Clinical trial NCT02622321: A Study to Evaluate the Efficacy, Safety, and Pharmacokinetics of Prophylactic Emicizumab Versus no Prophylaxis in Hemophilia A Participants With Inhibitors
Official title: A Randomized, Multicenter, Open-Label, Phase III Clinical Trial to Evaluate the Efficacy, Safety, and Pharmacokinetics of Prophylactic Emicizumab Versus no Prophylaxis in Hemophilia A Patients With Inhibitors
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Hemophilia A
Lead sponsor: Hoffmann-La Roche
Sponsor class: INDUSTRY
Collaborators: name: Chugai Pharmaceutical
First posted: 2015-12-04
Enrollment: 113
Sex: ALL
Minimum age (years): 12
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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).


Eligibility criteria: Inclusion Criteria:

* 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

Exclusion Criteria:

* 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

Primary outcomes:
measure: Model-Based Annualized Bleed Rate (ABR) for Treated Bleeds, Arm A: Emicizumab Versus Arm B: No Prophylaxis
timeFrame: 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:
measure: Model-Based Annualized Bleed Rate (ABR) for All Bleeds, Arm A: Emicizumab Versus Arm B: No Prophylaxis
timeFrame: 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)
measure: Intra-Participant Comparison of the Model-Based Annualized Bleed Rate (ABR) for All Bleeds in Arm A: Emicizumab Versus Previous Episodic Bypassing Agents
timeFrame: 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
measure: Intra-Participant Comparison of the Model-Based Annualized Bleed Rate (ABR) for Treated Bleeds in Arm A: Emicizumab Versus Previous Episodic Bypassing Agents
timeFrame: 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
measure: Model-Based Annualized Bleed Rate (ABR) for Treated Joint Bleeds, Arm A: Emicizumab Versus Arm B: No Prophylaxis
timeFrame: 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)
measure: Intra-Participant Comparison of the Model-Based Annualized Bleed Rate (ABR) for All Bleeds in Arm C: Emicizumab Versus Previous Prophylactic Bypassing Agents
timeFrame: 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
measure: Intra-Participant Comparison of the Model-Based Annualized Bleed Rate (ABR) for Treated Bleeds in Arm C: Emicizumab Versus Previous Prophylactic Bypassing Agents
timeFrame: 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
measure: Model-Based Annualized Bleed Rate (ABR) for Treated Spontaneous Bleeds, Arm A: Emicizumab Versus Arm B: No Prophylaxis
timeFrame: 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)
measure: Model-Based Annualized Bleed Rate (ABR) for Treated Target Joint Bleeds, Arm A: Emicizumab Versus Arm B: No Prophylaxis
timeFrame: 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)
measure: Mean Calculated Annualized Bleed Rates (ABR) for Treated Bleeds, All Bleeds, Treated Spontaneous Bleeds, Treated Joint Bleeds, and Treated Target Joint Bleeds, Arm A: Emicizumab Versus Arm B: No Prophylaxis
timeFrame: 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)
measure: Median Calculated Annualized Bleed Rates (ABR) for Treated Bleeds, All Bleeds, Treated Spontaneous Bleeds, Treated Joint Bleeds, and Treated Target Joint Bleeds, Arm A: Emicizumab Versus Arm B: No Prophylaxis
timeFrame: 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)
measure: Percentage of Participants With 0 Bleeds for Treated Bleeds, All Bleeds, Treated Spontaneous Bleeds, Treated Joint Bleeds, and Treated Target Joint Bleeds, Arm A: Emicizumab Versus Arm B: No Prophylaxis
timeFrame: 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)
measure: Hemophilia-Specific Quality of Life (Haem-A-QoL) Questionnaire Physical Health Score at Week 25 in Adult Participants (>/=18 Years Old), Arm A: Emicizumab Versus Arm B: No Prophylaxis
timeFrame: Week 25
measure: Haem-A-QoL Questionnaire Total Score at Week 25 in Adult Participants (>/=18 Years Old), Arm A: Emicizumab Versus Arm B: No Prophylaxis
timeFrame: Week 25
measure: European Quality of Life-5 Dimensions-5 Levels (EQ-5D-5L) Visual Analog Scale Score at Week 25, Arm A: Emicizumab Versus Arm B: No Prophylaxis
timeFrame: Week 25
measure: EQ-5D-5L Index Utility Score at Week 25, Arm A: Emicizumab Versus Arm B: No Prophylaxis
timeFrame: Week 25
