0 to 100, with a score of 0 signifying ‘the worst imaginable health state’ and 100 signifying ‘the best imaginable health state.’

The HAVEN 1 trial reported HRQoL using the EQ‐5D‐5L. No difference was found in EQ‐5D‐5L VAS at 25 weeks between emicizumab prophylaxis and on‐demand therapy (MD 7.40 points, 95% CI −1.57 to 16.37; 1 trial; 46 participants; low‐certainty evidence; Analysis 1.4). There was little to no difference in EQ‐5D‐5L utility index score for the same comparison (MD 0.23, 95% CI 0.04 to 0.42; 1 trial; 46 participants; Analysis 1.5).

1.4 — Comparison 1: Emicizumab prophylaxis versus on‐demand therapy in people with inhibitors, Outcome 4: HRQoL—EQ‐5D‐5L VAS

1.5 — Comparison 1: Emicizumab prophylaxis versus on‐demand therapy in people with inhibitors, Outcome 5: HRQoL—EQ‐5D‐5L Utility Index Score

4. Adverse events

a. All adverse events

Compared with on‐demand therapy, emicizumab prophylaxis likely increased total adverse events (RR 1.97, 95% CI 1.26 to 3.10; 1 trial; 52 participants; moderate‐certainty evidence; Analysis 1.6; HAVEN 1). Fitusiran prophylaxis also likely resulted in more adverse events compared with on‐demand therapy (RR 1.60, 95% CI 1.08 to 2.37; 1 trial; 60 participants; moderate‐certainty evidence; Analysis 2.4; ATLAS ‐ INH). Adverse events were not significantly different between concizumab prophylaxis and on‐demand therapy (RR 1.14, 95% CI 0.76 to 1.70; 2 trials; 78 participants; low‐certainty evidence; Analysis 3.4).

1.6 — Comparison 1: Emicizumab prophylaxis versus on‐demand therapy in people with inhibitors, Outcome 6: Adverse events

2.4 — Comparison 2: Fitusiran prophylaxis versus on‐demand therapy in people with inhibitors, Outcome 4: Adverse events

3.4 — Comparison 3: Concizumab prophylaxis versus on‐demand therapy in people with inhibitors, Outcome 4: Adverse events

b. Serious adverse events

The risk ratio for serious adverse events for emicizumab prophylaxis (RR 1.32, 95% CI 0.48 to 3.63; 1 trial; 52 participants; Analysis 1.6) (HAVEN 1), fitusiran prophylaxis (RR 0.65, 95% CI 0.24 to 1.78; 1 trial; 60 participants; Analysis 2.4; ATLAS ‐ INH), and concizumab prophylaxis (RR 0.45, 95% CI 0.06 to 3.38; 2 trials; 78 participants; low‐certainty evidence; Analysis 3.4), showed no significant difference between on‐demand treatment and any of the prophylactic therapies assessed.

No case of treatment‐related cancer or mortality was reported in the four studies assessing emicizumab, fitusiran, and concizumab (ATLAS ‐ INH; EXPLORER 4; EXPLORER 7; HAVEN 1). Fatal events were reported in three participants in the EXPLORER 7 trial (two in the concizumab group and one in the control group). None of these were estimated to be related to the treatment groups.

c. Other adverse events (not including serious events)

Other adverse events (not classified as serious events) occurred more frequently with emicizumab prophylaxis compared with on‐demand therapy (RR 1.94, 95% CI 1.22 to 3.09; 1 trial; 52 participants; moderate‐certainty evidence; Analysis 1.6; HAVEN 1). The most frequent adverse events were injection site reactions reported in 8 participants (24%), upper respiratory tract infections (7/34; 21%), headache (3/34; 9%), fatigue (3/34; 9%), and arthralgia (2/34; 6%). There was no mention of whether these were treatment‐related or not.

Non‐serious adverse events also occurred more frequently with fitusiran prophylaxis compared with on‐demand therapy (RR 1.85, 95% CI 1.07 to 3.22; 1 trial; 60 participants; moderate‐certainty evidence; Analysis 2.4; ATLAS ‐ INH). The most frequent treatment‐emergent adverse event was increased alanine aminotransferase reported in 13 participants (13/41; 32%) versus no participant in the on‐demand group.

No differences were observed in non‐serious infections between concizumab prophylaxis and on‐demand therapy (RR 0.98, 95% CI 0.63 to 1.52; 1 trial; 26 participants; very low‐certainty evidence; Analysis 3.4; EXPLORER 4). The most frequently reported adverse events were injection site erythema (6/33, 18%), pyrexia (2/33, 6%), arthralgia (2/33, 6%), upper respiratory tract infection (2/33, 6%), and increased levels of prothrombin fragments 1 and 2 (1/33, 3%) compared with upper respiratory tract infection (1/19, 5%), pyrexia (1/19, 5%), and no arthralgia or injection site erythema in the on‐demand group.

d. Development of inhibitors or antidrug antibodies

In the HAVEN 1 trial, no antidrug antibodies were identified in response to emicizumab, while one participant in the on‐demand therapy group developed inhibitors. In ATLAS ‐ INH, transient antidrug antibodies to fitusiran were found in one participant (1/38, 2.6%) on day 29; these were no longer present in subsequent assessments at three and eight months. Antibodies to concizumab were detected in three participants in EXPLORER 4, but with no observed clinical effect. Also in EXPLORER 7, antidrug antibodies to concizumab were observed at one or more visits in 33 of 127 participants (26%). This was reported in the combined groups exposed to concizumab in the combined randomized and non‐randomized (not review‐eligible) groups in EXPLORER 7.

Secondary outcomes

None of the studies included in this comparison reported on the effect of the interventions on secondary outcomes of this review including joint health (hemophilia joint health score (HJHS), the proportion of participants with target joints, radiologic scores, clinical joint function), pain scores, or economic outcomes (cost‐effectiveness, cost‐benefit, cost utilization, cost minimization, or budget impact). Trials that reported on the proportion of participants with target joints reported these only at baseline and not at the end of the trial.

Non‐clotting factor prophylaxis versus on‐demand therapy in people without inhibitors

See Table 4; Table 5.

We included two trials in this comparison (ATLAS ‐ A/B; HAVEN 3). None of the data were pooled across studies in this comparison. ATLAS ‐ A/B compared fitusiran prophylaxis (80 mg once a month) with on‐demand therapy. HAVEN 3 was a three‐arm trial comparing two different dose schedules of emicizumab with on‐demand therapy. We reported all the comparisons separately (i.e. fitusiran versus on‐demand therapy, emicizumab 1.5 mg/kg once‐weekly regimen versus on‐demand therapy, and emicizumab 3.0 mg/kg bi‐weekly versus on‐demand therapy) (Rücker 2017). We also reported the comparison between the two emicizumab dosing schedules.

Primary outcomes

1. Bleeding rates

a. Annualized Bleeding Rates (ABR)—all bleeds and treated bleeds

Compared with on‐demand therapy, emicizumab prophylaxis administered at 1.5 mg/kg per week likely resulted in a lower total ABR for all bleeds (MD −45.10, 95% CI −63.44 to −26.76; 1 trial; 54 participants) and reduced ABR for treated bleeds (MD −36.70, 95% CI −60.53 to −12.87; 1 trial; 54 participants; moderate‐certainty evidence; Analysis 4.1; HAVEN 3). Emicizumab prophylaxis at a dose of 3.0 mg/kg bi‐weekly versus on‐demand therapy also likely resulted in lower total ABR for all bleeds (MD −45.00, 95% CI −63.19 to −26.81; 1 trial; 53 participants) and reduced ABR for treated bleeds (MD −36.90, 95% CI −60.67 to −13.13; 1 trial; 53 participants; moderate‐certainty evidence; Analysis 5.1; HAVEN 3).

4.1 — Comparison 4: Emicizumab 1.5 mg/kg/week prophylaxis versus on‐demand therapy in people without inhibitors, Outcome 1: Bleeding rates

5.1 — Comparison 5: Emicizumab 3.0 mg/kg bi‐weekly prophylaxis versus on‐demand therapy in people without inhibitors, Outcome 1: Bleeding rates

b. Annualized joint Bleeding Rate (AjBR)

Compared to on‐demand therapy, emicizumab prophylaxis likely reduced AjBR at a dose of 1.5 mg/kg/week (MD −25.40, 95% CI −45.23 to −5.57; 1 trial; 54 participants; moderate‐certainty evidence; Analysis 4.1; HAVEN 3) as well as at a dose of 3.0 mg/kg bi‐weekly (MD −25.60, 95% CI −45.40 to −5.80; 1 trial; 53 participants; moderate‐certainty evidence; Analysis 5.1; HAVEN 3).

c. Annualized target joint Bleeding Rate (AtjBR)

There were no observed differences in AtjBR between on‐demand therapy and emicizumab prophylaxis either at 1.5 mg/kg/week (MD –12.40, 95% CI –25.00 to 0.20; 1 trial; 54 participants; moderate‐certainty evidence; Analysis 4.1; HAVEN 3) or at 3.0 mg/kg bi‐weekly (MD –12.30, 95% CI –24.91 to 0.31; 1 trial; 53 participants; moderate‐certainty evidence; Analysis 5.1; HAVEN 3).

d. Annualized spontaneous joint Bleeding Rate (AsBR)

Results from HAVEN 3 showed no difference in AsBR between emicizumab 1.5 mg/kg/week prophylaxis and on‐demand therapy (MD –14.60, 95% CI –29.78 to 0.58; 1 trial; 54 participants; moderate‐certainty evidence; Analysis 4.1; HAVEN 3). However, emicizumab at a dose of 3.0 mg/kg bi‐weekly likely reduced AsBR compared to on‐demand therapy (MD –15.30, 95% CI –30.46 to –0.14; 1 trial; 53 participants; moderate‐certainty evidence; Analysis 5.1; HAVEN 3).

e. Proportion with zero bleeds

At 24‐week follow‐up, emicizumab 1.5 mg/kg/week prophylaxis may result in more participants with zero bleeds compared with on‐demand therapy (50% versus 0%; RR 19.00, 95% CI 1.21 to 298.40; low‐certainty evidence; Analysis 4.2; HAVEN 3). Emicizumab 3.0 mg/kg bi‐weekly prophylaxis also may result in more participants with zero bleeds (40% versus 0%; RR 15.31, 95% CI 0.96 to 242.76; 1 trial; 53 participants; low‐certainty evidence; Analysis 5.2; HAVEN 3).

4.2 — Comparison 4: Emicizumab 1.5 mg/kg/week prophylaxis versus on‐demand therapy in people without inhibitors, Outcome 2: Proportion of participants with zero bleeds (risk ratio)

5.2 — Comparison 5: Emicizumab 3.0 mg/kg bi‐weekly prophylaxis versus on‐demand therapy in people without inhibitors, Outcome 2: Proportion of participants with zero bleeds

2. HRQoL

a. Haem‐A‐QoL

Scores on the Haem‐A‐QoL range from 0 to 100, with lower scores representing an improvement in quality of life; a change of seven points is estimated to be clinically meaningful.

At six months, there was no difference in Haem‐A‐QoL total score when on‐demand therapy was compared to emicizumab 1.5 mg/kg/week (MD −5.91, 95% CI −14.89 to 3.07; 1 trial; 47 participants; low‐certainty evidence; Analysis 4.3) or emicizumab 3.0 mg/kg bi‐weekly (MD −8.56, 95% CI −17.25 to 0.13; 1 trial; 42 participants; low‐certainty evidence; Analysis 5.3). There was also no difference in Haem‐A‐QoL physical health score when on‐demand therapy was compared to emicizumab 1.5 mg/kg/week (MD –12.51, 95% CI −25.72 to 0.70; 1 trial; 47 participants; low‐certainty evidence; Analysis 4.3). Emicizumab 3.0 mg/kg bi‐weekly reduced the physical health score compared to on‐demand treatment (MD –15.97, 95% CI −29.14 to –2.80; 1 trial; 42 participants; low‐certainty evidence; Analysis 5.3).

4.3 — Comparison 4: Emicizumab 1.5 mg/kg/week prophylaxis versus on‐demand therapy in people without inhibitors, Outcome 3: HRQoL—Haem‐A‐QoL

5.3 — Comparison 5: Emicizumab 3.0 mg/kg bi‐weekly prophylaxis versus on‐demand therapy in people without inhibitors, Outcome 3: HRQoL—Haem‐A‐QoL

b. EQ‐5D‐5L

The EQ‐5D‐5L reports a VAS and a utility index value. The VAS scores range from 0 to 100, with a score of 0 signifying ‘the worst imaginable health state’ and 100 signifying ‘the best imaginable health state.’ The utility index records the participant's current health state in five domains, and responses are used to calculate a single value ranging from 1 to 5, where 1 indicates a better health state (no problems) and 5 indicates a poor health state (confined to bed). One study used the EQ‐5D‐5L for HRQoL assessment in people without inhibitors (HAVEN 3).

At 24 weeks, there was no difference between prophylaxis with emicizumab 1.5 mg/kg/week and on‐demand therapy in EQ‐5D‐5L VAS (MD 4.04, 95% CI –4.22 to 12.30; 1 trial; 48 participants; low‐certainty evidence; Analysis 4.4) or EQ‐5D‐5L utility index score (MD 0.13, 95% CI –0.00 to 0.26; 1 trial; 48 participants; low‐certainty evidence; Analysis 4.5).

4.4 — Comparison 4: Emicizumab 1.5 mg/kg/week prophylaxis versus on‐demand therapy in people without inhibitors, Outcome 4: HRQoL—EQ‐5D‐5L VAS

4.5 — Comparison 4: Emicizumab 1.5 mg/kg/week prophylaxis versus on‐demand therapy in people without inhibitors, Outcome 5: HRQoL—EQ‐5D‐5L Utility Index Score

When emicizumab 3.0 mg/kg bi‐weekly was compared with on‐demand therapy, an improvement was observed in EQ‐5D‐5L VAS scores (MD 9.15, 95% CI 2.05 to 16.25; 1 trial; 43 participants; low‐certainty evidence; Analysis 5.4) but not in EQ‐5D‐5L utility index scores (MD 0.13, 95% CI 0.01 to 0.25; 1 trial; 43 participants; low‐certainty evidence; Analysis 5.5).

5.4 — Comparison 5: Emicizumab 3.0 mg/kg bi‐weekly prophylaxis versus on‐demand therapy in people without inhibitors, Outcome 4: HRQoL—EQ‐5D‐5L VAS

5.5 — Comparison 5: Emicizumab 3.0 mg/kg bi‐weekly prophylaxis versus on‐demand therapy in people without inhibitors, Outcome 5: HRQoL—EQ‐5D‐5L Utility Index Score

3. Adverse events

a. All adverse events

Compared to on‐demand therapy, bleed prevention with emicizumab 1.5 mg/kg/week likely resulted in more adverse events (RR 2.83, 95% CI 1.47 to 5.47; 1 trial; 54 participants; moderate‐certainty evidence; Analysis 4.6; HAVEN 3). Prophylaxis with emicizumab 3.0 mg/kg bi‐weekly also likely resulted in more adverse events (RR 1.71, 95% CI 1.06 to 2.77; 1 trial; 53 participants; moderate‐certainty evidence; Analysis 5.6; HAVEN 3).

4.6 — Comparison 4: Emicizumab 1.5 mg/kg/week prophylaxis versus on‐demand therapy in people without inhibitors, Outcome 6: Adverse events

5.6 — Comparison 5: Emicizumab 3.0 mg/kg bi‐weekly prophylaxis versus on‐demand therapy in people without inhibitors, Outcome 6: Adverse events

b. Serious adverse events

There was no difference in risk of serious adverse events when emicizumab 1.5 mg/kg/week (RR 0.50, 95% CI 0.03 to 7.54; 1 trial; 54 participants; moderate‐certainty evidence; Analysis 4.6; HAVEN 3) and emicizumab 3.0 mg/kg bi‐weekly (RR 1.54, 95% CI 0.17 to 13.79; 1 trial; 53 participants; moderate‐certainty evidence; Analysis 5.6; HAVEN 3) were compared with on‐demand therapy.

There was no occurrence of cancer or mortality in both study arms exposed to emicizumab or on‐demand therapy.

c. Other adverse events (not including serious adverse events)

Other adverse events (not including serious adverse events) occurred more frequently with both emicizumab 1.5 mg/kg/week (RR 3.50, 95% CI 1.66 to 7.39; 1 trial; 54 participants; moderate‐certainty evidence; Analysis 4.6; HAVEN 3) and emicizumab 3.0 mg/kg bi‐weekly (RR 3.39, 95% CI 1.60 to 7.18; 1 trial; 53 participants). The most common adverse events in HAVEN 3 (emicizumab 1.5 mg/kg/week versus emicizumab 3.0 mg/kg bi‐weekly versus on‐demand) were injection site reactions (25% versus 20% versus 12%), upper respiratory tract infections (11% versus 11% versus 0%), nasopharyngitis (6% versus 17% versus 0%), arthralgia (19% versus 17% versus 6%), headache (8% versus 11% versus 6%), and influenza (3% versus 9% versus 0%).

d. Development of inhibitors or antidrug antibodies

There was no development of antidrug antibodies to emicizumab or de novo inhibitors to Factor VIII in HAVEN 3.

Secondary outcomes

The study included in this comparison did not report on our secondary outcomes.

Comparison of different emicizumab dosing schedules in people without inhibitors

In the three‐arm HAVEN 3 trial, following a loading dose of 3.0 mg/kg per week over a period of four weeks, investigators compared two prophylactic dosing schedules of emicizumab (1.5 mg/kg/week and 3.0 mg/kg bi‐weekly) of emicizumab with on‐demand therapy. In this assessment, we compared the effects of emicizumab 1.5 mg/kg/week versus emicizumab 3.0 mg/kg/week.

See Table 6.

