A Clinical Trial to Evaluate Prophylactic Emicizumab Versus no Prophylaxis in Hemophilia A Participants Without Inhibitors

NCT ID: NCT02847637

Last Updated: 2022-11-16

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 152 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2016-09-27
• Study Completion Date: 2022-05-12

Brief Summary

This is a randomized, global, multicenter, open-label, Phase 3 clinical study in participants with severe hemophilia A without inhibitors against Factor VIII (FVIII) who are 12 years or older. The study evaluates two prophylactic emicizumab regimens versus no prophylaxis in this population with emphasis on efficacy, safety, and pharmacokinetics.

Conditions

Hemophilia A

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Arm C (Control): No Prophylaxis, Then Emicizumab

Participants who had received episodic treatment with FVIII prior to study entry were randomized to continue episodic FVIII treatment when they started the trial. After completing 24 weeks of no prophylaxis (i.e., episodic FVIII treatment) on study, then they were given the opportunity to switch to emicizumab prophylaxis of 3 mg/kg subcutaneously (SC) once per week (QW) for 4 weeks, followed by maintenance dosing of 3 mg/kg emicizumab SC once every 2 weeks (Q2W). Upon implementation of protocol version 4 (20-Dec-2019), treatment duration was extended. During this study prolongation, each participant was given the option to choose a preferred emicizumab dosing regimen among those permitted and continue on that dosing regimen until discontinuation from the study.

Group Type: ACTIVE_COMPARATOR

Emicizumab

Intervention Type: DRUG

Participants received emicizumab prophylaxis subcutaneously at the specified dose for each arm. After at least 24 weeks on prophylactic emicizumab, individuals who experienced suboptimal bleeding control on emicizumab (according to protocol-defined criteria) had the opportunity to increase their dose to 3 mg/kg weekly. Upon implementation of protocol version 4 (20-Dec-2019), treatment duration was extended. During this study prolongation, each participant had the option to choose a preferred emicizumab dosing regimen among those permitted (i.e., emicizumab 1.5 mg/kg once every week \[QW\], 3 mg/kg once every 2 weeks \[Q2W\], or 6 mg/kg once every 4 weeks \[Q4W\]) and continue on that dosing regimen until discontinuation from the study.

Factor VIII (FVIII)

Intervention Type: DRUG

FVIII was allowed to treat bleeds on an episodic basis, per the local prescribing information. Specific dosages of FVIII were not mandated in the study. Breakthrough bleeds were to be treated with the lowest FVIII dose expected to achieve hemostasis, which may have been lower than the participant's prior FVIII dose. To avoid bleeds before adequate emicizumab level is reached, patients in Arm D continued their regular FVIII prophylaxis until the second emicizumab loading dose. Concomitant routine FVIII prophylaxis was not permissible otherwise during the study.

Arm A: Emicizumab 1.5 mg/kg QW

Participants who had received episodic treatment with FVIII prior to study entry were randomized to receive emicizumab prophylaxis at a dose of 3 milligrams per kilogram (mg/kg) subcutaneously (SC) once per week (QW) for 4 weeks, followed by maintenance dosing of 1.5 mg/kg emicizumab SC QW. Upon implementation of protocol version 4 (20-Dec-2019), treatment duration was extended. During this study prolongation, each participant was given the option to choose a preferred emicizumab dosing regimen among those permitted and continue on that dosing regimen until discontinuation from the study.

Group Type: EXPERIMENTAL

Emicizumab

Intervention Type: DRUG

Participants received emicizumab prophylaxis subcutaneously at the specified dose for each arm. After at least 24 weeks on prophylactic emicizumab, individuals who experienced suboptimal bleeding control on emicizumab (according to protocol-defined criteria) had the opportunity to increase their dose to 3 mg/kg weekly. Upon implementation of protocol version 4 (20-Dec-2019), treatment duration was extended. During this study prolongation, each participant had the option to choose a preferred emicizumab dosing regimen among those permitted (i.e., emicizumab 1.5 mg/kg once every week \[QW\], 3 mg/kg once every 2 weeks \[Q2W\], or 6 mg/kg once every 4 weeks \[Q4W\]) and continue on that dosing regimen until discontinuation from the study.

