Safety and Efficacy of Damoctocog Alfa Pegol in Previously Treated Children Aged 7 to < 12 Years With Severe Haemophilia A in the Phase 3, Open Label Alfa‐PROTECT Main Study

ABSTRACT

Background

In the earlier PROTECT VIII Kids study (NCT01775618), damoctocog alfa pegol was efficacious for prevention and treatment of bleeds in children aged < 12 years with severe haemophilia A.

Objective

Assess the safety of damoctocog alfa pegol, including hypersensitivity and loss of efficacy (LoE) due to an immune response to polyethylene glycol, in children aged 7 to < 12 years with severe haemophilia A.

Methods

Alfa‐PROTECT is a phase 3, multicentre, open‐label, single‐arm study (NCT05147662). Primary endpoint was the incidence of adverse events of special interest (AESI) leading to discontinuation during the first 4 exposure days.

Results

Overall, 35 children enrolled; 32 completed the 6‐month study, 21 (60%) reported ≥ 1 AE. Median (range) treatment duration was 182 (172–198) days. All AEs were mild/moderate; 3/35 children (8.6%) had study drug‐related AEs. One (2.9%) LoE event was considered an AESI, and led to temporary treatment interruption. No AEs resulted in study drug discontinuation. The probability of < 5% of patients experiencing an AESI was 92.2%. Bleed protection was maintained with damoctocog alfa pegol prophylaxis.

Conclusions

These data confirm the safety profile of damoctocog alfa pegol in children aged 7 to < 12 years with severe haemophilia A. Secondary endpoints indicate treatment was efficacious.

Trial Registration

The Alfa‐PROTECT trial is registered at ClinicalTrial.gov (NCT05147662)

1. Introduction

Regular prophylaxis, with factor VIII (FVIII) replacement or non‐replacement therapies, is one of the recommended management approaches for haemophilia A [1]. In the last decade, prophylactic management of haemophilia with FVIII replacement has moved towards the use of extended half‐life (EHL) FVIII products [2, 3, 4]. Compared with standard half‐life products, EHL products offer improved protection against bleeds and less frequent dosing for people with haemophilia A [4, 5, 6].

The possibility of better protection from recurrent bleeds and the option for less frequent dosing could be of particular benefit in children under 12 years of age [2, 5], in whom the goal of maintaining undamaged joints is a priority. FVIII pharmacokinetics are known to be less favourable in children, compared with adolescents and adults [7]. The increased clearance results in a need for more frequent FVIII infusions to maintain plasma FVIII levels above the minimum threshold required for blood clotting. The frequent infusions in turn can lead to difficulties with treatment adherence due to the distressing nature of frequent infusions, and often poor venous access necessitating a central venous access device [2, 4, 5, 8, 9]. Failure to adhere to treatment regimens and consequent suboptimal treatment outcomes can have detrimental effects on joint health and quality of life [2, 4, 5]. Furthermore, as children grow older, they may need higher FVIII levels to prevent bleeds due to increased physical activity and participation in sport [10].

Damoctocog alfa pegol (Jivi, Bayer AG, Germany), is a B‐domain deleted, recombinant factor VIII (rFVIII) product that is site‐specifically PEGylated to extend its half‐life. In previously treated adults with haemophilia A, damoctocog alfa pegol demonstrated a ~1.4‐fold increase in half‐life and dose‐normalised area under the curve compared with a standard half‐life recombinant FVIII product [5]. The safety and efficacy of damoctocog alfa pegol were demonstrated in the phase 2/3 PROTECT VIII study, where it prevented bleeding in previously treated adults and adolescents with severe haemophilia A, at dosing intervals of up to every 7 days (E7D), and effectively treated bleeds when used on demand [11]. Based on these results, damoctocog alfa pegol was approved for the treatment and prophylaxis of bleeding in previously treated people aged ≥ 12 years with haemophilia A [12, 13].

The pivotal PROTECT VIII Kids study (NCT01775618), and its extension demonstrated long‐term efficacy and safety of prophylaxis and treatment of bleeds with damoctocog alfa pegol in previously treated children aged < 12 years with severe haemophilia A [14, 15].