Primary outcomes

1. Bleeding rates

a. Annualized Bleeding Rate (ABR)—all bleeds and all treated bleeds

There was no difference between emicizumab prophylaxis 1.5 mg/kg/week and 3.0 mg/kg bi‐weekly in total ABR for treated bleeds (MD 0.20, 95% CI −2.01 to 2.41; 1 trial; 71 participants; moderate‐certainty evidence; Analysis 6.1) and all bleeds (MD −0.10, 95% CI −3.39 to 3.19; 1 trial; 71 participants; moderate‐certainty evidence; Analysis 6.1).

6.1 — Comparison 6: Emicuzimab 1.5 mg/kg/week versus 3.0 mg/kg bi‐weekly in people without inhibitors, Outcome 1: Bleeding rates

b. Annualized joint Bleeding Rate (AjBR)

The two dosing schedules did not differ in AjBR (MD 0.20, 95% CI −1.32 to 1.72; 1 trial; 71 participants; moderate‐certainty evidence; Analysis 6.1).

c. Annualized target joint Bleeding Rate (AtjBR)

There was no difference between the two dosing schedules in AtjBR (MD −0.10, 95% CI −0.96 to 0.76; 1 trial; 71 participants; moderate‐certainty evidence; Analysis 6.1).

d. Annualized spontaneous Bleeding Rate (AsBR)

There was no difference between the two dosing schedules in AsBR (MD 0.70, 95% CI −0.26 to 1.66; 1 trial; 71 participants; moderate‐certainty evidence; Analysis 6.1).

e. Proportion with zero bleeds

There was no difference between the two dosing schedules in the proportion of participants with zero bleeds (50% versus 40%; RR 1.25, 95% CI 0.74 to 2.10; 1 trial; 71 participants; moderate‐certainty evidence; Analysis 6.2).

6.2 — Comparison 6: Emicuzimab 1.5 mg/kg/week versus 3.0 mg/kg bi‐weekly in people without inhibitors, Outcome 2: Proportion of participants with zero bleeds

2. HRQoL

There was no difference in Haem‐A‐QoL total score (MD 2.65, 95% CI −4.24 to 9.54; 1 trial; 63 participants; Analysis 6.3), Haem‐A‐QoL physical score (MD 3.46, 95% CI −9.74 to 16.66; 1 trial; 63 participants; low‐certainty evidence; Analysis 6.3), EQ‐5D‐5L VAS (MD −5.11, 95% CI −14.15 to 3.93; 1 trial; 63 participants; Analysis 6.4), and EQ‐5D‐5L utility index score (MD 0.00, 95% CI −0.10 to 0.10; 1 trial; 63 participants; low‐certainty evidence; Analysis 6.5) between the two dosing schedules.

6.3 — Comparison 6: Emicuzimab 1.5 mg/kg/week versus 3.0 mg/kg bi‐weekly in people without inhibitors, Outcome 3: HRQoL—Haem‐A‐QoL

6.4 — Comparison 6: Emicuzimab 1.5 mg/kg/week versus 3.0 mg/kg bi‐weekly in people without inhibitors, Outcome 4: HRQoL—EQ‐5D‐5L VAS

6.5 — Comparison 6: Emicuzimab 1.5 mg/kg/week versus 3.0 mg/kg bi‐weekly in people without inhibitors, Outcome 5: HRQoL—EQ‐5D‐5L Utility Index Score

3. Adverse events

There were no differences between dosing regimens in the total number of adverse events, serious adverse events, other adverse events (not including serious adverse events), serious infections, upper respiratory tract infections, injection site reactions, and other infections (1 trial; 71 participants; moderate‐certainty evidence; Analysis 6.6; HAVEN 3).

6.6 — Comparison 6: Emicuzimab 1.5 mg/kg/week versus 3.0 mg/kg bi‐weekly in people without inhibitors, Outcome 6: Adverse events

Secondary outcomes

The study included in this comparison did not report any of our secondary outcomes.

Fitusiran prophylaxis versus on‐demand therapy in people without inhibitors

See Table 7.

Primary outcomes

1. Bleeding rates

a. Annualized Bleeding Rates (ABR)—all bleeds and treated bleeds

In the ATLAS ‐ A/B trial, 80 mg fitusiran administered once monthly compared with on‐demand therapy likely resulted in a lower total ABR for all bleeds (MD −28.20, 95% CI −40.50 to −17.10; 1 trial; 120 participants; moderate‐certainty evidence; Analysis 7.1) and lower ABR for treated bleeds (MD –27.86, 95% CI −41.95 to −13.76; 1 trial; 119 participants; moderate‐certainty evidence; Analysis 7.1).

7.1 — Comparison 7: Fitusiran prophylaxis versus on‐demand therapy in people without inhibitors, Outcome 1: Bleeding rates

b. Annualized joint Bleeding Rate (AjBR)

Fitusiran prophylaxis likely resulted in a lower AjBR compared with on‐demand therapy (MD –21.13, 95% CI –33.06 to –9.20; 1 trial; 119 participants; moderate‐certainty evidence; Analysis 7.1; ATLAS ‐ A/B).

c. Annualized target joint Bleeding Rate (AtjBR)

This outcome was not reported (ATLAS ‐ A/B).

d. Annualized spontaneous joint Bleeding Rate (AsBR)

Fitusiran prophylaxis likely resulted in a lower AsBR compared with on‐demand therapy (MD −20.21, 95% CI –32.12 to −8.30; 1 trial; 119 participants; Analysis 7.1; ATLAS ‐ A/B).

e. Proportion with zero bleeds

Fitusiran prophylaxis likely resulted in more participants with zero bleeds compared with on‐demand therapy (40% versus 5%; RR 8.10, 95% CI 2.04 to 32.11; moderate‐certainty evidence; Analysis 7.2; ATLAS ‐ A/B).

7.2 — Comparison 7: Fitusiran prophylaxis versus on‐demand therapy in people without inhibitors, Outcome 2: Proportion of participants with zero bleeds (risk ratio)

2. HRQoL

Fitusiran prophylaxis may result in improved HRQoL as shown by a reduction in Haem‐A‐QoL total score by 7.00 points more from baseline than on‐demand therapy (MD –7.06, 95% CI −11.50 to –2.62; 1 trial; 103 participants; low‐certainty evidence; Analysis 7.3). Fitusiran prophylaxis may also reduce Haem‐A‐QoL physical health score compared with on‐demand treatment (MD –19.75, 95% CI −25.76 to −11.94; 1 trial; 103 participants; low‐certainty evidence).

7.3 — Comparison 7: Fitusiran prophylaxis versus on‐demand therapy in people without inhibitors, Outcome 3: Change in HRQoL—Haem‐A‐QoL

3. Adverse events

a. All adverse events

Fitusiran prophylaxis likely resulted in the occurrence of more adverse events compared with on‐demand therapy (RR 1.74, 95% CI 1.21 to 2.50; 1 trial; 119 participants; Analysis 7.4; ATLAS ‐ A/B).

7.4 — Comparison 7: Fitusiran prophylaxis versus on‐demand therapy in people without inhibitors, Outcome 4: Adverse events

b. Serious adverse events

Similar to the population with inhibitors, the risk of serious adverse events did not differ between fitusiran and on‐demand therapy (RR 0.50, 95% CI 0.15 to 1.63; 1 trial; 120 participants; moderate‐certainty evidence; Analysis 7.4).

There was no occurrence of cancer or mortality in the fitusiran or control group in ATLAS ‐ A/B.

c. Other adverse events (not including serious adverse events)

Non‐serious adverse events occurred more frequently with fitusiran prophylaxis when compared with on‐demand therapy (RR 2.85, 95% CI 1.49 to 5.45; 1 trial; 119 participants; moderate‐certainty evidence; Analysis 7.4; ATLAS ‐ A/B). The most frequent treatment‐emergent adverse event was increased alanine aminotransferase reported in 23% of participants on fitusiran prophylaxis versus 3% of participants in the on‐demand group.

d. Development of inhibitors or antidrug antibodies

In ATLAS ‐ A/B, three out of 80 participants (4%) had transient antidrug antibody responses to fitusiran, but this was shown to have had no effect on antithrombin lowering in these participants.

Secondary outcomes

The study included in this comparison did not report any of our secondary outcomes.

Discussion

Summary of main results

This review included six RCTs involving a total of 397 participants with hemophilia A or B who received non‐clotting factor therapies for the prevention of bleeds and bleed‐related complications (ATLAS ‐ A/B; ATLAS ‐ INH; EXPLORER 4; EXPLORER 7; HAVEN 1; HAVEN 3). Our assessment was grouped into two comparisons based on the presence or absence of inhibitors.

Non‐clotting factor prophylaxis versus no prophylaxis in people with inhibitors

Four studies (189 participants) provided data for this comparison (ATLAS ‐ INH; EXPLORER 4; EXPLORER 7; HAVEN 1).

For our primary outcome of ABR, we found moderate‐certainty evidence that emicizumab prophylaxis results in a large reduction in all bleeds, all treated bleeds, and spontaneous bleeds compared with on‐demand therapy. However, emicizumab prophylaxis likely did not reduce joint bleeds (MD −5.90, 95% CI −15.42 to 3.62; 1 trial; 53 participants; Analysis 1.1) or target joint bleeds (MD −2.90, 95% CI −8.61 to 2.81; 1 trial; 53 participants; Analysis 1.1) when compared with on‐demand therapy. Fitusiran prophylaxis reduced ABR for all bleeds, all treated bleeds, joint bleeds, and spontaneous bleeds (57 participants; Analysis 2.1; ATLAS ‐ INH). The effect of fitusiran on target joint bleeds was not assessed. Evidence from the EXPLORER 4 and EXPLORER 7 trials suggests that concizumab prophylaxis results in a large reduction in all bleeds, all treated bleeds, joint bleeds, and spontaneous bleeds, but not target joint bleeds (MD −1.00, 95% CI −3.26 to 1.26; 1 trial; 38 participants; low‐certainty evidence; Analysis 3.1).

The proportion of participants with zero bleeds was 11.31 times higher with emicizumab prophylaxis (62.9% versus 5.6%; RR 11.31, 95% CI 1.66 to 77.30; 1 trial; 53 participants; moderate‐certainty evidence; Analysis 1.2), 12.50 times higher with fitusiran prophylaxis (RR 12.50, 95% CI 1.83 to 85.38; 1 trial; 57 participants; moderate‐certainty evidence; Analysis 2.2), and 1.59 times higher with concizumab prophylaxis (RR 1.59, 95% CI 1.59 to 23.00; 1 trial; 52 participants; low‐certainty evidence; Analysis 3.2) than with on‐demand therapy.

Using the validated disease‐specific HRQoL instrument Haem‐A‐QoL (where a lower score indicates higher quality of life), bleed prophylaxis using emicizumab, fitusiran, and concizumab may improve both physical health and total health scores compared with on‐demand therapy (Analysis 1.3; Analysis 2.3; EXPLORER 7). No difference was found in HRQoL between emicizumab prophylaxis and on‐demand therapy for EQ‐5D‐5L VAS, while little to no increase was seen in EQ‐5D‐5L utility index scores (MD 0.23, 95% CI 0.04 to 0.42; 1 trial; 46 participants; low‐certainty evidence; Analysis 1.5; HAVEN 1). There was no difference between concizumab prophylaxis and on‐demand therapy in HRQoL as measured by the mental component and physical component scores of the SF‐36v2 (MD 4.20, 95% CI −0.50 to 8.90; 1 trial; 25 participants; very low‐certainty evidence; Analysis 3.3).

Prophylaxis with each of the three assessed therapies probably led to more adverse events compared with on‐demand therapy (Analysis 1.6; Analysis 2.4; Analysis 3.4). However, no differences were observed between prophylaxis with each of the non‐clotting factors and on‐demand therapy in serious adverse events. Given that these therapies are administered subcutaneously, injection site reactions contributed significantly to reported adverse events. Also, all events experienced by study participants were reported, some of which may not have been treatment‐related. No antidrug antibodies were identified in response to emicizumab (HAVEN 1). Transient antidrug antibodies were identified with fitusiran (ATLAS ‐ INH) and concizumab (EXPLORER 4; EXPLORER 7).

None of the studies included in this comparison reported on any of our secondary outcomes.

Non‐clotting factor prophylaxis versus no prophylaxis in people without inhibitors

Two studies (209 participants) provided data for this comparison. The studies assessed prophylaxis using fitusiran 80 mg once a month, emicizumab 1.5 mg/kg/week, and emicizumab 3.0 mg/kg bi‐weekly (ATLAS ‐ A/B; HAVEN 3).

Compared with on‐demand therapy, prophylaxis with emicizumab 1.5 mg/kg/week and emicizumab 3.0 mg/kg bi‐weekly likely resulted in a large reduction in ABR for all bleeds, all treated bleeds, and joint bleeds. Annualized target joint bleeds were not reduced with either of the two emicizumab dosing regimens. Spontaneous bleeds were likely reduced with emicizumab 3.0 mg/kg bi‐weekly (MD –15.30, 95% CI –30.46 to –0.14; 1 trial; 53 participants; moderate‐certainty evidence) but not with emicizumab 1.5 mg/kg/week (MD –14.60, 95% CI –29.78 to 0.58; 1 trial; 54 participants; moderate‐certainty evidence; Analysis 4.1; HAVEN 3).

Prophylaxis with fitusiran 80 mg monthly likely resulted in a large reduction in ABR for all bleeds, all treated bleeds, spontaneous bleeds, and joint bleeds. The effect of fitusiran prophylaxis on target joint bleeds was not assessed.

Similar to the population with inhibitors, bleed prophylaxis using the non‐clotting factor therapies resulted in more participants with zero bleeds compared with on‐demand therapy: emicizumab 1.5 mg/kg/week (50% versus 0%; RR 19.00, 95% CI 1.21 to 298.40; low‐certainty evidence; Analysis 4.2; HAVEN 3), emicizumab 3.0 mg/kg bi‐weekly (40% versus 0%; RR 15.31, 95% CI 0.96 to 242.75; low‐certainty evidence; Analysis 5.2; HAVEN 3), and fitusiran 80 mg monthly (40% versus 5%; RR 8.10, 95% CI 2.04 to 32.11; moderate‐certainty evidence; Analysis 7.2; ATLAS ‐ A/B).

At 25 weeks, emicizumab 1.5 mg/kg/week prophylaxis did not improve Haem‐A‐QoL physical health score (MD –12.51, 95% CI –25.72 to 0.70; 1 trial; 47 participants; low‐certainty evidence; Analysis 4.3), Haem‐A‐QoL total health scores (MD –5.91, 95% CI –14.89 to 3.07; 1 trial; 47 participants; low‐certainty evidence; Analysis 4.3), EQ‐5D‐5L VAS (MD 4.04, 95% CI –4.22 to 12.30; 1 trial; 48 participants; low‐certainty evidence; Analysis 4.4), or EQ‐5D‐5L utility index score (MD 0.13, 95% CI –0.00 to 0.26; 1 trial; 48 participants; low‐certainty evidence; Analysis 4.5) compared with on‐demand therapy.

Emicizumab 3.0 mg/kg bi‐weekly improved HRQoL as measured by the Haem‐A‐QoL physical health score (MD –15.97, 95% CI –29.14 to –2.80; 1 trial; 42 participants; low‐certainty evidence; Analysis 5.3) and EQ‐5D‐5L VAS (MD 9.15, 95% CI 2.05 to 16.25; 1 trial; 43 participants; low‐certainty evidence; Analysis 5.4).

Fitusiran may improve HRQoL as shown by a reduction in Haem‐A‐QoL total score (MD –7.06, 95% CI –11.50 to –2.62; 1 trial; 103 participants; low‐certainty evidence; Analysis 7.3) and physical health score (MD –19.75, 95% CI –25.76 to –11.94; 1 trial; 103 participants; low‐certainty evidence) compared with on‐demand treatment.

Data from both studies in this comparison showed that bleed prevention probably increased the risk of adverse events compared to on‐demand treatment. There was no difference in serious adverse events, but prophylaxis probably increased the risk of non‐serious adverse events compared to on‐demand treatment, especially injection site reactions.

Different dosing schedules for emicizumab

In the three‐arm HAVEN 3 trial, following a loading dose of 3.0 mg/kg per week of emicizumab for four weeks, investigators compared two prophylactic dosing schedules of emicizumab of 1.5 mg/kg/week or 3.0 mg/kg bi‐weekly and a no‐prophylaxis group.

Data from this trial suggest that emicizumab prophylaxis administered at 1.5 mg/kg/week or 3.0 mg/kg bi‐weekly does not influence the effects of treatment, as there were no differences seen between the two dosing schedules in bleeding rates (Analysis 6.1; Analysis 6.2), HRQoL (Analysis 6.3; Analysis 6.4; Analysis 6.5), or safety outcomes (Analysis 6.6).

Overall completeness and applicability of evidence

We included only RCTs in this review. Our primary outcomes, bleeding rates or events, HRQoL, and adverse events, were reported in all six included trials. However, none of the included studies reported on the secondary outcomes of this review: joint health (using the hemophilia joint health score (HJHS), radiologic scores, clinical joint function), pain scores, or economic outcomes.

Three studies enrolled only participants with severe hemophilia (ATLAS ‐ A/B; ATLAS ‐ INH; HAVEN 3), while the other three studies had no restrictions on disease severity (EXPLORER 4; EXPLORER 7; HAVEN 1). In the studies including all severities, one study reported severe Factor VIII deficiency in 92.5% (49/53) of participants, moderate in 3.8% (2/53), and mild in 3.8% (2/53), making the population predominantly those with severe disease (HAVEN 1). The severity of hemophilia in EXPLORER 4 and EXPLORER 7 was not reported. The evidence summarized in this review is therefore mostly applicable to individuals with moderate‐severe to severe hemophilia A and B with or without inhibitors using the non‐clotting factor prophylactic therapies emicizumab, concizumab, and fitusiran. None of the included studies assessed prophylaxis with marstacimab.

