Clotting factor concentrates for preventing bleeding and bleeding‐related complications in previously treated individuals with haemophilia A or B

Omotola O Olasupo; Megan S Lowe; Ashma Krishan; Peter Collins; Alfonso Iorio; Davide Matino

doi:10.1002/14651858.CD014201

. 2021 Aug 18;2021(8):CD014201. doi: 10.1002/14651858.CD014201

Clotting factor concentrates for preventing bleeding and bleeding‐related complications in previously treated individuals with haemophilia A or B

Omotola O Olasupo ¹, Megan S Lowe ², Ashma Krishan ³, Peter Collins ⁴, Alfonso Iorio ¹, Davide Matino ^5,^✉

Editor: Cochrane Cystic Fibrosis and Genetic Disorders Group

PMCID: PMC8407508 PMID: 34407214

Abstract

Background

The hallmark of severe hemophilia (A or B) is recurrent bleeding into joints and soft tissues with progressive joint damage, despite on‐demand treatment. Prophylaxis has long been used, but not universally adopted, because of medical, psychosocial, and cost controversies.

Objectives

To determine the effectiveness of clotting factor concentrate prophylaxis in managing previously‐treated individuals with hemophilia A or B.

Search methods

We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Coagulopathies Trials Register, compiled from electronic database searches and handsearching of journals and conference abstract books. In addition, we searched MEDLINE and Embase and online trial registries.

Most recent search of Group's Coagulopathies Trials Register: 24 February 2021.

Selection criteria

Randomised controlled trials (RCTs) and quasi‐RCTs evaluating people with hemophilia A or hemophilia B, who were previously treated with clotting factor concentrates to manage their hemophilia.

Data collection and analysis

Two authors independently reviewed trials for eligibility, assessed risk of bias and extracted data. The authors used the GRADE criteria to assess the certainty of the evidence.

Main results

Ten trials (including 608 participants) were eligible for inclusion. Eight of the trials (477 participants) had arms comparing two or more prophylactic regimens to one another and four of the trials (n = 258) compared prophylaxis to on‐demand treatment (two trials had multiple arms and were included in both comparisons).

Comparison of two or more prophylactic regimens

For trials comparing one prophylaxis regimen to another, given the heterogeneity of the data, none of the data were pooled for this comparison. Considering the individual trials, three trials reported the primary outcome of joint bleeding, and none showed a dfference between dosing regimens (low‐certainty evidence). For the secondary outcome of total bleeding events, prophylaxis with a twice‐weekly regimen of FIX likely results in reduced total bleeds compared to a once‐a‐week regimen of the same dose, mean difference (MD) 11.2 (5.81 to 16.59) (one trial, 10 participants, low‐certainty evidence).

Transient low‐titer anti‐FVIII inhibitors were reported in one of the trials. Blood‐transmitted infections were not identified. Other adverse events reported include hypersensitivity, oedema, and weight gain. These were, however, rare and unrelated to study drugs (very low‐certainty evidence).

Comparison of prophylactic and on‐demand regimens

Four of the trials (258 participants) had arms that compared prophylaxis to on‐demand treatment. Prophylaxis may result in a large decrease in the number of joint bleeds compared to on‐demand treatment, MD ‐30.34 (95% CI ‐46.95 to ‐13.73) (two trials, 164 participants, low‐certainty evidence). One of these trials (84 participants) also reported the long‐term effects of prophylaxis versus on‐demand therapy showing improved joint function, quality of life, and pain; but no differences between groups in joint structure when assessed by magnetic resonance imaging (MRI).

In one trial (84 participants) validated measures for joint health and pain assessment showed that prophylaxis likely improves joint health compared to an on‐demand regimen with an estimated change difference of 0.94 points (95% CI 0.23 to 1.65) and improves total pain scores, MD ‐17.20 (95% CI ‐27.48 to ‐6.92 (moderate‐certainty evidence).

Two trials (131 participants) reported that prophylaxis likely results in a slight increase in adverse events, risk ratio 1.71 (1.24 to 2.37) (moderate‐certainty evidence). No inhibitor development and blood‐transmitted infections were identified.

Overall, the certainty of the body of evidence was judged to be low because of different types of bias that could have altered the effect.

Authors' conclusions

There is evidence from RCTs that prophylaxis, as compared to on‐demand treatment, may reduce bleeding frequency in previously‐treated people with hemophilia. Prophylaxis may also improve joint function, pain and quality of life, even though this does not translate into a detectable improvement of articular damage when assessed by MRI.

When comparing two different prophylaxis regimens, no significant differences in terms of protection from bleeding were found. Dose optimization could, however, result in improved efficacy. Given the heterogeneity of the data, pooled estimates were not obtained for most comparisons.

Well‐designed RCTs and prospective observational controlled studies with standardised definitions and measurements are needed to establish the optimal and most cost‐effective treatment regimens.

Plain language summary

Regular clotting factor replacement therapy to prevent joint damage in people living with severe hemophilia A or B

Review question

Should people, who have previously been treated for joint bleeding, be given regular preventative treatment with clotting factor concentrates to manage their condition?

Background

Hemophilia A and B are X‐linked inherited bleeding disorders in which bleeding into joints is a major problem. Repeated joint bleeds can lead to affected joints (commonly referred to as 'target joints') becoming damaged and painful, with limited movement. Currently, bleeding is treated and prevented with plasma‐derived or recombinant clotting factor concentrates, and more recently non‐clotting factor formulations. This review looked at how useful and effective different clotting factor treatment strategies are for preventing joint bleeding and other outcomes in previously treated people with hemophilia A or B.

Search date

Date of last search: 24 February 2021.

Study characteristics

This review includes 10 randomised controlled trials. Eight had treatment arms that compared the regular use of clotting factor concentrates to prevent joint bleeds with different dosing schemes to identify regimens that may be better; four had treatment arms that compared the regular use of factor concentrates to prevent bleeds to their 'on demand' use to treat bleeds once they occur (two trials had multiple arms and were included in both comparisons).

Key results

In people living with hemophilia A or B previously treated for joint bleeding or with existing joint damage, preventive therapy may reduce the number of joint bleeds compared to 'on‐demand therapy'. This reduction in bleeds may lead to an improvement in joint function, pain, and quality of life. However, preventive therapy is linked to an increased use of factor concentrates and therefore higher treatment costs. Further studies are needed to establish the best preventive course of treatment in terms of starting time, frequency and dose level.

Certainty of the evidence

Overall, the certainty of the evidence was judged to be low because of different types of bias that could have affected the results. Future research might have an important role in changing our confidence in these results.

Summary of findings

Summary of findings 1. Comparison of two prophylaxis regimens.