Factor VIII (FVIII)

Intervention Type: DRUG

FVIII was allowed to treat bleeds on an episodic basis, per the local prescribing information. Specific dosages of FVIII were not mandated in the study. Breakthrough bleeds were to be treated with the lowest FVIII dose expected to achieve hemostasis, which may have been lower than the participant's prior FVIII dose. To avoid bleeds before adequate emicizumab level is reached, patients in Arm D continued their regular FVIII prophylaxis until the second emicizumab loading dose. Concomitant routine FVIII prophylaxis was not permissible otherwise during the study.

Arm B: Emicizumab 3 mg/kg Q2W

Participants who had received episodic treatment with FVIII prior to study entry were randomized to receive emicizumab prophylaxis at a dose of 3 mg/kg subcutaneously (SC) once per week (QW) for 4 weeks, followed by maintenance dosing of 3 mg/kg emicizumab SC once every 2 weeks (Q2W). Upon implementation of protocol version 4 (20-Dec-2019), treatment duration was extended. During this study prolongation, each participant was given the option to choose a preferred emicizumab dosing regimen among those permitted and continue on that dosing regimen until discontinuation from the study.

Group Type: EXPERIMENTAL

Emicizumab

Intervention Type: DRUG

Participants received emicizumab prophylaxis subcutaneously at the specified dose for each arm. After at least 24 weeks on prophylactic emicizumab, individuals who experienced suboptimal bleeding control on emicizumab (according to protocol-defined criteria) had the opportunity to increase their dose to 3 mg/kg weekly. Upon implementation of protocol version 4 (20-Dec-2019), treatment duration was extended. During this study prolongation, each participant had the option to choose a preferred emicizumab dosing regimen among those permitted (i.e., emicizumab 1.5 mg/kg once every week \[QW\], 3 mg/kg once every 2 weeks \[Q2W\], or 6 mg/kg once every 4 weeks \[Q4W\]) and continue on that dosing regimen until discontinuation from the study.

Factor VIII (FVIII)

Intervention Type: DRUG

FVIII was allowed to treat bleeds on an episodic basis, per the local prescribing information. Specific dosages of FVIII were not mandated in the study. Breakthrough bleeds were to be treated with the lowest FVIII dose expected to achieve hemostasis, which may have been lower than the participant's prior FVIII dose. To avoid bleeds before adequate emicizumab level is reached, patients in Arm D continued their regular FVIII prophylaxis until the second emicizumab loading dose. Concomitant routine FVIII prophylaxis was not permissible otherwise during the study.

Arm D: Emicizumab 1.5 mg/kg QW (Pre-study FVIII Prophylaxis)

Participants who had received FVIII prophylaxis prior to study entry were enrolled to receive emicizumab prophylaxis at a dose of 3 mg/kg subcutaneously (SC) once per week (QW) for 4 weeks, followed by maintenance dosing of 1.5 mg/kg emicizumab SC QW. Upon implementation of protocol version 4 (20-Dec-2019), treatment duration was extended. During this study prolongation, each participant was given the option to choose a preferred emicizumab dosing regimen among those permitted and continue on that dosing regimen until discontinuation from the study.

Group Type: EXPERIMENTAL

Emicizumab

Intervention Type: DRUG

Participants received emicizumab prophylaxis subcutaneously at the specified dose for each arm. After at least 24 weeks on prophylactic emicizumab, individuals who experienced suboptimal bleeding control on emicizumab (according to protocol-defined criteria) had the opportunity to increase their dose to 3 mg/kg weekly. Upon implementation of protocol version 4 (20-Dec-2019), treatment duration was extended. During this study prolongation, each participant had the option to choose a preferred emicizumab dosing regimen among those permitted (i.e., emicizumab 1.5 mg/kg once every week \[QW\], 3 mg/kg once every 2 weeks \[Q2W\], or 6 mg/kg once every 4 weeks \[Q4W\]) and continue on that dosing regimen until discontinuation from the study.

Factor VIII (FVIII)

Intervention Type: DRUG

FVIII was allowed to treat bleeds on an episodic basis, per the local prescribing information. Specific dosages of FVIII were not mandated in the study. Breakthrough bleeds were to be treated with the lowest FVIII dose expected to achieve hemostasis, which may have been lower than the participant's prior FVIII dose. To avoid bleeds before adequate emicizumab level is reached, patients in Arm D continued their regular FVIII prophylaxis until the second emicizumab loading dose. Concomitant routine FVIII prophylaxis was not permissible otherwise during the study.