The comparator group in the six included trials was no prophylaxis or on‐demand therapy, while one trial had three arms and compared two dosing schedules of a non‐clotting factor therapy with each other and with no prophylaxis. The findings of this review would therefore apply largely to the efficacy and safety of non‐clotting factor therapies compared to on‐demand therapy, as well as a dosing schedule comparison for emicizumab.

Quality of the evidence

All six included trials were open‐label RCTs with the method for random sequence generation described. We therefore judged all six trials to be at low risk of selection bias due to random sequence generation and high risk of performance bias due to lack of blinding of participants and personnel. We assessed the risk of selection bias due to allocation concealment to be low in all six studies as interactive voice/web response systems were used, suggesting that investigators were unaware of allocation groups. Given the open‐label nature of each trial, we judged the trials to be at high risk of performance and detection bias due to the lack of blinding of outcome assessors.

There was no deviation from intended interventions, little to no missing outcome data for bleeding outcomes, and no selective reporting of outcomes in the six included studies. We had no serious concerns about inconsistency, indirectness, or publication bias. We downgraded the certainty of evidence for all outcomes once to moderate due to the risk of bias from lack of randomization. In two studies, we assessed the risk of attrition bias to be unclear, EXPLORER 4, or high risk due to unbalanced attrition across intervention groups (EXPLORER 7). We also downgraded for imprecision in estimates with wide confidence intervals or insufficient sample sizes.

We downgraded the certainty of the evidence for HRQoL outcomes once across five studies due to incomplete outcome data and once due to high risk of bias from lack of blinding in these studies, for a rating of low certainty. We assessed one trial as at low risk of bias for incomplete HRQoL data (EXPLORER 4).

Potential biases in the review process

The possibility of bias was minimized in the review process. Our search strategy was as inclusive as possible, with no restrictions placed on the language or date of publication when searching the databases. We avoided missing potentially relevant trials by searching clinical trial registries and the grey literature, including websites, publications, and conference proceedings of professional associations of clinicians managing hemophilia. Furthermore, we screened articles, extracted data, and assessed the risk of bias independently and in duplicate, with any conflicts in assessment resolved by discussion and consultation with a third review author when necessary.

Agreements and disagreements with other studies or reviews

In the context of existing literature, only one review has assessed the efficacy and value of the non‐clotting factor therapy using emicizumab for the prevention of bleeds in people with hemophilia with inhibitors (Rind 2018). The findings of our review align with the authors’ conclusions that emicizumab reduces bleeding rates compared to on‐demand treatment or no prophylaxis.

No systematic review currently exists of the evidence for the use of emicizumab in people without inhibitors, or for the use of concizumab, fitusiran, and other non‐clotting factor therapies in people either with or without inhibitors.

Authors' conclusions

Implications for practice.

There is evidence from randomized controlled trials that the use of prophylactic non‐clotting factor therapies probably results in reduced annualized bleeding rates, increased percentage of people with zero bleeds, and increased non‐serious adverse events, and may improve health‐related quality of life in people with hemophilia A and B with or without inhibitors.

Implications for research.

Overall, the findings from this review suggest the following gaps in the data for evidence‐based decision‐making:

comparative efficacy and safety of non‐clotting factor therapies in comparison with other prophylactic regimens. The currently available comparisons are with no prophylaxis or on‐demand therapy, which is no longer a standard of care;
long‐term efficacy in randomized controlled trials and effectiveness in the real‐world setting; and
assessment of joint health outcomes, e.g. using the hemophilia joint health score, radiologic scores, clinical joint function, pain scores, or economic outcomes.

History

Protocol first published: Issue 8, 2021

Acknowledgements

The authors acknowledge and thank Dr Nancy Santeso and Dr Alfonso Iorio for providing guidance on the initial draft of the protocol. We acknowledge Tamara Navarro, Information Specialist, Health Information Research Unit, McMaster University, for reviewing the updated search strategy.

We appreciate Lisa Winer, Copy Editor, Cochrane Central Production Service, and the editorial team at the Cochrane Cystic Fibrosis and Genetic Disorders Group for providing comments and feedback on this review.

We thank the following peer reviewers for commenting on the draft protocol: Natalie Hall, Information Specialist, Cochrane Cystic Fibrosis and Genetic Disorders Group; Shannon Jackson, Department of Medicine, Division of Hematology, University of British Columbia; Hugh MacInnes; Maria Elisa Mancuso, Senior Hematology Consultant, Center for Thrombosis and Hemorrhagic Diseases, Humanitas Clinical and Research Center – IRCCS, Rozzano, Milan, Italy; Fiona Stewart, Cochrane Network Support Fellow.

This project was supported by the National Institute for Health Research (NIHR), via Cochrane Infrastructure funding to the Cochrane Cystic Fibrosis and Genetic Disorders Group. The views and opinions expressed therein are those of the authors and do not necessarily reflect those of the Systematic Reviews Programme, NIHR, NHS, or the UK Department of Health.

Appendices

Appendix 1. Electronic search strategies

Database

Ovid MEDLINE(R) and Epub Ahead of Print, In‐Process, In‐Data‐Review & Other Non‐Indexed Citations, Daily and Versions
<1946 to August 16, 2023>
1 Blood coagulation disorders, inherited/ or exp Hemophilia A/ or exp Hemophilia B/ 25446
2 H?emophilia.mp. 29861
3 hemorrhagic disorders/ 5408
4 (Factor VIII Deficiency or Factor 8 Deficiency or FVIII Deficiency or Classic Hemophilia or Factor IX Deficiency or Factor 9 Deficiency or FIX Deficiency or Christmas Disease).mp. 1676
5 ((H?emophili* or bleeding disorder) adj5 (FVIII or FIX or factor?VIII or factor?IX or congenital or classic or Christmas)).tw. 2136
6 1 or 2 or 3 or 4 or 5 35359
7 exp Antibodies, Bispecific/ 3746
8 (Emicizumab or Hemlibra or ACE910 or ACE‐910 or emicizumab‐kxwh or mAb 2021 or monoclonal antibody 2021).mp. 562
9 exp Antibodies, Monoclonal, Humanized/ or exp Anti‐tissue factor pathway inhibitor/ 85712
10 (concizumab or marstacimab or PF6741086).mp. 62
11 9 and 10 40
12 RNAi Therapeutics/ 774
13 fitusiran.mp. 42
14 12 and 13 1
15 7 and 8 345
16 11 or 14 or 15 374
17 6 and 16 354
18 (prophyla* or prevent*).ti,ab. 1879617
19 17 and 18 213
20 randomized controlled trial.pt. 598022
21 Controlled clinical trial.pt. 95406
22 randomized.ab. 613463
23 Placebo.ab. 240631
24 drug therapy.fs. 2615002
25 randomly.ab. 414518
26 trial.ab. 659774
27 groups.ab. 2555801
28 20 or 21 or 22 or 23 or 24 or 25 or 26 or 27 5729326
29 exp animals/ not humans/ 5146444
30 28 not 29 5002019
31 19 and 30 183

Ovid ‐ Embase <1996 to 2023 August 16>
1 Blood coagulation disorders, inherited/ or exp Hemophilia / or exp Hemophilia b/ 25432
2 H?emophilia.mp. 29816
3 hemorrhagic disorders/ 5408
4 (Factor VIII Deficiency or Factor 8 Deficiency or FVIII Deficiency or Classic Hemophilia or Factor IX Deficiency or Factor 9 Deficiency or FIX Deficiency or Christmas Disease).mp. 1674
5 ((H?emophili* or bleeding disorder) adj5 (FVIII or FIX or factor?VIII or factor?IX or congenital or classic or Christmas)).tw. 2135
6 1 or 2 or 3 or 4 or 5 35314
7 exp Antibodies, Bispecific/ 3732
1 Blood coagulation disorders, inherited/ or exp Hemophilia A/ or exp Hemophilia B/ 55027
2 H?emophilia.mp. 39595
3 Bleeding Disorders/ 2
4 (Factor VIII Deficiency or Factor 8 Deficiency or FVIII Deficiency or Classic Hemophilia or Factor IX Deficiency or Factor 9 Deficiency or FIX Deficiency or Christmas Disease).mp. 1379
5 ((H?emophili* or bleeding disorder) adj5 (FVIII or FIX or factor?VIII or factor?IX or congenital or classic or Christmas)).tw. 4492
6 1 or 2 or 3 or 4 or 5 69464
7 exp bispecific antibody/ 5549
8 (Emicizumab or Hemlibra or ACE910 or ACE‐910 or emicizumab‐kxwh or mAb 2021 or monoclonal antibody 2021).mp. 1814
9 exp monoclonal antibody/ or exp tissue factor pathway inhibitor/ or anti‐TFPI.mp. 692099
10 (concizumab or marstacimab or PF6741086).mp. 238
11 9 and 10 234
12 RNAi Therapeutics/ 1398
13 fitusiran.mp. 225
14 12 and 13 16
15 7 and 8 207
16 1 or 14 or 15 443
17 6 and 16 402
18 (prophyla* or prevent*).ti,ab. 2171959
19 17 and 18 218
20 random:.tw. or clinical trial:.mp. or exp health care quality/ 6259815
21 19 and 20 146
22 exp animals/ not human/ 3538524
23 21 not 22 144
24 19 and 23 144

Cochrane Library:
August 16, 2023
ID Search Hits
#1 MeSH descriptor: [Blood Coagulation Disorders, Inherited] explode all trees 921
#2 MeSH descriptor: [Hemophilia A] explode all trees 669
#3 MeSH descriptor: [Hemophilia B] explode all trees 196
#4 ((haemophilia* or hemophilia*)):ti,ab,kw (Word variations have been searched) 1775
#5 ((("Factor VIII" OR "factor 8") AND deficienc*)):ti,ab,kw (Word variations have been searched) 107
#6 ((("Factor IX" OR "factor 9" OR F9) AND deficienc*)):ti,ab,kw (Word variations have been searched) 46
#7 ((Christmas NEXT Disease*)):ti,ab,kw (Word variations have been searched) 5
#8 #1 OR #2 OR #3 OR #4 OR #5 OR #6 OR #7 1998
#9 MeSH descriptor: [Antibodies, Bispecific] explode all trees 102
#10 (Emicizumab or Hemlibra or ACE910 or ACE‐910 or emicizumab‐kxwh or mAb 2021 or monoclonal antibody 2021):ti,ab,kw (Word variations have been searched) 439
#11 MeSH descriptor: [Antibodies, Monoclonal] explode all trees 18796
#12 (concizumab or marstacimab or PF6741086):ti,ab,kw (Word variations have been searched) 46
#13 #9 AND #10 24
#14 #11 AND #12 4
#15 MeSH descriptor: [RNAi Therapeutics] explode all trees 19
#16 (fitusiran):ti,ab,kw (Word variations have been searched) 21
#17 #15 AND #16 1
#18 #13 OR #14 OR #17 29
#19 #8 AND #18 27
#20 ((prophyla* or prevent*)):ti,ab,kw (Word variations have been searched) 290842
#21 #19 AND #20 21

World Health Organization International Clinical Trials Registry Platform (trialsearch.who.int/)
August 16, 2023
Condition: haemophilia OR hemophilia
AND
Intervention: prophylactic OR prophylaxis OR prevent OR prevention or preventing
Recruitment status is: All
Hits = 37

ClinicalTrials.gov (www.clinicaltrials.gov)
August 16, 2023
Condition or disease: haemophilia OR hemophilia
Other terms: prophylactic OR prophylaxis OR prevent OR preventing OR prevention
Study type: Interventional Studies (Clinical Trials)
Also searched for Prophylaxis, Prophylactic treatment, Prevention
Hits = 240

Website and publication search
August 16, 2023
i. World Federation of Hemophilia (WFH), wfh.org
ii. National Hemophilia Foundation (NHF), hemophilia.org
iii. US Food and Drug Administration (FDA), fda.gov
iv. Canadian Agency for Drugs and Technologies in Health (CADTH), cadth.ca
v. National Institute for Health and Care Excellence (NICE), nice.org.uk
Hits: 26

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Data and analyses

Comparison 1. Emicizumab prophylaxis versus on‐demand therapy in people with inhibitors.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1.1 Annualized Bleeding Rates (ABR)	1		Mean Difference (IV, Random, 95% CI)	Subtotals only
1.1.1 ABR ‐ All treated bleeds	1	53	Mean Difference (IV, Random, 95% CI)	‐20.40 [‐35.19, ‐5.61]
1.1.2 Annualized spontaneous bleeding rate (AsBR)	1	53	Mean Difference (IV, Random, 95% CI)	‐15.50 [‐24.06, ‐6.94]
1.1.3 Annualized joint Bleeding Rates (AjBR)	1	53	Mean Difference (IV, Random, 95% CI)	‐5.90 [‐15.42, 3.62]
1.1.4 Annualized target joint Bleeding Rates (AtjBR)	1	53	Mean Difference (IV, Random, 95% CI)	‐2.90 [‐8.61, 2.81]
1.1.5 Annualized Bleeding Rates (ABR) ‐ all bleeds	1	53	Mean Difference (IV, Random, 95% CI)	‐22.80 [‐37.39, ‐8.21]
1.2 Proportion with zero bleeds (risk ratio)	1		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
1.2.1 Emicizumab	1	53	Risk Ratio (M‐H, Random, 95% CI)	11.31 [1.66, 77.30]
1.3 HRQoL—Haem‐A‐QoL	1		Mean Difference (IV, Random, 95% CI)	Subtotals only
1.3.1 Change from baseline in total score	1	40	Mean Difference (IV, Random, 95% CI)	‐13.20 [‐20.84, ‐5.56]
1.3.2 Change from baseline in physical health score	1	40	Mean Difference (IV, Random, 95% CI)	‐20.20 [‐32.38, ‐8.02]
1.4 HRQoL—EQ‐5D‐5L VAS	1		Mean Difference (IV, Random, 95% CI)	Subtotals only
1.4.1 EQ‐5D‐5L Visual Analog Scale Scores	1	46	Mean Difference (IV, Random, 95% CI)	7.40 [‐1.57, 16.37]
1.5 HRQoL—EQ‐5D‐5L Utility Index Score	1		Mean Difference (IV, Random, 95% CI)	Subtotals only
1.5.1 EQ‐5D‐5L Index utility score	1	46	Mean Difference (IV, Random, 95% CI)	0.23 [0.04, 0.42]
1.6 Adverse events	1		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
1.6.1 Adverse events ‐ All	1	52	Risk Ratio (M‐H, Random, 95% CI)	1.97 [1.26, 3.10]
1.6.2 Serious adverse events	1	52	Risk Ratio (M‐H, Random, 95% CI)	1.32 [0.48, 3.63]
1.6.3 Serious infections	1	52	Risk Ratio (M‐H, Random, 95% CI)	1.63 [0.07, 38.06]
1.6.4 Upper respiratory tract infections	1	52	Risk Ratio (M‐H, Random, 95% CI)	8.14 [0.49, 134.94]
1.6.5 Other infections	1	52	Risk Ratio (M‐H, Random, 95% CI)	0.26 [0.05, 1.31]
1.6.6 Injection site reactions	1	47	Risk Ratio (M‐H, Random, 95% CI)	3.06 [0.42, 22.11]
1.6.7 Other adverse events (not including serious adverse events)	1	52	Risk Ratio (M‐H, Random, 95% CI)	1.94 [1.22, 3.09]

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Comparison 2. Fitusiran prophylaxis versus on‐demand therapy in people with inhibitors.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
2.1 Bleeding rates	1		Mean Difference (IV, Random, 95% CI)	Subtotals only
2.1.1 All treated bleeds	1	57	Mean Difference (IV, Random, 95% CI)	‐16.80 [‐25.80, ‐7.80]
2.1.2 Annualized spontaneous bleeding rate (AsBR)	1	57	Mean Difference (IV, Random, 95% CI)	‐14.80 [‐24.90, ‐4.71]
2.1.3 Annualized joint bleeding rate (AjBR)	1	57	Mean Difference (IV, Random, 95% CI)	‐12.50 [‐19.91, ‐5.09]
2.1.4 Annualized bleeding rate (ABR) ‐ All bleeds	1	57	Mean Difference (IV, Random, 95% CI)	‐28.80 [‐40.07, ‐17.53]
2.2 Proportion with zero bleeds (risk ratio)	1		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
2.2.1 Fitusiran	1	57	Risk Ratio (M‐H, Random, 95% CI)	12.50 [1.83, 85.38]
2.3 HRQoL—Haem‐A‐QoL	1		Mean Difference (IV, Random, 95% CI)	Subtotals only
2.3.1 Change from baseline in total score	1	48	Mean Difference (IV, Random, 95% CI)	‐14.85 [‐21.04, ‐8.66]
2.3.2 Change from baseline in physical health score	1	49	Mean Difference (IV, Random, 95% CI)	‐28.73 [‐38.52, ‐18.94]
2.4 Adverse events	1		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

