A Study to Evaluate the Efficacy, Safety, Pharmacokinetics, and Pharmacodynamics of Emicizumab Given Every 4 Weeks in Participants With Hemophilia A

NCT03020160 | Completed Phase 3 Results FDA Drug

• 2 other identifiers: BO391822016-001094-33
• Study Type: interventional
• Target: 48
• Locations: 6 countries
• Sites: 17

Brief Summary

This multicenter, open-label, non-randomized study will assess the efficacy, safety, pharmacokinetics, and pharmacodynamics of emicizumab administered at a dose of 6 milligrams per kilogram (mg/kg) every 4 weeks in participants with hemophilia A with or without inhibitors against factor VIII (FVIII). The study consists of 2 parts: a pharmacokinetic (PK) run-in part followed by an expansion part.

Conditions

Hemophilia A

Outcome Measures

Primary Outcomes (5)

• Expansion Part: 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 analyzed using a negative binomial regression model with efficacy period as an offset to account for the difference in follow-up times. 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 time between treatment and the preceding bleed. A bleed and the first treatment thereafter and before a new bleed starts, are considered to be pairs, with the following exception: if multiple bleeds occur on the same calendar day, the subsequent treatment is considered to apply for each of these multiple bleeds. The 72-hour rule was implemented: two bleeds of the same type and at the same anatomical location are counted as one bleed if the second bleed occurs within 72 hours from the last treatment for the first bleed. Bleeds due to surgery/procedure are excluded.

  From Baseline to at least 24 weeks

• Expansion Part: Annualized Bleeding Rate (ABR) for All Bleeds

  The number of all bleeds over the efficacy period is presented as an annualized bleeding rate (ABR) that was analyzed using a negative binomial regression model with efficacy period as an offset to account for the difference in follow-up times (i.e., the time that each participant stays in the study). In this outcome measure, all bleeds are included, irrespective of treatment with coagulation factors, with the following exception: bleeds due to surgery/procedure are excluded. As "all bleeds" comprises both treated and non-treated bleeds, the 72-hour rule was implemented separately for treated and non-treated bleeds. For treated bleeds, the 72-hour rule was implemented exactly as defined for the "treated bleeds" outcome measure. For non-treated bleeds, the 72-hour rule was implemented by calculating a treatment-free period of 72 hours from the bleed itself.

  From Baseline to at least 24 weeks

• Expansion Part: Annualized Bleeding Rate (ABR) for Treated Spontaneous Bleeds

  The number of treated spontaneous bleeds over the efficacy period is presented as an annualized bleeding rate (ABR) that was analyzed using a negative binomial regression model with efficacy period as an offset to account for the difference in follow-up times (i.e., the time that each participant stays in the study). A bleed is classified as "spontaneous" if there is no other known contributing factor such as trauma or procedure/surgery. A "treated spontaneous bleed" is a spontaneous bleed that also fulfills the conditions of a treated bleed (see ABR for Treated Bleeds for the definition). Treated bleeds that fulfilled the 72-hour rule were included in the analysis of spontaneous bleeds. Bleeds due to surgery/procedure are excluded.

  From Baseline to at least 24 weeks

• Expansion Part: Annualized Bleeding Rate (ABR) for Treated Joint Bleeds

  The number of treated joint bleeds over the efficacy period is presented as an annualized bleeding rate (ABR) that was analyzed using a negative binomial regression model with efficacy period as an offset to account for the difference in follow-up times (i.e., the time that each participant stays in the study). A "joint bleed" is defined as a bleed with type reported as "joint" and with at least one of the following symptoms: increasing swelling or warmth of the skin over the joint and/or increasing pain, decreased range of motion, or difficulty using the joint compared with baseline. A "treated joint bleed" is a joint bleed that also fulfills the conditions of a treated bleed (see ABR for Treated Bleeds for the definition). Treated bleeds that fulfilled the 72-hour rule were included in the analysis of joint bleeds, excluding bleeds due to surgery/procedure.

