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

NCT02847637 | Completed Phase 3 Results DMC FDA Drug

• 2 other identifiers: BH300712016-000072-17
• Study Type: interventional
• Target: 152
• Locations: 14 countries
• Sites: 39

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

Keywords

Hemophilia A; Emicizumab

Outcome Measures

Primary Outcomes (1)

• Annualized Bleeding Rate (ABR) for Treated Bleeds

  The number of treated bleeds over the efficacy period is presented as an annualized bleeding rate (ABR) that was assessed using a negative binomial (NB) regression model, which accounts for different follow-up times, with the number of bleeds as a function of randomization and the time that each participant stays in the study (i.e., length of the efficacy period) included as an offset in the model. The model also includes the number of bleeds (\<9 or ≥9) in the last 24 weeks prior to study entry as a stratification factor. A bleed is considered a "treated bleed" if it is directly followed (i.e., no intervening bleed) by a hemophilia medication reported to be a "treatment for bleed", irrespective of the time between treatment and the preceding bleed. Bleeds due to surgery/procedure are excluded.

  From Baseline to at least 24 weeks (median [min-max] efficacy periods for Arm C: 24.00 [14.4-25.0] weeks; Arm A: 29.57 [17.3-49.6] weeks; Arm B: 31.29 [3.3-50.6] weeks; Arm D: 33.14 [18.4-48.6] weeks)

Secondary Outcomes (36)

• Annualized Bleeding Rate (ABR) for All Bleeds

  From Baseline to at least 24 weeks (median [min-max] efficacy periods for Arm C: 24.00 [14.4-25.0] weeks; Arm A: 29.57 [17.3-49.6] weeks; Arm B: 31.29 [3.3-50.6] weeks; Arm D: 33.14 [18.4-48.6] weeks)

• Annualized Bleeding Rate (ABR) for Treated Joint Bleeds

  From Baseline to at least 24 weeks (median [min-max] efficacy periods for Arm C: 24.00 [14.4-25.0] weeks; Arm A: 29.57 [17.3-49.6] weeks; Arm B: 31.29 [3.3-50.6] weeks; Arm D: 33.14 [18.4-48.6] weeks)

• Annualized Bleeding Rate (ABR) for Treated Spontaneous Bleeds

  From Baseline to at least 24 weeks (median [min-max] efficacy periods for Arm C: 24.00 [14.4-25.0] weeks; Arm A: 29.57 [17.3-49.6] weeks; Arm B: 31.29 [3.3-50.6] weeks; Arm D: 33.14 [18.4-48.6] weeks)

• Annualized Bleeding Rate (ABR) for Treated Target Joint Bleeds

  From Baseline to at least 24 weeks (median [min-max] efficacy periods for Arm C: 24.00 [14.4-25.0] weeks; Arm A: 29.57 [17.3-49.6] weeks; Arm B: 31.29 [3.3-50.6] weeks; Arm D: 33.14 [18.4-48.6] weeks)

• Intra-Participant Comparison of ABR for Treated Bleeds on Study Versus Pre-Study in Participants From the Non-Interventional Study Population Previously Treated With Factor VIII (FVIII) Prophylaxis (NISP)

  Efficacy periods: At least 24 weeks prior to study entry (median [min-max] for Dnisp-FVIII Prophylaxis: 30.07 [5.0-45.1] weeks); and From Baseline to at least 24 weeks on study (median [min-max] for Dnisp-Emicizumab Prophylaxis: 33.71 [20.1-48.6] weeks)

Study Arms (4)

Arm C (Control): No Prophylaxis, Then Emicizumab

ACTIVE COMPARATOR

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.

Drug: Emicizumab; Drug: Factor VIII (FVIII)

Arm A: Emicizumab 1.5 mg/kg QW

EXPERIMENTAL

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.

Drug: Emicizumab; Drug: Factor VIII (FVIII)

Arm B: Emicizumab 3 mg/kg Q2W

EXPERIMENTAL

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.

Drug: Emicizumab; Drug: Factor VIII (FVIII)

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

EXPERIMENTAL

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.

Drug: Emicizumab; Drug: Factor VIII (FVIII)

Interventions

Emicizumab 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.

Also known as: Hemlibra, RO5534262, ACE910

Arm A: Emicizumab 1.5 mg/kg QW; Arm B: Emicizumab 3 mg/kg Q2W; Arm C (Control): No Prophylaxis, Then Emicizumab; Arm D: Emicizumab 1.5 mg/kg QW (Pre-study FVIII Prophylaxis)

Factor VIII (FVIII) 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; Arm B: Emicizumab 3 mg/kg Q2W; Arm C (Control): No Prophylaxis, Then Emicizumab; Arm D: Emicizumab 1.5 mg/kg QW (Pre-study FVIII Prophylaxis)

Eligibility Criteria

• Age: 12 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Hoffmann-La Roche: lead
• Chugai Pharmaceutical: collaborator

Study Sites (39)