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Comparison 3. Concizumab prophylaxis versus on‐demand therapy in people with inhibitors.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
3.1 Bleeding rates	2		Mean Difference (IV, Random, 95% CI)	Subtotals only
3.1.1 Annualized Bleeding Rate (ABR), Treated Bleeds ‐ Concizumab	1	52	Mean Difference (IV, Random, 95% CI)	‐10.10 [‐17.74, ‐2.46]
3.1.2 Annualized spontaneous bleeding rate (AsBR) ‐ Concizumab	2	78	Mean Difference (IV, Random, 95% CI)	‐11.96 [‐19.89, ‐4.03]
3.1.3 Annualized joint bleeding rate (AjBR) ‐ Concizumab	2	78	Mean Difference (IV, Random, 95% CI)	‐9.55 [‐13.55, ‐5.55]
3.1.4 Annualized target joint bleeding rate (AtjBR) ‐ Concizumab	1	42	Mean Difference (IV, Random, 95% CI)	‐1.00 [‐3.26, 1.26]
3.1.5 Annualized bleeding rates (ABR), All bleeds ‐ Concizumab	2	68	Mean Difference (IV, Random, 95% CI)	‐12.31 [‐19.17, ‐5.45]
3.2 Proportion with zero bleeds (risk ratio)	1		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
3.2.1 Concizumab	1	52	Risk Ratio (M‐H, Random, 95% CI)	6.05 [1.59, 23.00]
3.3 HRQoL—SF‐36v2	1		Mean Difference (IV, Random, 95% CI)	Subtotals only
3.3.1 Change from baseline in SF‐36 mental component score	1	26	Mean Difference (IV, Random, 95% CI)	0.40 [‐4.45, 5.25]
3.3.2 Change from baseline in SF‐36 physical component score	1	25	Mean Difference (IV, Random, 95% CI)	4.20 [‐0.50, 8.90]
3.4 Adverse events	2		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
3.4.1 All adverse events	2	78	Risk Ratio (M‐H, Random, 95% CI)	1.14 [0.76, 1.70]
3.4.2 Serious adverse events	2	78	Risk Ratio (M‐H, Random, 95% CI)	0.45 [0.06, 3.38]
3.4.3 Other adverse events (not including serious adverse events)	1	26	Risk Ratio (M‐H, Random, 95% CI)	0.98 [0.63, 1.52]
3.4.4 Serious infections	1	26	Risk Ratio (M‐H, Random, 95% CI)	0.18 [0.02, 1.46]
3.4.5 Upper respiratory tract infection	2	78	Risk Ratio (M‐H, Random, 95% CI)	0.82 [0.14, 4.73]
3.4.6 Injection site reaction	2	78	Risk Ratio (M‐H, Random, 95% CI)	12.49 [1.78, 87.56]
3.4.7 Other infections	2	68	Risk Ratio (M‐H, Random, 95% CI)	0.81 [0.39, 1.68]
3.5 Bleeding rates (fixed effects model)	2		Mean Difference (IV, Fixed, 95% CI)	Subtotals only
3.5.1 Annualized Bleeding Rate (ABR), Treated Bleeds ‐ Concizumab	1	52	Mean Difference (IV, Fixed, 95% CI)	‐10.10 [‐17.74, ‐2.46]
3.5.2 Annualized spontaneous bleeding rate (AsBR) ‐ Concizumab	2	78	Mean Difference (IV, Fixed, 95% CI)	‐11.50 [‐15.73, ‐7.26]
3.5.3 Annualized joint bleeding rate (AjBR) ‐ Concizumab	2	78	Mean Difference (IV, Fixed, 95% CI)	‐9.53 [‐13.40, ‐5.67]
3.5.4 Annualized target joint bleeding rate (AtjBR) ‐ Concizumab	1	42	Mean Difference (IV, Fixed, 95% CI)	‐1.00 [‐3.26, 1.26]
3.5.5 Annualized bleeding rates (ABR), All bleeds ‐ Concizumab	2	68	Mean Difference (IV, Fixed, 95% CI)	‐12.23 [‐17.23, ‐7.23]

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3.5 — Comparison 3: Concizumab prophylaxis versus on‐demand therapy in people with inhibitors, Outcome 5: Bleeding rates (fixed effects model)

Comparison 4. Emicizumab 1.5 mg/kg/week prophylaxis versus on‐demand therapy in people without inhibitors.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
4.1 Bleeding rates	1		Mean Difference (IV, Random, 95% CI)	Subtotals only
4.1.1 Annualized bleeding rate (ABR) ‐ All treated bleeds	1	54	Mean Difference (IV, Random, 95% CI)	‐36.70 [‐60.53, ‐12.87]
4.1.2 Annualized joint bleeding rate (AjBR)	1	54	Mean Difference (IV, Random, 95% CI)	‐25.40 [‐45.23, ‐5.57]
4.1.3 Annualized target joint bleeding rate (AtjBR)	1	54	Mean Difference (IV, Random, 95% CI)	‐12.40 [‐25.00, 0.20]
4.1.4 Annualized spontaneous bleeding rate (AsBR)	1	54	Mean Difference (IV, Random, 95% CI)	‐14.60 [‐29.78, 0.58]
4.1.5 Annualized bleeding rates (ABR) ‐ All bleeds	1	54	Mean Difference (IV, Random, 95% CI)	‐45.10 [‐63.44, ‐26.76]
4.2 Proportion of participants with zero bleeds (risk ratio)	1		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
4.2.1 Proportion with zero bleeds (risk ratio)	1	54	Risk Ratio (M‐H, Random, 95% CI)	19.00 [1.21, 298.40]
4.3 HRQoL—Haem‐A‐QoL	1		Mean Difference (IV, Random, 95% CI)	Subtotals only
4.3.1 Haem‐A‐QoL total score, adjusted for baseline score	1	47	Mean Difference (IV, Random, 95% CI)	‐5.91 [‐14.89, 3.07]
4.3.2 Haem‐A‐QoL physical health score, adjusted for baseline score	1	47	Mean Difference (IV, Random, 95% CI)	‐12.51 [‐25.72, 0.70]
4.4 HRQoL—EQ‐5D‐5L VAS	1		Mean Difference (IV, Random, 95% CI)	Subtotals only
4.4.1 EQ‐5D‐5L Visual Analog Scale scores, adjusted for baseline score	1	48	Mean Difference (IV, Random, 95% CI)	4.04 [‐4.22, 12.30]
4.5 HRQoL—EQ‐5D‐5L Utility Index Score	1		Mean Difference (IV, Random, 95% CI)	Subtotals only
4.5.1 EQ‐5D‐5L index utility score, adjusted for baseline score	1	48	Mean Difference (IV, Random, 95% CI)	0.13 [‐0.00, 0.26]
4.6 Adverse events	1		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
4.6.1 All adverse events	1	54	Risk Ratio (M‐H, Random, 95% CI)	2.83 [1.47, 5.47]
4.6.2 Serious adverse events	1	54	Risk Ratio (M‐H, Random, 95% CI)	0.50 [0.03, 7.54]
4.6.3 Other adverse events (not including serious adverse events)	1	54	Risk Ratio (M‐H, Random, 95% CI)	3.50 [1.66, 7.39]
4.6.4 Serious infections	1	54	Risk Ratio (M‐H, Random, 95% CI)	3.59 [0.20, 66.06]
4.6.5 Upper respiratory tract infection	1	54	Risk Ratio (M‐H, Random, 95% CI)	2.25 [0.54, 9.34]
4.6.6 Injection site reaction	1	54	Risk Ratio (M‐H, Random, 95% CI)	2.50 [0.61, 10.23]

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Comparison 5. Emicizumab 3.0 mg/kg bi‐weekly prophylaxis versus on‐demand therapy in people without inhibitors.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
5.1 Bleeding rates	1		Mean Difference (IV, Random, 95% CI)	Subtotals only
5.1.1 Annualized bleeding rate (ABR) ‐ All treated bleeds	1	53	Mean Difference (IV, Random, 95% CI)	‐36.90 [‐60.67, ‐13.13]
5.1.2 Annualized bleeding rate (ABR) ‐ All treated bleeds	1	53	Mean Difference (IV, Random, 95% CI)	‐36.90 [‐60.67, ‐13.13]
5.1.3 Annualized joint bleeding rate (AjBR)	1	53	Mean Difference (IV, Random, 95% CI)	‐25.60 [‐45.40, ‐5.80]
5.1.4 Annualized target joint bleeding rate (AtjBR)	1	53	Mean Difference (IV, Random, 95% CI)	‐12.30 [‐24.91, 0.31]
5.1.5 Annualized spontaneous bleeding rate (AsBR)	1	53	Mean Difference (IV, Random, 95% CI)	‐15.30 [‐30.46, ‐0.14]
5.1.6 Annualized bleeding rates (ABR) ‐ All bleeds	1	53	Mean Difference (IV, Random, 95% CI)	‐45.00 [‐63.19, ‐26.81]
5.2 Proportion of participants with zero bleeds	1		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
5.2.1 Proportion with zero bleeds	1	53	Risk Ratio (M‐H, Random, 95% CI)	15.31 [0.96, 242.76]
5.3 HRQoL—Haem‐A‐QoL	1		Mean Difference (IV, Random, 95% CI)	Subtotals only
5.3.1 Haem‐A‐QoL total score, adjusted for baseline score	1	42	Mean Difference (IV, Random, 95% CI)	‐8.56 [‐17.25, 0.13]
5.3.2 Haem‐A‐QoL physical health score, adjusted for baseline score	1	42	Mean Difference (IV, Random, 95% CI)	‐15.97 [‐29.14, ‐2.80]
5.4 HRQoL—EQ‐5D‐5L VAS	1		Mean Difference (IV, Random, 95% CI)	Subtotals only
5.4.1 EQ‐5D‐5L Visual Analog Scale scores, adjusted for baseline score	1	43	Mean Difference (IV, Random, 95% CI)	9.15 [2.05, 16.25]
5.5 HRQoL—EQ‐5D‐5L Utility Index Score	1		Mean Difference (IV, Random, 95% CI)	Subtotals only
5.5.1 EQ‐5D‐5L index utility score, adjusted for baseline score	1	43	Mean Difference (IV, Random, 95% CI)	0.13 [0.01, 0.25]
5.6 Adverse events	1		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
5.6.1 All adverse events	1	53	Risk Ratio (M‐H, Random, 95% CI)	1.71 [1.06, 2.77]
5.6.2 Serious adverse events	1	53	Risk Ratio (M‐H, Random, 95% CI)	1.54 [0.17, 13.79]
5.6.3 Other adverse events (not including serious adverse events)	1	53	Risk Ratio (M‐H, Random, 95% CI)	3.39 [1.60, 7.18]
5.6.4 Upper respiratory tract infection	1	53	Risk Ratio (M‐H, Random, 95% CI)	1.80 [0.42, 7.79]
5.6.5 Injection site reaction	1	53	Risk Ratio (M‐H, Random, 95% CI)	2.06 [0.49, 8.70]

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Comparison 6. Emicuzimab 1.5 mg/kg/week versus 3.0 mg/kg bi‐weekly in people without inhibitors.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
6.1 Bleeding rates	1		Mean Difference (IV, Random, 95% CI)	Subtotals only
6.1.1 Annualized bleeding rate (ABR) ‐ All treated bleeds	1	71	Mean Difference (IV, Random, 95% CI)	0.20 [‐2.01, 2.41]
6.1.2 Annualized joint bleeding rate (AjBR)	1	71	Mean Difference (IV, Random, 95% CI)	0.20 [‐1.32, 1.72]
6.1.3 Annualized target joint bleeding rate (AtjBR)	1	71	Mean Difference (IV, Random, 95% CI)	‐0.10 [‐0.96, 0.76]
6.1.4 Annualized spontaneous bleeding rate (AsBR)	1	71	Mean Difference (IV, Random, 95% CI)	0.70 [‐0.26, 1.66]
6.1.5 Annualized bleeding rates (ABR) ‐ All bleeds	1	71	Mean Difference (IV, Random, 95% CI)	‐0.10 [‐3.39, 3.19]
6.2 Proportion of participants with zero bleeds	1		Risk Ratio (IV, Random, 95% CI)	Subtotals only
6.2.1 Proportion with zero bleeds	1	71	Risk Ratio (IV, Random, 95% CI)	1.25 [0.74, 2.10]
6.3 HRQoL—Haem‐A‐QoL	1		Mean Difference (IV, Random, 95% CI)	Subtotals only
6.3.1 Difference in Haem‐A‐QoL total score, adjusted for baseline score (Emicizumab)	1	63	Mean Difference (IV, Random, 95% CI)	2.65 [‐4.24, 9.54]
6.3.2 Difference in Haem‐A‐QoL physical health score, adjusted for baseline score (Emicizumab)	1	63	Mean Difference (IV, Random, 95% CI)	3.46 [‐9.74, 16.66]
6.4 HRQoL—EQ‐5D‐5L VAS	1		Mean Difference (IV, Fixed, 95% CI)	Subtotals only
6.4.1 EQ‐5D‐5L Visual Analog Scale scores, adjusted for baseline score	1	63	Mean Difference (IV, Fixed, 95% CI)	‐5.11 [‐14.15, 3.93]
6.5 HRQoL—EQ‐5D‐5L Utility Index Score	1		Mean Difference (IV, Fixed, 95% CI)	Subtotals only
6.5.1 EQ‐5D‐5L index utility score, adjusted for baseline score	1	63	Mean Difference (IV, Fixed, 95% CI)	0.00 [‐0.10, 0.10]
6.6 Adverse events	1		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
6.6.1 All adverse events	1	71	Risk Ratio (M‐H, Random, 95% CI)	1.10 [0.94, 1.29]
6.6.2 Serious adverse events	1	71	Risk Ratio (M‐H, Random, 95% CI)	0.32 [0.04, 2.97]
6.6.3 Other adverse events (not including serious adverse events)	1	71	Risk Ratio (M‐H, Random, 95% CI)	1.03 [0.93, 1.14]
6.6.4 Serious infections	1	54	Risk Ratio (M‐H, Random, 95% CI)	3.59 [0.20, 66.06]
6.6.5 Upper respiratory tract infection	1	71	Risk Ratio (M‐H, Random, 95% CI)	1.25 [0.52, 2.99]
6.6.6 Injection site reaction	1	71	Risk Ratio (M‐H, Random, 95% CI)	1.22 [0.54, 2.72]

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Comparison 7. Fitusiran prophylaxis versus on‐demand therapy in people without inhibitors.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
7.1 Bleeding rates	1		Mean Difference (IV, Random, 95% CI)	Subtotals only
7.1.1 Annualized bleeding rate (ABR) ‐ All treated bleeds	1	119	Mean Difference (IV, Random, 95% CI)	‐27.86 [‐41.95, ‐13.76]
7.1.2 Annualized joint bleeding rate (AjBR)	1	119	Mean Difference (IV, Random, 95% CI)	‐21.13 [‐33.06, ‐9.20]
7.1.3 Annualized spontaneous bleeding rate (AsBR)	1	119	Mean Difference (IV, Random, 95% CI)	‐20.21 [‐32.12, ‐8.30]
7.1.4 Annualized bleeding rates (ABR) ‐ All bleeds	1	120	Mean Difference (IV, Random, 95% CI)	‐28.80 [‐40.50, ‐17.10]
7.2 Proportion of participants with zero bleeds (risk ratio)	1		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
7.2.1 Proportion with zero bleeds (risk ratio)	1	119	Risk Ratio (M‐H, Random, 95% CI)	8.10 [2.04, 32.11]
7.3 Change in HRQoL—Haem‐A‐QoL	1		Mean Difference (IV, Random, 95% CI)	Subtotals only
7.3.1 Change from baseline in Haem‐A‐QoL, total health score	1	103	Mean Difference (IV, Random, 95% CI)	‐7.06 [‐11.50, ‐2.62]
7.3.2 Change from baseline in Haem‐A‐QoL, physical health score	1	103	Mean Difference (IV, Random, 95% CI)	‐19.75 [‐27.56, ‐11.94]
7.4 Adverse events	1		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
7.4.1 All adverse events	1	119	Risk Ratio (M‐H, Random, 95% CI)	1.74 [1.21, 2.50]
7.4.2 Serious adverse events	1	120	Risk Ratio (M‐H, Random, 95% CI)	0.50 [0.15, 1.63]
7.4.3 Other adverse events (not including serious adverse events)	1	119	Risk Ratio (M‐H, Random, 95% CI)	2.85 [1.49, 5.45]
7.4.4 Serious infections	1	119	Risk Ratio (M‐H, Random, 95% CI)	0.25 [0.02, 2.71]
7.4.5 Upper respiratory tract infection	1	119	Risk Ratio (M‐H, Random, 95% CI)	9.74 [0.58, 163.17]

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Characteristics of studies

Characteristics of included studies [ordered by study ID]

ATLAS ‐ A/B.

*Study characteristics*
Methods	Open‐label, phase 2, parallel, multicenter, proof‐of‐concept RCT. Investigators randomized 120 participants in a 2:1 ratio into intervention and control groups. Duration: up to a total of 9 months.
Participants	Males with hemophilia A or B, 12 years of age or older, with severe hemophilia (FVIII level less than 1% or FIX level was less than or equal to 2%), and without inhibitors. Number of participants randomized: 120
Interventions	Arm 1 Non‐clotting factor therapy (n = 80): fitusiran 80 mg administered SC as prophylaxis once monthly from Day 1 up to a total of 9 months. Participants received on‐demand factor concentrates (per investigator's discretion and within bleeding dosing guidelines) for the treatment of breakthrough bleeding episodes. Arm 2 Comparator (n = 40): on‐demand factor concentrates (as needed, for episodic bleeding episodes, and not on a regular regimen intended to prevent spontaneous bleeding) per investigator's discretion for the treatment of breakthrough bleeding episodes from Day 1 up to a total of 9 months.
Outcomes	(i) ABR for treated bleeds, (ii) AsBR, (iii) AjBR, and (iv) proportion with zero bleeds. HRQoL measured by Haem‐A‐QoL. Adverse events.
Notes	Dates of study: 1 March 2018 to 14 July 2021. Source of funding: Genzyme, a Sanofi Company. ClinicalTrials.gov identifier: NCT03417245.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	To protect against bias, participants assigned to fitusiran (fitusiran treatment arm; n = 80) or on‐demand factor concentrate therapy (on‐demand arm; n = 40) by stratified randomization. Stratification was by the number of bleeding episodes in the 6 months prior to screening (≤ 10 versus >10) and hemophilia type (hemophilia A or B).
Allocation concealment (selection bias)	Low risk	Eligible participants were randomly assigned, in a 2:1 ratio using an interactive response system, to receive either fitusiran prophylaxis or on‐demand clotting factor concentrates.
Blinding of participants and personnel (performance bias) All outcomes	High risk	No blinding, open‐label.
Blinding of outcome assessment (detection bias) All outcomes	High risk	No blinding, open‐label.
Incomplete outcome data (attrition bias) Bleeding outcomes	Low risk	Three participants in the on‐demand arm and one participant in the fitusiran prophylaxis arm discontinued treatment. Reasons for attrition were discussed and were unlikely to be due to allocated treatment.
Incomplete outcome data (HRQoL)	High risk	10 participants (12.7%) in the fitusiran group do not have HRQoL outcome data compared with 6 participants (15%) in the on‐demand group.
Selective reporting (reporting bias)	Low risk	All outcomes planned for assessment in the protocol were reported.
Other bias	Low risk	No other sources of bias were perceived.

