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

Severe Hemophilia A Clinical Trial

— HAVEN 7  

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT04431726
• Other study ID #: MO41787
• Secondary ID: 2020-001733-12
• Status: Active, not recruiting
• Phase: Phase 3
• Start date: February 4, 2021
• Est. completion date: May 20, 2030

Study information

• Verified date: February 2024
• Source: Hoffmann-La Roche
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 55
• Est. completion date: May 20, 2030
• Est. primary completion date: May 22, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 0 Months to 12 Months

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

Related Conditions & MeSH terms

• Hemophilia A
• 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.

Locations

Country	Name	City	State
Australia	Perth Children's Hospital	Nedlands	Western Australia
Australia	Royal Children's Hospital	Parkville	Victoria
Australia	The Children's Hospital at Westmead	Westmead	New South Wales
Austria	Medizinische Universität Wien; Univ. Klinik für Kinder und Jugendheilkunde	Wien
Belgium	Cliniques Universitaires St-Luc	Bruxelles
Belgium	UZ Leuven Gasthuisberg	Leuven
Brazil	Hospital das Clínicas Faculdades Médicas de Ribeirão Preto	Ribeirao Preto	SP
Canada	Children's Hospital of Eastern Ontario	Ottawa	Ontario
Canada	The Hospital for Sick Children	Toronto	Ontario
France	Groupe Hospitalier Necker Enfants Malades	Paris
Germany	Universitätsklinikum Bonn; Institut für Experimentelle Hämatologie und Transfusionsmedizin	Bonn
Germany	Hämophilie-Zentrum Rhein Main GmbH	Mörfelden-Walldorf
Israel	Sheba Medical Center - National Hemophilia Center	Tel Hashomer
Italy	AOU Careggi; SOD Malattie Emorragiche	Firenze	Toscana
Italy	IRCCS Ca' Granda Ospedale Maggiore Policlinico; Centro Emofilia e Trombosi "Angelo Bianchi e Bonomi"	Milano	Lombardia
Italy	AORN Santobono Pausilipon; UOC di Ematologia ? Centro Emofilia e Trombosi	Napoli	Campania
Italy	AOU di Parma; Dip Emergenza-Urgenza Centro Riferimento Regionale per l'emofilia	Parma	Emilia-Romagna
South Africa	Charlotte Maxeke Johannesburg Hospital; Haemophilia Comprehensive Care Center	Johannesburg
Spain	Hospital Sant Joan de Deu; Servicio de Oncologia y Hematologia	Esplugues de Llobregat	Barcelona
Spain	Hospital Universitario la Paz; Servicio de Hematologia	Madrid
Spain	Hospital Universitario Virgen del Rocio; Servicio de Hematologia	Sevilla
Turkey	Adana Acibadem Hospital; Pediatric Hematology	Adana
Turkey	Hacettepe University Medical Faculty; Hacettepe University Medical Faculty	Ankara
Turkey	Ege University, School of Medicine; Pediatrics Department	Izmir
Turkey	Ondokuz Mayis Univ. Med. Fac.	Samsun
United Kingdom	Arthur Bloom Haemophilia Centre	Cardiff
United Kingdom	Queen Elizabeth University Hospital	Glasgow
United Kingdom	The Royal London Hospital	London
United States	University of Michigan	Ann Arbor	Michigan
United States	University of Colorado Denver, Children's Hospital	Aurora	Colorado
United States	Children's Hospital Los Angeles	Los Angeles	California
United States	Tulane University Health Sciences Center	New Orleans	Louisiana
United States	Phoenix Children's Hospital	Phoenix	Arizona
United States	Seattle Children's Hospital	Seattle	Washington

Sponsors (1)

Lead Sponsor	Collaborator
Hoffmann-La Roche

Countries where clinical trial is conducted

United States,  Australia,  Austria,  Belgium,  Brazil,  Canada,  France,  Germany,  Israel,  Italy,  South Africa,  Spain,  Turkey,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Model-Based Annualized Bleeding Rate for Treated Bleeds		From Baseline to 52 weeks, and during 7-year long-term follow-up period until study completion (up to 8 years)
Primary	Median Calculated Annualized Bleeding Rate for Treated Bleeds		From Baseline to 52 weeks, and during 7-year long-term follow-up period until study completion (up to 8 years)
Primary	Mean Calculated Annualized Bleeding Rate for Treated Bleeds		From Baseline to 52 weeks, and during 7-year long-term follow-up period until study completion (up to 8 years)
Primary	Model-Based Annualized Bleeding Rate for All Bleeds		From Baseline to 52 weeks, and during 7-year long-term follow-up period until study completion (up to 8 years)
Primary	Median Calculated Annualized Bleeding Rate for All Bleeds		From Baseline to 52 weeks, and during 7-year long-term follow-up period until study completion (up to 8 years)
Primary	Mean Calculated Annualized Bleeding Rate for All Bleeds		From Baseline to 52 weeks, and during 7-year long-term follow-up period until study completion (up to 8 years)
Primary	Model-Based Annualized Bleeding Rate for Treated Spontaneous Bleeds		From Baseline to 52 weeks, and during 7-year long-term follow-up period until study completion (up to 8 years)
Primary	Median Calculated Annualized Bleeding Rate for Treated Spontaneous Bleeds		From Baseline to 52 weeks, and during 7-year long-term follow-up period until study completion (up to 8 years)
Primary	Mean Calculated Annualized Bleeding Rate for Treated Spontaneous Bleeds		From Baseline to 52 weeks, and during 7-year long-term follow-up period until study completion (up to 8 years)
Primary	Model-Based Annualized Bleeding Rate for Treated Joint Bleeds		From Baseline to 52 weeks, and during 7-year long-term follow-up period until study completion (up to 8 years)
Primary	Median Calculated Annualized Bleeding Rate for Treated Joint Bleeds		From Baseline to 52 weeks, and during 7-year long-term follow-up period until study completion (up to 8 years)
Primary	Mean Calculated Annualized Bleeding Rate for Treated Joint Bleeds		From Baseline to 52 weeks, and during 7-year long-term follow-up period until study completion (up to 8 years)
Secondary	Hemophilia Joint Health Score (HJHS) Total Score at Specified Timepoints During the Long-Term Follow-Up Period		At 4, 5, 6, 7, and 8 years
Secondary	Magnetic Resonance Imaging (MRI) Score of Specific Joints at Specified Timepoints During the Long-Term Follow-Up Period		At 5 and 8 years
Secondary	Incidence and Severity of Adverse Events, with Severity Determined According to World Health Organization (WHO) Toxicity Grading Scale		From Baseline until study completion (up to 8 years)
Secondary	Incidence of Thromboembolic Events		From Baseline until study completion (up to 8 years)
Secondary	Incidence of Thrombotic Microangiopathy		From Baseline until study completion (up to 8 years)
Secondary	Incidence and Severity of of Injection Site Reactions, with Severity Determined According to WHO Toxicity Grading Scale		From Baseline until study completion (up to 8 years)
Secondary	Incidence of Severe Hypersensitivity, Anaphylaxis, and Anaphylactoid Events		From Baseline until study completion (up to 8 years)
Secondary	Incidence of Adverse Events Leading to Study Drug Discontinuation		From Baseline until study completion (up to 8 years)
Secondary	Incidence of Laboratory Abnormalities in Serum Chemistry and Hematology Tests		Baseline, Weeks 4, 13, 21, 29, 37, 45, and 53
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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
Secondary	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)
Secondary	Incidence of De Novo Development of Factor VIII Inhibitors		As clinically indicated from baseline until study completion (up to 8 years)