A Study to Evaluate the Efficacy, Safety, Pharmacokinetics, and Pharmacodynamics of Subcutaneous Emicizumab in Participants From Birth to 12 Months of Age With Hemophilia A Without Inhibitors

NCT04431726 | Active Not Recruiting Phase 3 Results FDA Drug

• 3 other identifiers: MO417872020-001733-122023-505964-13-00
• Study Type: interventional
• Target: 55
• Locations: 13 countries
• Sites: 29

Brief Summary

This is a Phase IIIb, multicenter, open-label, single-arm study of prophylactic emicizumab in previously untreated and minimally treated patients at study enrollment from birth to ≤12 months of age with severe hemophilia A (intrinsic factor VIII \[FVIII\] level \<1%) without FVIII inhibitors. The study is designed to evaluate the efficacy, safety, pharmacokinetics, and pharmacodynamics of emicizumab administered at 3 milligrams per kilogram of body weight (mg/kg) once every 2 weeks (Q2W) for 52 weeks. After 1 year of treatment, participants will continue to receive emicizumab (1.5 mg/kg once every week \[QW\], 3 mg/kg Q2W or 6 mg/kg once every 4 weeks \[Q4W\]) over a 7-year long-term follow-up period under this study frame.

Conditions

Severe Hemophilia A

Keywords

Severe hemophilia A Without Factor VIII Inhibitors

Outcome Measures

Primary Outcomes (12)

• Model-Based Annualized Bleeding Rate for Treated Bleeds

  The number of treated bleeds over the efficacy period was estimated as an annualized bleeding rate (ABR) using a negative binomial regression model, which accounts for different follow-up times. A treated bleed was defined as a bleed that was directly followed by a hemophilia medication reported to be a "treatment for bleed". The 72-hour rule was implemented: two bleeds of the same type and at the same anatomical location were counted as one bleed if the second bleed occurred within 72 hours from the last treatment for the first bleed. Bleeds due to surgery/procedure were excluded.

  From first dose of emicizumab to the clinical cutoff date or withdrawal date, whichever was earlier (median [range, min-max] efficacy period: 101.9 [52.6-119.7] weeks)

• Mean Calculated Annualized Bleeding Rate for Treated Bleeds

  The number of treated bleeds over the efficacy period is presented here as a calculated annualized bleeding rate (ABR) that was annualized for each participant using the following formula: ABR = (number of bleeds/number of days during the efficacy period) x 365.25. A treated bleed was defined as a bleed that was directly followed by a hemophilia medication reported to be a "treatment for bleed". The 72-hour rule was implemented: two bleeds of the same type and at the same anatomical location were counted as one bleed if the second bleed occurred within 72 hours from the last treatment for the first bleed. Bleeds due to surgery/procedure were excluded.

  From first dose of emicizumab to the clinical cutoff date or withdrawal date, whichever was earlier (median [range, min-max] efficacy period: 101.9 [52.6-119.7] weeks)

• Median Calculated Annualized Bleeding Rate for Treated Bleeds

  The number of treated bleeds over the efficacy period is presented here as a calculated annualized bleeding rate (ABR) that was annualized for each participant using the following formula: ABR = (number of bleeds/number of days during the efficacy period) x 365.25. A treated bleed was defined as a bleed that was directly followed by a hemophilia medication reported to be a "treatment for bleed". The 72-hour rule was implemented: two bleeds of the same type and at the same anatomical location were counted as one bleed if the second bleed occurred within 72 hours from the last treatment for the first bleed. Bleeds due to surgery/procedure were excluded.