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ATLAS ‐ INH.

*Study characteristics*
Methods	Open‐label, phase 3, parallel, multicenter RCT. The study randomized 57 participants in a 2:1 ratio into intervention or control groups. Duration: up to 9 months.
Participants	Males aged 12 years and older with severe hemophilia A or B with inhibitors (defined as inhibitor titer of ≥ 0.6 BU/mL or as evidenced by medical records). Participant eligibility criteria and intervention in ATLAS ‐ INH were similar to ATLAS ‐ A/B, with the major difference being the presence of inhibitors in the ATLAS ‐ INH population.
Interventions	Arm 1 Non‐clotting factor therapy (n = 38): SC fitusiran 80 mg as prophylaxis once monthly from Day 1 up to a total of 9 months. Arm 2 Comparator (n = 19): on‐demand factor concentrates (as needed, for episodic bleeding episodes, and not on a regular regimen intended to prevent spontaneous bleeding) per investigator discretion for the treatment of breakthrough bleeding episodes from Day 1 up to a total of 9 months.
Outcomes	Frequency of bleeding episodes, ABR for treated bleeds, AsBR, AjBR. Pharmacodynamics and pharmacokinetics. HRQoL: change from baseline in Haem‐A‐QoL score. Adverse events.
Notes	Dates of study: 14 February 2018 to 23 June 2021. Source of funding: Genzyme, a Sanofi Company. ClinicalTrials.gov identifier: NCT03417102.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Participants are randomized 2:1 to the fitusiran treatment arm and the on‐demand arm. Randomization is stratified by the number of bleeding episodes in the 6 months prior to screening (≤ 10 versus >10).
Allocation concealment (selection bias)	Low risk	The use of an interactive voice/web response system suggests that investigators were unaware of the allocation group.
Blinding of participants and personnel (performance bias) All outcomes	High risk	No blinding, open‐label.
Blinding of outcome assessment (detection bias) All outcomes	High risk	No blinding, open‐label.
Incomplete outcome data (attrition bias) Bleeding outcomes	Low risk	Five participants did not complete the intervention in the fitusiran prophylaxis arm (1 due to adverse events, 3 due to the Coronavirus pandemic, and 1 for other reasons) compared to no participants dropping out of the on‐demand arm. However, all analyses were done in the ITT population. Also the registry entry states: "On the eDiary device, it is not possible to leave questions unanswered or to enter partial data. In the bleeding diary pages of the case report form, it is possible to have missing time of a treatment or a bleed. In that case, it is assumed that the bleeds and treatments with missing time occurred at 12:00 am".
Incomplete outcome data (HRQoL)	High risk	7 participants (18.4%) in the fitusiran group do not have HRQoL outcome data as measured by Haem‐A‐QoL versus 2 participants (10.5%) in the on‐demand group.
Selective reporting (reporting bias)	Low risk	All outcomes proposed in the protocol were reported.
Other bias	Low risk	No other perceived bias.

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EXPLORER 4.

*Study characteristics*
Methods	Open‐label, phase 2, parallel, multicenter RCT.
Participants	Males with hemophilia A and B with inhibitors aged 18 years or older currently in need of treatment with bypassing agents. Total number randomized: 26.
Interventions	Arm 1 Non‐clotting factor therapy (n = 17): an initial loading dose of 0.15 mg/kg concizumab was administered, which was escalated to 0.20 and 0.25 mg/kg based on the number of spontaneous bleeding episodes. A single injection of 90 μg/kg rFVIIa was administered in a non‐bleeding state 1 week after dosing with concizumab had been initiated. Arm 2 Comparator (n = 9): on‐demand therapy with rFVIIa for 24 weeks. Participants who completed the main part of the study were enrolled in an extension phase to receive SC concizumab once daily for 52 to 94 weeks. Participants who received concizumab during the main part continued with their treatment at last dose by the end of the main part, and those who received rFVIIa started their treatment with 0.15 mg/kg of concizumab. The dose was then escalated to 0.20 and 0.25 mg/kg based on the number of spontaneous bleeding episodes. A loading dose of 0.5 mg/kg was given as the first concizumab dose in the extension phase.
Outcomes	ABR, AsBR, AjBR. HRQoL: change from baseline in SF‐36v2, mental component summary and physical component summary. Adverse events.
Notes	Dates of study: 10 August 2017 to 31 January 2020. Source of funding: Novo Nordisk. ClinicalTrials.gov identifier: NCT03196284.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	During the main part of the trial, participants were randomized 2:1 to receive either concizumab prophylaxis or on‐demand treatment with recombinant activated factor VII (rFVIIa). At the end of the main part, participants in the rFVIIa on‐demand arm were switched to 0.15 mg/kg concizumab for the extension part. There was no randomization in the extension phase. Randomization was performed using an interactive web‐response system.
Allocation concealment (selection bias)	Low risk	The use of an interactive web‐response system suggests that investigators were unaware of allocation group.
Blinding of participants and personnel (performance bias) All outcomes	High risk	No blinding, open ‐label.
Blinding of outcome assessment (detection bias) All outcomes	High risk	No blinding, open ‐label.
Incomplete outcome data (attrition bias) Bleeding outcomes	Unclear risk	Long‐term results for the Explorer 4 trial and results from both Explorer 4 and 5 were reported together in included articles, with a chance of overlap in the reporting. More detail is required and this was judged to be at an unclear risk of bias for incomplete outcome data.
Incomplete outcome data (HRQoL)	Low risk	There were no missing outcome data.
Selective reporting (reporting bias)	Unclear risk	The reporting was unclear for bleeding and safety outcomes. We estimated the dosing of the intervention in general to be unclear.
Other bias	Low risk	No other perceived bias.

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EXPLORER 7.

*Study characteristics*
Methods	Open‐label, parallel, multicenter, phase 3 RCT.
Participants	People with hemophilia A or B with inhibitors (of any severity) aged 12 years or older, previously treated with bypassing agents in the 24 weeks before screening.
Interventions	Participants were randomized in a 2:1 ratio to: concizumab prophylaxis for 32 weeks or more (n = 33); or on‐demand treatment (i.e. no prophylaxis) for 24 weeks or more (n = 19). On completion of the main part of the trial, participants on on‐demand treatment could receive concizumab prophylaxis. Participants who had previously received concizumab in the EXPLORER 4 trial were transferred to group 3 and received concizumab prophylaxis. Participants who had received prophylaxis with a bypassing agent and additional participants receiving on‐demand treatment were recruited to group 4 and received concizumab prophylaxis. Groups 3 and 4, which were not randomized, are not included in this review. Concizumab treatment was paused by the safety committee of the sponsor due to a non‐fatal thromboembolic event (renal infarct) in 1 participant. (3 participants in total, but 1 participant enrolled in EXPLORER 7.) Treatment was restarted with updated guidance on the management of breakthrough bleeds and a new dosing regimen, i.e. 1 mg/kg loading dose, followed by a daily dose of 0.25 mg. Dose adjustments could be considered at 5 to 8 weeks to 0.2 mg/kg or 0.15 mg/kg based on concizumab plasma concentrations.
Outcomes	ABR, AsBR, AjBR, AtjBR HRQoL: Haem‐A‐QoL, SF‐36v2; bodily pain and physical functioning scores from the start of treatment to week 24. Safety endpoints.
Notes	Dates of study: 21 October 2019 to 27 December 2021. Sponsor: Novo Nordisk. ClinicalTrials.gov identifier: NCT04083781.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	"For the randomized arms 1 and 2, patients meeting randomization criteria were centrally randomized using an interactive web response system and assigned to the next available treatment according to the randomization schedule".
Allocation concealment (selection bias)	Low risk	The use of an interactive web‐response system suggests that investigators were unaware of allocation group.
Blinding of participants and personnel (performance bias) All outcomes	High risk	No blinding, open ‐label.
Blinding of outcome assessment (detection bias) All outcomes	High risk	No blinding, open ‐label.
Incomplete outcome data (attrition bias) Bleeding outcomes	High risk	28/33 completed treatment at 32 wk of treatment (concizumab arm), and 14/19 completed at 24 wk of treatment (on‐demand group)
Incomplete outcome data (HRQoL)	High risk	23/33 and 9/19 participants provided data for SF‐36v2 for the concizumab and on‐demand groups respectively, and 13/33 and 1/19 participants provided data for Haem‐A‐QoL for the concizumab and on‐demand groups.
Selective reporting (reporting bias)	Low risk	All outcomes proposed in the protocol were reported.
Other bias	Unclear risk	The study was paused and re‐started, and changes were made to the initial study protocol. On‐demand treatment in the comparator group continued during the pause and patients in the concizumab prophylaxis group switched to alternative therapies at the investigator’s discretion. Although the investigators stated that "The results of the primary analysis were not affected by the treatment pause (Table S5)." The effects of this on study results are unclear from a clinical and methodological perspective.

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HAVEN 1.

*Study characteristics*
Methods	Open‐label, parallel, multicenter, phase 3 RCT. The study randomized 53 participants in a 2:1 ratio into intervention or control arms. Duration: 24 weeks.
Participants	Participants aged ≥ 12 years with congenital hemophilia A of any severity and documented history of high‐titer inhibitor (i.e. ≥ 5 BUs). Receiving episodic treatment with bypassing agents prior to study entry. Total number of participants randomized: 53.
Interventions	Arm 1 Non‐clotting factor therapy (n = 35): emicizumab prophylaxis administered at a loading dose of 3 mg/kg SC once a week for the first 4 weeks followed by a maintenance dose of 1.5 mg/kg SC once a week up to the end of study. Participants continued to receive bypassing agent therapy to treat any breakthrough bleeds. Arm 2 Comparator (n = 18): participants continued with their prior episodic treatment regimen for the first 24 weeks of the study. After completing at least 24 weeks of study, participants in Arm 2 were allowed to switch to emicizumab prophylaxis (as described for Arm 1) up to the end of study. Participants continued to receive bypassing agent therapy to treat any breakthrough bleeds. Study also has 2 additional arms of non‐randomized emicizumab treatment involving 60 participants; results for these arms are not included in this review.
Outcomes	Bleeding rates (ABR for all bleeds, ABR for treated bleeds, AsBR, AtjBR, proportion with zero bleeds) over at least 24 weeks. HRQoL measured by change from baseline at 25 weeks in Haem‐A‐QoL total score and EQ‐5D‐DL. Adverse events (including injection site reactions, serious adverse events, thromboembolic events, abnormal laboratory values, and antidrug antibodies).
Notes	Dates of study: 18 November 2015 to 1 December 2020. Source of funding: Hoffmann‐La Roche. ClinicalTrials.gov identifier: NCT02476942.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Supplementary Appendix: Participants were randomized in 2:1 ratio to Arm A or Arm B using permutated blocks method, and were stratified by bleeds in the prior 24 weeks (conducted centrally by a vendor via interactive voice/web response system).
Allocation concealment (selection bias)	Low risk	The use of an interactive voice/web response system suggests that investigators were unaware of allocation group.
Blinding of participants and personnel (performance bias) All outcomes	High risk	Open‐label.
Blinding of outcome assessment (detection bias) All outcomes	High risk	No blinding, open ‐label.
Incomplete outcome data (attrition bias) Bleeding outcomes	Low risk	Low risk of attrition bias for bleeding and safety outcomes. There were no missing outcome data.
Incomplete outcome data (HRQoL)	High risk	9 participants (26%) in the emicizumab group and 4 participants (22%) in the on‐demand group do not have outcome data (measured by Haem‐A‐QoL). 5 participants (14.3%) in the emicizumab group and 8 participants (44.4%) in the on‐demand group do not have HRQoL outcome data (measured by EQ5D5L).
Selective reporting (reporting bias)	Low risk	All outcomes in the protocol were reported.
Other bias	Low risk	No other bias perceived.

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HAVEN 3.

*Study characteristics*
Methods	Open‐label, parallel, multicenter, phase 3 RCT. 3‐armed trial involving 152 participants, of which 89 were randomly assigned in a 2:2:1 ratio to 2 intervention arms and a control arm. A fourth group of participants (n = 63) who had been receiving FVIII prophylaxis received emicizumab and were not included in this review, as they were not included in the randomization process. Duration: 24 weeks.
Participants	Eligible participants were 12 years of age or older with severe congenital hemophilia A (endogenous FVIII activity, < 1%), without current FVIII inhibitors (< 0.6 BU/mL), who were receiving episodic or prophylactic FVIII infusions.
Interventions	Participants were randomized to 4 initial loading doses of 3 mg/kg per week of emicizumab, followed by an SC maintenance dose of emicizumab or no prophylaxis. Arm 1 Weekly prophylaxis (n = 36): emicizumab prophylaxis 1.5 mg/kg per week. Arm 2 Bi‐weekly prophylaxis (n = 35): emicizumab prophylaxis 3 mg/kg bi‐weekly. Arm 3 Comparator (n = 18): no prophylaxis The no‐prophylaxis group was switched to emicizumab prophylaxis after completion of the first 24 weeks of the study period. 1 participant randomized to no prophylaxis (Arm 3) switched to emicizumab before the completion of the first 24 weeks of the study period (at 23.5 weeks).
Outcomes	Difference in ABR (Arm 1 versus Arm 3 and Arm 2 versus Arm 3) including ABR for all bleeds, ABR for treated bleeds, AjBR, AsBR, and proportion with zero bleeds. HRQoL: change from baseline in Haem‐A‐QoL total score andHaemo‐QoL short form questionnaire. Haemo‐QoL short form questionnaire score in adolescent participants (12 to 17 years) in the randomized population at week 25 was not analyzed in any of the participants. Safety outcomes.
Notes	Dates of study: 27 September 2016 to 12 May 2022. Source of funding: Hoffmann‐La Roche. ClinicalTrials.gov identifier: NCT02847637.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Randomization was conducted centrally by means of an interactive voice Web‐response system and was stratified according to the number of bleeding events that had occurred in the preceding 24 weeks.
Allocation concealment (selection bias)	Low risk	The use of an interactive voice/web response system suggests that investigators were unaware of allocation group.
Blinding of participants and personnel (performance bias) All outcomes	High risk	No blinding, open ‐labeled trial.
Blinding of outcome assessment (detection bias) All outcomes	High risk	No blinding, open ‐labeled trial.
Incomplete outcome data (attrition bias) Bleeding outcomes	Low risk	There were no missing outcome data.
Incomplete outcome data (HRQoL)	High risk	6% (2 of 36 participants), 17% (6 of 35 participants), and 28% (5 of 18 participants) do not have HRQoL outcome data in study arms A, B, and C.
Selective reporting (reporting bias)	Low risk	Reporting bias not perceived. Protocol was available and all expected outcomes were reported.
Other bias	Low risk	No other bias perceived.

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ABR: annualized bleeding rate  AjBR: annualized joint bleeding rates AsBR: annualized bleeding rate for treated spontaneous bleeds AtjBR: annualized target joint bleeding rates BU: Bethesda units FIX: Factor IX FVIII: Factor VIII Haem‐A‐QoL: Haemophilia Quality of Life Questionnaire for Adults HRQoL: health‐related quality of life ITT: intention‐to‐treat RCT: randomized controlled trial rFVIIa: recombinant factor VIIa SC: subcutaneous

Characteristics of excluded studies [ordered by study ID]

Study	Reason for exclusion
A‐LONG 2011	Non‐clotting factor not included in intervention or control
Agers 2014	Outcomes not of interest (pharmacokinetics)
AKATSUKI	Not an RCT
Aledort 2017	Letter to the editor
Aledort 2019	Letter to the journal editor
Aledort 2020	Letter to the journal editor
ATLAS ‐ PPX	Not an RCT
B‐YOND	Non‐clotting factor not included in intervention or control.
Barg 2019	Not an RCT
Barg 2020	Not an RCT
Barg 2021	Not an RCT
Batsuli 2019	Case series
Benton 2019	Outcome not of interest (patient preference)
Bertolet 2020a	Study terminated early, and no results available.
Bertolet 2020b	Study terminated early, and no results available.
Beyond ABR	Not an RCT
Biron‐Andreani 2020	Case series
Blair 2019	Expert review
Brophy 2019	Letter to the editor
Brown 2020	Not an RCT
Buckner 2020	Commentary
Bukkems 2021	Not an RCT (simulation study)
Cafuir 2019	Expert review
Callaghan 2018	Narrative review
Cardinal 2018	Participants were healthy volunteers, not people with hemophilia.
Chowdary 2015	Phase I/II dose escalation trial
Cortesi 2020	Not an RCT (economic evaluation not based on an RCT)
CTRI201106001832	Intervention (non‐clotting factor not included in intervention or control)
CTRI201204002596	Intervention (non‐clotting factor not included in intervention or control)
CTRI201307003823	Not an RCT
CTRI201807014754	Not an RCT (prospective cohort study)
Donners 2021	Not an RCT (review)
Ebbert 2020	Not an RCT
Eichler 2018	Phase I/II dose escalation trial
Explorer 5	Not an RCT
Fontana 2020	Consensus document
Franchini 2018	Narrative review
Franchini 2019	Narrative review
Franchini 2020	Expert opinion
FRONTIER1	Includes healthy volunteers
Hassan 2021	Letter to the journal editor
HAVEN 2	Not an RCT
HAVEN 4	Not an RCT
HAVEN 6	Not an RCT
Hilden 2012	Non‐human population
ISRCTN57549638	Non‐clotting factor not included in intervention or control.
JapicCTI‐173710	Not an RCT
Klamroth 2021	Not an RCT (indirect comparison of 2 studies)
Krumb 2021	Wrong study design (survey results, real‐world evidence)
Kruse‐Jarres 2020	Narrative review
Kruse‐Jarres 2022	Outcome not of interest (perioperative outcomes)
Le Quellec 2020	Narrative review
Lee 2021	Not an RCT (economic analysis based on Markov modeling)
Levy‐Mendelovich 2020	Commentary on excluded study Barg 2020
Lewandowska 2021	Not an RCT (real‐world evidence)
Machin 2018	Not an RCT (review)
Mahlangu 2019	Expert opinion
Mahlangu 2023	Narrative review
McCary 2020	Not an RCT
Misgav 2021	Not an RCT
NCT04030052	Not an RCT
NCT05935358	Not an RCT
Nogami 2016	Phase I/II dose escalation trial
Nogami 2017	Phase I/II dose escalation trial
Nogami 2019	Not an RCT
Pasi 2021	Phase I/II dose escalation study involving healthy volunteers
Patel 2019	Not an RCT (economic analysis not involving an RCT)
Pierce 2019	Letter to the journal editor
Polack 2021	Not an RCT (economic analysis based on Markov modeling)
PRIORITY	Outcome not of interest (inhibitor recurrence)
RBR 8z787r 2018	Not an RCT (observational study)
Recht 2021	Commentary
Shima 2017	Not an RCT
Shima 2019	Not an RCT
Stonebraker 2021	Not an RCT (simulation study)
Stonebraker 2021a	Not an RCT (simulation study)
Teeter 2022	Not an RCT
Wada 2017	Letter to the journal editor
Warren 2021	Not an RCT (adverse event tracking in a single center)
Yuan 2019	Not an RCT (simulation study)
Zhou 2020	Not an RCT (simulation study)

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RCT: randomized controlled trial

Characteristics of ongoing studies [ordered by study ID]

EXPLORER 8.

