Prophylaxis Study of Marstacimab in Pediatric Hemophilia Participants With or Without Inhibitors

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Pfizer Inc.

Participant type

Pediatric, Patients

Age range

0-17 years

Gender

Male

Therapeutic area

Diseases [C] - Hemic and Lymphatic Diseases [C15]

Trial duration

6 Dec 2023 → ongoing

Decision date (initial)

2023-04-24

Transition trial

No

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

Pfizer Inc.

External identifiers

EU CT number

2022-500495-65-00

ClinicalTrials.gov

NCT05611801

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Prophylaxis, Efficacy, Safety, Others

To demonstrate the efficacy and safety of marstacimab for routine prophylaxis in severe hemophilia A or moderately severe to severe hemophilia B (FVIII activity <1% or FIX activity ≤2%, respectively) participants 1 to <18 years of age with or without inhibitors.

Secondary objectives 2

1. To evaluate additional efficacy of marstacimab.
2. To evaluate the effect of marstacimab on HRQoL.

Conditions and MedDRA coding

Haemophilia

Regulatory references

Scientific advice from competent authorities

European Medicines Agency

EMA paediatric investigation plan (PIP)

EMEA-002285-PIP02-19

Plan to share IPD

Yes

IPD plan description

Pfizer will provide access to individual de-identified participant data and related study documents (e.g. protocol, Statistical Analysis Plan (SAP), Clinical Study Report (CSR)) upon request from qualified researchers, and subject to certain criteria, conditions, and exceptions. Further details on Pfizer's data sharing criteria and process for requesting access can be found at: https://www.pfizer.com/science/clinical_trials/trial_data_and_results/data_requests.

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 5

1. Participants must be male, of appropriate age, and of a minimum body weight at the time of signing the informed consent/assent as follows: •For enrollment in the first age group, participant must be ≥12 to <18 years of age with a minimum body weight of 25 kg at the time of informed consent/assent. •For enrollment in the second age group, participant must be ≥6 to <12 years of age with a minimum body weight of 19 kg at the time of informed consent/assent. •For enrollment in the third age group, participant must be ≥1 to <6 years of age at the time of informed consent/assent. The minimum body weight for this age group will be determined based on emerging data from prior enrolled age groups.
2. Participants with a diagnosis of severe hemophilia A or moderately severe to severe hemophilia B (FVIII activity <1% or FIX activity ≤2%, respectively) documented by historical evidence prior to Day 1 Pre-Dose (Visit 2). If the participant’s historical factor activity is not available or documented, the severity of the participant’s hemophilia may be confirmed by a local clinical laboratory or the central laboratory for this study prior to Day 1 Pre-Dose (Visit 2).
3. Participants who have at least 1 year of diary information and/or medical records available in which exogenous FVIII or FIX replacement or bypass agent infusions and hemophilic bleeding episodes were consistently documented over the 12 months prior to the time of informed consent/assent.