At the time of marketing authorisation application (MAA), the indication for damoctocog alfa pegol was restricted to previously treated haemophilia A patients aged 12 years and older, due to a regulatory age restriction for all PEGylated FVIII products in the EU, and partly because of the observation of an immune response to polyethylene glycol (PEG) in some children younger than 6 years, which manifested as hypersensitivity and/or loss of efficacy (LoE) [14, 15]. The immune response was associated with the development of transient anti‐PEG immunoglobulin M (IgM) antibodies and occurred within the first 4 exposure days (EDs) in 23% of children aged 2–5 years, leading to study discontinuation in all cases [14, 15]. In all cases, no class switching from IgM to immunoglobulin G (IgG) was observed, and antibody levels declined to undetectable levels over time. No clinically relevant intervention was required in addition to discontinuation of treatment, and all children were able to resume treatment with their pre‐study rFVIII product and regimen with good efficacy.

This response was not observed in children aged 7 to < 12 years and in the main study of PROTECT VIII Kids, nor in its long‐term extension study of up to 6 years of treatment [14, 15]. These findings suggest a decreased risk of immune response to PEG with increasing age. However, due to the small sample size for children aged 7 to < 12 years and as a safety precaution, the 7 to < 12 years age group was excluded from the initial MAA for damoctocog alfa pegol. Thus, the Alfa‐PROTECT study was conducted to expand the number of patients in that age group.

The Alfa‐PROTECT study (NCT05147662) aimed to assess the safety, tolerability and efficacy of damoctocog alfa pegol in a new group of previously treated children aged 7 to < 12 years with severe haemophilia A, with a particular focus on potential anti‐PEG immune responses in the first few EDs. The additional safety and efficacy data generated in this study were pooled with that from the PROTECT VIII Kids study to increase the sample size of children being treated with damoctocog alfa pegol and to draw meaningful conclusions on its safety and efficacy in the respective age range.

2. Methods

2.1. Study Design

Alfa‐PROTECT is a multicentre, open‐label, single‐arm investigational study of previously treated children aged 7 to < 12 years with severe haemophilia A (FVIII:C < 1%). The study has two parts (Figure 1): a 6‐month main study (Part A, completed) with ≥ 50 EDs, followed by an 18‐month extension study (Part B, ongoing).

FIGURE 1.

Study design. Bleeding episodes and infusions are documented in an eDiary; training on how to complete the eDiary was provided and content is reviewed for accuracy and completion at regular scheduled visits. ^‡At investigators' discretion. ^§Patients can either continue their Part A regimen or adjust the dose/frequency at investigators' discretion during the extension, based on bleeding events and individual needs. Abbreviations: 2× W, twice weekly; E5D, every 5 days; ED, exposure day; IUMS, infusions under medical supervision; M, Month; S, screening; W, Week.

In Part A, children received 40 IU/kg (up to 60 IU/kg at the investigators' discretion) damoctocog alfa pegol as twice‐weekly (2× W) prophylaxis. The first four doses were administered under medical supervision, so that safety could be closely monitored using both laboratory and clinical measures. During the extension (Part B), children could continue the same prophylaxis dosing regimen as prescribed in Part A, or the regimen could be adjusted to 60 IU/kg every 5 days (E5D) at the investigators' discretion.

2.2. Study Population

The study aimed to enrol at least 30 previously treated boys aged 7 to < 12 years with severe haemophilia A and follow them for up to 2 years while they were treated prophylactically with damoctocog alfa pegol. Eligible children must have been receiving treatment with any FVIII concentrate for ≥ 50 EDs at the time of study enrolment. Exclusion criteria included a history or evidence of FVIII inhibitors (Bethesda titre > 0.6 BU/mL), other inherited or acquired bleeding disorders and a platelet count < 100 000 cells/μL.