Prophylaxis regimen compared with another prophylaxis regimen for previously treated individuals with haemophilia A or B
Patient or population: children or adults with hemophilia A or B Settings: outpatient Intervention: secondary prophylaxis Comparison: secondary prophylaxis
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of Participants (studies)	Certainty of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	Prophylaxis regimen	Prophylaxis regimen
Number of joint bleeding episodes per year (AJBR) Follow‐up: 12 months	No difference was seen between prophylaxis regimens in any of the studies. Thrice‐weekly higher dose prophylaxis regimen compared to a twice‐weekly lower dose regimen, MD ‐1.70 (95% CI ‐5.06 to 1.66) (LEOPOLD II 2015). PK‐guided prophylaxis targeting trough levels of 8% to 12% compared to targeting trough levels of 1% to 3%, MD ‐1.50 (95% CI ‐3.54 to 0.54) (n = 115 participants) (PROPEL III 2020). Low frequency prophylaxis (100 IU / kg once a week) compared to standard frequency regimen (50 IU / kg twice a week, MD of 1.70 (95% CI ‐1.09 to 4.49) (Valentino 2014).		N/A	219 participants (3 trials)	⊕⊕⊝⊝ low^a	We were unable to combine results in a meta‐analysis due to the different prophylaxis regimens used in each trial.
Number of total bleeds per year (ABR) Follow‐up: 12 months	There was no difference in total number of bleeds between prophylactic regimens in five trials (Aronstam 1977; LEOPOLD II 2015; PROPEL III 2020; Valentino 2012; Valentino 2014). A twice‐a‐week regimen (7.5 IU/kg) was favoured over a once‐a‐week regimen (15 IU/kg), MD 11.20 (5.81 to 16.59) (Morfini 1976) and a prophylaxis group with dosing producing at least 0.25 IU/mL of factor VIII showed a significant reduction in overall bleeding frequency compared to a dosing regimen producing at least 0.01IU/mL once weekly, MD 3.44 (95% CI 2.42 to 4.46) (Aronstam 1976).		N/A	310 participants (7 trials)	⊕⊝⊝⊝ low^b,c	Due to heterogeneity of intervention and design, none of the trials we were unable to combine data from any of the trials (LEOPOLD II 2015).
Treatment‐related adverse events Follow‐up: 32 weeks to 12 months	One trial reported no difference in total treatment‐emergent adverse events, MD 1.00 (95% CI 0.54 to 1.84) at 32 weeks (Valentino 2014). A further trial reported no difference between treatment regimens in mean rates of adverse events (Valentino 2012). In the study targeting different trough levels, no serious adverse event was treatment‐related in the arm targeting trough levels of of 1% to ‐3%, and in the arm targeting trough levels of 8% to ‐12%, one serious adverse event was estimated to be treatment‐related (PROPEL III 2020).		N/A	223 participants (3 trials)	⊕⊝⊝⊝ very low^a,d	Three trials did not report the rate of adverse events by treatment groups (Aronstam 1977; LEOPOLD II 2015; Morfini 1976). The LEOPOLD II trial reported three treatment related adverse events but gave no further detail (LEOPOLD II 2015). There was no reported inhibitor development reported in six of the trials in this comparison (Aronstam 1976; Aronstam 1977; LEOPOLD II 2015; Morfini 1976; Valentino 2012; Valentino 2014).
The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). ABR: annualised bleed rate; AJBR: annualised joint bleed rate; CI: confidence interval; FIX*: factor IX; RR: risk ratio; MD: mean difference.
GRADE Working Group grades of evidence High certainty: further research is very unlikely to change our confidence in the estimate of effect. Moderate certainty: further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low certainty: further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low certainty: we are very uncertain about the estimate.

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a. Downgraded twice due to risk of bias in the included trials, particularly across the domains of randomisation and allocation concealment. The trials were also considererd at high risk of bias due to lack of blinding  b. Downgraded once due to imprecision as a result of small sample sizes. Although the total number of participants included in this outcome is 390, none of the studies could be combined and so we have based our assessment on the numbers in individual trials. The two trials that showed a difference between regimens included nine and 10 participants.

c. Downgraded twice due to an unclear or high risk of bias across many of the domains with particular concern around randomisation procedures, allocation concealment and blinding.

d. Downgraded once due to imprecision from small sample size and low event rates. Although the total number of participants is reasonable, none of the trials could be combined and so we have based our judgement on the numbers in the individual trials.

Summary of findings 2. Prophylaxis with standard therapeutic factor concentrate compared to pegylated liposome FVIII formulation.

Prophylaxis with standard clotting factor concentrate compared with pegylated liposome FVIII formulation for previously treated individuals with haemophilia A
Patient or population: children or adults with hemophilia A Settings: outpatient Intervention: prophylaxis using investigational BAY 79‐4980 Comparison: standard secondary prophylaxis
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of Participants (studies)	Certainty of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	Prophylaxis using investigational BAY 79‐4980	Standard prophylaxis
AJBR Follow‐up: 12 months	The mean number of joint bleeding in the prophylaxis arm using investigational drug BAY 79‐4980 was 12.2.	The mean number of joint bleeding in the standard prophylaxis regimen (5.0), was 7.20 lower (11.01 lower to 3.39 lower)	MD ‐7.20 (‐11.01 to ‐3.39)	143 participants (1 trial)	⊕⊕⊝⊝ low^a,b	More participants withdrew consent in the investigational drug arm. The trial was prematurely discontinued by the sponsor based on the recommendation of an independent data and safety monitoring board.
ABR Follow‐up: 12 months	The mean number of total bleeds in the prophylaxis arm using investigational drug BAY 79‐4980 was 15.	The mean number of total bleeds in the standard prophylaxis regimen (5.8), was 9.20 lower (13.07 lower to 5.33 lower)	MD ‐7.20 (‐13.07 to ‐5.33 )	143 participants (1 trial)	⊕⊕⊝⊝ low^a,b	More participants withdrew consent in the investigational drug arm. The trial was prematurely discontinued by the sponsor based on the recommendation of an independent data and safety monitoring board.
Any reported adverse effects Follow‐up: 12 months	No specific information was given about the presence/absence of adverse events in the BAY 70‐4980 group.	One participant in the prophylaxis group reported three serious adverse events, which were deemed to be drug related.	Not estimable	143 participants (1 trial)	⊕⊕⊝⊝ low^a,b
The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). ABR: annualised bleed rate; AJBR*: annualised joint bleed rate; CI: confidence interval; MD: mean difference.
GRADE Working Group grades of evidence High certainty: further research is very unlikely to change our confidence in the estimate of effect. Moderate certainty: further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low certainty: further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low cerainty: we are very uncertain about the estimate.

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a. Downgraded once due to high risk of bias due to attrition bias from incomplete outcome data. b. Downgraded once due to premature study discontinuation.

Summary of findings 3. Prophylaxis regimen versus on‐demand treatment.

