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

Phase 3

Active, not recruiting

Conditions: Severe Hemophilia A

Interventions: Drug: Emicizumab

Registration Number: NCT04431726

Lead Sponsor: Hoffmann-La Roche

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.

Detailed Description: Not available

Recruitment & Eligibility

Status: ACTIVE_NOT_RECRUITING

Sex: All

Target Recruitment: 55

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Emicizumab	Emicizumab	-

Primary Outcome Measures

Name	Time	Method
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.

Secondary Outcome Measures

Name	Time	Method
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)
Incidence and Severity of of Injection Site Reactions, With Severity Determined According to WHO Toxicity Grading Scale	From first dose of emicizumab until study completion (8 years)
Incidence of Severe Hypersensitivity, Anaphylaxis, and Anaphylactoid Events	From first dose of emicizumab until study completion (8 years)
Incidence of Adverse Events Leading to Study Drug Discontinuation	From first dose of emicizumab until study completion (8 years)
Number of Participants According to Hematology and Serum Chemistry Laboratory Test Result Shifts From Baseline WHO Grade to the Highest WHO Grade Post-Baseline	Baseline, Weeks 4, 13, 21, 29, 37, 45, and 53	Laboratory parameters for hematology and blood chemistry were measured at baseline and over time, and the values were compared with a standard reference range. Values outside the standard reference range were considered laboratory abnormalities and graded according to the World Health Organization (WHO) toxicity grading scale, ranging from lowest (Grade 1) to greatest (Grade 4) deviation from standard in the direction indicated for the abnormality (i.e., below (Low) or above (High) the reference range; 'Not Low' and 'Not High' indicate values within the reference range). Participants were categorized according to their laboratory test result shift from baseline WHO grade to highest WHO grade at any point post-baseline (up to Week 53) for each parameter. 'Missing' indicates that the test result was not available.
Change From Baseline in Pulse Rate Over Time	Baseline, Weeks 1, 2, 3, 4, 5, 7, 9, 13, 17, 21, 25, 29, 33, 37, 41, 45, 49, and 53, and annually during the 7-year follow-up period until study completion (up to 8 years)
Change From Baseline in Respiratory Rate Over Time	Baseline, Weeks 1, 2, 3, 4, 5, 7, 9, 13, 17, 21, 25, 29, 33, 37, 41, 45, 49, and 53, and annually during the 7-year follow-up period until study completion (up to 8 years)
Change From Baseline in Body Temperature Over Time	Baseline, Weeks 1, 2, 3, 4, 5, 7, 9, 13, 17, 21, 25, 29, 33, 37, 41, 45, 49, and 53, and annually during the 7-year follow-up period until study completion (up to 8 years)
Change From Baseline in Systolic Blood Pressure Over Time	Baseline, Weeks 1, 2, 3, 4, 5, 7, 9, 13, 17, 21, 25, 29, 33, 37, 41, 45, 49, and 53, and annually during the 7-year follow-up period until study completion (up to 8 years)
Change From Baseline in Diastolic Blood Pressure Over Time	Baseline, Weeks 1, 2, 3, 4, 5, 7, 9, 13, 17, 21, 25, 29, 33, 37, 41, 45, 49, and 53, and annually during the 7-year follow-up period until study completion (up to 8 years)
Plasma Trough Concentrations (Ctrough) of Emicizumab	Predose at Weeks 1, 3, 5, 7, 9, 13, 17, 21, 25, 29, 33, 37, 41, 45, 49, and 53
Incidence of Anti-Emicizumab Antibodies	Weeks 1, 5, 17, 29, 41, and 53, and thereafter as clinically indicated until study completion (up to 8 years)
Incidence of De Novo Development of Factor VIII Inhibitors	As clinically indicated from baseline until study completion (up to 8 years)	As per the protocol, after any 3 exposure days to FVIII or a block of FVIII exposure days (e.g., a block is defined as a minimum of two consecutive doses of FVIII) administered for treatment of a bleed, a surgical procedure, or other (e.g., preventative doses before activity), one plasma sample for anti-FVIII antibodies (for centralized analysis) had to be collected 14 days after the final dose of FVIII administered.

Trial Locations

Locations (31): Ondokuz Mayis Univ. Med. Fac.
🇹🇷
Samsun, Turkey
AORN Santobono Pausilipon
🇮🇹
Napoli, Campania, Italy
AOU di Parma
🇮🇹
Parma, Emilia-Romagna, Italy
AOU Careggi
🇮🇹
Firenze, Toscana, Italy
Charlotte Maxeke Johannesburg Hospital
🇿🇦
Johannesburg, South Africa
Hospital Universitario la Paz
🇪🇸
Madrid, Spain
Hospital Universitario Virgen del Rocio
🇪🇸
Sevilla, Spain
Adana Acibadem Hospital
🇹🇷
Adana, Turkey
Hacettepe University Medical Faculty
🇹🇷
Ankara, Turkey
Ege University, School of Medicine
🇹🇷
Izmir, Turkey
UZ Leuven Gasthuisberg
🇧🇪
Leuven, Belgium
Medizinische Universität Wien
🇦🇹
Wien, Austria
Universitätsklinikum Bonn
🇩🇪
Bonn, Germany
Hospital Sant Joan de Deu
🇪🇸
Esplugues de Llobregat, Barcelona, Spain
Phoenix Children's Hospital
🇺🇸
Phoenix, Arizona, United States
Tulane University Health Sciences Center
🇺🇸
New Orleans, Louisiana, United States
Seattle Children's Hospital
🇺🇸
Seattle, Washington, United States
Children's Hospital Los Angeles
🇺🇸
Los Angeles, California, United States
University of Colorado Denver, Children's Hospital
🇺🇸
Aurora, Colorado, United States
The Children's Hospital at Westmead
🇦🇺
Westmead, New South Wales, Australia
Royal Children's Hospital
🇦🇺
Parkville, Victoria, Australia
Cliniques Universitaires St-Luc
🇧🇪
Bruxelles, Belgium
Sheba Medical Center - National Hemophilia Center
🇮🇱
Tel Hashomer, Israel
University of Michigan
🇺🇸
Ann Arbor, Michigan, United States
Perth Children's Hospital
🇦🇺
Nedlands, Western Australia, Australia
Hospital das Clínicas Faculdades Médicas de Ribeirão Preto
🇧🇷
Ribeirao Preto, São Paulo, Brazil
The Hospital for Sick Children
🇨🇦
Toronto, Ontario, Canada
Groupe Hospitalier Necker Enfants Malades
🇫🇷
Paris, France
Hämophilie-Zentrum Rhein Main GmbH
🇩🇪
Mörfelden-Walldorf, Germany
Queen Elizabeth University Hospital
🇬🇧
Glasgow, United Kingdom
Children's Hospital of Eastern Ontario
🇨🇦
Ottawa, Ontario, Canada