Clinical trial NCT04431726: 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
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE3
Conditions: Severe Hemophilia A
Keywords: Severe hemophilia A Without Factor VIII Inhibitors
Lead sponsor: Hoffmann-La Roche
Sponsor class: INDUSTRY
First posted: 2020-06-16
Enrollment: 55
Sex: ALL
Minimum age (years): 0
Maximum age (years): 12
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.


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

Primary outcomes:
measure: Model-Based Annualized Bleeding Rate for Treated Bleeds
timeFrame: 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)
measure: Mean Calculated Annualized Bleeding Rate for Treated Bleeds
timeFrame: 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)
measure: Median Calculated Annualized Bleeding Rate for Treated Bleeds
timeFrame: 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)
measure: Model-Based Annualized Bleeding Rate for All Bleeds
timeFrame: 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)
measure: Mean Calculated Annualized Bleeding Rate for All Bleeds
timeFrame: 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)
measure: Median Calculated Annualized Bleeding Rate for All Bleeds
timeFrame: 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)
measure: Model-Based Annualized Bleeding Rate for Treated Spontaneous Bleeds
timeFrame: 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)
measure: Mean Calculated Annualized Bleeding Rate for Treated Spontaneous Bleeds
timeFrame: 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)
measure: Median Calculated Annualized Bleeding Rate for Treated Spontaneous Bleeds
timeFrame: 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)
measure: Model-Based Annualized Bleeding Rate for Treated Joint Bleeds
timeFrame: 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)
measure: Mean Calculated Annualized Bleeding Rate for Treated Joint Bleeds
timeFrame: 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)
measure: Median Calculated Annualized Bleeding Rate for Treated Joint Bleeds
timeFrame: 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:
measure: Hemophilia Joint Health Score (HJHS) Total Score at Specified Timepoints During the Long-Term Follow-Up Period
timeFrame: At Years 4, 5, 6, 7, and 8 of follow-up
measure: Magnetic Resonance Imaging (MRI) Score of Specific Joints at Specified Timepoints During the Long-Term Follow-Up Period
timeFrame: At Years 5 and 8 of follow-up
measure: Incidence and Severity of Adverse Events, With Severity Determined According to World Health Organization (WHO) Toxicity Grading Scale
timeFrame: From first dose of emicizumab until study completion (8 years)
measure: Incidence of Thromboembolic Events
timeFrame: From first dose of emicizumab until study completion (8 years)
measure: Incidence of Thrombotic Microangiopathy
timeFrame: From first dose of emicizumab until study completion (8 years)
measure: Incidence and Severity of of Injection Site Reactions, With Severity Determined According to WHO Toxicity Grading Scale
timeFrame: From first dose of emicizumab until study completion (8 years)
measure: Incidence of Severe Hypersensitivity, Anaphylaxis, and Anaphylactoid Events
timeFrame: From first dose of emicizumab until study completion (8 years)
measure: Incidence of Adverse Events Leading to Study Drug Discontinuation
timeFrame: From first dose of emicizumab until study completion (8 years)
measure: Number of Participants According to Hematology and Serum Chemistry Laboratory Test Result Shifts From Baseline WHO Grade to the Highest WHO Grade Post-Baseline
timeFrame: Baseline, Weeks 4, 13, 21, 29, 37, 45, and 53
measure: Change From Baseline in Pulse Rate Over Time
timeFrame: 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)
measure: Change From Baseline in Respiratory Rate Over Time
timeFrame: 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)
measure: Change From Baseline in Body Temperature Over Time
timeFrame: 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)
measure: Change From Baseline in Systolic Blood Pressure Over Time
timeFrame: 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)
measure: Change From Baseline in Diastolic Blood Pressure Over Time
timeFrame: 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)
measure: Plasma Trough Concentrations (Ctrough) of Emicizumab
timeFrame: Predose at Weeks 1, 3, 5, 7, 9, 13, 17, 21, 25, 29, 33, 37, 41, 45, 49, and 53
measure: Incidence of Anti-Emicizumab Antibodies
timeFrame: Weeks 1, 5, 17, 29, 41, and 53, and thereafter as clinically indicated until study completion (up to 8 years)
measure: Incidence of De Novo Development of Factor VIII Inhibitors
timeFrame: As clinically indicated from baseline until study completion (up to 8 years)
Other outcomes:
Locations:
city: Phoenix
country: United States
facility: Phoenix Children's Hospital
state: Arizona
city: Los Angeles
country: United States
facility: Children's Hospital Los Angeles
state: California
city: Aurora
country: United States
facility: University of Colorado Denver, Children's Hospital
state: Colorado
city: New Orleans
country: United States
facility: Tulane University Health Sciences Center
state: Louisiana
city: Ann Arbor
country: United States
facility: University of Michigan
state: Michigan
city: Seattle
country: United States
facility: Seattle Children's Hospital
state: Washington
city: Westmead
country: Australia
facility: The Children's Hospital at Westmead
state: New South Wales
city: Parkville
country: Australia
facility: Royal Children's Hospital
state: Victoria
city: Nedlands
country: Australia
facility: Perth Children's Hospital
state: Western Australia
city: Wien
country: Austria
facility: Medizinische Universität Wien
city: Bruxelles
country: Belgium
facility: Cliniques Universitaires St-Luc
city: Leuven
country: Belgium
facility: UZ Leuven Gasthuisberg
city: Ribeirao Preto
country: Brazil
facility: Hospital das Clínicas Faculdades Médicas de Ribeirão Preto
state: São Paulo
city: Ottawa
country: Canada
facility: Children's Hospital of Eastern Ontario
state: Ontario
city: Toronto
country: Canada
facility: The Hospital for Sick Children
state: Ontario
city: Paris
country: France
facility: Groupe Hospitalier Necker Enfants Malades
city: Bonn
country: Germany
facility: Universitätsklinikum Bonn
city: Mörfelden-Walldorf
country: Germany
facility: Hämophilie-Zentrum Rhein Main GmbH
city: Tel Hashomer
country: Israel
facility: Sheba Medical Center - National Hemophilia Center
city: Napoli
country: Italy
facility: AORN Santobono Pausilipon
state: Campania
city: Parma
country: Italy
facility: AOU di Parma
state: Emilia-Romagna
city: Firenze
country: Italy
facility: AOU Careggi
state: Toscana
city: Johannesburg
country: South Africa
facility: Charlotte Maxeke Johannesburg Hospital
city: Esplugues de Llobregat
country: Spain
facility: Hospital Sant Joan de Deu
state: Barcelona
city: Madrid
country: Spain
facility: Hospital Universitario la Paz
city: Sevilla
country: Spain
facility: Hospital Universitario Virgen del Rocio
city: Adana
country: Turkey
facility: Adana Acibadem Hospital
city: Ankara
country: Turkey
facility: Hacettepe University Medical Faculty
city: Izmir
country: Turkey
facility: Ege University, School of Medicine
city: Samsun
country: Turkey
facility: Ondokuz Mayis Univ. Med. Fac.
city: Glasgow
country: United Kingdom
facility: Queen Elizabeth University Hospital
Study officials:
affiliation: Hoffmann-La Roche
name: Clinical Trials
role: STUDY_DIRECTOR
References:
citation: 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.