Prophylaxis regimen compared with on‐demand treatment for previously treated individuals with haemophilia A or B
Patient or population: children and adults with haemophilia A or B Settings: outpatient Intervention: secondary prophylaxis Comparison: on‐demand treatment
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of Participants (studies)	Certainty of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	On‐demand treatment	Prophylaxis regimen
Number of joint bleeding episodes or joint bleeding frequency Follow‐up: 12 months	The mean number of joint bleeding episodes in the on‐demand treatment group was 34	The mean number of joint bleeding episodes in the prophylaxis regimen group was 30.34 lower (46.95 lower to 13.73 lower)	MD ‐30.34 (‐46.95 to ‐13.73)	164 (2 trials)	⊕⊕⊝⊝ low^a,b	The data from the A‐LONG trial suggests the same; however, these data were reported with medians, hence could not be included in the analysis.
Number of total bleeds per year or bleeding frequency Follow‐up: 12 months	The mean number of total bleeds in the on‐demand treatment group was 44	The mean number of total bleeds in the prophylaxis regimen group was 40.24 lower (64.04 lower to 16.44 lower)	MD ‐40.24 (‐64.04 to ‐16.44)	164 (2 trials)	⊕⊕⊝⊝ low^a,b	The data from the A‐LONG trial suggests the same effect; however, these data were reported with medians, hence could not be included in the analysis (A‐LONG 2014). When comparing the overall bleeding frequency in 9 participants in the Aronstam cross‐over trial, there was a significant reduction in the overall bleeding frequency in the prophylaxis group
Any reported adverse events Follow‐up: 12 months	415 per 1000 (27 per 65)	712 per 1000 (47 per 66) The number of participants with adverse events in the prophylaxis regimen group was 1.71 times higher (1.24 times higher to 2.37 times higher)	RR 1.71 (1.24 to 2.37)	131 (2 trials)	⊕⊕⊕⊝ moderate^a	The 2 trials were open‐label trials with unclear risk of bias for randomised sequence generation (A‐LONG 2014; SPINART 2013). The LEOPOLD II trial did not give the distribution of adverse events across groups, but there were 3 reported treatment‐related adverse events while no participant developed an inhibitor during the course of treatment (LEOPOLD II 2015). In the 1976 Aronstam trial, one participant developed antigen‐negative hepatitis and was removed from the remaining duration of the trial (Aronstam 1976).
*Th\e basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; RR: risk ratio; MD: mean difference
GRADE Working Group grades of evidence High certainty: further research is very unlikely to change our confidence in the estimate of effect. Moderate certainty: further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low certainty: further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low certainty: we are very uncertain about the estimate.

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a. Downgraded once due to high risk of bias due to performance and detection bias attributed to open‐label studies. b. Downgraded once due to high levels of heterogeneity across trials.

Background

Description of the condition

Congenital hemophilia is a rare x‐linked bleeding disorder caused by a deficiency in clotting factor VIII (FVIII) in hemophilia A and factor IX (FIX) in hemophilia B (Srivastava 2020). Severity of disease is classified according to level of clotting factor naturally present in the blood: severe (with a baseline coagulation factor level of less than 1% of normal); moderate (with clotting factor levels of 1% to 5%); and mild (6% to 49%) (Blanchette 2014).

The physical manifestation of hemophilia varies with the severity of disease. People with mild and moderate hemophilia rarely experience spontaneous bleeding episodes, and often only bleed abnormally following trauma or in association with invasive procedures. People with severe hemophilia are at highest risk for experiencing frequent and severe spontaneous bleeding incidents. This group is also prone to experiencing recurrent or chronic bleeding into joints and muscles, which can develop into haemophilic joint arthropathy and muscle atrophy.

Description of the intervention

While there is no routinely‐available cure for hemophilia, symptoms of the disease can be effectively managed by the infusion of exogenous clotting factor concentrates (either FVIII or FIX). The availability of clotting factor concentrates has improved the morbidity, mortality and quality of life (QoL) of people with hemophilia (Lusher 1997; Tobase 2016). Availability of factor concentrate allows for early treatment of acute bleeding incidents, and has resulted in a decrease in joint deformities in untreated or minimally‐treated individuals (Ahlberg 1965; Hilgartner 1974; Liddle 2017).

Factor concentrates are generally administered according to two treatment regimens:

on‐demand (also termed episodic) treatment, where individuals receive clotting factor only in response to a bleeding event; or
prophylaxis treatment, where individuals receive regular infusions of clotting factor with the aim to prevent bleeds.

A 1994 study by Aledort, showed that prophylaxis treatment reduced the number of bleeding events and may reduce the incidence of bleeding‐related adverse events, such as haemophilic arthropathy (Aledort 1994). This same study showed progressive joint deterioration over the six‐year follow‐up period in participants using on‐demand treatment only (Aledort 1994). Given its preferable outcomes, prophylaxis treatment, in comparison to on‐demand treatment, has been recommended for all children with severe hemophilia (Berntorp 2003; MASAC 2010; MASAC 2016; Rayment 2020; Richards 2010; Srivastava 2020).

How the intervention might work

There are two main categories of prophylactic treatment: primary prophylaxis, which is established before joint deterioration (before the second clinically‐evident joint bleed and age three years); and secondary prophylaxis, which is established after some joint deterioration. Given the differences in starting times, the aims of primary and secondary prophylaxis differ. Primary prophylaxis aims to use regular infusions of factor concentrate to maintain the individuals' factor level above a desired target, usually in the mild or moderate range (above 1% of clotting factor present in blood), to prevent spontaneous bleeding episodes and joint arthropathy. Secondary prophylaxis aims to slow the progression of existing arthropathy, prevent the development of new arthropathies, and prevent further spontaneous bleeding incidents (Hay 2007).

Secondary prophylaxis is generally started after some degree of joint arthropathy has already occurred (Hay 2007) and can theoretically be started at any time in life. The existing evidence shows that starting secondary prophylaxis in adulthood can reduce bleeding frequency, and delay the progression of joint arthropathy (Tagliaferri 2008). For these reasons, the Medical and Scientific Advisory Council of the US National Hemophilia Foundation (MASAC) has identified that individuals, especially those with severe hemophilia, may benefit from continuing prophylaxis throughout their life (MASAC 2010; MASAC 2016).

Why it is important to do this review

Despite the known benefits of prophylaxis, there are medical, psychosocial and cost barriers that preclude the universal use of prophylaxis (Blanchette 2004; Thornburg 2017). Such concerns may be balanced by strong evidence of the efficacy of prophylaxis treatment. Numerous studies exist citing the efficacy of primary prophylaxis and the previous systematic review (from which this review has been derived) showed that primary prophylaxis was significantly better at preserving joint function in children with hemophilia, in comparison to on‐demand treatment (Iorio 2011). Similar evidence, including evidence from randomised controlled trials, for the efficacy of secondary prophylaxis started in adulthood is accumulating, but has not yet been systematically reviewed.

This review aims to clarify the efficacy and safety of secondary prophylaxis in adults by systematically reviewing and summarising the available evidence of prophylactic administration of factor concentrates in previously‐treated individuals with hemophilia A or B.

Objectives

To determine the effectiveness of clotting factor concentrate prophylaxis in managing previously treated individuals with hemophilia A or B, for improving short‐ and long‐term outcomes measured by one or more of the following.