2.3. Study Assessments

The primary endpoint was the incidence of adverse events of special interest (AESI), defined as hypersensitivity or LoE, leading to discontinuation during the first 4 EDs. Hypersensitivity was defined as a reaction related to the administration of damoctocog alfa pegol and did not include hypersensitivity reactions not related to drug administration. LoE was defined as unexpected clinical symptoms of bleeding or no response to treatment of a bleed, and had to be confirmed by a low recovery (< 0.5 kg/dL) or no detectable post‐infusion FVIII level (considered as not detectable or less than 15% associated with high‐titre [1:16 or greater] anti‐PEG IgM antibodies), with a negative inhibitor test and presence of anti‐PEG antibodies. The events described above were considered LoE even in the absence of a bleeding event. A reduced recovery/post‐infusion FVIII level is not considered LoE if adequate prophylaxis can be achieved with an increased dose and/or decreased interval. Immunogenicity was assessed by measurement of FVIII inhibitors and anti‐drug antibodies (anti‐PEG and anti‐PEG IgM). Binding antibodies to damoctocog alfa pegol were determined by an enzyme‐linked immunosorbent assay (ELISA). Other long‐term safety assessments included drug‐related adverse events, neurological examinations, renal biomarkers (serum and urine), hepatic function and plasma PEG measurements. Secondary efficacy endpoints included annualised bleeding rate (ABR), study drug utilisation and number of infusions per year. Assessment of bleeds was patient reported. Efficacy endpoints during the study were collected in an electronic patient diary (eDiary). Training on how to complete the eDiary was given, and content was reviewed for accuracy and completion at regular scheduled visits. To ensure that no infusions and/or bleeds were missing, the investigators regularly checked with the patients/caregivers that eDiary entries were accurate and complete. In addition, regular monitoring was done to ensure that documentation in patient files and the diaries was consistent. Pre‐study bleed rate was collected by the investigator using patients' retrospective medical records. Pre‐injection FVIII trough levels were measured using a chromogenic assay 3 days (61–84 h) and 4 days (85–108 h) after the last infusion according to the 2× W dosing schedule in Part A. Trough levels measured at shorter intervals from the last infusion were excluded, and FVIII levels of more than 30% were considered invalid for trough level analysis.

Other endpoints included health‐related quality of life, assessed using the haemophilia‐specific quality of life (Haemo‐QoL) short‐form questionnaire for children, and the Patient/Caregiver Global Impression of Severity and Change. Baseline characteristics and patient demographics were collected at screening.

2.4. Statistics

Hypothesis testing was not planned for this study. Based on the findings from the PROTECT VIII Kids study, the incidence of AESI was expected to be low in the studied age group; therefore, the posterior probability of AESIs being < 5% in patients aged 7 to < 12 years was estimated by applying a Bayesian beta‐binomial model incorporating data from PROTECT VIII Kids.

If a bleed had a missing date or time, then the date of the associated infusion was used as the bleed date or time. If the infusion for a bleed had a missing date or time, then the date and time of the bleed were used to determine the infusion date or time. Statistical analyses were descriptive. Descriptive statistics were used to summarise the number of bleedings and ABR. A post hoc analysis considered the magnitude of change from baseline in each Haemo‐QoL score to judge the extent to which they were likely to exceed measurement error. The minimal detectable change statistic at the 95% confidence level, adapted for group‐level interpretations (MDC_{95_group}), was calculated based on Cronbach's alpha reliability and standard deviation (SD) of scores at baseline.

2.5. Ethics and Dissemination

The study was conducted in compliance with ethical principles derived from international guidelines, including the Declaration of Helsinki and Council for International Organizations of Medical Sciences (CIOMS), the ICH Good Clinical Practice guideline, local data protection legislation and all applicable laws and regulations. All guardians were required to sign the informed consent form, and where possible, children were to provide written assent (dependent on age, intellectual status and local legislation) witnessed and countersigned by the authorised person obtaining consent, prior to study participation. In line with applicable regulations, results from this trial are published on ClinicalTrials.gov and the EU clinical trials register. Personal patient records were not made public and will be kept confidential.

3. Results

3.1. Patient Demographics and Baseline Characteristics

In total, 35 children enrolled in Part A were included in the safety analysis set, as all 35 had received at least 1 dose of study drug. Of these, 32 children completed Part A and had a documented record of bleed and utilisation data for at least 3 months; they were thus included in the modified intent to treat analysis (mITT). Overall, 31/32 children received treatment for ≥ 50 EDs (Figure 2). The median (range) treatment duration was 182 (172–198) days. All 35 participants were male, the majority (94%) were white, the median (range) age at baseline was 8 (7–11) years, and most children were treated with standard half‐life FVIII and had received prophylaxis treatment prior to enrolment (Table 1).

FIGURE 2.

Patient disposition. ^†Three patients failed screening; one patient did not complete the screening process. ^‡At investigator's discretion. ^§31/32 had ≥ 50 damoctocog alfa pegol EDs. Abbreviations: 2× W, twice per week; ED, exposure day; mITT, modified intent to treat; SAF, safety analysis set.