  From first dose of emicizumab to the clinical cutoff date or withdrawal date, whichever was earlier (median [range, min-max] efficacy period: 101.9 [52.6-119.7] weeks)

• Model-Based Annualized Bleeding Rate for All Bleeds

  The number of all bleeds over the efficacy period was estimated as an annualized bleeding rate (ABR) using a negative binomial regression model, which accounts for different follow-up times. In this outcome measure, all bleeds are included, irrespective of treatment with coagulation factors, with the following exception: bleeds due to surgery/procedure are excluded. As "all bleeds" comprises both treated and non-treated bleeds, the 72-hour rule was implemented separately for treated and non-treated bleeds. For treated bleeds, the 72-hour rule meant that two bleeds of the same type and at the same anatomical location were counted as one bleed if the second bleed occurred within 72 hours from the last treatment for the first bleed. For non-treated bleeds, the 72-hour rule was implemented by calculating a treatment-free period of 72 hours from the bleed itself.

  From first dose of emicizumab to the clinical cutoff date or withdrawal date, whichever was earlier (median [range, min-max] efficacy period: 101.9 [52.6-119.7] weeks)

• Mean Calculated Annualized Bleeding Rate for All Bleeds

  The number of all bleeds over the efficacy period is presented here as a calculated annualized bleeding rate (ABR) that was annualized for each participant using the following formula: ABR = (number of bleeds/number of days during the efficacy period) x 365.25. In this outcome measure, all bleeds are included, irrespective of treatment with coagulation factors, with the following exception: bleeds due to surgery/procedure are excluded. As "all bleeds" comprises both treated and non-treated bleeds, the 72-hour rule was implemented separately for treated and non-treated bleeds. For treated bleeds, the 72-hour rule meant that two bleeds of the same type and at the same anatomical location were counted as one bleed if the second bleed occurred within 72 hours from the last treatment for the first bleed. For non-treated bleeds, the 72-hour rule was implemented by calculating a treatment-free period of 72 hours from the bleed itself.

  From first dose of emicizumab to the clinical cutoff date or withdrawal date, whichever was earlier (median [range, min-max] efficacy period: 101.9 [52.6-119.7] weeks)

• Median Calculated Annualized Bleeding Rate for All Bleeds

  The number of all bleeds over the efficacy period is presented here as a calculated annualized bleeding rate (ABR) that was annualized for each participant using the following formula: ABR = (number of bleeds/number of days during the efficacy period) x 365.25. In this outcome measure, all bleeds are included, irrespective of treatment with coagulation factors, with the following exception: bleeds due to surgery/procedure are excluded. As "all bleeds" comprises both treated and non-treated bleeds, the 72-hour rule was implemented separately for treated and non-treated bleeds. For treated bleeds, the 72-hour rule meant that two bleeds of the same type and at the same anatomical location were counted as one bleed if the second bleed occurred within 72 hours from the last treatment for the first bleed. For non-treated bleeds, the 72-hour rule was implemented by calculating a treatment-free period of 72 hours from the bleed itself.

  From first dose of emicizumab to the clinical cutoff date or withdrawal date, whichever was earlier (median [range, min-max] efficacy period: 101.9 [52.6-119.7] weeks)

• Model-Based Annualized Bleeding Rate for Treated Spontaneous Bleeds

  The number of treated spontaneous bleeds over the efficacy period was estimated as an annualized bleeding rate (ABR) using a negative binomial regression model, which accounts for different follow-up times. A treated spontaneous bleed was defined as a treated bleed (bleed directly followed by a hemophilia medication reported to be a "treatment for bleed") with no other known contributing factor such as trauma or procedure/surgery. The 72-hour rule was implemented: two bleeds of the same type and at the same anatomical location were counted as one bleed if the second bleed occurred within 72 hours from the last treatment for the first bleed. Bleeds due to surgery/procedure were excluded.