Short‐term outcomes

Number of joint bleeding episodes per year or bleeding frequency
Number of total bleeds per year or bleeding frequency
Clotting factor concentrate levels in plasma

Long‐term outcomes

Clinical joint function
Orthopedic joint score
Radiologic joint score
QoL measurements

Methods

Criteria for considering studies for this review

Types of studies

Randomised or quasi‐randomised controlled trials. All identified trials, unpublished or published as an article, an abstract or a letter, without any language limitations, were eligible for inclusion.

Types of participants

Trials including individuals with congenital hemophilia A or B, receiving secondary prophylaxis were eligible. We included all trials which enrolled adults (aged 18 or over) and those trials with participants under 18 years of age if the participants met one of the three following criteria:

proven haemophilic arthropathy;
presence of one or more target joint;
previous on‐demand treatment.

We did not exclude based on degree of disease severity, type of previous treatment (if any), or presence of previous joint damage. Trials including participants with factor VIII or IX inhibitors at baseline were excluded.

Types of interventions

We compared intravenous clotting factor concentrates administered as prophylactic treatment in any formulation (e.g. fresh frozen plasma, cryoprecipitate, lyophilised plasma‐derived clotting factor concentrate, or recombinant clotting factor concentrate), any concentration, any frequency and any dose, with no treatment, placebo, on‐demand treatment, or with one or more different prophylaxis regimens. We did not include trials of a single treatment and at least one treatment must have been a clotting factor concentrate.

Therefore the anticipated comparison groups were as follows:

prophylaxis versus prophylaxis with a different regimen;
prophylaxis versus on‐demand treatment;
prophylaxis versus no treatment;
prophylaxis versus placebo.

Types of outcome measures

The following primary and secondary outcomes were assessed based on clinical relevance.

Primary outcomes

Number of joint bleeding episodes or joint bleeding frequency during the trial
Orthopedic joint score or clinical joint function
QoL on validated scales (disease‐specific where possible)

Secondary outcomes

Number of total bleeding episodes or total bleeding frequency during the trial period
Pain scores
Radiologic joint score or radiologic measurements or descriptions of joint damage
Clotting factor concentrate plasma levels
Time loss to school or employment
Integration into society (i.e. absenteeism)
Scores on scales recording feeling of well‐being and global functioning
Economic data: cost‐effectiveness, cost‐benefit, cost‐utilisation, cost‐minimisation
Any reported adverse effects or toxicity of clotting factor concentrates (e.g. inhibitors, reactions, transmission of infection)

Search methods for identification of studies

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

Electronic searches

We identified relevant trials from the Group's Coagulopathies Trials Register using the term: prophylaxis and (hemophilia* or haemophilia*).

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 searching activities for the register, please see the relevant section of the Cochrane Cystic Fibrosis and Genetic Disorders Group's website.

Date of the most recent search of the Group's Coagulopathies Trials Register: 24 February 2021.

We also searched the following databases and trial registries:

MEDLINE Ovid (1946 to June 2016 – search carried out by authors of a previous version of this review
Embase Ovid (1974 to June 2016 – search carried out by authors of a previous version of this review);
ISRCTN registry (www.isrctn.com/; searched 06 August 2020);
US National Institutes of Health Ongoing Trials Register Clinicaltrials.gov (www.clinicaltrials.gov; searched 06 August 2020);
World Health Organization International Clinical Trials Registry Platform (WHO ICTRP) (https://apps.who.int/trialsearch; we were unable to carry out a search as access was temporarily unavailable due to the current COVID‐19 pandemic. We will try and search this resource when the review is updated).

For details of the search strategies, please see (Appendix 1).

Searching other resources

We checked the bibliographies of included trials and any relevant systematic reviews identified for further references to relevant trials.

The following conference proceedings were also hand searched:

International Society for Thrombosis and Haemostasis Biannual Meeting (2004 to 2016);
European Association for Haemophilia and Allied Disorders (2004 to 2016).

Data collection and analysis

Selection of studies

Two authors independently screened the titles and abstracts of the retrieved citations and retrieved all available complete manuscripts for potentially relevant trials. The same two authors assessed the full‐text manuscripts to select the final trials to be included according to the review's inclusion criteria. A third‐party arbitrator helped to settle any differences between the two authors.

Data extraction and management

Two authors independently extracted data using a pre‐designed data extraction form. The structured data form included the following information.

Inclusion criteria of the trial
Characteristics of the trial (i.e. trial design, location and time frame)
Participant number and demographics
The intervention and co‐interventions (including dosing and frequency of clotting factor concentrate)
Outcomes (including primary and secondary outcome measures and description)
Information regarding limitations and biases

We considered any outcome data recorded as either individual events or as events grouped by time periods.

Assessment of risk of bias in included studies

The authors used the tool in RevMan 5.4 to measure the risk of bias and to produce summary figures (RevMan 2020).

The authors assessed the risk of bias using the 'Risk of bias' assessment tool as documented in section 8.5 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2017). The following domains were assessed as having either a low, high, or unclear risk of bias:

sequence generation;
allocation concealment;
blinding (of participants, personnel and outcome assessors);
incomplete outcome data;
selective outcome reporting;
other sources of bias.

To estimate selective outcome reporting, we identified original protocols and compared the results and outcomes reported in the final report to those proposed in the protocol.

Measures of treatment effect

We anticipated that the primary outcome (number of joint bleeding episodes or joint bleeding frequency during the trial) would be reported using mean and standard deviation (SD). For the secondary outcomes, we anticipated continuous outcomes to be reported as either a rate of event, mean and SD, or median and interquartile range (IQR). We anticipated dichotomous outcomes to be reported as the frequency of each option. Given these assumptions, we measured the treatment effect of the primary outcome using a mean difference (MD). We measured the treatment effects of secondary outcomes using the risk difference (RD) or MD for continuous outcomes and risk ratio (RR) for dichotomous outcomes. We reported the 95% confidence interval (CI) of each measure of treatment effect.

Unit of analysis issues

We anticipated that the unit of analysis would be the individual, as disease progression and treatment can vary between individuals. Given the chronic nature of the condition, as well as the rapid onset and short duration of the intervention (factor VIII and IX physiological half‐lives are 12 and 24 hours respectively), we anticipated that some trials included would be cross‐over in design. We used the generic inverse variance (GIV) method to include cross‐over trials in any meta‐analyses conducted, as reported in chapter 23 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2021). Whenever possible we have used individual patient data to analyze the results of cross‐over trials (Aronstam 1976; Aronstam 1977; Morfini 1976). In the Leopold II trial (LEOPOLD II 2015) participants were randomised to receive on‐demand or prophylactic therapy with FVIII (two different regimens); participants were crossed‐over within their treatment groups, but only with respect to the methods for measuring the content of FVIII in the vials, therefore, we treated this trial as if it had a parallel design.