TABLE 1.

Baseline disease characteristics and patient demographics in the safety analysis set.

Characteristic	Patients (N = 35)
Male, n (%)	35 (100.0)
Age at enrolment
Years, median (range)	8.0 (7–11)
Baseline BMI
kg/m2, mean (SD)	18.1 (3.4)
Race, n (%)
White	33 (94.3)
Not reported	2 (5.7)
Family history of haemophilia, n (%)
Yes	19 (54.3)
No	16 (45.7)
Family history of inhibitors, n (%)
Yes	2 (5.7)
No	22 (62.9)
Unknown	11 (31.4)
Previous treatment, n (%)
Prophylaxis	32 (91.4)
On demand	3 (8.6)
Prior Factor VIII treatment, n (%) a
Extended half‐life products
Efmoroctocog alfa	2 (5.7%)
Rurioctocog alfa pegol	1 (2.9%)
Turoctocog alfa pegol	1 (2.9%)
Standard half‐life products
Moroctocog alfa	7 (20.0%)
Octocog alfa	10 (28.6%)
Factor VIII (antihaemophilic factor)	2 (5.7%)
Factor VIII, recombinant	12 (34.3%)

Abbreviations: BMI, body mass index; SD, standard deviation.

^a Per protocol, patients received prior therapy for Factor VIII deficiency for at least 50 exposure days prior to entry to Alfa‐PROTECT study.

3.2. Safety

At least one adverse event was reported in 21/35 children (60%); all were mild or moderate in severity (Table 2). In total, an AESI with LoE was reported in one (2.9%) child aged 8 years after ED 2. This child had post‐infusion FVIII levels of 4.5% and 3.8% and a recovery of 0.075 (IU/dL)/(IU/kg) and 0.06 (IU/dL)/(IU/kg) at ED 3 and 4, respectively, leading to treatment interruption after ED 5. At ED 3, the site noticed bleeding after the venipuncture for blood withdrawal which was treated with ice. The event coincided with a transient high titre (1:64) anti‐PEG IgM antibody, which was detected at study day 8 (after ED 2). At the same time, the patient presented with bacterial pneumonia. Anti‐PEG antibodies had disappeared 1 month later, and the patient restarted treatment with the study drug after 2 months of treatment interruption, at study day 89. During the study drug interruption, the patient received his previous standard half‐life FVIII treatment. After ED 5 and until the end of Part A, all further assays were negative and treatment with damoctocog alfa pegol resumed with no further LoE and with normal recovery. This patient also participated in the extension study (Part B).

TABLE 2.

Adverse events occurring during the study period (safety analysis set).

	Patients (N = 35), n (%)
Any AE	21 (60.0)
Mild	14 (40.0)
Moderate	7 (20.0)
Any study drug–related AE	3 (8.6) a
Mild	0
Moderate	3 (8.6)
Severe	0
Discontinuation of study drug due to AE	0
Any AESI	1 (2.9) b
Any study drug–related AESI	1 (2.9) b
Mild	0
Moderate	1 (2.9)
Discontinuation of study drug due to AESI within first 4 EDs	0
Any SAE	1 (2.9) c
Any study drug–related SAE	0
Discontinuation of study drug due to SAE	0

Abbreviations: AE, adverse event; AESI, adverse event of special interest; ED, exposure day; FVIII, factor VIII; IgM, immunoglobulin M; PEG, polyethylene glycol; SAE, serious adverse event.

^a Study drug‐related AEs of injection site pain or injection site itch occurred in two children. These were moderate in intensity and resolved without treatment disruption; loss of drug efficacy after ED 2, considered an AESI, occurred in one child, leading to treatment interruption.

^b A transient positive anti‐PEG IgM antibody titre was observed between EDs 2 and 4 in one patient; this coincided with a loss of drug efficacy and was considered a study drug–related AESI.

^c One instance of abdominal pain occurred in one child; this was deemed as not related to study drug and resolved without treatment disruption.

Study drug–related AEs were reported in two further participants (injection site reactions, n = 2). Both injection site reactions were moderate in intensity and resolved without treatment disruption.

A treatment‐emergent serious AE of abdominal pain occurred in one patient; it was deemed unrelated to the study drug and had no impact on treatment. No AEs resulted in permanent study drug discontinuation and no deaths were reported.