  From first dose of emicizumab to the clinical cutoff date or withdrawal date, whichever was earlier (median [range, min-max] efficacy period: 101.9 [52.6-119.7] weeks)

• Mean Calculated Annualized Bleeding Rate for Treated Spontaneous Bleeds

  The number of treated spontaneous bleeds over the efficacy period is presented here as a calculated annualized bleeding rate (ABR) that was annualized for each participant using the following formula: ABR = (number of bleeds/number of days during the efficacy period) x 365.25. A treated spontaneous bleed was defined as a treated bleed (bleed directly followed by a hemophilia medication reported to be a "treatment for bleed") with no other known contributing factor such as trauma or procedure/surgery. The 72-hour rule was implemented: two bleeds of the same type and at the same anatomical location were counted as one bleed if the second bleed occurred within 72 hours from the last treatment for the first bleed. Bleeds due to surgery/procedure were excluded.

  From first dose of emicizumab to the clinical cutoff date or withdrawal date, whichever was earlier (median [range, min-max] efficacy period: 101.9 [52.6-119.7] weeks)

• Median Calculated Annualized Bleeding Rate for Treated Spontaneous Bleeds

  The number of treated spontaneous bleeds over the efficacy period is presented here as a calculated annualized bleeding rate (ABR) that was annualized for each participant using the following formula: ABR = (number of bleeds/number of days during the efficacy period) x 365.25. A treated spontaneous bleed was defined as a treated bleed (bleed directly followed by a hemophilia medication reported to be a "treatment for bleed") with no other known contributing factor such as trauma or procedure/surgery. The 72-hour rule was implemented: two bleeds of the same type and at the same anatomical location were counted as one bleed if the second bleed occurred within 72 hours from the last treatment for the first bleed. Bleeds due to surgery/procedure were excluded.

  From first dose of emicizumab to the clinical cutoff date or withdrawal date, whichever was earlier (median [range, min-max] efficacy period: 101.9 [52.6-119.7] weeks)

• Model-Based Annualized Bleeding Rate for Treated Joint Bleeds

  The number of treated joint bleeds over the efficacy period was estimated as an annualized bleed rate (ABR) using a negative binomial regression model, which accounts for different follow-up times. A treated joint bleed was defined as a bleed with type reported as "joint" based on at least one of the following symptoms: increasing swelling or warmth of the skin over the joint and/or increasing pain, decreased range of motion, or difficulty using the joint compared with baseline, and the bleed was directly followed by a hemophilia medication reported to be a "treatment for bleed". The 72-hour rule was implemented: two bleeds of the same type and at the same anatomical location were counted as one bleed if the second bleed occurred within 72 hours from the last treatment for the first bleed. Bleeds due to surgery/procedure were excluded.

  From first dose of emicizumab to the clinical cutoff date or withdrawal date, whichever was earlier (median [range, min-max] efficacy period: 101.9 [52.6-119.7] weeks)

• Mean Calculated Annualized Bleeding Rate for Treated Joint Bleeds

  The number of treated joint bleeds over the efficacy period is presented here as a calculated annualized bleed rate (ABR) that was annualized for each participant using the following formula: ABR = (number of bleeds/number of days during the efficacy period) x 365.25. A treated joint bleed was defined as a bleed with type reported as "joint" based on at least one of the following symptoms: increasing swelling or warmth of the skin over the joint and/or increasing pain, decreased range of motion, or difficulty using the joint compared with baseline, and the bleed was directly followed by a hemophilia medication reported to be a "treatment for bleed". The 72-hour rule was implemented: two bleeds of the same type and at the same anatomical location were counted as one bleed if the second bleed occurred within 72 hours from the last treatment for the first bleed. Bleeds due to surgery/procedure were excluded.

  From first dose of emicizumab to the clinical cutoff date or withdrawal date, whichever was earlier (median [range, min-max] efficacy period: 101.9 [52.6-119.7] weeks)

• Median Calculated Annualized Bleeding Rate for Treated Joint Bleeds

  The number of treated joint bleeds over the efficacy period is presented here as a calculated annualized bleed rate (ABR) that was annualized for each participant using the following formula: ABR = (number of bleeds/number of days during the efficacy period) x 365.25. A treated joint bleed was defined as a bleed with type reported as "joint" based on at least one of the following symptoms: increasing swelling or warmth of the skin over the joint and/or increasing pain, decreased range of motion, or difficulty using the joint compared with baseline, and the bleed was directly followed by a hemophilia medication reported to be a "treatment for bleed". The 72-hour rule was implemented: two bleeds of the same type and at the same anatomical location were counted as one bleed if the second bleed occurred within 72 hours from the last treatment for the first bleed. Bleeds due to surgery/procedure were excluded.