Dealing with missing data

We attempted to contact trial authors to provide any missing data. We reported the level of missing data and reason for missing data where possible.

Assessment of heterogeneity

Given the small number of trials that were included in a meta‐analysis in this review, we did not assess for heterogeneity in most of the analyses. However, where sufficient trials were included in a meta‐analysis, we identified the presence of statistical heterogeneity using the Chi² value. We also reported the I² value as a measure of heterogeneity in the meta‐analysis. We applied the following thresholds, as suggested in the Cochrane Handbook for Systematic Reviews of Interventions (Deeks 2021):

0% to 40%: might not be important;
30% to 60%: may represent moderate heterogeneity;
50% to 90%: may represent substantial heterogeneity;
75% to 100%: represents considerable heterogeneity.

Assessment of reporting biases

In future versions of this review, if there are more than 10 trials in the same analysis, we will construct a funnel plot and assess it for symmetry.

Data synthesis

In comparisons where only one trial was assessed, we used the fixed‐effect model in the analyses. We used a random‐effects model in analyses including multiple trials to account for possible heterogeneity.

Subgroup analysis and investigation of heterogeneity

In future versions of this review, depending on data availability, we plan a subgroup analysis based on Pattersson scores and other measures indicating the extent of disease progression.

Sensitivity analysis

We were unable to aggregate data for a majority of outcomes in this review. However, if there are a sufficient number of eligible and included trials, we will undertake a sensitivity analysis by looking at trials with a low risk of bias versus a high risk of bias, as measured above.

Summary of findings and assessment of the certainty of the evidence

We presented a summary of findings table for each of the following comparisons.

Comparison between two prophylaxis regimens
Prophylaxis with standard therapeutic factor concentrate compared to pegylated liposome FVIII formulation
Prophylaxis versus on‐demand comparison.

The following outcomes were chosen based on relevance to clinicians and consumers and reported in the table.

Number of joint bleeding episodes per year or bleeding frequency;
Number of total bleeds per year or bleeding frequency;
Any reported adverse event.

We determined the certainty of the evidence using the GRADE approach; and downgraded evidence in the presence of a high risk of bias in at least one trial, indirectness of the evidence, unexplained heterogeneity or inconsistency, imprecision of results, high probability of publication bias. We downgraded evidence by one level if we considered the limitation to be serious and by two levels if very serious.

Results

Description of studies

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

Results of the search

Our search strategies yielded 322 unique references, of which 68 articles reporting seven studies were included in this review (A‐LONG 2014; LEOPOLD II 2015; LipLong 2012; PROPEL III 2020; SPINART 2013; Valentino 2012; Valentino 2014). A further three trials (three articles) (Aronstam 1976; Aronstam 1977; Morfini 1976) were accessed from a previous Cochrane Review (which this current review and one more Cochrane Review in progress, supersedes), and were also included in this review (Iorio 2011). No additional articles were found from searching reference lists of included articles or conference proceedings.

We excluded a further 251 references to 89 trials.

Included studies

See Characteristics of included studies for a full description of each trial.

Trial design

10 trials, with a total of 608 participants were included in the review (A‐LONG 2014 (n = 47); Aronstam 1976 (n = 9); Aronstam 1977 (n = 4); LEOPOLD II 2015 (n = 80); LipLong 2012 (n = 143); Morfini 1976 (n = 10); PROPEL III 2020 (n = 115); SPINART 2013 (n = 84); Valentino 2012 (n = 66); Valentino 2014 (n = 50). There was no disagreement between authors regarding trial relevance and inclusion.

One trial was conducted in Italy (Morfini 1976), two in England (Aronstam 1976; Aronstam 1977) and seven were multicentre trials (A‐LONG 2014; LEOPOLD II 2015; LipLong 2012; PROPEL III 2020; SPINART 2013; Valentino 2012; Valentino 2014).

Four trials were cross‐over in design (Aronstam 1976; Aronstam 1977; Morfini 1976; Valentino 2014). In these trials, the order of intervention was randomised, and all participants received both the control and active treatment. All of the cross‐over trials included an adequate washout period before the second treatment intervention was administered. The remaining six trials were parallel in design, four trials were randomised open‐label trials (A‐LONG 2014; PROPEL III 2020; SPINART 2013; Valentino 2012), one was a randomised double‐blind trial with an active control (LipLong 2012). The remaining randomised trial, the LEOPOLD II study, was reported as cross‐over, with participants randomised to one of six treatment arms (two low‐dose prophylaxis groups, two high‐dose prophylaxis groups, and two on‐demand treatment groups); participants received treatment based on CS/EP (chromogenic substrate assay per European Pharmacopoeia) or adjusted by a predefined factor to mimic results obtained with the one‐stage assay (CS/ADJ) for six months each with an intraindividual cross‐over after six months (LEOPOLD II 2015). However, since participants were crossed‐over within their treatment groups but only with respect to the methods for measuring the content of FVIII activity in the vials (using the CS/EP or the CS/ADJ). This cross‐over trial has been analysed as a parallel trial.

Types of participants

All trials included participants receiving secondary prophylaxis. Two trials included individuals with hemophilia B: the Morfini trial included individuals with severe hemophilia B (FIX levels < 1%) (Morfini 1976); and the 2014 Valentino trial included individuals with moderately severe and severe hemophilia B (FIX levels ≤ 2%) (Valentino 2014). Seven trials included individuals with severe haemophilia A only (FVIII levels < 1% of normal) (A‐LONG 2014; Aronstam 1976; Aronstam 1977; LEOPOLD II 2015; LipLong 2012; PROPEL III 2020; SPINART 2013). One trial included participants with moderately severe to severe hemophilia A (FVIII levels ≤ 2% of normal) (Valentino 2012). All trials included participants who were previously exposed to FVIII or FIX, whether through on‐demand treatment or through a prophylaxis regimen. All included participants were males and between five years and 65 years of age. None of the participants had an inhibitory antibody to FVIII or FIX at baseline.

There were some boys in the Aronstam 1976 trial who were also included in the 1977 trial: "Those boys who had been on the first double‐blind controlled trial (Aronstam 1976) and were still available for a further two terms were selected. There were four such boys, patients 1, 3, 8, and 9 of that trial. The boys selected had each had at least one full school term off prophylaxis before entering the second trial" (Aronstam 1976; Aronstam 1977).

Types of interventions

Two of the trials had multiple arms where a prophylaxis regimen was compared to another prophylaxis regimen, as well as a comparison of a prophylaxis and on‐demand regimen (LEOPOLD II 2015; Valentino 2014). Therefore, we included these two trials in two comparisons.

Comparison between two prophylaxis regimens

Eight trials compared two different prophylactic regimens (Aronstam 1976: Aronstam 1977; LEOPOLD II 2015; LipLong 2012; Morfini 1976; PROPEL III 2020; Valentino 2012; Valentino 2014). Of these, four trials had a fixed prophylaxis dose in both arms (LEOPOLD II 2015; LipLong 2012; Morfini 1976; Valentino 2014). We describe the intervention and comparison in the included trials below.