Six children had anti‐PEG antibodies detected (two pre‐existing, four de novo); all were transient and IgM class. One child with AESI has been described above. In five other children, anti‐PEG antibodies occurred without hypersensitivity or LoE. These were low titre (≤ 1:4) and were detected either prior to treatment (n = 2) or de novo (n = 3) in the first four EDs. Two of the patients with de novo antibodies had mildly reduced recovery (lowest 0.8 kg/dL).

Adding prior information on AESI from the 25 children aged 7 to < 12 years from PROTECT VIII Kids, the posterior probability from a Bayesian beta‐binomial model of < 5% incidence of AESI was 92.2%, translating to an approximation that it is 92.2% likely that < 5% of patients would experience an AESI. The mean and median of the posterior distribution of the true incidence of AESI were 2.1% and 1.6%, respectively, with a 90% confidence interval (CI; 0.18; 5.76).

3.3. Efficacy

Mean (SD) total number of bleeds and joint bleeds during the 12 months before screening in the mITT population were 3.25 (5.57) and 1.78 (3.24), respectively; median (quartile [Q]1; Q3) 1.0 (0.0; 3.0) and 0.5 (0.0; 1.5). Mean (SD) total and joint ABR for treated bleeds were 1.34 (2.65) and 0.71 (1.8), respectively, while receiving damoctocog alfa pegol (median [Q1; Q3] 0.0 [0.0; 1.93] and 0.0 [0.0; 0.0]) (Figure 3). While using damoctocog alfa pegol, 23 (71.9%) children had no treated total bleeds; 27 (84.4%) and 26 (81.3%) children had no treated spontaneous and joint bleeds, respectively.

FIGURE 3.

Annualised bleeding rates during Alfa‐PROTECT mITT. ^†All bleeds in the 12 months before screening. ^‡Treated bleeds. Abbreviations: ABR, annualised bleeding rate; mITT, modified intent to treat; Q, quartile; SD, standard deviation.

In the mITT population, 64 bleeds were reported, the majority of which (43/64, 67%) did not require treatment. Most untreated bleeds (30/43, 70%) were skin/mucosa bleeds, and were reported by a single participant (nose bleeds). All untreated bleeds were mild or moderate, as were the majority of treated bleeds (16/21, 76%). Most treated bleeds were treated with one (15/21, 71%) or two (5/21, 24%) infusions of damoctocog alfa pegol. Response to treatment was rated ‘good’ or ‘excellent’ for 15/21 (71%) of bleeds.

The mean (SD) and median (range) total FVIII dose per damoctocog alfa pegol prophylaxis infusion were 55.1 (6.84) IU/kg and 55.0 (39–69) IU/kg, respectively, with a mean (SD) and median (range) of 104.8 (7.04) and 106.3 (67–110) infusions per year. The mean (SD) and median (range) annual FVIII utilisation for damoctocog alfa pegol prophylaxis were 5770 (826.31) IU/kg/year and 5831 (3920–7468) IU/kg/year. The median (range) recovery across all visits was 1.69 (1.1–2.9) (IU/dL)/(IU/kg).

Mean (SD) pre‐injection FVIII trough levels in plasma were 2.93% (2.30) for the 2× W group at 3 days (n = 31) and 1.73% (1.69) at 4 days (n = 30) since their last injection.

Baseline quality of life data were available for 33 children completing the Haemo‐QoL short‐form questionnaire (mean [SD] total score: 26.67 [12.28]). Mean (SD) change from baseline in the Haemo‐QoL total score at Visit 11 was −6.27 (8.49 [n = 31]) (Figure 4). For the total Haemo‐QoL short‐form questionnaire score, as well as in the domains for physical health, feelings, sports and others, the change from baseline exceeded the MDC_{95_group} statistic. Data from the Caregiver Global Impression of Severity and Change questionnaire completed at the end of Part A of the study were available for 32 children. Briefly, at baseline, caregivers reported ‘no problems at all’ for 10 (31.3%) children, which increased to 21 (65.6%) children at the end of the study (Table S1).

FIGURE 4.

Mean (SD) change from baseline in Haemo‐QoL scores. Abbreviations: Haemo‐QoL, haemophilia‐specific quality of life questionnaire; Phys. hlth, physical health; SD, standard deviation; Self perc., self‐perception.