  From Baseline to at least 24 weeks

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

  The number of treated target joint bleeds over the efficacy period is presented as an annualized bleeding rate (ABR) that was analyzed using a negative binomial regression model with efficacy period as an offset to account for the difference in follow-up times (i.e., the time that each participant stays in the study). A "target joint bleed" is defined as a joint bleed in a target joint, which is a joint location where at least 3 bleeds have occurred over the last 24 weeks prior to study entry. A "treated target joint bleed" is a target joint bleed that also fulfills the conditions of a treated bleed (see ABR for Treated Bleeds for the definition). Bleeds due to surgery/procedure are excluded.

  From Baseline to at least 24 weeks

Secondary Outcomes (43)

• Expansion Part: Change From Baseline to Week 25 in the Hemophilia A Quality of Life (Haem-A-QoL) Questionnaire Total Score for Adult Participants (≥18 Years of Age)

  Baseline, Week 25

• Expansion Part: Percentage of Adult Participants (≥18 Years of Age) With a Clinically Meaningful Improvement From Baseline to Week 25 in the Haem-A-QoL Questionnaire Total Score

  Baseline, Week 25

• Expansion Part: Change From Baseline to Week 25 in the Haem-A-QoL Questionnaire Physical Health Score for Adult Participants (≥18 Years of Age)

  Baseline, Week 25

• Expansion Part: Percentage of Adult Participants (≥18 Years of Age) With a Clinically Meaningful Improvement From Baseline to Week 25 in the Haem-A-QoL Questionnaire Physical Health Score

  Baseline, Week 25

• Expansion Part: Change From Baseline to Week 25 in the Hemophilia-Quality of Life-Short Form (Haemo-QoL-SF) Questionnaire Total Score for Adolescent Participants (12-17 Years of Age)

  Baseline, Week 25

Study Arms (2)

Emicizumab: PK Run-in Cohort

EXPERIMENTAL

Participants received emicizumab subcutaneously (SC) at a dose of 6 mg/kg once every 4 weeks, with no loading dose, for at least 24 weeks.

Drug: Emicizumab

Emicizumab: Expansion Cohort

EXPERIMENTAL

Participants received emicizumab subcutaneously (SC) at a loading dose of 3 mg/kg once every week for the first 4 weeks followed by a maintenance dose of 6 mg/kg emicizumab SC once every 4 weeks for at least 24 weeks.

Drug: Emicizumab

Interventions

Emicizumab DRUG

Emicizumab will be administered according to dose and schedule described in respective arms. 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 5 (20-Dec-2019), treatment duration was extended. During this study prolongation, participants had the opportunity to switch to a preferred emicizumab dosing regimen (1.5 mg/kg weekly, 3 mg/kg every 2 weeks, or 6 mg/kg every 4 weeks) in order to provide them the same flexibility as with commercial product.

Also known as: Hemlibra, RO5534262, ACE910

Emicizumab: Expansion Cohort; Emicizumab: PK Run-in Cohort

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 greater than or equal to (\>/=) 40 kilograms (kg) at screening
• Diagnosis of severe congenital hemophilia A or hemophilia A with FVIII inhibitors
• Participants using rFVIIa or willing to switch to recombinant activated factor VII (rFVIIa) as primary bypassing agent for the treatment of breakthrough bleeds
• FVIII inhibitor test during screening with titer results available prior to first administration of study drug
• Participants without FVIII inhibitors, that is with less than (\<) 0.6 Bethesda unit per milliliter \[BU/mL\];\< 1.0 BU/mL only for laboratories with an historical sensitivity cutoff for inhibitor detection of 1.0 BU/mL, who completed successful immune tolerance induction (ITI) must have done so at least 5 years before screening and must have no evidence of inhibitor recurrence (permanent or temporary) indicated by detection of an inhibitor greater than (\>) 0.6 BU/mL (\> 1.0 BU/mL only for laboratories with an historical sensitivity cutoff for inhibitor detection of 1.0 BU/mL) since ITI
• Adequate hematologic, hepatic, and renal function

You may not qualify if:

• Inherited or acquired bleeding disorder other than hemophilia A
• Ongoing or planned ITI therapy; participants in whom ITI has failed will be eligible with a 72-hour washout period prior to the first emicizumab administration
• History of illicit drug or alcohol abuse within 48 weeks prior to screening, in the investigator's judgment
• 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
• Previous (within the last 12 months) or current treatment for thromboembolic disease (with the exception of previous catheter-associated thrombosis for which anti-thrombotic treatment is not currently ongoing) or signs of thromboembolic disease
• Other conditions (for example, certain autoimmune diseases) that may currently increase the risk of bleeding or thrombosis
• History of clinically significant hypersensitivity associated with monoclonal antibody therapies or components of the emicizumab injection
• Known HIV infection with cluster of differentiation (CD) 4 cells counts \<200 cells per microliter (cells/mcL)
• Use of systemic immunomodulators (for example, interferon) at enrollment or planned use during the study, with the exception of anti-retroviral therapy
• Concomitant disease, condition, significant abnormality on screening evaluations or laboratory tests, or treatment that could interfere with the conduct of the study, or that would, in the opinion of the investigator, pose an additional unacceptable risk in administering study drug to the participant
• Pregnancy or lactation or intention to become pregnant during the study
• Women with a positive serum pregnancy test result within 7 days prior to initiation of study drug

Sponsors & Collaborators

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

Study Sites (17)

University of California Davis

Sacramento, California, 95817, United States

Location

Indiana Hemophilia & Thrombosis center

Indianapolis, Indiana, 46260, United States

Location

University of Michigan, C.S. Mott Children's Hospital

Ann Arbor, Michigan, 48109, United States

Location

Univ of N Carolina Chapel Hill; Hematology/Oncology

Chapel Hill, North Carolina, 27514, United States

Location

Royal Brisbane Hospital; Clinical Haematology

Brisbane, Queensland, 4029, Australia

Location

Royal Adelaide Hospital; Haematology Clinical Trials

Adelaide, South Australia, 5000, Australia

Location

Cliniques Universitaires St-Luc

Brussels, 1200, Belgium

Location

UZ Leuven Gasthuisberg

Leuven, 3000, Belgium

Location

Hokkaido University Hospital

Hokkaido, 060-8648, Japan

Location

Nara Medical University Hospital

Nara, 634-8522, Japan

Location

National Center for Child Health and Development

Tokyo, 157-8535, Japan

Location

Tokyo Medical University Hospital

Tokyo, 160-0023, Japan

Location

Instytut Hematologii i Transfuzjologii; Klinika Zaburzeń Hemostazy i Chorób Wewnętrznych

Warsaw, 02-776, Poland

Location

Uniwersytecki Szpital Kliniczny; Klinika Hematologii, Nowotworów Krwi i Transplantacji Szpiku

Wroclaw, 50-367, Poland

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

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

• Pipe SW, Shima M, Lehle M, Shapiro A, Chebon S, Fukutake K, Key NS, Portron A, Schmitt C, Podolak-Dawidziak M, Selak Bienz N, Hermans C, Campinha-Bacote A, Kiialainen A, Peerlinck K, Levy GG, Jimenez-Yuste V. Efficacy, safety, and pharmacokinetics of emicizumab prophylaxis given every 4 weeks in people with haemophilia A (HAVEN 4): a multicentre, open-label, non-randomised phase 3 study. Lancet Haematol. 2019 Jun;6(6):e295-e305. doi: 10.1016/S2352-3026(19)30054-7. Epub 2019 Apr 16.

  PMID: 31003963 DERIVED

MeSH Terms

Conditions

Hemophilia A

Interventions

emicizumab

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

Limitations and Caveats

Given the small number of adolescent participants, the results of the Haemo-QoL-SF questionnaire should be interpreted with caution.

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: NON RANDOMIZED
• Masking: NONE
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 21, 2016
• First Posted: January 13, 2017
• Study Start: January 30, 2017
• Primary Completion: December 15, 2017
• Study Completion: June 29, 2022
• Last Updated: January 11, 2023
• Results First Posted: December 26, 2018

Record last verified: 2022-12

Locations

US (4); JP (4); PL (2); AU (2); BE (2); ES (3)