Aronstam 1977: prophylaxis arm A: sufficient dose to increase the FVIII level to 10% of normal versus prophylaxis arm B: sufficient dose to raise the FVIII level to 30% of normal.

Aronstam 1976: prophylaxis arm A: sufficient dose to increase FVIII levels to >/= 0.25 IU/mL versus prophylaxis arm B: sufficient dose to increase FVIII levels to >/= 0.1 IU/mL once weekly.

Morfini 1976: prophylaxis arm A: FIX 7.5 U/kg twice per week versus prophylaxis arm B: FIX 15 U/kg once per week.

Valentino 2012: prophylaxis arm A: standard prophylactic treatment of 20 to 40 IU/kg FVIII every 48 hours versus prophylaxis arm B: PK‐tailored prophylactic treatment of 20 to 80 IU/kg FVIII every 72 hours (dose‐dependent on PK evaluation).

LEOPOLD II 2015: prophylaxis arm A: high‐dose regimen (FVIII 30 to 40 IU/kg thrice‐weekly versus prophylaxis arm B: low‐dose regimen (FVIII 20 to 30 IU/kg twice‐weekly). The factor concentrate used was an experimental full‐length rFVIII product referred to as BAY 81‐8973. This product was created to improve clinical efficacy by alterations in glycosylation and was also free of any human or animal‐derived products. BAY 81‐8973 was co‐expressed with heat shock protein 70 to improve the in vivo viability of the product.

LipLong 2012: prophylaxis arm A: the investigational drug, BAY 79‐4980 consisting of 35 IU/kg of rFVIII and 13 mg/kg of pegylated liposome, administered at a reduced frequency of once per week versus prophylaxis arm B: standard prophylaxis treatment with rFVIII at a dose of 25 IU/kg three times per week.

Valentino 2014: prophylaxis arm A: high‐frequency schema (50 IU/kg twice‐weekly) versus prophylaxis arm B: low‐frequency schema (100 IU/kg once‐weekly).

PROPEL III 2020: prophylaxis arm A: PK‐guided prophylaxis to achieve FVIII trough levels of 1% to 3% versus treatment arm B: prophylaxis targeting trough levels of 8% to 12%.

Prophylaxis regimen compared to on‐demand (episodic) treatment

Four trials compared on‐demand treatment to prophylaxis treatment (A‐LONG 2014; LEOPOLD II 2015; SPINART 2013; Valentino 2014).

SPINART 2013: on‐demand treatment administered on the basis of investigator recommendations versus prophylaxis treatment administered at a dosage of 25 IU/kg three times per week. This amount could be increased to a maximum of 35 IU/kg over two years in participants with 12 or more bleeding episodes per year on the trial.

A‐LONG 2014: on‐demand treatment administered at a dose of 10 to 50 IU/kg FVIII as needed versus standard prophylaxis administered at a dose of 65 IU/kg rFVIII once weekly. Additionally, this trial also enrolled individuals who were previously on prophylaxis or on‐demand therapy but not willing to be randomised (Arm 1) to be treated with an individualized prophylaxis regimen (N = 118). Since this was a non‐randomised arm we did not include it in the analysis.

Valentino 2014: prophylaxis A: high‐frequency schema (50 IU/kg twice‐weekly) versus prophylaxis B: low‐frequency schema (100 IU/kg once‐weekly). These two regimens were compared to an on‐demand treatment where FIX was given to treat bleeding events as needed. The factor product used for all study arms was nonacog alfa (BeneFIX).

LEOPOLD II 2015: on‐demand treatment with BAY 81‐8973, a recombinant factor VIII product, was compared with two arms of prophylaxis treatment (prophylaxis A: high‐dose regimen (FVIII 30 to 40 IU/kg thrice‐weekly and prophylaxis B: low‐dose regimen (FVIII 20 to 30 IU/kg twice‐weekly).

Types of outcomes

Our primary outcome of interest, joint bleeding events or joint bleeding frequency, was reported in seven out of the 10 studies (A‐LONG 2014; LEOPOLD II 2015; LipLong 2012; PROPEL III 2020; SPINART 2013; Valentino 2012; Valentino 2014). Clinical joint function and radiologic measurements were reported in two trials (Morfini 1976; SPINART 2013). Two trials also reported conducting QoL measurements (SPINART 2013; Valentino 2012) and one trial (SPINART 2013) reported the results of pain assessment.

Overall bleeding events or overall bleeding frequency were reported in all 10 trials. The quantity of factor concentrate used was reported in four trials (LEOPOLD II 2015; PROPEL III 2020; SPINART 2013; Valentino 2012). Adverse event reporting, including the development of inhibitors, was reported in seven of the trials (A‐LONG 2014; LEOPOLD II 2015; LipLong 2012; PROPEL III 2020; SPINART 2013; Valentino 2012; Valentino 2014).

Excluded studies

See Characteristics of excluded studies for more details of the excluded trials.

We excluded 89 trials (251 references) from this review. A total of 40 trials were excluded because they were not randomised studies, including 22 prospective and 18 retrospective observational studies. 15 trials had an intervention arm that included non‐clotting factors, e.g. concizumab (n = 9), emicizumab (n = 5), investigational RNA inteference therapeutic (n = 1). Six trials were excluded because they were conducted in participants with inhibitors, 13 additional trials were not eligible because they included individuals on primary prophylaxis. 10 trials assessed pharmacokinetic parameters and four were reported in conference abstracts only and detailed descriptions of trial participants were not available. One trial was a feasibility study with no hypothesis testing, no useable results and concluded that the trial lacked feasibility.

Risk of bias in included studies

We present an overall risk of bias assessment graphically in the figures section (Figure 1; Figure 2).

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

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

Allocation

Random sequence generation

While all trial reports indicated that the trial was randomised, only four of the 10 included trials provided some detail of the method used for random sequence generation (LEOPOLD II 2015; PROPEL III 2020; SPINART 2013; Valentino 2012). In two of these trials, the method used was judged to be sound and of low risk of bias (PROPEL III 2020; Valentino 2012). Eight trials were judged to be of unclear risk of bias.

Allocation concealment

Four trials indicated the method for allocation concealment; these were judged to be at low risk of bias for this domain (LEOPOLD II 2015; Morfini 1976; SPINART 2013; Valentino 2012). The remaining six trials had an unclear risk of bias (A‐LONG 2014; Aronstam 1976; Aronstam 1977; LipLong 2012; PROPEL III 2020; Valentino 2014).