  From first dose of emicizumab to the clinical cutoff date or withdrawal date, whichever was earlier (median [range, min-max] efficacy period: 101.9 [52.6-119.7] weeks)

Secondary Outcomes (17)

• Hemophilia Joint Health Score (HJHS) Total Score at Specified Timepoints During the Long-Term Follow-Up Period

  At Years 4, 5, 6, 7, and 8 of follow-up

• Magnetic Resonance Imaging (MRI) Score of Specific Joints at Specified Timepoints During the Long-Term Follow-Up Period

  At Years 5 and 8 of follow-up

• Incidence and Severity of Adverse Events, With Severity Determined According to World Health Organization (WHO) Toxicity Grading Scale

  From first dose of emicizumab until study completion (8 years)

• Incidence of Thromboembolic Events

  From first dose of emicizumab until study completion (8 years)

• Incidence of Thrombotic Microangiopathy

  From first dose of emicizumab until study completion (8 years)

Study Arms (1)

Emicizumab

EXPERIMENTAL

Drug: Emicizumab

Interventions

Emicizumab DRUG

Initially, all participants will receive 4 loading doses of 3 milligrams per kilogram (mg/kg) emicizumab subcutaneously (SC) once every week (QW) for 4 weeks followed by the maintenance dosing regimen 3 mg/kg emicizumab SC once every 2 weeks (Q2W) for a total of 52 weeks. Starting from Week 17 of treatment, individual participants may have their dose up-titrated to 3 mg/kg SC QW if they experience suboptimal bleeding control. At the Week 53 clinic visit following consultation with the treating physician, parents/caregivers may elect for their child to continue with the maintenance 3-mg/kg SC Q2W dosing regimen or to switch to the maintenance 1.5-mg/kg SC QW or 6-mg/kg SC once every 4 weeks (Q4W) dosing regimen for the subsequent 7-year long-term follow-up period. During the study, participants will be treated with emicizumab until unacceptable toxicity, discontinuation from the study due to any cause, or other criteria specified in the protocol, whichever occurs first.

Also known as: Hemlibra, RO5534262, RG6013, ACE910

Emicizumab

Eligibility Criteria

• Age: 0 Months - 12 Months
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• Age from birth to ≤12 months at time of informed consent
• Body weight ≥3 kilograms (kg) at time of informed consent. Patients with a lower body weight can be enrolled after they have reached a body weight of 3 kg. Premature babies (gestational age \<38 weeks) may be enrolled as long as they have reached a body weight of 3 kg. For premature babies, the corrected gestational age should be reported.
• Mandatory receipt of vitamin K prophylaxis according to local standard practice
• Diagnosis of severe congenital hemophilia A (intrinsic FVIII level \<1%)
• A negative test for FVIII inhibitor (i.e., \<0.6 Bethesda units \[BU\]/mL) locally assessed during the 2-week screening period
• No history of documented FVIII inhibitor (i.e., \<0.6 BU/mL), FVIII drug-elimination half-life \<6 hours, or FVIII recovery \<66%
• Previously untreated patients or minimally treated patients (i.e., up to 5 days of exposure with hemophilia-related treatments, such as plasma-derived FVIII, recombinant FVIII, fresh frozen plasma, cryoprecipitate, or whole blood products)
• Documentation of the details of the hemophilia-related treatments received since birth
• Documentation of the details of the bleeding episodes since birth
• For patients from birth to \<3 months of age at the time of study entry: no evidence of active intracranial hemorrhage, as confirmed by a negative cranial ultrasound at screening irrespective of delivery mode
• Adequate hematologic, hepatic, and renal function, as defined in the protocol
• For parents/caregivers: willingness and ability to comply with the study protocol requirements, scheduled visits, treatment plans, laboratory tests, completion of applicable questionnaires, and other study procedures