Study name	Research study to look at how well the drug concizumab works in your body if you have haemophilia without inhibitors (Explorer8)
Methods	Open‐label, parallel, multicenter, phase 3 RCT.
Participants	Male participants aged 12 years or older with severe hemophilia A (FVIII below 1%) or B (FIX equal to or below 2%) without inhibitors previously treated on‐demand. Number of participants randomized: 158.
Interventions	Arm 1: no prophylaxis but on‐demand treatment with usual replacement therapy until visit 9a (week 24; end of main part) at which point they will receive concizumab prophylaxis consisting of a loading dose of 1.0 mg/kg concizumab followed by an initial daily dose of 0.20 mg/kg concizumab from treatment day 2. Within an initial 5‐ to 8‐week dose adjustment period on 0.20 mg/kg concizumab, participants can be increased or decreased in dose to 0.25 mg/kg or 0.15 mg/kg concizumab. A potential dose adjustment will take place at visit 9a.3 (Wk 30) and will be based on the concizumab exposure level measured at the previous visit 9a.2 (Wk 28). Participants who have concizumab exposure levels of 200 to 4000 ng/mL will stay at 0.20 mg/kg concizumab. Arm 2: concizumab prophylaxis consisting of a loading dose of 1.0 mg/kg concizumab at visit 2a (week 0), followed by an initial daily dose of 0.20 mg/kg concizumab from treatment day 2. Within an initial 5‐ to 8‐week dose adjustment period on 0.20 mg/kg concizumab, participants can be increased or decreased in dose to 0.25 mg/kg or 0.15 mg/kg concizumab. A potential dose adjustment will take place at visit 4a.1 (Wk 6) and will be based on the concizumab exposure level measured at the previous visit 4a (Wk 6). Participants who have concizumab exposure levels of 200 to 4000 ng/mL will stay at 0.20 mg/kg concizumab. Arm 3: for participants with hemophilia A, concizumab prophylaxis consisting of a loading dose of 1.0 mg/kg concizumab at visit 2a (week 0) followed by an initial daily dose of 0.20 mg/kg concizumab from treatment day 2. Within an initial 5‐ to 8‐week dose adjustment period on 0.20 mg/kg concizumab, participants can be increased or decreased in dose to 0.25 mg/kg or 0.15 mg/kg concizumab. A potential dose adjustment will take place at visit 4a.1 (Wk 6) and will be based on the concizumab exposure level measured at the previous visit 4a (Wk 6). Participants who have concizumab exposure levels of 200 to 4000 ng/mL will stay at 0.20 mg/kg concizumab. Arm 4: concizumab prophylaxis consisting of a loading dose of 1.0 mg/kg concizumab at visit 2a (week 0) for participants with hemophilia A or B on factor prophylaxis with a minimum of 24 weeks observation in Explorer 6. Then an initial daily dose of 0.20 mg/kg concizumab from treatment day 2. Within an initial 5‐ to 8‐week dose adjustment period on 0.20 mg/kg concizumab, participants can be increased or decreased in dose to 0.25 mg/kg or 0.15 mg/kg concizumab. This arm will also include (i) participants who were randomized to Arms 1 and 2 before the treatment pause; (ii) participants in Explorer 5 at the time of the treatment pause, and who have now completed Explorer 5; (iii) participants on on‐demand therapy included after Arms 1 and 2 are closed.
Outcomes	The number of treated spontaneous and traumatic bleeding episodes. Adverse events. Pharmacokinetics.
Starting date	13 November 2019.
Contact information	Novo Nordisk A/S.
Notes	Estimated study completion date: 20 December 2025. No results posted yet. NCT04082429.

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HAVEN 5.

Study name	Efficacy, safety, and pharmacokinetic study of prophylactic emicizumab versus no prophylaxis in hemophilia A participants (HAVEN 5)
Methods	Open‐label, parallel, multicenter, phase 3 RCT.
Participants	Participants with hemophilia A regardless of FVIII inhibitor status. Participants without FVIII inhibitors (< 0.6 BU/mL) who completed successful ITI must have done so at least 5 years before screening and have no evidence of inhibitor recurrence. Total number randomized: 85
Interventions	Participants aged 12 years and older who received episodic therapy with FVIII or bypassing agents prior to study entry and experienced at least 5 bleeds over the prior 24 weeks will be randomized to Arms A, B, or C. Arm A: SC emicizumab prophylaxis at 3 mg/kg once every week for 4 weeks, followed by SC 1.5 mg/kg once every week. Arm B: SC emicizumab prophylaxis at 3 mg/kg once every week for 4 weeks, followed by SC 6 mg/kg once every 4 weeks. Arm C: no prophylaxis (control arm). Participants younger than 12 years old with hemophilia A and FVIII inhibitors who received episodic therapy with bypassing agents prior to study entry will be enrolled to Arm D: SC emicizumab prophylaxis at 3 mg/kg once every week for 4 weeks, followed by SC 1.5 mg/kg once every week. Participants will continue to receive standard‐of‐care treatments on an episodic basis for the treatment of breakthrough bleeds during the study.
Outcomes	ABR for treated bleeds, ABR for all bleeds, AsBR, AjBR, AtjBR HRQoL: change from baseline in Haem‐A‐QoL, Haemo‐QoL short form questionnaire, EQ‐5D‐5L, and caregiver‐reported adapted HRQoL for Hemophilia Patients With Inhibitors (Adapted Inhib‐QoL) including aspects of caregiver burden questionnaire score over time. Adverse events. Pharmacokinetics. Laboratory abnormalities.
Starting date	26 April 2018.
Contact information	Hoffmann‐La Roche.
Notes	Estimated study completion date: 31 May 2025. Full results not yet reported; some results reported in an abstract. NCT03315455.

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NCT05053139.

Study name	A research study investigating Mim8 in adults and adolescents with haemophilia A with or without inhibitors
Methods	Open‐label, parallel, multicenter, phase 3 RCT.
Participants	Males or females aged 12 years or older with congenital hemophilia A of any severity, previously treated with FVIII concentrates or bypassing agent in the last 26 weeks prior to screening. Total number randomized: 267
Interventions	Participants will be randomized into the following regimens: Arm 1: continue no prophylaxis (on‐demand treatment with their standard of care products) or Mim8 once‐weekly or once‐monthly prophylaxis in agreement with investigators in the main part of the study (26 weeks). Arm 2a: Mim8 once‐weekly prophylaxis in the main part of the study (26 weeks). Arm 2b: Mim8 once‐monthly prophylaxis in the main part of the study (26 weeks). Arm 3: once‐weekly Mim8 prophylaxis regimen in the main part of the study (26 weeks). Arm 4: once‐monthly Mim8 prophylaxis regimen in the main part of the study (26 weeks). Participants not receiving prophylaxis will not enter the run‐in period. After the main part, participants will continue in the extension part of the study (26 weeks) on once‐monthly Mim8 prophylaxis regimen.
Outcomes	Number of treated bleeds from randomization (week 0) to end of main study (week 26), including all treated spontaneous and traumatic bleeds, joint bleeds, target joint bleeds. Factor consumption per bleed treatment. HRQoL: change in physical function domain of PedsQL. Change in treatment burden using the Hemo‐TEM. Change in participant's joint pain score using Joint Pain Rating Scale. Adverse events: injection site reactions and occurrence of anti‐Mim8 antibodies.
Starting date	2 December 2021.
Contact information	Novo Nordisk, (+1) 866‐867‐7178, clinicaltrials@novonordisk.com
Notes	Estimated study completion date: 1 May 2025. No results posted yet. NCT05053139.

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ABR: annualized bleeding rate  AjBR: annualized joint bleeding rates AsBR: annualized bleeding rate for treated spontaneous bleeds AtjBR: annualized target joint bleeding rates BU: Bethesda units FVIII: Factor VIII FIX: Factor IX Haem‐A‐QoL: Hemophilia Quality of Life Questionnaire for Adults Hemo‐TEM: Hemophilia Treatment Experience Measure HRQoL: health‐related quality of life ITI: immune tolerance induction PedsQL: Pediatric Quality of Life Inventory RCT: randomized controlled trial SC: subcutaneously Wk: week

Differences between protocol and review

No major methodological changes were made to the review protocol (Olasupo 2021a). In the screening stages, phase 1 and phase 1/2 extension studies with no comparative study arms and studies with no results were excluded. We planned to report outcomes of interest at one week, one month, three months, six months, up to one year, and then annually thereafter. However, only annualized bleed rates were provided in the review, as the included trials consistently used this standardized measure. We added a further measure of bleeding rates (annualized target joint bleeding rates (AtjBR)) to those already listed under our primary outcome. Insufficient data precluded are planned subgroup analyses based on condition (hemophilia A or B) and age (pediatric and adult populations). There was no separation of data based on these subgroups in the included trials.

Contributions of authors

Conceiving and designing the review: OO, DM
Co‐ordinating the review: OO, DM
Data collection for the review: OO, NN, ML
Designing search strategies: OO
Undertaking searches: OO, NN, ML
Screening search results: OO, NN, ML
Organizing retrieval of papers: OO, NN, ML
Screening retrieved papers against eligibility criteria: OO, NN, ML
Appraising quality of papers: OO, NN, ML
Extracting data from papers: OO, NN, ML
Obtaining and screening data on unpublished studies: OO, NN, ML
Data management for the review: OO, NN, ML
Entering data into RevMan: OO
Providing a methodological perspective: OO
Writing the review (or protocol): all authors

Sources of support

Internal sources

Internal sources of funding, Canada

None

External sources

National Institute for Health Research, UK

This systematic review was supported by the National Institute for Health Research, via Cochrane Infrastructure funding to the Cochrane Cystic Fibrosis and Genetic Disorders Group.

Declarations of interest

Omotola Olasupo: no relevant conflict of interest.

Noella Noronha: no relevant conflict of interest.

Megan Lowe: no relevant conflict of interest.

Derek Ansel: no relevant conflict of interest.

Mihir Bhatt: no relevant conflict of interest.

Davide Matino: reports research grants paid directly to the Institution from Bayer, Pfizer, Novo Nordisk, Sanofi, Spark, Octapharma; personal fees outside the submitted work from Sanofi, Sobi, Novo Nordisk, Bayer, Pfizer, Octapharma for participation in advisory boards, lectures, and preparation of educational material.

New

References

References to studies included in this review

ATLAS ‐ A/B {published data only}

CTRI/2018/07/014698. A phase 3 study to evaluate the efficacy and safety of fitusiran in patients with hemophilia A or B, without inhibitory antibodies to factor VIII or IX [ATLAS-A/B: A Phase 3 Study to Evaluate the Efficacy and Safety of Fitusiran in Patients With Hemophilia A or B, Without Inhibitory Antibodies to Factor VIII or IX]. trialsearch.who.int/Trial2.aspx?TrialID=CTRI/2018/07/014698 (first received 2 Jul 2018).
EUCTR2016-001464-11-IE. A study of fitusiran (ALN-AT3SC) in hemophilia A and B patients without inhibitors. trialsearch.who.int/Trial2.aspx?TrialID=EUCTR2016-001464-11-IE (first received 5 Jul 2017). [CFGD REGISTER: HG135c]
EUCTR2016-001464-11-NL. A study of fitusiran (ALN-AT3SC) in hemophilia A and B patients without inhibitors. trialsearch.who.int/Trial2.aspx?TrialID=EUCTR2016-001464-11-NL (first received 6 Jun 2018). [CFGD REGISTER: HG135b]
NCT03417245. A study of fitusiran (ALN-AT3SC) in severe hemophilia a and b patients without inhibitors. clinicaltrials.gov/show/NCT03417245 (first received 31 Jan 2018). [CFGD REGISTER: HG135a]
Srivastava A, Rangarajan S, Kavakli K, Klamroth R, Kenet G, Khoo L, et al. Fitusiran prophylaxis in people with severe haemophilia A or haemophilia B without inhibitors (ATLAS-A/B): a multicentre, open-label, randomised, phase 3 trial. Lancet Haematology 2023;10(5):e322-e332. [DOI: 10.1016/S2352-3026(23)00037-6] [PMID: ] [DOI] [PubMed] [Google Scholar]

ATLAS ‐ INH {published data only}

CTRI/2018/06/014682. A Phase 3 study to Evaluate the Efficacy and Safety of Fitusiran in Patients with Hemophilia A or B, with Inhibitory Antibodies to Factor VIII or IX [ATLAS-INH: A Phase 3 Study to Evaluate the Efficacy and Safety of Fitusiran in Patients with Hemophilia A or B, with Inhibitory Antibodies to Factor VIII or IX]. trialsearch.who.int/Trial2.aspx?TrialID=CTRI/2018/06/014682 (first received 29 Jun 2018).
EUCTR2016-001463-36-BG. A Study of fitusiran (ALN-AT3SC) in hemophilia A and B patients with inhibitors. trialsearch.who.int/Trial2.aspx?TrialID=EUCTR2016-001463-36-BG (first received 6 Jul 2017). [CFGD REGISTER: HG136b]
NCT03417102. A study of fitusiran (ALN-AT3SC) in severe hemophilia a and b patients with inhibitors. clinicaltrials.gov/ct2/show/NCT03417102 (first received 31 Jan 2018). [CFGD REGISTER: HG136a]
Young G, Srivastava A, Kavakli K, Ross C, Sathar J, You CW, et al. Efficacy and safety of fitusiran prophylaxis in people with haemophilia A or haemophilia B with inhibitors (ATLAS-INH): a multicentre, open-label, randomised phase 3 trial. Lancet 2023;401(10386):1427-1437. [DOI: 10.1016/S0140-6736(23)00284-2] [PMID: ] [DOI] [PubMed] [Google Scholar]

