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 (HAVEN 7)

• ClinicalTrials.gov Identifier: NCT04431726
• Recruitment Status: Active, not recruiting
• First Posted: June 16, 2020
• Last Update Posted: February 13, 2024
• Sponsor: Hoffmann-La Roche
• Information provided by (Responsible Party): Hoffmann-La Roche

Tracking Information

• First Submitted Date: June 11, 2020
• First Posted Date: June 16, 2020
• Last Update Posted Date: February 13, 2024
• Actual Study Start Date: February 4, 2021
• Actual Primary Completion Date: May 22, 2023 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: June 11, 2020)

• Model-Based Annualized Bleeding Rate for Treated Bleeds [ Time Frame: From Baseline to 52 weeks, and during 7-year long-term follow-up period until study completion (up to 8 years) ]
• Median Calculated Annualized Bleeding Rate for Treated Bleeds [ Time Frame: From Baseline to 52 weeks, and during 7-year long-term follow-up period until study completion (up to 8 years) ]
• Mean Calculated Annualized Bleeding Rate for Treated Bleeds [ Time Frame: From Baseline to 52 weeks, and during 7-year long-term follow-up period until study completion (up to 8 years) ]
• Model-Based Annualized Bleeding Rate for All Bleeds [ Time Frame: From Baseline to 52 weeks, and during 7-year long-term follow-up period until study completion (up to 8 years) ]
• Median Calculated Annualized Bleeding Rate for All Bleeds [ Time Frame: From Baseline to 52 weeks, and during 7-year long-term follow-up period until study completion (up to 8 years) ]
• Mean Calculated Annualized Bleeding Rate for All Bleeds [ Time Frame: From Baseline to 52 weeks, and during 7-year long-term follow-up period until study completion (up to 8 years) ]
• Model-Based Annualized Bleeding Rate for Treated Spontaneous Bleeds [ Time Frame: From Baseline to 52 weeks, and during 7-year long-term follow-up period until study completion (up to 8 years) ]
• Median Calculated Annualized Bleeding Rate for Treated Spontaneous Bleeds [ Time Frame: From Baseline to 52 weeks, and during 7-year long-term follow-up period until study completion (up to 8 years) ]
• Mean Calculated Annualized Bleeding Rate for Treated Spontaneous Bleeds [ Time Frame: From Baseline to 52 weeks, and during 7-year long-term follow-up period until study completion (up to 8 years) ]
• Model-Based Annualized Bleeding Rate for Treated Joint Bleeds [ Time Frame: From Baseline to 52 weeks, and during 7-year long-term follow-up period until study completion (up to 8 years) ]
• Median Calculated Annualized Bleeding Rate for Treated Joint Bleeds [ Time Frame: From Baseline to 52 weeks, and during 7-year long-term follow-up period until study completion (up to 8 years) ]
• Mean Calculated Annualized Bleeding Rate for Treated Joint Bleeds [ Time Frame: From Baseline to 52 weeks, and during 7-year long-term follow-up period until study completion (up to 8 years) ]

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: June 11, 2020)

• Hemophilia Joint Health Score (HJHS) Total Score at Specified Timepoints During the Long-Term Follow-Up Period [ Time Frame: At 4, 5, 6, 7, and 8 years ]
• Magnetic Resonance Imaging (MRI) Score of Specific Joints at Specified Timepoints During the Long-Term Follow-Up Period [ Time Frame: At 5 and 8 years ]
• Incidence and Severity of Adverse Events, with Severity Determined According to World Health Organization (WHO) Toxicity Grading Scale [ Time Frame: From Baseline until study completion (up to 8 years) ]
• Incidence of Thromboembolic Events [ Time Frame: From Baseline until study completion (up to 8 years) ]
• Incidence of Thrombotic Microangiopathy [ Time Frame: From Baseline until study completion (up to 8 years) ]
• Incidence and Severity of of Injection Site Reactions, with Severity Determined According to WHO Toxicity Grading Scale [ Time Frame: From Baseline until study completion (up to 8 years) ]
• Incidence of Severe Hypersensitivity, Anaphylaxis, and Anaphylactoid Events [ Time Frame: From Baseline until study completion (up to 8 years) ]
• Incidence of Adverse Events Leading to Study Drug Discontinuation [ Time Frame: From Baseline until study completion (up to 8 years) ]
• Incidence of Laboratory Abnormalities in Serum Chemistry and Hematology Tests [ Time Frame: Baseline, Weeks 4, 13, 21, 29, 37, 45, and 53 ]
• Change from Baseline in Pulse Rate Over Time [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: As clinically indicated from baseline until study completion (up to 8 years) ]

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: 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
• Official Title: A Phase IIIb, Multicenter, Open-Label, Single-Arm Study to Evaluate the Efficacy, Safety, Pharmacokinetics, and Pharmacodynamics of Subcutaneous Emicizumab in Patients From Birth to 12 Months of Age With Hemophilia A Without Inhibitors
• 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 Provided
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Severe Hemophilia A

Intervention

Drug: 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.

Other Names:

• Hemlibra
• RO5534262
• RG6013
• ACE910

Study Arms

Experimental: Emicizumab

Intervention: Drug: Emicizumab

• Publications *: 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.

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: September 6, 2022): 55
• Original Estimated Enrollment (submitted: June 11, 2020): 50
• Estimated Study Completion Date: May 20, 2030
• Actual Primary Completion Date: May 22, 2023 (Final data collection date for primary outcome measure)

Eligibility Criteria

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 0 Months to 12 Months (Child)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Australia, Austria, Belgium, Brazil, Canada, France, Germany, Israel, Italy, South Africa, Spain, Turkey, United Kingdom, United States
• Removed Location Countries: Netherlands, Switzerland

Administrative Information

• NCT Number: NCT04431726
• Other Study ID Numbers: MO41787; 2020-001733-12 ( EudraCT Number )
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: Yes

Plan Description

Qualified researchers may request access to individual patient level data through the request platform (www.vivli.org). Further details on Roche's criteria for eligible studies are available here (https://vivli.org/ourmember/roche/).

For further details on Roche's Global Policy on Sharing of Clinical Study Information and how to request access to related clinical study documents, see here (https://www.roche.com/research_and_development/who_we_are_how_we_work/clinical_trials/our_commitment_to_data_sharing.htm).

• Current Responsible Party: Hoffmann-La Roche
• Original Responsible Party: Same as current
• Current Study Sponsor: Hoffmann-La Roche
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Clinical Trials; Hoffmann-La Roche

• PRS Account: Hoffmann-La Roche
• Verification Date: February 2024