You may not qualify if:

• Inherited or acquired bleeding disorder other than severe hemophilia A
• Use of systemic immunomodulators (e.g., interferon) at enrollment or planned use during the study
• Receipt of any of the following: Prior use of emicizumab prophylaxis including investigational or commercial emicizumab; An investigational drug to treat or reduce the risk of hemophilic bleeds within 5 drug-elimination half-lives of last drug administration; A non-hemophilia-related investigational drug within the last 30 days or 5 drug-elimination half-lives, whichever is shorter; An investigational drug concurrently
• Current active severe bleed, such as intracranial hemorrhage
• Planned surgery (excluding minor procedures, e.g., circumcision, CVAD placement) during the study
• History of clinically significant hypersensitivity associated with monoclonal antibody therapies or components of the emicizumab injection
• Patients who are at high risk for thrombotic microangiopathy (TMA) (e.g., have a previous medical or family history of TMA, such as thrombotic thrombocytopenic purpura, atypical hemolytic uremic syndrome) in the investigator's judgment
• Previous or current treatment for thromboembolic disease (with the exception of previous catheter-associated thrombosis in patients for whom anti-thrombotic treatment is not currently ongoing) or signs of thromboembolic disease
• Any hereditary or acquired maternal condition that may predispose the patient to thrombotic events (e.g., inherited thrombophilias antiphospholipid syndrome)
• Other diseases (e.g., certain autoimmune diseases) that may increase risk of bleeding or thrombosis
• Known infection with HIV, hepatitis B virus, or hepatitis C virus
• Serious infection requiring antibiotics or antiviral treatments within 14 days prior to screening
• Concurrent disease, treatment, abnormality in clinical laboratory tests, vital signs measurements, or physical examination findings that could interfere with the conduct of the study or that would, in the opinion of the investigator or Sponsor, preclude the patient's safe participation in and completion of the study or interpretation of the study results
• Unwillingness of the parent or caregiver to allow receipt of blood or blood products, or any standard-of-care treatment for a life-threatening condition
• Any other medical, social, or other condition that may prevent adequate compliance with the study protocol in the opinion of the investigator

Sponsors & Collaborators

• Hoffmann-La Roche: lead

Study Sites (32)