EXPLORER 4 {published data only}

Astermark J, Angchaisuksiri P, Benson G, Castaman G, Chowdary P, Eichler H, et al. Longer-term efficacy and safety of concizumab prophylaxis in hemophilia A and hemophilia A/B with inhibitors: Results from the main and extension parts of concizumab phase 2 trials. In: Research and Practice in Thrombosis and Haemostasis. Vol. 5. 2021. [DOI: ]
Astermark J, Angchaisuksiri P, Benson G, Castaman G, Chowdary P, Eichler H, et al. Subcutaneous prophylaxis with the anti-TFPI monoclonal antibody concizumab in hemophilia A and hemophilia A/B with inhibitors: Phase 2 trial results. Research and Practice in Thrombosis and Haemostasis 2019;3(Supplement 2):1. [DOI: ] [Google Scholar]
Astermark J, Angchaisuksiri P, Benson G, Castaman G, Chowdary P, Eichler H, et al. Subcutaneous prophylaxis with the anti-TFPI monoclonal antibody concizumab in hemophilia A and hemophilia A/B with inhibitors: phase 2 trial results. Research and Practice in Thrombosis and Haemostasis 2019;3(Suppl 2):1. [CFGD REGISTER: HG119c] [Google Scholar]
EUCTR2016-000510-30-ES. A trial evaluating the efficacy and safety of prophylactic administration of concizumab in haemophilia a and b patients with inhibitors. trialsearch.who.int/Trial2.aspx?TrialID=EUCTR2016-000510-30-ES (first received 4 Jul 2017). [CFGD REGISTER: HG119b]
Faller M, Toonder SM, Porstmann T. Improvement in health-related quality of life measures after long-term, daily, subcutaneous concizumab prophylaxis in patients with hemophilia a/b with and without inhibitors: Results from the main and extension parts of phase 2 clinical trials. Blood 2021;138(Suppl 1):1041. [DOI: 10.1182/blood-2021-152257] [DOI] [Google Scholar]
Hummelshoj Landsy L, Castaman G, Cepo K, Lenting P, Oldenburg J. Immunogenicity in the concizumab phase 2 clinical trials: Clinical impact of antidrug antibodies. In: Research and Practice in Thrombosis and Haemostasis. Vol. 5. 2021. [DOI: ]
Lee XY, Cepo K, Porstmann T. Concizumab Subcutaneous Prophylaxis Improves Health-Related Quality-of-Life Measures in Patients with Congenital Hemophilia with Inhibitors: Phase 2 Trial Results. Blood 2019;134(Supplement 1):2419. [DOI: ] [Google Scholar]
Lee XY, Cepo K, Porstmann T. Concizumab subcutaneous prophylaxis improves health-related quality-of-life measures in patients with congenital hemophilia with inhibitors: phase 2 trial results. Blood 2019;134 Suppl 1:2419. [CFGD REGISTER: HG119f] [Google Scholar]
Mancuso M, Skov Neergaard J, Cepo K, Porstmann T. Treatment experience in hemophilia patients with and without inhibitors on concizumab prophylaxis: Hemo-TEM results from the phase 2 explorer4 & 5 studies. In: Research and Practice in Thrombosis and Haemostasis. Vol. 6. 2022. [DOI: ]
NCT03196284. A trial evaluating the efficacy and safety of prophylactic administration of concizumab in haemophilia a and b patients with inhibitors. clinicaltrials.gov/show/NCT03196284 (first received 22 Jun 2017). [CFGD REGISTER: HG119a]
Shapiro A, Castaman G, Cepo K, Hvitfeldt Poulsen L, Hollensen C, Matsushita T, et al. Efficacy and Safety of Subcutaneous Prophylaxis with Concizumab in Patients with Hemophilia a or B with Inhibitors: Results from explorer4, a Phase 2, Randomized, Open-Label, Controlled Trial. Blood 2019;134(Supplement 1):1139. [DOI: ] [Google Scholar]
Shapiro A, Castaman G, Cepo K, Hvitfeldt Poulsen L, Hollensen C, Matsushita T, et al. Efficacy and safety of subcutaneous prophylaxis with concizumab in patients with hemophilia A or B with inhibitors: results from explorer4, a phase 2, randomized, open-label, controlled trial. Blood 2019;134 Suppl 1:1139. [CFGD REGISTER: HG119e] [Google Scholar]
Shapiro A, Castaman G, Cepo K, Tonder SM, Matsushita T, Hvitfeldt Poulsen L, et al. Safety and longer-term efficacy of concizumab prophylaxis in patients with haemophilia A or B with inhibitors: Results from the extension part of the phase 2 EXPLORER4 trial. Haemophilia 2021;27(SUPPL 2):128. [DOI: ] [Google Scholar]
Shapiro A, Cepo K, Tonder SM, Young G, Jimenez-Yuste V. Safety and efficacy of concizumab prophylaxis following a switch from rFVIIa on-demand treatment: Subanalysis results from the phase 2 explorer4 trial in patients with hemophilia A or B with inhibitors. Research and Practice in Thrombosis and Haemostasis 2021;5(SUPPL 2). [DOI: ]
Shapiro AD, Angchaisuksiri P, Astermark J, Benson G, Castaman G, Chowdary P, et al. Subcutaneous concizumab prophylaxis in hemophilia A and hemophilia A/B with inhibitors: phase 2 trial results. Blood 2019;134(22):1973-82. [CFGD REGISTER: HG119d] [DOI] [PMC free article] [PubMed] [Google Scholar]
Shapiro AD, Angchaisuksiri P, Astermark J, Benson G, Castaman G, Eichler H, et al. Long-term efficacy and safety of subcutaneous concizumab prophylaxis in hemophilia A and hemophilia A/B with inhibitors. Blood Advances 2022;6(11):3422-3432. [DOI: 10.1182/bloodadvances.2021006403] [DOI] [PMC free article] [PubMed] [Google Scholar]
Shapiro AD, Castaman G, Cepo K, Tonder SM, Matsushita T, Poulsen LH, et al. Safety and longer-term efficacy of concizumab prophylaxis in patients with hemophilia a or b with inhibitors: Results from the extension part of the phase 2 explorer4 trial. Blood 2020;136(SUPPL 1):40-41. [DOI: ] [Google Scholar]

EXPLORER 7 {published data only}

Hampton K, Knoebl P, Neergaard JS, Odgaard-Jensen J, Stasyshyn O, Thaung Zaw JJ, et al. Treatment burden and patient preference in patients with haemophilia A or B with inhibitors on concizumab prophylaxis: results from the phase 3 EXPLORER 7 study. Haemophilia 2023;29(Supplement 1):77-78. [DOI: ] [Google Scholar]
Kaushik C, Jimenez-Yuste V, Angchaisuksiri P, Castaman G, Cepo K, Haaning J, et al. Concizumab Prophylaxis in Patients with Haemophilia A or B with Inhibitors: Efficacy and Safety Results from the Primary Analysis of the Phase 3 EXPLORER7 Trial. Indian Journal of Hematology and Blood Transfusion 2022;38(Supplement 1):S3. [DOI: ] [Google Scholar]
Linari S, Shapiro A, Neergaard JS, Odgaard-Jensen J, Thaung Zaw JJ, Tran H. Health-related quality of life in patients with haemophilia A or B with inhibitors on concizumab prophylaxis: results from the phase 3 EXPLORER 7 study. Haemophilia 2023;29(Supplement 1):94-95. [DOI: ] [Google Scholar]
Mathias M, Cepo K, D'Oiron R, Frei-Jones M, Goh A-S, Odgaard-Jensen J. Subcutaneous concizumab prophylaxis in patients with haemophilia A or B with inhibitors: efficacy and safety results by haemophilia subtype from the EXPLORER t trial. Haemophilia 2023;29(Supplement 1):17. [DOI: ] [Google Scholar]
Matsushita T, Shapiro A, Abraham A, Angchaisuksiri P, Castaman G, Cepo K, et al, Explorer7 Investigators. Phase 3 Trial of Concizumab in Hemophilia with Inhibitors. New England Journal of Medicine 2023;389(9):783-794. [DOI: 10.1056/NEJMoa2216455] [PMID: ] [DOI] [PubMed] [Google Scholar]
NCT04083781. Research study to look at how well the drug concizumab works in your body if you have haemophilia with inhibitors (Explorer 7). www.clinicaltrials.gov/show/NCT04083781 (first received 10 Sep 2019). [CFGD REGISTER: HG138]
Windyga J, Cepo K, Laursen J, Odgaard-Jensen J, You CW, Villarreal Martinez L. Active lifestyle in patients with haemophilia A or B with inhibitors on once-daily subcutaneous concizumab prophylaxis: results from the phase 3 EXPLORER 7 study. Haemophilia 2023;29(Supplement 1):138. [DOI: ] [Google Scholar]

HAVEN 1 {published data only}

Adamkewicz JI, Schmitt C, Asikanius E, Xu J, Levy G, Kim B, et al. Factor VIII (FVIII) inhibitor testing using a validated chromogenic bethesda assay (CBA) in HAVEN 1 (BH29884), a Phase 3 trial of emicizumab in persons with hemophilia a (PwHA) with inhibitors. Research and Practice in Thrombosis and Haemostasis 2017;1(Supplement 1):724-5. [CFGD REGISTER: HA149l] [Google Scholar]
Callaghan M, Negrier C, Young G, Khoo L, Mahlangu J, Windyga J, et al. Use of bypassing agents prior to and post bypassing agent dosing guidance during emicizumab prophylaxis: Analyses from the haven 1 study. British Journal of Haematology 2018;181(Supplement 1):129. [CFGD REGISTER: HA149d] [Google Scholar]
Callaghan M, Negrier C, Young G, Khoo L, Mahlangu J, Windyga J, et al. Use of bypassing agents prior to and post bypassing agent dosing guidance during emicizumab prophylaxis: analyses from the haven 1 study. British Journal of Haematology 2018;181:129. [DOI: 10.1111/bjh.15226] [DOI] [Google Scholar]
Callaghan MU, Negrier C, Paz-Priel I, Chang T, Chebon S, Lehle M, et al. Long-term outcomes with emicizumab prophylaxis for hemophilia A with or without FVIII inhibitors from the HAVEN 1-4 studies. Blood 2021;137(16):2231-42. [CFGD REGISTER: HA149s // HA150m] [DOI: 10.1182/blood.2020009217] [DOI] [PMC free article] [PubMed] [Google Scholar]
Callaghan MU, Negrier C, Paz-Priel I, Chang T, Chebon S, Lehle M, et al. Safety and efficacy of emicizumab in persons with haemophilia a with/without FVIII inhibitors: pooled data from four phase III studies (Haven 1-4). Haemophilia 2021;27(Suppl 2):126-7. [CFGD REGISTER: HA149r // HA150l] [Google Scholar]
Callaghan MU, Negrier C, Paz-Priel I, Chang T, Chebon S, Lehle M, et al. Safety and efficacy of emicizumab in persons with hemophilia a with or without fviii inhibitors: pooled data from four phase iii studies (haven 1-4). Blood 2020;136(Suppl 1):3-5. [CFGD REGISTER: HA149q // HA150k] [Google Scholar]
Callaghan MU, Negrier C, Young G, Khoo L, Mahlangu J, Windyga J, et al. Use of bypassing agents prior to and post bypassing agent dosing guidance during emicizumab prophylaxis: analyses from the HAVEN 1 study. Blood 2017;130(Suppl 1):3668. [CFGD REGISTER: HA149c] [Google Scholar]
EUCTR2015-002866-21-ES. A phase III study to evaluate the efficacy, safety, and pharmacokinetics of prophylactic RO5534262 versus no prophylaxis in hemophilia a patients with inhibitors. trialsearch.who.int/Trial2.aspx?TrialID=EUCTR2015-002866-21-ES (first received 5 Oct 2015). [CFGD REGISTER: HA149p]
Kruse-Jarres R, Callaghan M, Croteau SE, JimenezYuste V, Khoo L, Liesner R, et al. Surgical experience in two multicentre, openlabel phase 3 studies of emicizumab in persons with haemophilia a with inhibitors (HAVEN 1 and HAVEN 2). British Journal of Haematology 2018;181(Suppl 1):128. [CFGD REGISTER: HA149f] [Google Scholar]
Kruse-Jarres R, Callaghan MU, Croteau SE, Jimenez-Yuste V, Khoo L, Liesner R, et al. Surgical experience in two multicenter, open-label phase 3 studies of emicizumab in persons with hemophilia A with inhibitors (HAVEN 1 and HAVEN 2). Blood 2017;130 Suppl 1:89. [CFGD REGISTER: HA149b] [Google Scholar]
Levy GG, Asikanius E, Kuebler P, Benchikh El Fegoun S, Esbjerg S, Seremetis S. Safety analysis of rFVIIa with emicizumab dosing in congenital hemophilia A with inhibitors: experience from the HAVEN clinical program. Journal of Thrombosis and Haemostasis 2019;17(9):1470-7. [CFGD REGISTER: HA149n] [DOI] [PubMed] [Google Scholar]
Mancuso ME, Callaghan MU, Kruse-Jarres R, Kempton CL, Xu J, Catalani O, et al. Emicizumab prophylaxis in adolescent/adult patients with hemophilia a previously receiving episodic or prophylactic bypassing agent treatment: updated analyses from the haven 1 study. Blood 2017;130(Suppl 1):1071. [CFGD REGISTER: HA149h] [Google Scholar]
Mancuso ME, Callaghan MU, Kruse-Jarres R, Kempton CL, Xu J, Catalani O, et al. Emicizumab prophylaxis in adolescent/adult patients with hemophilia a previously receiving episodic or prophylactic bypassing agent treatment: updated analyses from the haven 1 study. Blood 2017;130:1071. [DOI: 10.1182/blood.V130.Suppl_1.1071.1071] [DOI] [Google Scholar]
Mancuso ME, Oldenburg J, Callaghan M, Kruse-Jarres R, Kempton C, Xu J, et al. Emicizumab prophylaxis in adolescent/adult patients with haemophilia A previously receiving episodic or prophylactic bypassing agent treatment: updated analyses from the HAVEN 1 study. Blood 2018;181(Suppl 1):127. [Google Scholar]
Mancuso ME, Oldenburg J, Callaghan M, Kruse-Jarres R, Kempton C, Xu J, et al. Emicizumab prophylaxis in adolescent/adult patients with haemophilia a previously receiving episodic or prophylactic bypassing agent treatment: updated analyses from the haven 1 study. British Journal of Haematology 2018;181(Suppl 1):127. [CFGD REGISTER: HA149e] [Google Scholar]
NCT02622321. A Study to Evaluate the Efficacy, Safety, and Pharmacokinetics of Prophylactic Emicizumab Versus no Prophylaxis in Hemophilia A Participants With Inhibitors. Cilinicaltrials.gov 2015.
NCT02622321. A study to evaluate the efficacy, safety, and pharmacokinetics of prophylactic emicizumab versus no prophylaxis in hemophilia a participants with inhibitors. www.clinicaltrials.gov/show/NCT02622321 (first received 4 Dec 2015). [CFGD REGISTER: HA149j]
Oldenburg J, Mahlangu J, Kim B, Schmitt C, Callaghan M, Young G, et al. Efficacy, safety and pharmacokinetics (PK) of emicizumab (ACE910) prophylaxis (Px) in persons with haemophilia A with inhibitors (PwHAwl): randomized, multicenter, open-label, phase 3 study (HAVEN 1). Hamostaseologie 2018;38(Supplement 1):A6. [CFGD REGISTER: HA149i] [Google Scholar]
Oldenburg J, Mahlangu J, Kim B, Schmitt C, Callaghan M, Young G, et al. Efficacy, safety and pharmacokinetics (PK) of emicizumab (ACE910) prophylaxis (Px) in persons with haemophilia A with inhibitors (PwHAwl): randomized, multicenter, open-label, phase 3 study (HAVEN 1). Hämostaseologie 2018;38:A6. [DOI: 10.1055/s00034925] [DOI] [Google Scholar]
Oldenburg J, Mahlangu JN, Bujan W, Trask P, Callaghan MU, Young G, et al. The effect of emicizumab prophylaxis on health-related outcomes in persons with haemophilia A with inhibitors: HAVEN 1 Study. Haemophilia 2019;25(1):33-44. [CFGD REGISTER: HA149m] [DOI] [PubMed] [Google Scholar]
Oldenburg J, Mahlangu JN, Bujan W, Trask P, Callaghan MU, Young G, et al. The effect of emicizumab prophylaxis on health-related outcomes in persons with haemophilia A with inhibitors: HAVEN 1 Study. Haemophilia : the official journal of the World Federation of Hemophilia 2019;25(1):33-44. [DOI: 10.1111/hae.13618] [DOI] [PubMed] [Google Scholar]
Oldenburg J, Mahlangu JN, Kim B, Schmitt C, Callaghan MU, Young G, et al. Emicizumab Prophylaxis in Hemophilia A with Inhibitors. New England Journal of Medicine 2017;377(9):809-18. [CFGD REGISTER: HA149a] [DOI: 10.1056/NEJMoa1703068] [DOI] [PubMed] [Google Scholar]
Schmitt C, Adamkewicz J, Xu J, Chang T, Petry C, Calatzis A, et al. Pharmacokinetics (PK), PK/PD relationships of emicizumab in persons with haemophilia a (PWHA) with inhibitors from adolescent/adult (HAVEN 1) and paediatric (HAVEN 2) phase 3 studies. Haemophilia 2018;24(Suppl 1):27. [CFGD REGISTER: HA149g] [Google Scholar]
Schmitt C, Petry C, Adamkewicz JI, Xu J, Catalani O, Young G, et al. Pharmacokinetics and Pharmacodynamics of Emicizumab in Persons with Hemophilia A with Factor VIII Inhibitors: HAVEN 1 Study. Thrombosis and Haemostasis 2021;121(3):351-60. [CFGD REGISTER: HA149o] [DOI] [PMC free article] [PubMed] [Google Scholar]
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HAVEN 3 {published data only}

Callaghan M, Trzaskoma B, Ko RH, Lee L, Patel AM, Tzeng E, et al. Factor VIII use in the treatment of breakthrough bleeds in hemophilia A patients without inhibitors on emicizumab prophylaxis: the phase 3 haven 3 study experience. Blood 2019;134(Suppl 1):2395. [CFGD REGISTER: HA150j] [Google Scholar]
Callaghan MU, Negrier C, Paz-Priel I, Chang T, Chebon S, Lehle M, et al. Long-term outcomes with emicizumab prophylaxis for hemophilia A with or without FVIII inhibitors from the HAVEN 1-4 studies. Blood 2021;137(16):2231-42. [CFGD REGISTER: HA149s // HA150m] [DOI] [PMC free article] [PubMed] [Google Scholar]
Callaghan MU, Negrier C, Paz-Priel I, Chang T, Chebon S, Lehle M, et al. Safety and efficacy of emicizumab in persons with haemophilia a with/without FVIII inhibitors: pooled data from four phase III studies (Haven 1-4). Haemophilia 2021;27(Suppl 2):126-7. [CFGD REGISTER: HA149r // HA150l] [Google Scholar]
Callaghan MU, Negrier C, Paz-Priel I, Chang T, Chebon S, Lehle M, et al. Safety and efficacy of emicizumab in persons with hemophilia a with or without fviii inhibitors: pooled data from four phase iii studies (haven 1-4). Blood 2020;136(SUPPL 1):3-5. [CFGD REGISTER: HA149q // HA150k] [Google Scholar]
EUCTR2016-000072-17-ES. A Study to Evaluate the Effectiveness and Safety of Prophylactic Emicizumab Versus no Prophylaxis in Haemophilia A Patients Without Inhibitors. EUCTR 2016.
EUCTR2016-000072-17-ES. A study to evaluate the effectiveness and safety of prophylactic emicizumab versus no prophylaxis in haemophilia a patients without inhibitors. trialsearch.who.int/Trial2.aspx?TrialID=EUCTR2016-000072-17-ES (first received 18 Mar 2016). [CFGD REGISTER: HA150g]
Jain N, Lethagen S. RE: Reyes A, Révil C, Niggli M, et al. Efficacy of emicizumab prophylaxis versus factor VIII prophylaxis for treatment of hemophilia A without inhibitors: network meta-analysis and sub-group analyses of the intra-patient comparison of the HAVEN 3 trial. Curr Med Res Opin. 2019;35(12):2079–2087. Current Medical Research and Opinion 2020;36(7):1125-7. [DOI: 10.1080/03007995.2020.1744549] [DOI] [PubMed] [Google Scholar]
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Kempton C, Trask P, Parnes A, Niggli M, Campinha-Bacote A, Callaghan MU, et al. Development and testing of the Satisfaction Questionnaire with Intravenous or Subcutaneous Hemophilia Injection and results from the Phase 3 HAVEN 3 study of emicizumab prophylaxis in persons with haemophilia A without FVIII inhibitors. Haemophilia 2021;27(2):221-228. [CFGD REGISTER: HA150o] [DOI: 10.1111/hae.14222] [DOI] [PMC free article] [PubMed] [Google Scholar]
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Klamroth R, Wojciechowski P, Aballéa S, Diamand F, Hakimi Z, Nazir J, et al. Efficacy of rFVIIIFc versus Emicizumab for the Treatment of Patients with Hemophilia A without Inhibitors: Matching-Adjusted Indirect Comparison of A-LONG and HAVEN Trials. Journal of Blood Medicine 2021;12:115-22. [DOI: 10.2147/jbm.S288283] [DOI] [PMC free article] [PubMed] [Google Scholar]
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Oldenburg J, Mahlangu J, Paz-Priel I, Negrier C, Niggli M, Mancuso ME, et al. Emicizumab prophylaxis administered once-weekly or every two weeks provides effective bleed prevention in persons with hemophilia A (PwHA) without inhibitors-results from the phase III HAVEN 3 study. Hӓmostaseologie 2019;39(S 01):SY17. [CFGD REGISTER: HA150h] [DOI: 10.1055/s-0039-1680140] [DOI] [Google Scholar]
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References to studies excluded from this review

Agers 2014 {published data only}

Agersø H, Overgaard RV, Petersen MB, Hansen L, Hermit MB, Sørensen MH, et al. Pharmacokinetics of an anti-TFPI monoclonal antibody (concizumab) blocking the TFPI interaction with the active site of FXa in Cynomolgus monkeys after iv and sc administration. European Journal of Pharmaceutical Sciences 2014;56:65-9. [DOI: 10.1016/j.ejps.2014.02.009] [DOI] [PubMed] [Google Scholar]

AKATSUKI {published data only}

JPRN-jRCTs041200037. AKATSUKI Study [A prospective, multicenter study to evaluate the safety of emicizumab under and after immune tolerance induction in patients with congenital hemophilia A with FVIII inhibitors]. trialsearch.who.int/Trial2.aspx?TrialID=JPRN-jRCTs041200037 (registered 3 Aug 2020).