4. 4.Participants who are enrolled into the Non-Inhibitor Cohort must also meet the following criteria: •No detectable inhibitor (≥0.6 BU/mL at the central testing lab) against FVIII or FIX prior to Day 1 Pre-Dose (Visit 2). (o)Participants who have a de novo low titer inhibitor (<5 BU/mL) at the central lab at the time of screening but have a documented absence of an inhibitor while on factor-replacement therapy at a local lab and FVIII or FIX recovery ≥60% of expected value or during Screening, and who receive a negative inhibitor result (<0.6 BU/mL, at the central lab) upon retest within 6 weeks after the initial positive result may be considered for eligibility on a case-by-case basis with discussion and agreement from the Pfizer medical monitor. •No documented history of high titer inhibitors (≥5 BU/mL or greater than the ULN for the testing laboratory) against FVIII or FIX in the 5 years prior to the time of informed consent/assent. •No low titer inhibitor (<5 BU/mL) refractory to FVIII or FIX replacement and with recovery <60% of expected in the 5 years prior to the time of informed consent/assent. •For participants who have undergone ITI, successful completion of ITI at least 5 years prior to the time of informed consent/assent and no evidence of inhibitor recurrence (permanent or temporary) as indicated by detection of an inhibitor, or FVIII or FIX recovery <60% since completing ITI. •Participants who have at least 50 documented exposure days to FVIII/FIX replacement product (recombinant, plasma-derived, or long-acting FIX product). •Participants must be on a stable routine prophylaxis regimen (defined as treatment by IV injection of factor concentrate to prevent bleeding) with FVIII/FIX replacement and have demonstrated at least 80% compliance with a stable prophylaxis regimen. a.Participants must be on a stable prophylaxis regimen during the 12 months prior to informed consent/assent. b.Exogenous FVIII/FIX replacement infusions and hemophilic bleeding episodes were documented over the previous 12 months prior to the time of informed consent/assent.
5. 5.Participants who are enrolled into the Inhibitor Cohort must also meet the following criteria: •Documentation of current high titer inhibitor (≥5 BU/mL); or current low titer inhibitor (<5 BU/mL) refractory to FVIII or FIX replacement and with FVIII or FIX recovery <60% of expected within previous 12 months prior to the time of informed consent/assent. •Participants who have documented inhibitors while on factor-replacement therapy but who do not meet the high quantitative inhibitor criteria described in the prior bullet at the time of screening (eg, participant with a previously documented high-titer inhibitor ≥5 BU/mL) and whose condition precludes re-challenge with FVIII or FIX replacement) may be considered for eligibility on a case-by-case basis with discussion and agreement from the Pfizer medical monitor. •Hemophilia A participants with on-demand treatment regimen with ≥12 bleeding episodes or hemophilia B participants with on-demand treatment regimen with ≥8 bleeding episodes (spontaneous or traumatic) necessitating treatment with bypass factor in the 12 months prior to informed consent/assent. a.Participants must be on an on-demand bypass treatment regimen during the 12 months prior to informed consent/assent. b.On-demand bypass infusions and hemophilic bleeding episodes were documented over the previous 12 months prior to the time of informed consent/assent. c.Surgical bleeding episodes do not apply to this criterion. •Participants who meet the bleeding criteria noted above and who are on routine prophylaxis (defined regularly scheduled and regimented administration by IV injection of bypass factor to prevent bleeding) and have demonstrated at least 80% compliance with scheduled prophylaxis regimen during the 12 months prior to the time of informed consent/assent, may be considered for eligibility on a case-by-case basis with discussion and agreement from the Pfizer medical monitor.

