Study type

Study topic

Disease /health condition
Human medicinal product

Study type

Non-interventional study

Scope of the study

Assessment of risk minimisation measure implementation or effectiveness
Effectiveness study (incl. comparative)
Safety study (incl. comparative)

Data collection methods

Secondary use of data
Non-interventional study

Non-interventional study design

Cohort
Study drug and medical condition

Name of medicine

HEMLIBRA

Study drug International non-proprietary name (INN) or common name

EMICIZUMAB

Anatomical Therapeutic Chemical (ATC) code

(B02BX06) emicizumab
emicizumab

Medical condition to be studied

Haemophilia A without inhibitors
Haemophilia A with anti factor VIII
Population studied

Age groups

  • Paediatric Population (< 18 years)
    • Neonate
      • Term newborn infants (0 – 27 days)
    • Infants and toddlers (28 days – 23 months)
    • Children (2 to < 12 years)
    • Adolescents (12 to < 18 years)

Estimated number of subjects

743
Study design details

Main study objective

The primary objective for this study is to evaluate the overall safety and tolerability of emicizumab administration in all pediatric patients with haemophilia A in real-world conditions, and in subgroups determined by age and inhibitor status, as well as by severity for patients without inhibitors

Setting

PedNet Registry is the largest registry in the world for pediatric patients with hemophilia. Currently, 19 European countries, comprising 17 European countries (including the United Kingdom), Israel, and Canada, with approximately 34 hemophilia treatment centers (HTCs) participate in the registry. The Registry includes all ages groups up to age 18 years and all severities of hemophilia, including mild hemophilia A patients with Factor VIII <25 IU/dL. This setting provides substantial coverage and is an adequate representation of the pediatric patient population.

The following criteria describe the population eligible for this study, which is a subset of the overall population participating in the PedNet Registry.

Inclusion criteria for inclusion in the PedNet Registry:
- Diagnosis of hemophilia A
- Factor VIII activity <25 IU/dL
- Treated in one of the participating HTCs
Additional inclusion for emicizumab-specific analysis:
- Received prophylactic treatment with emicizumab

Exclusion criteria for the PedNet Registry:
- Referral to a participating HTC after development of Factor VIII inhibitors
- Informed consent for participation in the PedNet Registry not obtained
Exclusion criteria for emicizumab-specific analysis:
- Inherited or acquired bleeding disorder other than hemophilia A

Outcomes

Primary safety endpoints:
- Frequency and incidence of thromboembolic events (TEs), thrombotic microangiopathy (TMA), and anaphylaxis (including terms of systemic hypersensitivity, anaphylaxis, and anaphylactoid events), overall and in subgroups determined by age and inhibitor status, as well as by severity of hemophilia A for patients without inhibitors.

Secondary safety endpoints:
- Frequency and incidence of any adverse events (overall, and by age, inhibitor status, and severity of hemophilia A).

Effectiveness endpoints (overall, and by age, inhibitor status, and severity of hemophilia A):
- Annual bleeding rate (ABR) for all bleeds* and percentage of patients with zero bleeds*;
- ABR for joint bleeds and major bleeds
- Bleeds count for all bleeds, major bleeds, minor and major joint bleeds, and minor non-joint bleeds.
*As per PedNet data collection, all bleeds reported are treated bleeds.

Data analysis plan

This is a secondary data use non-interventional study. There is no pre-defined hypothesis testing and all analyses are regarded as exploratory.

The Marketing Authorisation Holder (MAH) receives aggregate level data of patients treated with emicizumab from the PedNet Registry on an annual basis. Based on the number of patients, number of adverse events (AEs), and exposure to emicizumab provided by the PedNet Registry, the MAH performs analyses of frequencies/incidence of AEs overall and grouped by age during emicizumab initiation, severity, and inhibitor status. The youngest age group is newborns (birth to 28 days). Other age groups include: 29 days to less than(<)6 months, 6 months–<2 years, 2 years–<6 years, 6 years–<12 years, and 12 years–18 years. The MAH reports annual bleeding rate (ABR) for all bleeds, percentage of patients with zero bleeds, ABR for joint bleeds and major bleeds overall and grouped by age, severity, and inhibitor status as sent by the PedNet Registry. As per PedNet data collection, all bleeds reported are treated bleeds.

Summary results

Since the beginning of the PedNet Registry up until the clinical cutoff date of 31-Dec-2024, 743 patients with hemophilia A received treatment with emicizumab. Of these, 578 patients with updated follow-up until 1-Jul-2023 were included in this report. Among them, 532 patients with a treatment period of a minimum of 6 consecutive months were included for a reliable negative binomial regression model-based ABR calculation.

Overall, no TMA or anaphylaxis was reported in the 578 patients through the study period. The following 15 AEs were reported cumulatively as of the final report:
- One case of antibodies against emicizumab, 2 local subcutaneous (SC) reactions, and 1 death unrelated to the study drug reported in the 2nd interim report;
- One injection site reaction reported in the 4th interim report;
- One TE following sepsis and port-a-cath removal, 2 local SC reactions, 2 cases of redness at injection site, and 3 other AEs reported in the 5th interim report;
- Two local SC reactions reported in the 6th (final) report.

Following a median duration of emicizumab exposure of 28.1 months (inter-quartile range: 16.6–41.9) in 578 patients, 264 patients (46%) had zero bleeds and 436 (75%) had zero joint bleeds. Of the 993 bleeds reported, 277 (28%) were major bleeds and 716 (72%) were minor bleeds. Moreover, 321 (32%) were joint bleeds.

The model-based ABR for the 532 patients with a minimum 6 consecutive months of treatment was 0.7 (95% CI: 0.6–0.8) for all bleeds, 0.2 (95% CI: 0.2–0.2) for major bleeds (joint and non-joint), and 0.2 (95% CI: 0.2–0.3) for joint bleeds (major and minor).