Blinding

Performance and detection bias

Three of the included trials employed an appropriate method to blind participants and personnel to minimise performance bias (Aronstam 1976; Aronstam 1977; LipLong 2012). The remaining seven trials were open‐label and we judged these to be at high risk of bias (A‐LONG 2014; LEOPOLD II 2015; Morfini 1976; PROPEL III 2020; SPINART 2013; Valentino 2014; Valentino 2012). In the Manco‐Johnson trial, bleeding events were patient‐reported using an electronic diary, but for other outcomes such as the MRI evaluation of hemophilic arthropathy by radiologists and the joint physical examination performed by the physiotherapists, the assessors were blinded. The open‐label trial design may also have influenced the results of the HRQoL (SPINART 2013). Similarly, in the Morfini trial, even though this is an open‐label trial, it is reported that the assessors of orthopedic and radiological outcomes were blinded (Morfini 1976).

Incomplete outcome data

Eight of the 10 included trials either had no missing data or the losses to follow‐up were balanced and explained. We judged these trials to be at low risk of bias (A‐LONG 2014; Aronstam 1976; Aronstam 1977; LEOPOLD II 2015; Morfini 1976; PROPEL III 2020; SPINART 2013; Valentino 2014). One included trial had dropouts not balanced across groups and with the reason cited as “PK results”. Since this seems to be a treatment‐related difference, we judged this to be at a high risk of bias (Valentino 2012). The LipLong trial was prematurely discontinued by the sponsor based on the recommendation of an independent data and safety monitoring board and was analysed per protocol (LipLong 2012). Also, higher consent withdrawal was reported in the investigational drug arm (N = 8 versus N = 2).

Selective reporting

We judged all included trials to have a low risk of bias for this domain. The protocols were not available in four of the 10 trials, but all expected outcomes were reported in these trials (Aronstam 1976; Aronstam 1977; Morfini 1976; Valentino 2014). We acquired the protocols for five trials and there was agreement between the outcomes outlined in the protocol and those presented in the final reports (A‐LONG 2014; LEOPOLD II 2015; LipLong 2012; SPINART 2013; Valentino 2012). For one trial, authors provided a three‐month timeframe from the time of request to make the protocol available; all expected and stated outcomes in this trial were, however, reported (PROPEL III 2020).

Other potential sources of bias

In three of the cross‐over trials, the washout period was unclear, therefore we judged these to have an unclear risk of bias (Aronstam 1976, Aronstam 1977; Morfini 1976). The Liplong trial is marked high risk for other potential sources of bias due to the possibility of over‐estimation or "freezing‐effect" that could arise from premature discontinuation of clinical trials (LipLong 2012; Wang 2016). In the remaining six trials, we did not identify any other potential sources of bias and so marked them as low risk for other potential sources of bias A‐LONG 2014; LEOPOLD II 2015; PROPEL III 2020; SPINART 2013; Valentino 2012; Valentino 2014).

Effects of interventions

See: Table 1; Table 2; Table 3

Comparison between two prophylaxis regimens

The certainty of the evidence has been graded for those outcomes included in the summary of findings table (Table 1). For the definitions of these gradings, please refer to the summary of findings tables.

We included eight trials (477 participants) in this comparison (Aronstam 1976; Aronstam 1977; Morfini 1976; LEOPOLD II 2015; LipLong 2012; PROPEL III 2020; Valentino 2012; Valentino 2014). One of the included trials compared a standard prophylaxis treatment regimen to a PK‐tailored regimen (Valentino 2012). One trial compared prophylaxis with a standard therapeutic factor concentrate to a pegylated liposome FVIII formulation (LipLong 2012), this comparison is reported separately below. Overall, given the heterogeneity in reporting these trials, we did not aggregate data.

Primary outcomes

1. Number of joint bleeding episodes or joint bleeding frequency

Three included trials reported on joint bleeding (LEOPOLD II 2015; PROPEL III 2020; Valentino 2014). The LEOPOLD II trial found no difference in joint bleed prevention when a thrice‐weekly, higher‐dose prophylaxis regimen was compared to a twice‐weekly (at 12 months follow‐up) lower‐dose prophylaxis, MD ‐1.70 (95% CI ‐5.06 to 1.66) (59 participants) (moderate‐certainty evidence) (Analysis 1.1) (LEOPOLD II 2015). Comparing a PK‐guided prophylaxis regimen targeting trough levels of 8% to 12% or 1% to 3% in the PROPEL III trial, no difference was also found between the two prophylaxis arms (at 12 months follow‐up); MD ‐1.50 (95% CI ‐3.54 to 0.54) (115 participants) (moderate‐certainty evidence) (Analysis 1.2) (PROPEL III 2020). No difference was also seen in spontaneous joint bleeds between the two regimens, MD ‐1.50 (95% CI ‐3.22 to 0.22) (Analysis 1.3) (PROPEL III 2020). In the Valentino 2014 trial, no difference was also reported in annualized joint bleeding in the low‐frequency prophylaxis arm (100 IU/kg once weekly) compared to the standard frequency regimen (50 IU/kg twice weekly); MD of 1.70 (95% CI ‐1.09 to 4.49) (50 participants) (Analysis 1.4) (Valentino 2014).

1.1 — Comparison 1: Comparison between two prophylaxis regimens, Outcome 1: Joint bleeds per year

1.2 — Comparison 1: Comparison between two prophylaxis regimens, Outcome 2: Joint bleeds per year (2)

1.3 — Comparison 1: Comparison between two prophylaxis regimens, Outcome 3: Spontaneous joint bleeds

1.4 — Comparison 1: Comparison between two prophylaxis regimens, Outcome 4: Joint bleeds per year (3)

2. Orthopedic joint score or clinical joint function

One included (cross‐over) trial (10 participants) assessed joint function (Morfini 1976). While joint evaluations were conducted, data were not presented for individual treatment groups, rather results were presented that encompassed both arms. It was noted that through the 12 months of replacement therapy, range of motion was improved in 23 of 26 target joints. As well, there was also no deterioration in any joint, target or normal, over the course of treatment.

3. QoL on validated scales

One included trial (66 participants) assessed QoL using the SF36v1 scale (Valentino 2012). Data for individual treatment arms were not provided. Rather trial authors stated that there was no difference in overall QoL between prophylactic regimens.

Secondary outcomes

1. Number of total bleeding episodes or total bleeding frequency

Given the differences in treatment regimens and populations, we did not pool data for these trials and instead we report the results individually.

Seven trials reported on total bleeding. When comparing the use of a thrice‐weekly, higher‐dose prophylaxis with a twice‐weekly, lower‐dose prophylaxis regimen (at 12 months follow‐up), results suggested no difference in overall bleeding rate, MD ‐1.40 (95% CI ‐4.91 to 2.11) (moderate‐certainty evidence) (Analysis 1.5) (LEOPOLD II 2015). There was also no difference seen in total bleeding between prophylaxis to increase FVIII level to 30% or 15%, MD 10.20 (95% CI ‐1.29 to 21.69) (Analysis 1.6) (Aronstam 1977).