Interventions

Emicizumab

Participants received emicizumab prophylaxis subcutaneously at the specified dose for each arm. After at least 24 weeks on prophylactic emicizumab, individuals who experienced suboptimal bleeding control on emicizumab (according to protocol-defined criteria) had the opportunity to increase their dose to 3 mg/kg weekly. Upon implementation of protocol version 4 (20-Dec-2019), treatment duration was extended. During this study prolongation, each participant had the option to choose a preferred emicizumab dosing regimen among those permitted (i.e., emicizumab 1.5 mg/kg once every week \[QW\], 3 mg/kg once every 2 weeks \[Q2W\], or 6 mg/kg once every 4 weeks \[Q4W\]) and continue on that dosing regimen until discontinuation from the study.

Intervention Type: DRUG

Factor VIII (FVIII)

FVIII was allowed to treat bleeds on an episodic basis, per the local prescribing information. Specific dosages of FVIII were not mandated in the study. Breakthrough bleeds were to be treated with the lowest FVIII dose expected to achieve hemostasis, which may have been lower than the participant's prior FVIII dose. To avoid bleeds before adequate emicizumab level is reached, patients in Arm D continued their regular FVIII prophylaxis until the second emicizumab loading dose. Concomitant routine FVIII prophylaxis was not permissible otherwise during the study.

Intervention Type: DRUG

Other Intervention Names

Hemlibra; RO5534262; ACE910

Eligibility Criteria

Inclusion Criteria

• Body weight >/= 40 kilogram (kg) at the time of screening
• Diagnosis of severe congenital hemophilia A
• Documentation of the details of prophylactic or episodic FVIII treatment and of number of bleeding episodes for at least the last 24 weeks
• Adequate hematologic function
• Adequate hepatic function
• Adequate renal function
• For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods that result in a failure rate of less than (<) 1 percent (%) per year during the treatment period and for at least 5 elimination half-lives (24 weeks) after the last dose of study drug

Exclusion Criteria

• Inherited or acquired bleeding disorder other than hemophilia A
• Previous or current treatment for thromboembolic disease or signs of thromboembolic disease
• Conditions that may increase risk of bleeding or thrombosis
• History of clinically significant hypersensitivity associated with monoclonal antibody therapies or components of the emicizumab injection
• Known human immunodeficiency virus (HIV) infection with cluster of differentiation (CD) 4 count <200 cells per microliter (cells/mcL) within 24 weeks prior to screening. Participants with HIV infection who has CD4 greater than (>) 200 and meet all other criteria are eligible
• Use of systemic immunomodulators at enrollment or planned use during the study, with the exception of anti-retroviral therapy
• Participants who are at high risk for thrombotic microangiopathy (TMA) (for example, have a previous medical or family history of TMA), in the investigator's judgment
• Concurrent disease, treatment, or abnormality in clinical laboratory tests that could interfere with the conduct of the study, may pose additional risk, or would, in the opinion of the investigator, preclude the participant's safe participation in and completion of the study
• Planned surgery (excluding minor procedures) during the study
• Receipt of emicizumab in a prior investigational study; an investigational drug to treat or reduce the risk of hemophilic bleeds within 5 half-lives of last drug administration; a non-hemophilia-related investigational drug concurrently, within last 30 days or 5 half-lives, whichever is shorter
• Pregnant or lactating, or intending to become pregnant during the study

• Minimum Eligible Age: 12 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Chugai Pharmaceutical

INDUSTRY

Sponsor Role: collaborator

Hoffmann-La Roche

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Clinical Trials

Role: STUDY_DIRECTOR

Hoffmann-La Roche

Locations

Santa Monica Oncology Center

Santa Monica, California, United States

Georgetown Uni Medical Center; Lombardi Cancer Center

Washington D.C., District of Columbia, United States

University of Florida

Gainesville, Florida, United States

Winship Cancer Institute

Atlanta, Georgia, United States

Dana-Farber Cancer Institute; Brigham and Women's Cancer Center

Boston, Massachusetts, United States

Children's Hospital of Michigan; Pediatrics

Detroit, Michigan, United States

Cornell Univ Medical College; Hematology-Oncolog

New York, New York, United States

Bloodworks Northwest (formerly Puget Sound Blood Center); Hemophilia

Seattle, Washington, United States

Royal Adelaide Hospital

Adelaide, South Australia, Australia

The Alfred Hospital, Melbourne; Thrombosis and Haemostasis Unit

Melbourne, Victoria, Australia

The Perth Blood Institute

Nedlands, Western Australia, Australia

ICIC

San José, , Costa Rica

Hopital Cardio-vasculaire Louis Pradel; Hemostase clinique

Bron, , France

CH de Bicetre; Centre de Traitement d' Hemophilie

Le Kremlin-Bicêtre, , France

Groupe Hospitalier Necker Enfants Malades

Paris, , France

Universitätsklinikum Bonn; Institut für Experimentelle Hämatologie und Transfusionsmedizin