Santa Monica Oncology Center

Santa Monica, California, 90403, United States

Location

Georgetown Uni Medical Center; Lombardi Cancer Center

Washington D.C., District of Columbia, 20007, United States

Location

University of Florida

Gainesville, Florida, 32607, United States

Location

Winship Cancer Institute

Atlanta, Georgia, 30322, United States

Location

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

Boston, Massachusetts, 02115, United States

Location

Children's Hospital of Michigan; Pediatrics

Detroit, Michigan, 48201, United States

Location

Cornell Univ Medical College; Hematology-Oncolog

New York, New York, 10021, United States

Location

Bloodworks Northwest (formerly Puget Sound Blood Center); Hemophilia

Seattle, Washington, 98104, United States

Location

Royal Adelaide Hospital

Adelaide, South Australia, 5000, Australia

Location

The Alfred Hospital, Melbourne; Thrombosis and Haemostasis Unit

Melbourne, Victoria, 3004, Australia

Location

The Perth Blood Institute

Nedlands, Western Australia, 6009, Australia

Location

ICIC

San José, 1000, Costa Rica

Location

Hopital Cardio-vasculaire Louis Pradel; Hemostase clinique

Bron, 69677, France

Location

CH de Bicetre; Centre de Traitement d' Hemophilie

Le Kremlin-Bicêtre, 94275, France

Location

Groupe Hospitalier Necker Enfants Malades

Paris, 75015, France

Location

Universitätsklinikum Bonn; Institut für Experimentelle Hämatologie und Transfusionsmedizin

Bonn, 53127, Germany

Location

St James's Hospital

Dublin, 8, Ireland

Location

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

Milan, Lombardy, 20122, Italy

Location

AOU Careggi; SOD Malattie Emorragiche

Florence, Tuscany, 50134, Italy

Location

Nagoya University Hospital

Aichi, 466-8560, Japan

Location

St. Marianna University Hospital

Kanagawa, 216-8511, Japan

Location

Sendai Medical Center

Miyagi, 983-8520, Japan

Location

Nara Medical University Hospital

Nara, 634-8522, Japan

Location

NHO Osaka National Hospital

Osaka, 540-0006, Japan

Location

Tokyo Medical University Hospital

Tokyo, 160-0023, Japan

Location

Ogikubo Hospital

Tokyo, 167-0035, Japan

Location

Uniwersyteckie Centrum Kliniczne; Klinika Hematologii i Transplantologii

Gdansk, 80-952, Poland

Location

SPSK Nr1 Klinika Hematoo&Transpl.Szpiku

Lublin, 20-081, Poland

Location

ALVAMED Lekarskie Gabinety Specjalistyczne

Poznan, 60-549, Poland

Location

Instytut Hematologii i Transfuzjologii; Klinika Zaburzeń Hemostazy i Chorób Wewnętrznych

Warsaw, 02-776, Poland

Location

Charlotte Maxeke Johannesburg Hospital; Haemophilia Comprehensive Care Center

Johannesburg, 2193, South Africa

Location

Severance Hospital

Seoul, 03722, South Korea

Location

Hospital Universitario la Paz; Servicio de Hematologia

Madrid, 28046, Spain

Location

Hospital Universitario Virgen del Rocio; Servicio de Hematologia

Seville, 41013, Spain

Location

Changhua Christian Hospital

Chang-hua, 500, Taiwan

Location

Taichung Veterans General Hospital

Taichung, 40705, Taiwan

Location

Taipei Medical University Hospital

Taipei, 110, Taiwan

Location

Cardiff and Vale NHS Trust

Cardiff, CF14 4XW, United Kingdom

Location

Royal Free Hospital; Haemophilia Centre

London, NW3 2QG, United Kingdom

Location

Related Publications (3)

• 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.

  PMID: 35939785 DERIVED

• 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.

  PMID: 35905294 DERIVED

• 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.

  PMID: 30157389 DERIVED

MeSH Terms

Conditions

Hemophilia A

Interventions

emicizumab; Factor VIII

Condition Hierarchy (Ancestors)

Blood Coagulation Disorders, Inherited; Blood Coagulation Disorders; Hematologic Diseases; Hemic and Lymphatic Diseases; Coagulation Protein Disorders; Hemorrhagic Disorders; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities

Intervention Hierarchy (Ancestors)

Blood Coagulation Factors; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Protein Precursors; Biological Factors

Results Point of Contact

• Title: Medical Communications
• Organization: Hoffmann-La Roche

genentech@druginfo.com

800-821-8590

Study Officials

• Clinical Trials

  Hoffmann-La Roche

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 26, 2016
• First Posted: July 28, 2016
• Study Start: September 27, 2016
• Primary Completion: September 15, 2017
• Study Completion: May 12, 2022
• Last Updated: November 16, 2022
• Results First Posted: November 14, 2018

Record last verified: 2022-10

Locations

GB (2); IT (2); US (8); CO (1); AU (3); FR (3); PL (4); JP (7); KR (1); IE (1); DE (1); ZA (1); ES (2); TW (3)