4. Discussion

The primary aim of this study was to generate additional safety data in children of the specified age group, to address the uncertainty of risk for an anti‐PEG IgM immune response with clinical symptoms, as noted in the first paediatric study of damoctocog alfa pegol (PROTECT VIII Kids) in children < 6 years old [14, 15]. All these events observed in PROTECT VIII Kids occurred during the first 4 EDs, with no such events having been reported at later exposure times. Further, all instances of hypersensitivity were associated with anti‐PEG antibodies of the IgM type that declined over time [14, 15]. IgM antibodies can trigger complement activation and lead to accelerated blood clearance and inhibition of FVIII [16], which may explain the implication of anti‐PEG IgM antibodies in the hypersensitivity reactions and poor recoveries observed during early exposures in the first paediatric study. No cross‐reactivity events were noted in PROTECT VIII Kids, and good efficacy was demonstrated when these children transitioned to their previous FVIII replacement therapy.

As a precaution, strict safety measures were employed to safeguard participants' health in Alfa‐PROTECT, including the administration of the first four doses of study intervention under medical supervision with pre‐ and post‐infusion FVIII levels measured at each of the first four exposures, at ED 50 and every 6 months thereafter. Medical supervision was also provided at the request of the investigator in case of clinical suspicion of LoE. Transient LoE due to high titre anti‐PEG IgM antibodies was reported in one 8‐year‐old child within the first four EDs; however it declined over time and was resolved, only leading to temporary damoctocog alfa pegol treatment interruption. In this particular instance, the coincidence of bacterial pneumonia during the first exposure to the study drug could have played a role because of the strong activation of the immune system, and may have triggered the unspecific immune response to PEG. This observation supports previous findings from PROTECT VIII Kids that these antibodies are associated with early exposure, and that they decrease over time without clinically relevant intervention and without a class switch to IgG. Unlike PROTECT VIII Kids, the Alfa‐PROTECT study did not have any permanent discontinuations, primarily due to the older age group in the latter. Furthermore, data from the Alfa‐PROTECT study show that treatment with damoctocog alfa pegol can be resumed with good efficacy.

Other AEs associated with the study drug resolved without any treatment interruption and were moderate in severity. The median incidence of AESI associated with the first four EDs was low (1.6%), supporting the favourable safety profile of damoctocog alfa pegol.

Bleeding rates with damoctocog alfa pegol were lower compared with the 12 months prior to screening, and approximately three‐quarters of patients had zero bleeds requiring treatment. These data indicate that protection from bleeds is improved with damoctocog alfa pegol prophylaxis, consistent with efficacy data from PROTECT VIII Kids [14, 15].

Moreover, results indicate there may be a QoL benefit for this population when treated prophylactically using damoctocog alfa pegol. Though no other explicit patient outcomes were assessed that may be linked to specific areas, mean change from baseline in several domains of the Haemo‐QoL exceeded the MDC_{95_group} statistic, indicating a high likelihood of clinically relevant improvement in areas such as sports, physical health, and overall QoL due to treatment with damoctocog alfa pegol. Based on the results from the Alfa‐PROTECT study and the PROTECT VIII Kids study, damoctocog alfa pegol was approved in 2025 by the US Food and Drug Administration and the European Medicines Agency for treatment of children aged 7 to < 12 years with haemophilia A [12, 13].

One of the limitations of the study is the patient‐reported assessment of bleeds, which may introduce bias or misclassification; nevertheless, this is the standard approach for clinical trials in patients with haemophilia A. Moreover, since this is an open‐label study, there may be a bias in the reporting of AEs as well as QoL assessments. The sample size for the study is relatively small, which may limit generalisability; however these data were pooled with the PROTECT VIII Kids study in this age group to increase the sample size and those results will be presented separately. The 6‐month study design for Part A may mean that late‐onset AEs are missed. However, in Part B, the 18‐month extension of the study will evaluate the long‐term safety and efficacy of damoctocog alfa pegol. Results for Part B are expected by the end of 2025.

Overall, damoctocog alfa pegol exhibited a favourable safety and tolerability profile in previously treated children aged 7 to < 12 years with severe haemophilia A. The additional data generated in the 6‐month main treatment period of the Alfa‐PROTECT study support the use of damoctocog alfa pegol as a treatment for this population.