Phoenix Children's Hospital

Phoenix, Arizona, 85016, United States

Location

Children's Hospital Los Angeles

Los Angeles, California, 90027, United States

Location

University of Colorado Denver, Children's Hospital

Aurora, Colorado, 80045, United States

Location

Tulane University Health Sciences Center

New Orleans, Louisiana, 70112, United States

Location

University of Michigan

Ann Arbor, Michigan, 48109-0934, United States

Location

Seattle Children's Hospital

Seattle, Washington, 98105, United States

Location

The Children's Hospital at Westmead

Westmead, New South Wales, 2145, Australia

Location

Royal Children's Hospital

Parkville, Victoria, 3052, Australia

Location

Perth Children's Hospital

Nedlands, Western Australia, 6009, Australia

Location

Medizinische Universität Wien

Vienna, 1090, Austria

Location

Cliniques Universitaires St-Luc

Brussels, 1200, Belgium

Location

UZ Leuven Gasthuisberg

Leuven, 3000, Belgium

Location

Hospital das Clínicas Faculdades Médicas de Ribeirão Preto

Ribeirão Preto, São Paulo, 14051-140, Brazil

Location

Children's Hospital of Eastern Ontario

Ottawa, Ontario, K1H 8L1, Canada

Location

The Hospital for Sick Children

Toronto, Ontario, M5G 1X8, Canada

Location

Groupe Hospitalier Necker Enfants Malades

Paris, 75015, France

Location

Universitätsklinikum Bonn

Bonn, 53127, Germany

Location

Hämophilie-Zentrum Rhein Main GmbH

Mörfelden-Walldorf, 64546, Germany

Location

Sheba Medical Center - National Hemophilia Center

Tel Litwinsky, 5262100, Israel

Location

AORN Santobono Pausilipon

Naples, Campania, 80123, Italy

Location

AOU di Parma

Parma, Emilia-Romagna, 43126, Italy

Location

IRCCS Ca' Granda Ospedale Maggiore Policlinico

Milan, Lombardy, 20122, Italy

Location

AOU Careggi

Florence, Tuscany, 50134, Italy

Location

Charlotte Maxeke Johannesburg Hospital

Johannesburg, 2193, South Africa

Location

Hospital Sant Joan de Deu

Esplugues de Llobregat, Barcelona, 08950, Spain

Location

Hospital Universitario la Paz

Madrid, 28046, Spain

Location

Hospital Universitario Virgen del Rocio

Seville, 41013, Spain

Location

Adana Acibadem Hospital

Adana, 01130, Turkey (Türkiye)

Location

Hacettepe University Medical Faculty

Ankara, 06100, Turkey (Türkiye)

Location

Ege University, School of Medicine

Izmir, 35100, Turkey (Türkiye)

Location

Ondokuz Mayis Univ. Med. Fac.

Samsun, 55139, Turkey (Türkiye)

Location

Queen Elizabeth University Hospital

Glasgow, G51 4TF, United Kingdom

Location

Related Publications (3)

• Pipe SW, Collins P, Dhalluin C, Kenet G, Schmitt C, Buri M, Jimenez-Yuste V, Peyvandi F, Young G, Oldenburg J, Mancuso ME, Kavakli K, Kiialainen A, Deb S, Niggli M, Chang T, Lehle M, Fijnvandraat K. Emicizumab prophylaxis in infants with hemophilia A (HAVEN 7): primary analysis of a phase 3b open-label trial. Blood. 2024 Apr 4;143(14):1355-1364. doi: 10.1182/blood.2023021832.

  PMID: 38127586 DERIVED

• Lopez-Jaime FJ, Benitez O, Diaz Jordan BL, Montano A, Coll J, Quintana Paris L, Gomez-Del Castillo Solano MDC. Expert opinion paper on the treatment of hemophilia a with emicizumab. Hematology. 2023 Dec;28(1):2166334. doi: 10.1080/16078454.2023.2166334.

  PMID: 36636993 DERIVED

• Hart DP. Commentary on "Development of a novel fully functional coagulation factor VIII with reduced immunogenicity utilizing an in silico prediction and deimmunization approach" - Will we ever be able to avoid inhibitor formation in hemophilia A? J Thromb Haemost. 2021 Sep;19(9):2125-2126. doi: 10.1111/jth.15404. No abstract available.

  PMID: 34435432 DERIVED

MeSH Terms

Conditions

Hemophilia A

Interventions

emicizumab

Condition Hierarchy (Ancestors)

Blood Coagulation Disorders, Inherited; Blood Coagulation Disorders; Hematologic Diseases; Hemic and Lymphatic Diseases; Coagulation Protein Disorders; Hemorrhagic Disorders; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities

Results Point of Contact

• Title: Medical Communications
• Organization: Hoffmann-La Roche

genentech@druginfo.com

800-821-8590

Study Officials

• Clinical Trials

  Hoffmann-La Roche

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 11, 2020
• First Posted: June 16, 2020
• Study Start: February 4, 2021
• Primary Completion: May 22, 2023
• Study Completion (Estimated): May 18, 2030
• Last Updated: April 13, 2026
• Results First Posted: June 14, 2024

Record last verified: 2026-04

Data Sharing

• IPD Sharing: Will share

Locations

AU (1); TU (4); BE (2); BR (1); DE (2); IL (1); IT (4); US (6); ZA (1); ES (3); GB (1); CA (2); FR (1)