Active, not recruiting
Phase 3
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
Condition(s) studied
Severe Hemophilia A
Investigational drug(s) / intervention(s)
Emicizumab
Emicizumab: 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.
Study 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.
Eligibility
Inclusion Criteria:
* 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
Exclusion Criteria:
* 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
Primary outcome measure(s)
- Model-Based Annualized Bleeding Rate for Treated Bleeds — 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)
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.
- Mean Calculated Annualized Bleeding Rate for Treated Bleeds — 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)
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.
- Median Calculated Annualized Bleeding Rate for Treated Bleeds — 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)
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.
- Model-Based Annualized Bleeding Rate for All Bleeds — 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)
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.
- Mean Calculated Annualized Bleeding Rate for All Bleeds — 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)
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.
- Median Calculated Annualized Bleeding Rate for All Bleeds — 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)
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.
- Model-Based Annualized Bleeding Rate for Treated Spontaneous Bleeds — 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)
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.
- Mean Calculated Annualized Bleeding Rate for Treated Spontaneous Bleeds — 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)
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.
- Median Calculated Annualized Bleeding Rate for Treated Spontaneous Bleeds — 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)
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.
- Model-Based Annualized Bleeding Rate for Treated Joint Bleeds — 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)
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.
- Mean Calculated Annualized Bleeding Rate for Treated Joint Bleeds — 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)
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.
- Median Calculated Annualized Bleeding Rate for Treated Joint Bleeds — 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)
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.
Trial sites (32)
| Facility | City | Region | Status |
|---|
| Phoenix Children's Hospital |
Phoenix |
Arizona |
|
| Children's Hospital Los Angeles |
Los Angeles |
California |
|
| University of Colorado Denver, Children's Hospital |
Aurora |
Colorado |
|
| Tulane University Health Sciences Center |
New Orleans |
Louisiana |
|
| University of Michigan |
Ann Arbor |
Michigan |
|
| Seattle Children's Hospital |
Seattle |
Washington |
|
| The Children's Hospital at Westmead |
Westmead |
New South Wales |
|
| Royal Children's Hospital |
Parkville |
Victoria |
|
| Perth Children's Hospital |
Nedlands |
Western Australia |
|
| Medizinische Universität Wien |
Vienna |
Austria |
|
| Cliniques Universitaires St-Luc |
Brussels |
Belgium |
|
| UZ Leuven Gasthuisberg |
Leuven |
Belgium |
|
| Hospital das Clínicas Faculdades Médicas de Ribeirão Preto |
Ribeirão Preto |
São Paulo |
|
| Children's Hospital of Eastern Ontario |
Ottawa |
Ontario |
|
| The Hospital for Sick Children |
Toronto |
Ontario |
|
| Groupe Hospitalier Necker Enfants Malades |
Paris |
France |
|
| Universitätsklinikum Bonn |
Bonn |
Germany |
|
| Hämophilie-Zentrum Rhein Main GmbH |
Mörfelden-Walldorf |
Germany |
|
| Sheba Medical Center - National Hemophilia Center |
Tel Litwinsky |
Israel |
|
| AORN Santobono Pausilipon |
Naples |
Campania |
|
| AOU di Parma |
Parma |
Emilia-Romagna |
|
| IRCCS Ca' Granda Ospedale Maggiore Policlinico |
Milan |
Lombardy |
|
| AOU Careggi |
Florence |
Tuscany |
|
| Charlotte Maxeke Johannesburg Hospital |
Johannesburg |
South Africa |
|
| Hospital Sant Joan de Deu |
Esplugues de Llobregat |
Barcelona |
|
| Hospital Universitario la Paz |
Madrid |
Spain |
|
| Hospital Universitario Virgen del Rocio |
Seville |
Spain |
|
| Adana Acibadem Hospital |
Adana |
Turkey (Türkiye) |
|
| Hacettepe University Medical Faculty |
Ankara |
Turkey (Türkiye) |
|
| Ege University, School of Medicine |
Izmir |
Turkey (Türkiye) |
|
| Ondokuz Mayis Univ. Med. Fac. |
Samsun |
Turkey (Türkiye) |
|
| Queen Elizabeth University Hospital |
Glasgow |
United Kingdom |
|
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