Author Contributions

M.C.O., M.L., H.G., K.K., N.S., L.C.O., S.G., M.G.A., M.D., A.K.C.C. and M.E.M. were principal investigators who treated patients and contributed to data acquisition and interpretation. G.C.M., C.T., M.M.E. were responsible for study conceptualisation and data interpretation. C.T. was responsible for the formal data analysis. All authors contributed to the development of the manuscript and approved the final draft.

Ethics Statement

The study was conducted in compliance with ethical principles derived from international guidelines, including the Declaration of Helsinki and the Council for International Organizations of Medical Sciences (CIOMS), the ICH Good Clinical Practice guideline, local data protection legislation and all applicable laws and regulations.

Consent

All guardians were required to sign the informed consent form, and where possible, children were to provide written assent (dependent on age, intellectual status and local legislation) witnessed and countersigned by the authorised person obtaining consent, prior to study participation. In line with applicable regulations, results from this trial are published on ClinicalTrials.gov and the EU clinical trials register. Personal patient records were not made public and will be kept confidential.

Conflicts of Interest

Margareth C. Ozelo: has received research grants from BioMarin, Pfizer, Roche, and Takeda; has participated as a clinical trial Investigator for Bayer, BioMarin, Novo Nordisk, Pfizer, Roche, and Sanofi; has received speaker honoraria from BioMarin, CSL Behring, Novo Nordisk, Pfizer, Roche, Sanofi, and Takeda; has received consulting fees from Bayer, BioMarin, Novo Nordisk, Pfizer, Roche, and Takeda; and has participated in grant reviewing for CSL Behring and Novo Nordisk. Matteo Luciani: has received research grants from Bayer and Novo Nordisk. Heidi Glosli: has acted as Principal Investigator and conducted several clinical trials for different companies over the last 10 years. She has received medical writing support from Sobi. Kaan Kavakli: has received research support from Pfizer, Novo Nordisk and Roche; has participated in advisory boards for Pfizer, Roche, Bayer, Novo Nordisk and Takeda. Nasrin Samji: has acted as a site Principal Investigator for Bayer and been on a Bayer advisory board. Gregory C. Makris: is an employee of Bayer. Claudia Tueckmantel: is an employee of Bayer. Monika Maas Enriquez: is an employee of Bayer. Luciana C. Oliveira: has participated as a clinical trial Investigator for Bayer, BioMarin, Pfizer, Roche, and Takeda; has received speaker honoraria from Novo Nordisk, Pfizer, Roche, Sanofi, and Takeda; has received consulting fees from Bayer, BioMarin, Novo Nordisk, Pfizer, Roche, and Takeda. Shveta Gupta: has acted as Principal Investigator for clinical trials with Novo Nordisk and Bayer; has been a paid consultant/speaker for Octapharma, Sanofi, Bayer and Novo Nordisk. Mario Guillermo Arbesú: has acted as Principal Investigator, speaker and advisor for Biomarin, Roche, Pfizer and Bayer. Speaker and advisor for Novo Nordisk. Mauro Davoli: has received research support from Roche; has acted as a paid consultant/advisor/speaker for Bayer, Roche, Novo Nordisk, Takeda, Biomarin and Pfizer. Anthony K. C. Chan: has received research support from Bayer, C17, the Canadian Hemophilia Society, CIHR, Novo Nordisk, Daiichi, Pfizer, Sanofi, Sobi and Takeda; has received speaker honoraria from Bayer, Novo Nordisk, Takeda, Pfizer, Sanofi, and Octapharma; has been a consultant for Bayer, Novo Nordisk, Takeda, Roche and Sanofi; holds patents on an anticoagulant and its applications. Maria E. Mancuso: has acted as a paid Consultant/Advisor/Speaker for Bayer, BioMarin, CSL Behring, Kedrion, LFB, Novo Nordisk, Octapharma, Pfizer, Roche, Sanofi, Sobi, Takeda and Regeneron.

Supporting information

Table S1: Caregiver Global Impression of Severity at baseline and at end of Alfa‐PROTECT main study (Part A).

Ozelo M. C., Luciani M., Glosli H., et al., “Safety and Efficacy of Damoctocog Alfa Pegol in Previously Treated Children Aged 7 to < 12 Years With Severe Haemophilia A in the Phase 3, Open Label Alfa‐PROTECT Main Study,” European Journal of Haematology 116, no. 4 (2026): 435–442, 10.1111/ejh.70059.

Data Availability Statement

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