Aledort 2017 {published data only}

Aledort LM, Ewenstein BM. Emicizumab prophylaxis in hemophilia A with inhibitors. New England Journal of Medicine 2017;377(22):2193. [DOI: 10.1056/NEJMc1712683] [PMID: ] [DOI] [PubMed] [Google Scholar]

Aledort 2019 {published data only}

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CTRI/2011/11/002103. Study to evaluate the safety, pharmacokinetics and efficacy of recombinant factor VIII Fc fusion protein (rFVIIIFc) in subjects with severe hemophilia A [An open-label, multicenter evaluation of the safety, pharmacokinetics, and efficacy of recombinant factor VIII Fc fusion protein (rFVIIIFc) in the prevention and treatment of bleeding in previously treated subjects with severe hemophilia A - A LONG]. trialsearch.who.int/Trial2.aspx?TrialID=CTRI/2011/11/002103 (registered 2 Nov 2011).
Klamroth R, Wojciechowski P, Aballéa S, Diamand F, Hakimi Z, Nazir J, et al. Efficacy of rFVIIIFc versus emicizumab for the treatment of patients with Hemophilia A without Inhibitors: matching-adjusted indirect comparison of A-LONG and HAVEN trials. Journal of Blood Medicine 2021;12:115-22. [DOI: 10.2147/jbm.S288283] [DOI] [PMC free article] [PubMed] [Google Scholar]

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NCT03549871. A study of fitusiran in severe hemophilia A and B patients previously receiving factor or bypassing agent prophylaxis (ATLAS-PPX). clinicaltrials.gov/ct2/show/NCT03549871 (first posted 18 Jun 2018).

Barg 2019 {published data only}

Barg AA, Avishai E, Budnik I, Levy-Mendelovich S, Barazani TB, Kenet G, et al. Emicizumab prophylaxis among infants and toddlers with severe hemophilia A and inhibitors-a single-center cohort. Pediatric Blood and Cancer 2019;1(11):e27886. [DOI: 10.1002/pbc.27886] [DOI] [PubMed] [Google Scholar]

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Bertolet 2020b {published data only}

Bertolet M, Brooks MM, Ragni MV. The design of a Bayesian platform trial to prevent and eradicate inhibitors in patients with hemophilia. Blood Advances 2020;4(21):5433-41. [CFGD REGISTER: HA160b // HA161b] [DOI] [PMC free article] [PubMed] [Google Scholar]
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Beyond ABR {published data only}

NCT05181618. A study to evaluate overall health, physical activity, and joint outcomes in participants with severe or moderate hemophilia A without Factor VIII inhibitors on emicizumab prophylaxis (Beyond ABR). clinicaltrials.gov/study/NCT05181618 (first received 6 December 2021).

Biron‐Andreani 2020 {published data only}

Biron-Andreani C, Diaz-Cau I, Ranc A, Navarro R, Leonardi C, Dischino M, et al. Major surgery management in patients with haemophilia A and inhibitors on emicizumab prophylaxis without global coagulation monitoring. British Journal of Haematology 2020;1(3):e100-e103. [DOI: 10.1111/bjh.16512] [DOI] [PubMed] [Google Scholar]

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Cafuir 2019 {published data only}

Cafuir L, Kruse-Jarres R, Mancuso ME, Kempton CL. Emicizumab for hemophilia A without inhibitors. Expert Review of Hematology 2019;12(7):515-524. [DOI: 10.1080/17474086.2019.1624519] [PMID: ] [DOI] [PubMed] [Google Scholar]

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CTRI/2011/06/001832. A clinical trial to study the effects of IB1001 in previously treated patients children with hemophilia B [Study of recombinant factor IX product, IB1001, in previously treated pediatric subject with hemophilia BÂ - NIL]. trialsearch.who.int/Trial2.aspx?TrialID=CTRI/2011/06/001832 (registered 24 Jun 2011).

CTRI201204002596 {published data only}

CTRI/2012/04/002596. A clinical trial to see the effect of EMOCLOT drug (Kedrion factor VIII concentrate) in 50 previously treated haemophilia A children [Open label, phase III, multicenter study on pharmacokinetic, efficacy and safety evaluation of Kedrion Factor VIII concentrate (EMOCLOT) in 50 previously treated haemophilia A children]. trialsearch.who.int/Trial2.aspx?TrialID=CTRI/2012/04/002596 (first registered 24 Apr 2012).

CTRI201307003823 {published data only}

CTRI/2013/07/003823. A clinical trial to study the effect of an unregistered drug in hemophilia B patients [BAX326 (Recombinant Factor IX): evaluation of safety, immunogenicity, and hemostatic efficacy in previously treated patients with severe (FIX level 1%) or moderately severe (FIX level â?¤ 2%) hemophilia B â?? A continuation study]. trialsearch.who.int/Trial2.aspx?TrialID=CTRI/2013/07/003823 (registered 19 Jul 2013).

CTRI201807014754 {published data only}

CTRI/2018/07/014754. A post-marketing study receiving RIXUBIS as on-demand or prophylaxis under standard clinical practice in patients with Hemophilia B [Phase IV Multi-center, Prospective, Interventional, Post-marketing study in Hemophilia B Patients in India receiving RIXUBIS as on-demand or Prophylaxis under standard clinical practice - None]. trialsearch.who.int/Trial2.aspx?TrialID=CTRI/2018/07/014754 (registered 5 Jul 2018).

Donners 2021 {published data only}

Donners AA, Rademaker CM, Bevers LA, Huitema AD, Schutgens RE, Egberts TC, et al. Pharmacokinetics and associated efficacy of emicizumab in humans: a systematic review. Clinical Pharmacokinetics 2021;60(11):1395-406. [DOI: 10.1007/s40262-021-01042-w] [DOI] [PMC free article] [PubMed] [Google Scholar]

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Explorer 5 {published data only}

TCTR20170512002. A multi-centre trial evaluating efficacy and safety of prophylactic administration of concizumab in patients with severe haemophilia A without inhibitors [Explorer 5]. trialsearch.who.int/Trial2.aspx?TrialID=TCTR20170512002 (registered 12 May 2017).

Fontana 2020 {published data only}

Fontana P, Alberio L, Albisetti M, Angelillo-Scherrer A, Asmis LM, Casini A, et al. Management of bleeding events and invasive procedures in patients with haemophilia A without inhibitors treated with emicizumab. Swiss Medical Weekly 2020;150:w20422. [DOI: 10.4414/smw.2020.20422] [DOI] [PubMed] [Google Scholar]

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Franchini M, Mannucci PM. Non-factor replacement therapy for haemophilia: a current update. Trasfusione del sangue [Blood Transfusion] 2018;16(5):457-461. [DOI: 10.2450/2018.0272-17] [DOI] [PMC free article] [PubMed] [Google Scholar]

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EUCTR2019-000465-20-ES. A research study of how a new medicine NNC0365-3769 (Mim8) works in the body of healthy people and patients with bleeding disorder. trialsearch.who.int/Trial2.aspx?TrialID=EUCTR2019-000465-20-ES (registered 28 Feb 2020). [CFGD REGISTER: HA140b]
NCT04204408. A research study investigating mim8 in people with haemophilia a. www.clinicaltrials.gov/show/NCT04204408 (first posted 19 Dec 2019). [CFGD REGISTER: HA140a]

Hassan 2021 {published data only}

Hassan E, Motwani J. Management and outcomes of paediatric patients on emicizumab prophylaxis undergoing surgical procedures: experience from a large haemophilia centre in the UK. Haemophilia 2021;27(5):e620-3. [DOI: 10.1111/hae.14358] [DOI] [PubMed] [Google Scholar]

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Young G, Callaghan M, Dunn A, Kruse-Jarres R, Pipe S. Emicizumab for hemophilia A with factor VIII inhibitors. Expert Review of Hematology 2018 Nov;11(11):835-846. [DOI: 10.1080/17474086.2018.1531701] [PMID: ] [DOI] [PubMed] [Google Scholar]
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JapicCTI-163391. Phase III clinical study of emicizumab given every 4 weeks (Q4W) in patients with hemophilia A. trialsearch.who.int/Trial2.aspx?TrialID=JPRN-JapicCTI-163391 (registered 30 Sep 2016). [CFGD REGISTER: HA167]
Jimenez-Yuste V, Shima M, Paz-Priel I, Parnes A, Lehle M, Giermasz A, et al. Preference for emicizumab over prior factor treatments: results from the HAVEN 3 and HAVEN 4 studies. Blood 2018;132(Suppl 1):1187. [Google Scholar]
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Negrier C, Mahlangu J, Lehle M, Chowdary P, Catalani O, Bernardi RJ, et al. Emicizumab in people with moderate or mild haemophilia A (HAVEN 6): a multicentre, open-label, single-arm, phase 3 study. The Lancet Haematology 2023;10(3):e168-e177. [DOI: 10.1016/S2352-3026(22)00377-5] [DOI] [PubMed] [Google Scholar]
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Hilden I, Lauritzen B, Sørensen BB, Clausen JT, Jespersgaard C, Krogh BO, et al. Hemostatic effect of a monoclonal antibody mAb 2021 blocking the interaction between FXa and TFPI in a rabbit hemophilia model. Blood 2012;119(24):5871-8. [DOI: 10.1182/blood-2012-01-401620] [DOI] [PubMed] [Google Scholar]

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ISRCTN57549638. Prevention of bleeding in haemophilia A by prophylactic treatment with Nuwiq® [Prevention of bleeding in haemophilia A by prophylactic treatment with Nuwiq®: a prospective, multi-national, non-interventional study to evaluate routine practice prophylactic treatment schedules – NIS-Previq]. trialsearch.who.int/Trial2.aspx?TrialID=ISRCTN57549638 (registered 23 Mar 2015).

JapicCTI‐173710 {published data only}

JPRN-JapicCTI-173710. Phase III clinical trial of emicizumab given every 2 weeks and 4 weeks in hemophilia A pediatric patients without inhibitors (HOHOEMI). https://jrct.niph.go.jp/latest-detail/jRCT2080223654 (first received September 12, 2017).

Klamroth 2021 {published data only}

Klamroth R, Wojciechowski P, Aballéa S, Diamand F, Hakimi Z, Nazir J, et al. Efficacy of rFVIIIFc versus emicizumab for the treatment of patients with Hemophilia A without Inhibitors: matching-adjusted indirect comparison of A-LONG and HAVEN trials. Journal of Blood Medicine 2021;12:115-22. [DOI: 10.2147/jbm.S288283] [DOI] [PMC free article] [PubMed] [Google Scholar]

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Krumb E, Fijnvandraat K, Makris M, Peyvandi F, Ryan A, Athanasopoulos A, et al. Adoption of emicizumab (Hemlibra®) for hemophilia A in Europe: Data from the 2020 European Association for Haemophilia and Allied Disorders survey. Haemophilia 2021;27(5):736-43. [DOI: 10.1111/hae.14372] [DOI] [PubMed] [Google Scholar]

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Kruse-Jarres R, Peyvandi F, Oldenburg J, Chang T, Chebon S, Doral MY, et al. Surgical outcomes in people with hemophilia A taking emicizumab prophylaxis: experience from the HAVEN 1-4 studies. Blood Advances 2022;6(24):6140-6150. [DOI: 10.1182/bloodadvances.2022007458] [DOI] [PMC free article] [PubMed] [Google Scholar]

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Lee H, Cho H, Han JW, Kim AY, Park S, Lee M, et al. Cost-utility analysis of emicizumab prophylaxis in haemophilia A patients with factor VIII inhibitors in Korea. Haemophilia 2021;27(1):e12-e21. [DOI: 10.1111/hae.14143] [DOI] [PubMed] [Google Scholar]

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Le Quellec S. Clinical evidence and safety profile of emicizumab for the management of children with hemophilia A. Drug Design, Development and Therapy 2020 Feb;3(14):469-481. [DOI: 10.2147/DDDT.S167731] [PMID: ] [DOI] [PMC free article] [PubMed] [Google Scholar]

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NCT04030052. Emicizumab PUPs and Nuwiq ITI Study. https://clinicaltrials.gov/study/NCT04030052 (first received 23 July 2019).

NCT05935358 {published data only}

NCT05935358. Nuwiq for Perioperative Management Of Patients With Haemophilia A on Emicizumab Regular Prophylaxis Study (NuPOWER). https://clinicaltrials.gov/study/NCT05935358 (first received 7 July 2023).

Nogami 2016 {published data only}

Nogami K, Hanabusa H, Taki M, Matsushita T, Sato T, Fukutake K, et al. Updated results of an ongoing long-term phase 1/2 study of emicizumab (ACE910) in hemophilia A patients with or without inhibitors. Haemophilia 2016;22(Suppl 4):76. [DOI: 10.1111/hae.12980] [PMID: ] [DOI] [PubMed] [Google Scholar]

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Nogami, K, Taki, M, Matsushita, T, Sato, T, Fukutake, K, Kasai, R, Yoneyama, K, Yoshida, H, Shima, M. Updated results of a long-term phase 1/2 study of emicizumab (ACE910) in haemophilia A patients. British Journal of Haematology 2017;176(Suppl 1):112. [DOI: 10.1111/bjh.14613] [PMID: ] [DOI] [PubMed] [Google Scholar]

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PERMALINK

Non‐clotting factor therapies for preventing bleeds in people with congenital hemophilia A or B

Omotola O Olasupo

Noella Noronha

Megan S Lowe

Derek Ansel

Mihir Bhatt

Davide Matino

Abstract

Background

Objectives

Search methods

Selection criteria

Data collection and analysis

Main results

Authors' conclusions

Plain language summary

Summary of findings

Summary of findings 1. Summary of findings table ‐ Emicizumab prophylaxis compared to on‐demand therapy in people with inhibitors.

Summary of findings 2. Summary of findings table ‐ Fitusiran prophylaxis compared to on‐demand therapy in people with inhibitors.

Summary of findings 3. Summary of findings table ‐ Concizumab prophylaxis compared to on‐demand therapy in people with inhibitors.

Summary of findings 4. Summary of findings table ‐ Emicuzimab 1.5 mg/kg weekly prophylaxis compared to on‐demand therapy in people without inhibitors.

Summary of findings 5. Summary of findings table ‐ Emicuzimab 3.0 mg/kg bi‐weekly prophylaxis compared to on‐demand therapy in people without inhibitors.

Summary of findings 6. Summary of findings table ‐ Emicizumab 1.5 mg/kg once weekly compared to emicizumab 3.0 mg/kg every 2 weeks in people without inhibitors.

Summary of findings 7. Summary of findings table ‐ Fitusiran prophylaxis compared to on‐demand therapy in people without inhibitors.

Background

Description of the condition

Description of the intervention

How the intervention might work

Why it is important to do this review

Objectives

Methods

Criteria for considering studies for this review

Types of studies

Types of participants

Types of interventions

Types of outcome measures

Primary outcomes

Secondary outcomes

Search methods for identification of studies

Electronic searches

Searching other resources

Data collection and analysis

Selection of studies

Data extraction and management

Assessment of risk of bias in included studies

Measures of treatment effect

Unit of analysis issues

Dealing with missing data

Assessment of heterogeneity

Assessment of reporting biases

Data synthesis

Subgroup analysis and investigation of heterogeneity

Sensitivity analysis

Summary of findings and assessment of the certainty of the evidence

Results

Description of studies

Results of the search

1.

Included studies

Methods

Participants

Interventions

Outcome measures

Excluded studies

Ongoing studies

Risk of bias in included studies

2.

3.

Allocation

Random sequence generation

Allocation concealment

Blinding

Incomplete outcome data

Selective reporting

Other potential sources of bias

Effects of interventions

Non‐clotting factor prophylaxis versus on‐demand therapy in people with inhibitors

Primary outcomes

1. Bleeding rates