A Study to Evaluate the Efficacy, Safety, and Pharmacokinetics of Prophylactic Emicizumab Versus no Prophylaxis in Hemophilia A Participants With Inhibitors

NCT02622321 | Completed Phase 3 Results DMC FDA Drug

• 2 other identifiers: BH298842015-002866-21
• Study Type: interventional
• Target: 113
• Locations: 14 countries
• Sites: 44

Brief Summary

This multicenter, open-label study will evaluate the safety, efficacy and pharmacokinetics of prophylactic emicizumab treatment in participants previously treated with episodic or prophylactic bypassing agents. Episodic bypassing agent participants will be randomized in a 2:1 fashion to receive emicizumab prophylaxis (Arm A) versus no prophylaxis (Arm B) and will be stratified across Arms A and B according to the number of bleeds they experienced over the last 24 weeks prior to study entry (less than \[\<\] 9 or greater than or equal to \[\>/=\] 9 bleeds); Arm B participants will have the opportunity to switch to emicizumab prophylaxis after at least 24 weeks on-study. Prophylactic bypassing agent participants will switch to emicizumab prophylaxis (Arm C) from the start of the trial; enrollment will be extended for 24 weeks after the last participant has enrolled in Arms A or B or until approximately 50 participants have enrolled in Arm C, whichever occurs first. Episodic bypassing agent participants who previously participated in the non-interventional study BH29768 (NCT02476942) who were unable to enroll in Arms A or B, or participants on prophylactic bypassing agents who were unable to enroll in Arm C, prior to their closure will have the opportunity to enroll in Arm D. Like participants in Arms A and C, Arm D participants will receive emicizumab prophylaxis from the start of the trial. All participants will continue to receive episodic bypassing agent therapy to treat breakthrough bleeds, preferably with recombinant activated factor VII (rFVIIa).

Conditions

Hemophilia A

Outcome Measures

Primary Outcomes (1)

• Model-Based Annualized Bleed Rate (ABR) for Treated Bleeds, Arm A: Emicizumab Versus Arm B: No Prophylaxis

  The number of treated bleeds over the efficacy period was assessed as an annualized bleed rate (ABR) using a negative binomial (NB) regression model, which accounts for different follow-up times. Treated bleeds were defined as a bleed that was directly followed by a hemophilia medication reported to be a "treatment for bleed". The 72-hour rule was implemented: two bleeds of the same type and at the same anatomical location were counted as one bleed if the second bleed occurred within 72 hours from the last treatment for the first bleed. Bleeds due to surgery/procedure were excluded. For participants whose dose was up-titrated, the efficacy period ended the day before the first day on the up-titrated dose.

  From Baseline up to 24 weeks (median [min-max] efficacy observation periods in Arm A vs. Arm B: 29.29 [0.1-48.9] weeks vs. 24.14 [23.0-26.0] weeks)

Secondary Outcomes (28)

• Model-Based Annualized Bleed Rate (ABR) for All Bleeds, Arm A: Emicizumab Versus Arm B: No Prophylaxis

  From Baseline up to 24 weeks (median [min-max] efficacy observation periods in Arm A vs. Arm B: 29.29 [0.1-48.9] weeks vs. 24.14 [23.0-26.0] weeks)

• Intra-Participant Comparison of the Model-Based Annualized Bleed Rate (ABR) for All Bleeds in Arm A: Emicizumab Versus Previous Episodic Bypassing Agents

  Median [min-max] efficacy observation periods: for Arm A, 1.5 mg/kg Emicizumab QW: 30.86 [0.1-48.9] weeks; for Arm A (NIS), Previous Episodic Bypassing Agents: 21.14 [10.6-33.9] weeks

• Intra-Participant Comparison of the Model-Based Annualized Bleed Rate (ABR) for Treated Bleeds in Arm A: Emicizumab Versus Previous Episodic Bypassing Agents

  Median [min-max] efficacy observation periods: for Arm A, 1.5 mg/kg Emicizumab QW: 30.86 [0.1-48.9] weeks; for Arm A (NIS), Previous Episodic Bypassing Agents: 21.14 [10.6-33.9] weeks

• Model-Based Annualized Bleed Rate (ABR) for Treated Joint Bleeds, Arm A: Emicizumab Versus Arm B: No Prophylaxis

  From Baseline up to 24 weeks (median [min-max] efficacy observation periods in Arm A vs. Arm B: 29.29 [0.1-48.9] weeks vs. 24.14 [23.0-26.0] weeks)

• Intra-Participant Comparison of the Model-Based Annualized Bleed Rate (ABR) for All Bleeds in Arm C: Emicizumab Versus Previous Prophylactic Bypassing Agents

  Median [min-max] efficacy observation periods: for Arm C, 1.5 mg/kg Emicizumab QW: 30.14 [6.9-45.3] weeks; for Arm C (NIS), Previous Prophylactic Bypassing Agents: 32.14 [8.1-49.3] weeks

Study Arms (4)

Arm A: 1.5 mg/kg Emicizumab QW

EXPERIMENTAL

Participants who were receiving episodic treatment with bypassing agents prior to study entry and were randomized to study Arm A started to receive emicizumab prophylaxis. Emicizumab was administered at a loading dose of 3 milligrams per kilogram (mg/kg) once a week (QW) subcutaneously (SC) for the first 4 weeks followed by a maintenance dose of 1.5 mg/kg emicizumab QW SC up to the end of study. Participants continued to receive bypassing agent therapy to treat any breakthrough bleeds.