Bonn, , Germany

St James's Hospital

Dublin, , Ireland

IRCCS Ca' Granda Ospedale Maggiore Policlinico; Centro Emofilia e Trombosi "Angelo Bianchi e Bonomi"

Milan, Lombardy, Italy

AOU Careggi; SOD Malattie Emorragiche

Florence, Tuscany, Italy

Nagoya University Hospital

Aichi, , Japan

St. Marianna University Hospital

Kanagawa, , Japan

Sendai Medical Center

Miyagi, , Japan

Nara Medical University Hospital

Nara, , Japan

NHO Osaka National Hospital

Osaka, , Japan

Tokyo Medical University Hospital

Tokyo, , Japan

Ogikubo Hospital

Tokyo, , Japan

Uniwersyteckie Centrum Kliniczne; Klinika Hematologii i Transplantologii

Gdansk, , Poland

SPSK Nr1 Klinika Hematoo&Transpl.Szpiku

Lublin, , Poland

ALVAMED Lekarskie Gabinety Specjalistyczne

Poznan, , Poland

Instytut Hematologii i Transfuzjologii; Klinika Zaburzeń Hemostazy i Chorób Wewnętrznych

Warsaw, , Poland

Charlotte Maxeke Johannesburg Hospital; Haemophilia Comprehensive Care Center

Johannesburg, , South Africa

Severance Hospital

Seoul, , South Korea

Hospital Universitario la Paz; Servicio de Hematologia

Madrid, , Spain

Hospital Universitario Virgen del Rocio; Servicio de Hematologia

Seville, , Spain

Changhua Christian Hospital

Chang-hua, , Taiwan

Taichung Veterans General Hospital

Taichung, , Taiwan

Taipei Medical University Hospital

Taipei, , Taiwan

Cardiff and Vale NHS Trust

Cardiff, , United Kingdom

Royal Free Hospital; Haemophilia Centre

London, , United Kingdom

Countries

United States; Australia; Costa Rica; France; Germany; Ireland; Italy; Japan; Poland; South Africa; South Korea; Spain; Taiwan; United Kingdom

References

Kruse-Jarres R, Peyvandi F, Oldenburg J, Chang T, Chebon S, Doral MY, Croteau SE, Lambert T, Kempton CL, Pipe SW, Ko RH, Trzaskoma B, Dhalluin C, Bienz NS, Niggli M, Lehle M, Paz-Priel I, Young G, Jimenez-Yuste V. Surgical outcomes in people with hemophilia A taking emicizumab prophylaxis: experience from the HAVEN 1-4 studies. Blood Adv. 2022 Dec 27;6(24):6140-6150. doi: 10.1182/bloodadvances.2022007458.

Reference Type: DERIVED

PMID: 35939785 (View on PubMed)

Kiialainen A, Niggli M, Kempton CL, Castaman G, Chang T, Paz-Priel I, Adamkewicz JI, Levy GG. Effect of emicizumab prophylaxis on bone and joint health markers in people with haemophilia A without factor VIII inhibitors in the HAVEN 3 study. Haemophilia. 2022 Nov;28(6):1033-1043. doi: 10.1111/hae.14642. Epub 2022 Jul 29.

Reference Type: DERIVED

PMID: 35905294 (View on PubMed)

Mahlangu J, Oldenburg J, Paz-Priel I, Negrier C, Niggli M, Mancuso ME, Schmitt C, Jimenez-Yuste V, Kempton C, Dhalluin C, Callaghan MU, Bujan W, Shima M, Adamkewicz JI, Asikanius E, Levy GG, Kruse-Jarres R. Emicizumab Prophylaxis in Patients Who Have Hemophilia A without Inhibitors. N Engl J Med. 2018 Aug 30;379(9):811-822. doi: 10.1056/NEJMoa1803550.

Reference Type: DERIVED

PMID: 30157389 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Other Identifiers

2016-000072-17

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

BH30071

Identifier Type: -

Identifier Source: org_study_id