1.5 — Comparison 1: Comparison between two prophylaxis regimens, Outcome 5: Total bleeds per year

1.6 — Comparison 1: Comparison between two prophylaxis regimens, Outcome 6: Overall bleeding frequency (bleeds per 100 days)

Comparing a standard prophylaxis regimen to a PK‐tailored regimen, no reduction in bleeds across the comparison was indicated, MD ‐0.30 (95% CI ‐0.86 to 0.26) (66 participants) (Analysis 1.7) (Valentino 2012). When considering the effect of prophylaxis on 10 participants with haemophilia B, we see that the twice‐a‐week regimen (7.5 IU/kg) was favoured over the once‐a‐week regimen (15 IU/kg), MD 11.20 (5.81 to 16.59) (moderate‐certainty evidence) (Analysis 1.8) (Morfini 1976). In the 2014 Valentino trial, comparing two different dosing frequencies in people with haemophilia B, only a P value of 0.22 was reported in the comparison of the two treatment regimens (50 IU/kg twice‐weekly versus 100 IU/kg once‐weekly) (Valentino 2014).

1.7 — Comparison 1: Comparison between two prophylaxis regimens, Outcome 7: Annualised bleeding rates

1.8 — Comparison 1: Comparison between two prophylaxis regimens, Outcome 8: Total bleeding frequency (HB)

When comparing the overall bleeding frequency in nine participants in the Aronstam cross‐over trial, there was a significant reduction in the overall bleeding frequency in the prophylaxis group with dosing producing at least 0.25 IU/mL of factor VIII compared to the dosing producing at least 0.01 IU/mL once weekly, MD 3.44 (95% CI 2.42 to 4.46) (Analysis 1.9) (Aronstam 1976).

1.9 — Comparison 1: Comparison between two prophylaxis regimens, Outcome 9: Overall bleeding frequency

In the comparison between the prophylactic arm targeting trough levels of 1% to 3% or 8% to 12% in the PROPEL III trial, no difference was seen in bleeding frequency between the two groups, MD 2.00 (95% CI ‐0.13, 4.13) (115 participants) (Analysis 1.10) (PROPEL III 2020).

1.10 — Comparison 1: Comparison between two prophylaxis regimens, Outcome 10: Total bleeds per year (2)

2. Pain scores

None of the included trials reported this outcome.

3. Radiologic joint score or radiologic measurements or descriptions of joint damage

Only one trial (10 participants) reported this outcome (Morfini 1976). Trial authors stated that the 12 months of prophylaxis treatments improved the radiological picture in six cases with grade II or III arthropathy, but had no effect in those with grade IV arthropathy, but no numeric data were given.

4. Clotting factor concentrate plasma levels

One included trial (115 participants) assessed clotting factor concentrate plasma levels (PROPEL III 2020). In this trial, initial PK assessments showed mean (SD) plasma half‐lives (t½) of 15.3 (4.2) and 14.7 (5.1) hour in the 1% to 3% and 8% to 12% arms to be respectively. FVIII activity was a median (Q1 to Q3) 17.30 (15.2‐21.7) and 35.0 (29.2 ‐ 40.9) IU/dL during the first six months, and 17.30 (14.5 ‐ 22.4) and 30.9 (24.9 ‐ 41.2) IU/dL during the second six months for the 1% to 3% and 8% to 12% arms, respectively. Observed FVIII activity trough levels during the second six months were within the intended ranges of 1% to 3% and 8% to 12%; with median FVIII troughs ranging from 2.1 to 3.0 IU/dL and 10.7 to 11.7 IU/dL.

5. Time loss to school or employment

None of the included trials reported this outcome.

6. Integration into society

None of the included trials reported this outcome.

7. Scores on scales recording feeling of well‐being and global functioning

None of the included trials reported this outcome.

8. Economic data

None of the included trials reported this outcome.

9. Any reported adverse effects or toxicity of clotting factor concentrates

There was no reported inhibitor development reported in six of the trials in this comparison (Aronstam 1976; Aronstam 1977; LEOPOLD II 2015; Morfini 1976; Valentino 2012; Valentino 2014).

Transient low‐titer anti‐FVIII inhibitory antibodies, which resolved before the end of the trial, was reported in one out of 58 participants in the PROPEL III trial, in the arm targeting trough levels of 8% to 12% (PROPEL III 2020).

The Valentino trial reported (at 32 weeks follow‐up) no differences in total treatment‐emergent adverse events, MD 1.00 (95% CI 0.54, 1.84) (Analysis 1.11) (Valentino 2014).

1.11 — Comparison 1: Comparison between two prophylaxis regimens, Outcome 11: Total treatment emergent adverse event

Three trials did not report the rate of adverse events by treatment groups (Aronstam 1977; LEOPOLD II 2015; Morfini 1976). However, in the LEOPOLD II trial, there were three reported treatment‐related adverse events, but no details regarding the type of event or group were given (LEOPOLD II 2015).

In the 2012 Valentino trial that compared standard prophylaxis to a PK‐tailored regimen, there was no difference in mean rates of adverse events between the two regimens at 12 months follow‐up, MD 0.27 (95% CI ‐0.44 to 0.98) (Analysis 1.12) (Valentino 2012).

1.12 — Comparison 1: Comparison between two prophylaxis regimens, Outcome 12: Rate of adverse events

Serious and non‐serious adverse events were reported in the PROPEL III trial. However, two out of 101 and two out of 103 of these events were estimated to be treatment‐related in the arm targeting 1% to 3% and 8% to 12% respectively (PROPEL III 2020). In the arm targeting trough levels of 1% to 3%, no serious adverse event was treatment‐related, and in the arm targeting trough levels of 8% to 12%, one serious adverse event was estimated to be treatment‐related.

We assessed the certainty of the evidence as very low.

Prophylaxis with standard therapeutic factor concentrate compared to pegylated liposome FVIII formulation

The certainty of the evidence has been graded for those outcomes included in the summary of findings table (Table 2). For the definitions of these gradings, please refer to the summary of findings tables.

One trial was included in this comparison (LipLong 2012).

The 2012 LipLong trial (143 participants) compared a standard prophylaxis dose to a new investigational drug, pegylated liposome FVIII formulation (BAY 79‐4980), given once‐weekly (LipLong 2012); 73 participants were randomised to the prophylaxis group and 70 to the BAY79‐4980 group. Four randomised participants did not receive the intervention drugs, leaving 139 participants (n = 67 in BAY 79‐4980 and n = 72 in the prophylaxis group) for analysis. The sponsor halted the trial prematurely based on the recommendations of the data safety and monitoring board, indicating that the primary and secondary endpoints of non‐inferiority with prophylaxis with rFVIII‐FS three times/week would not be met. No safety issues were cited as the reason for early termination. The efficacy outcomes of this trial were reported as a per‐protocol analysis set.

Primary outcomes

1. Number of joint bleeding episodes or joint bleeding frequency

This outcome was reported in terms of annualised bleeding rates. This comparison showed fewer joint bleeding with the standard prophylaxis regimen compared to the investigational drug BAY 79‐4980, MD ‐7.20 (95% CI ‐11.01 to ‐3.39) (low‐certainty evidence) (Analysis 2.1) (LipLong 2012).