Drug: Emicizumab; Drug: rFVIIa; Drug: aPCC

Arm B (Control): No Prophylaxis, Then Emicizumab

ACTIVE COMPARATOR

Participants who were receiving episodic treatment with bypassing agents prior to study entry and were randomized to study Arm B continued with their prior episodic treatment regimen for the first 24 weeks of the study; they did not receive emicizumab prophylaxis during that time. After completing at least 24 weeks on study, participants in Arm B were allowed to switch to emicizumab prophylaxis (as described for Arm A) up to the end of study. Participants continued to receive bypassing agent therapy to treat any breakthrough bleeds.

Drug: Emicizumab; Drug: rFVIIa; Drug: aPCC

Arm C: 1.5 mg/kg Emicizumab QW

EXPERIMENTAL

Participants who were receiving prophylactic bypassing agents prior to study entry were enrolled in Arm C to receive prophylactic emicizumab. Emicizumab was administered at a loading dose of 3 mg/kg QW SC for the first 4 weeks followed by a maintenance dose of 1.5 mg/kg emicizumab QW SC up to the end of study. Participants continued to receive bypassing agent therapy to treat any breakthrough bleeds.

Drug: Emicizumab; Drug: rFVIIa; Drug: aPCC

Arm D: 1.5 mg/kg Emicizumab QW

EXPERIMENTAL

Participants who were either: 1) Receiving episodic bypassing agents prior to study entry but were unable to enroll in Arms A or B; or 2) Receiving bypassing agent prophylaxis prior to study entry but were unable to enroll in Arm C, were enrolled in Arm D to receive emicizumab prophylaxis. Emicizumab was administered at a loading dose of 3 mg/kg QW SC for the first 4 weeks followed by a maintenance dose of 1.5 mg/kg emicizumab QW SC up to the end of study. Participants continued to receive bypassing agent therapy to treat any breakthrough bleeds.

Drug: Emicizumab; Drug: rFVIIa; Drug: aPCC

Interventions

Emicizumab DRUG

Emicizumab will be administered at a loading dose of 3 milligrams per kilogram per week (mg/kg/week) subcutaneously (SC) for the first 4 weeks followed by a maintenance dose of 1.5 mg/kg/week SC up to the end of study. After at least 24 weeks on prophylactic emicizumab, individuals who experience suboptimal bleeding control on emicizumab (according to protocol-defined criteria) will have the opportunity to increase their dose to 3 mg/kg weekly.

Also known as: Hemlibra, RO5534262, RG6013, ACE910

Arm A: 1.5 mg/kg Emicizumab QW; Arm B (Control): No Prophylaxis, Then Emicizumab; Arm C: 1.5 mg/kg Emicizumab QW; Arm D: 1.5 mg/kg Emicizumab QW

rFVIIa DRUG

Participants will continue to receive rFVIIa.

Also known as: NovoSeven®

Arm A: 1.5 mg/kg Emicizumab QW; Arm B (Control): No Prophylaxis, Then Emicizumab; Arm C: 1.5 mg/kg Emicizumab QW; Arm D: 1.5 mg/kg Emicizumab QW

aPCC DRUG

Participants will continue to receive aPCC.

Also known as: Factor Eight Inhibitor Bypassing Activity (FEIBA®)

Arm A: 1.5 mg/kg Emicizumab QW; Arm B (Control): No Prophylaxis, Then Emicizumab; Arm C: 1.5 mg/kg Emicizumab QW; Arm D: 1.5 mg/kg Emicizumab QW

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 kilograms (kg) at the time of screening
• Diagnosis of congenital hemophilia A of any severity and documented history of high-titer inhibitor ( that is \[i.e.\], \>/= 5 Bethesda Units \[BU\])
• Documentation of treatment with episodic or prophylactic bypassing agents for at least the last 24 weeks
• \>/= 6 bleeds in the last 24 weeks prior to screening (if on an episodic bypassing agent regimen) or \>/=2 bleeds in the last 24 weeks prior to screening (if on a prophylactic bypassing agent regimen)
• Adequate hematologic, hepatic and renal function
• For women who are not postmenopausal or surgically sterile: agreement to remain abstinent or use single or combined highly effective contraceptive methods

You may not qualify if:

• Participants with inherited or acquired bleeding disorder other than hemophilia A
• Participants with ongoing (or plan to receive during the study) immune tolerance induction therapy or prophylaxis with Factor VIII (FVIII), with the exception of participants who have received a treatment regimen of FVIII prophylaxis with concurrent bypassing agent prophylaxis
• Previous (in the past 12 months) or current treatment for thromboembolic disease (with the exception of previous catheter-associated thrombosis for which antithrombotic treatment is not currently ongoing) or current signs of thromboembolic disease
• Participants with other conditions (for example \[e.g.\], certain autoimmune diseases) that may increase the 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 4 (CD4) count \< 200 cells per microliter (cells/mcL) within 24 weeks prior to screening
• Use of systemic immunomodulators (e.g., interferon or rituximab) at enrolment or planned use during the study, with the exception of antiretroviral therapy
• Participants who are at high risk for thrombotic microangiopathy (TMA; e.g., 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 or that would, in the opinion of the investigator or Sponsor, preclude the participant's safe participation in and completion of the study or interpretation of the study results
• Planned surgery (excluding minor procedures such as tooth extraction or incision and drainage) 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 within last 30 days or 5 half-lives, whichever is shorter; An investigational drug concurrently
• Unwillingness to use highly effective contraception methods for the specified duration in the protocol (females only, unless required otherwise by the local health authority)
• Clinically significant abnormality on screening evaluations or laboratory tests that, in the opinion of the investigator, may pose an additional risk in administering study drug to the participant
• Pregnancy or lactation, or intent to become pregnant during the study

Sponsors & Collaborators

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

Study Sites (44)

Children's Hospital Los Angeles

Los Angeles, California, 90010, United States

Location

Santa Monica Oncology Center

Santa Monica, California, 90403, United States

Location

University of Colorado Denver, Children's Hospital

Aurora, Colorado, 80045, United States

Location

Winship Cancer Institute

Atlanta, Georgia, 30322, United States

Location

Boston Childrens Hospital

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

Oregon Health & Science Uni ; Dept of Pediatrics

Portland, Oregon, 97201, United States

Location

Pennsylvania State Hershey Medical Center; Division of Hematology/Oncology, H046

Hershey, Pennsylvania, 17033-0850, United States

Location

Univ of TX Health Science Ctr; Gulf States Hemo and Throm Ctr

Houston, Texas, 77030, United States

Location

Bloodworks Northwest (formerly Puget Sound Blood Center); Hemophilia

Seattle, Washington, 98104, United States

Location

Royal Prince Alfred Hospital; Haematology

Camperdown, New South Wales, 2050, Australia

Location

The Alfred Hospital, Melbourne; Thrombosis and Haemostasis Unit

Melbourne, Victoria, 3004, 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

Hopital Cardiologique; Hematologie B

Lille, 59037, France

Location

Groupe Hospitalier Necker Enfants Malades

Paris, 75015, France

Location

Universitätsklinikum Bonn; Institut für Experimentelle Hämatologie und Transfusionsmedizin

Bonn, 53127, Germany

Location

CTC North GmbH & Co. KG am Universitätsklinikum Hamburg-Eppendorf

Hamburg, 20251, Germany

Location

Hämophilie-Zentrum Rhein Main GmbH

Mörfelden-Walldorf, 64546, Germany

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

Hiroshima University Hospital

Hiroshima, 734-8551, Japan

Location

Hyogo College of Medicine Hospital

Hyōgo, 663-8501, Japan

Location

St. Marianna University School of Medicine Hospital

Kanagawa, 216-8511, Japan

Location

Hospital of the University of Occupational and Environmental Health,Japan

Kitakyushu-shi, 807-8556, Japan

Location

Nara Medical University Hospital

Nara, 634-8522, Japan

Location

Tokyo Medical University Hospital

Tokyo, 160-0023, Japan

Location

Auckland City Hospital; Auckland Haemophilia Centre

Auckland, 1023, New Zealand

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

Hospital Universitario la Fe; Servicio de Hematologia

Valencia, 46026, Spain

Location

National Taiwan Uni Hospital

Taipei, 10041, Taiwan

Location

Cardiff and Vale NHS Trust

Cardiff, CF14 4XW, United Kingdom

Location

St Thomas' Hospital; Haemostasis & Thromboisis Centre

London, SE1 7EH, United Kingdom

Location

Oxford University Hospitals NHS Trust - Churchill Hospital

Oxford, OX3 7LE, United Kingdom

Location

Related Publications (2)

• 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

• Oldenburg J, Mahlangu JN, Kim B, Schmitt C, Callaghan MU, Young G, Santagostino E, Kruse-Jarres R, Negrier C, Kessler C, Valente N, Asikanius E, Levy GG, Windyga J, Shima M. Emicizumab Prophylaxis in Hemophilia A with Inhibitors. N Engl J Med. 2017 Aug 31;377(9):809-818. doi: 10.1056/NEJMoa1703068. Epub 2017 Jul 10.

  PMID: 28691557 DERIVED

MeSH Terms

Conditions

Hemophilia A

Interventions

emicizumab; recombinant FVIIa; anti-inhibitor coagulant complex

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

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
• Expanded Access: Yes

Study Record Dates

• First Submitted: December 2, 2015
• First Posted: December 4, 2015
• Study Start: November 18, 2015
• Primary Completion: October 25, 2016
• Study Completion: December 1, 2020
• Last Updated: June 24, 2021
• Results First Posted: November 24, 2017

Record last verified: 2021-05

Locations

PL (4); TW (1); US (11); GB (3); ES (3); NZ (1); DE (3); ZA (1); CO (1); AU (2); JP (7); KR (1); IT (2); FR (4)