Exclusion criteria 16

1. Known coronary artery, thrombotic, or ischemic disease, or current evidence of congenital or acquired thrombophilic disease such as: • Anti-thrombin III deficiency (Screening test result below LLN), • Factor V Leiden mutation (Screening test result of heterozygous or homozygous mutation), • Prothrombin 20210 mutation (Screening test result of heterozygous or homozygous mutation), • Protein C deficiency (Screening test result below LLN), • Protein S deficiency (Screening test result below LLN), and • Antiphospholipid syndrome (dPT and/or DRVVT Screening test result positive for lupus anticoagulants).
2. Participation in other studies involving investigational drug(s) or investigational vaccine(s) within 30 days (or as determined by local requirements) or 5 half-lives prior to study entry or during study participation.
3. Previous exposure to marstacimab during participation in other marstacimab clinical studies.
4. CD4 cell count ≤200/uL if HIV-positive.
5. Screening 12-lead ECG, interpreted by a central reader, that demonstrates clinically relevant abnormalities that may affect participant safety or interpretation of study results.
6. Investigator site staff members directly involved in the conduct of the study and their family members, site staff members otherwise supervised by the investigator, and sponsor and sponsor delegate employees directly involved in the conduct of the study and their family members.
7. Known planned surgical procedure during the planned study period.
8. Known hemostatic defect other than hemophilia A or B.
9. Abnormal renal or hepatic function as defined by any of the following laboratory results at screening: a. ALT >2 × ULN. b. Bilirubin >1.5 × ULN (isolated bilirubin >1.5 × ULN is acceptable if bilirubin is fractionated and direct bilirubin <35%). c. Current unstable liver or biliary disease per investigator assessment defined by the presence of ascites, encephalopathy, coagulopathy, hypoalbuminaemia, oesophageal or gastric varices, persistent jaundice, or cirrhosis. NOTE: Stable chronic liver disease (including Gilbert’s syndrome, asymptomatic gallstones, and chronic stable hepatitis B or C -eg, presence of HBsAg or positive hepatitis C antibody test result at screening or within 3 months prior to starting study intervention) is acceptable if the participant otherwise meets entry criteria. d. Serum albumin less than the LLN. e. Adolescents (≥12 to <18 years) with estimated CrCl <30 ml/min (by Cockcroft-Gault Formula performed by central lab; see Appendix 2 Table 3 for calculation); f. Children (≥6 to <12 years) with estimated CrCl <30 ml/min/1.73m2 (by Modified Schwartz Equation performed by central lab; see Appendix 2 Table 5 for calculation).
10. Abnormal hematology values as defined by the following laboratory tests at Screening: • Platelet count <100,000/uL • Hemoglobin level <10 g/dL • Fibrinogen level 1.25 × ULN.
11. Other acute or chronic medical or psychiatric condition including recent (within the past year) or active suicidal ideation or behavior or laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the participant inappropriate for entry into this study.
12. Individuals with known allergic reaction or hypersensitivity to hamster protein or other components of the study intervention.
13. Current routine prophylaxis with bypassing agent (eg, aPCC, BYCLOT, PCC, or rFVIIa), non-coagulation non-factor replacement therapy (eg, emicizumab), or any previous treatment with a gene therapy product for treatment of hemophilia. • Participants with inhibitors who are being treated using a prophylaxis treatment regimen with a bypass agent will be considered on a case-by-case basis, only after discussion and agreement between the investigator and the Pfizer medical monitor. • Participants who have previously received non-factor-based hemophilia therapy (eg, fitusiran, concizumab, emicizumab) will be considered on a case-by-case basis, only after discussion and agreement between the investigator and the Pfizer medical monitor.
14. Ongoing or planned use of ITI, or prophylaxis with FVIII or FIX replacement at any time after initiation of treatment with study intervention.
15. Regular, concomitant therapy with immunomodulatory medications (eg, IVIG, routine systemic corticosteroids, rituximab).
16. Use of systemic antifibrinolytic agents (eg, tranexamic acid, etc), medications that may increase the risk of bleeding (eg, aspirin, etc), and certain non-steroidal anti-inflammatory drugs (eg, ibuprofen, other COX non-specific NSAIDs, etc.) within 120 hours prior to the first dose of study intervention and throughout the duration of the study.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. The primary efficacy endpoint is the ABR of treated bleeding events.
2. Safety Endpoints:•AEs and SAEs •Incidence and severity of thrombotic events •Incidence and severity of thrombotic microangiopathy •Disseminated intravascular coagulation/consumption coagulopathy •Immunogenicity (incidence of ADA and clinically significant persistent NAb against marstacimab) •Incidence and severity of injection site reaction •Incidence of severe hypersensitivity and anaphylactic reactions

Secondary endpoints 2

1. The following parameters will be assessed: •Incidence of joint bleeds (treated) •Incidence of spontaneous bleeds (treated) •Incidence of target joint bleeds (treated) •Incidence of total bleeds (treated and untreated) •Number of target joints •Change from baseline in joint health as measured by the HJHS for participants ≥4 years of age
2. HRQoL: •Haem-A-QoL (≥17 years of age)/Haemo-QoL (age-dependent versions ≥12 to <17 years of age and 8 to <12 years of age) •pedHAL (children/teenager version 8 to ≤17 years of age, parent proxy version 4 to <8 years of age) •PGIC-H for participants ≥4 years of age •Health Utilities Measure (EQ-5D-Y) for participants ≥4 years of age

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Pfizer Inc.

Sponsor organisation

Pfizer Inc.

Address

66 Hudson Boulevard East

City

New York

Postcode

10001-2189

Country

United States

Scientific contact point

Organisation

Pfizer Inc.

Contact name

Clinical Medical Lead

Public contact point

Organisation

Pfizer Inc.

Contact name

Clinical Medical Lead

Third parties 14

Locations

8 EU/EEA countries · 17 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Oversight and notifications

Regulatory notifications under CTR Articles 38, 52, 53, 54 and 77

Temporary halts 1 · Art. 38 CTR

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 254 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

10 submissions — initial application plus substantial / non-substantial modifications