measure: Hemophilia-Specific Quality of Life - Short Form (Haemo-Qol-SF) Questionnaire Total Score at Baseline and Week 25 in Adolescent Participants (12-17 Years Old)
timeFrame: Baseline and Week 25 (for Arm B (Emi), Study Weeks are relative to first emicizumab dose)
measure: Long-Term Efficacy of Emicizumab: Model-Based Annualized Bleed Rates (ABR) for Treated Bleeds, All Bleeds, Treated Spontaneous Bleeds, Treated Joint Bleeds, and Treated Target Joint Bleeds, All Enrolled Participants
timeFrame: From start of emicizumab treatment to study completion (median [min-max] efficacy observation period for all participants: 109.29 [0.1-249.1] weeks)
measure: Long-Term Efficacy of Emicizumab: Mean Calculated Annualized Bleed Rates (ABR) for Treated Bleeds, All Bleeds, Treated Spontaneous Bleeds, Treated Joint Bleeds, and Treated Target Joint Bleeds, All Enrolled Participants
timeFrame: From start of emicizumab treatment to study completion (median [min-max] efficacy observation period for all participants: 109.29 [0.1-249.1] weeks)
measure: Long-Term Efficacy of Emicizumab: Median Calculated Annualized Bleed Rates (ABR) for Treated Bleeds, All Bleeds, Treated Spontaneous Bleeds, Treated Joint Bleeds, and Treated Target Joint Bleeds, All Enrolled Participants
timeFrame: From start of emicizumab treatment to study completion (median [min-max] efficacy observation period for all participants: 109.29 [0.1-249.1] weeks)
measure: Long-Term Efficacy of Emicizumab: Mean Calculated Annualized Bleed Rates (ABR) for Treated Bleeds Per 12-Week Intervals Over Time, All Enrolled Participants
timeFrame: 1-12, 13-24, 25-36, 37-48, 49-60, 61-72, 73-84, 85-96, 97-108, 109-120, 121-132, 133-144, 145-156, 157-168, 169-180, 181-192, 193-204, 205-216, 217-228, and 229-240 weeks
measure: Long-Term Efficacy of Emicizumab: Median Calculated Annualized Bleed Rates (ABR) for Treated Bleeds Per 12-Week Intervals Over Time, All Enrolled Participants
timeFrame: 1-12, 13-24, 25-36, 37-48, 49-60, 61-72, 73-84, 85-96, 97-108, 109-120, 121-132, 133-144, 145-156, 157-168, 169-180, 181-192, 193-204, 205-216, 217-228, and 229-240 weeks
measure: Long-Term Efficacy of Emicizumab: Mean Calculated Annualized Bleed Rates (ABR) for All Bleeds Per 12-Week Intervals Over Time, All Enrolled Participants
timeFrame: 1-12, 13-24, 25-36, 37-48, 49-60, 61-72, 73-84, 85-96, 97-108, 109-120, 121-132, 133-144, 145-156, 157-168, 169-180, 181-192, 193-204, 205-216, 217-228, and 229-240 weeks
measure: Long-Term Efficacy of Emicizumab: Median Calculated Annualized Bleed Rates (ABR) for All Bleeds Per 12-Week Intervals Over Time, All Enrolled Participants
timeFrame: 1-12, 13-24, 25-36, 37-48, 49-60, 61-72, 73-84, 85-96, 97-108, 109-120, 121-132, 133-144, 145-156, 157-168, 169-180, 181-192, 193-204, 205-216, 217-228, and 229-240 weeks
measure: Long-Term Efficacy of Emicizumab: Mean Calculated Annualized Bleed Rates (ABR) for Treated Spontaneous Bleeds Per 12-Week Intervals Over Time, All Enrolled Participants
timeFrame: 1-12, 13-24, 25-36, 37-48, 49-60, 61-72, 73-84, 85-96, 97-108, 109-120, 121-132, 133-144, 145-156, 157-168, 169-180, 181-192, 193-204, 205-216, 217-228, and 229-240 weeks
measure: Long-Term Efficacy of Emicizumab: Median Calculated Annualized Bleed Rates (ABR) for Treated Spontaneous Bleeds Per 12-Week Intervals Over Time, All Enrolled Participants
timeFrame: 1-12, 13-24, 25-36, 37-48, 49-60, 61-72, 73-84, 85-96, 97-108, 109-120, 121-132, 133-144, 145-156, 157-168, 169-180, 181-192, 193-204, 205-216, 217-228, and 229-240 weeks
measure: Safety Summary of the Overall Number and Percentage of Participants With at Least One Adverse Event, Severity Assessed According to the WHO Toxicity Grading Scale
timeFrame: From Baseline until study completion (median [min-max] safety observation period for all participants: 133.97 [0.1-249.1] weeks)
measure: Number of Participants Testing Negative or Positive for the Presence of Anti-Drug Antibodies (ADAs), Including Neutralizing ADAs, During the Study
timeFrame: From Baseline until study completion (median [min-max] safety observation period for all participants: 133.97 [0.1-249.1] weeks)
measure: Plasma Trough Concentrations of Emicizumab at Specified Timepoints
timeFrame: Pre-dose (0 hour [hr]) on Weeks 1-5, 7, 9, 13, 17, 21, 25, 33, 41, 49, 61, 73, 85, 97, 109, 121, 133, 145, 157, and 169 (For Arm B (Emi), Study Weeks are relative to first emicizumab dose)
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: Children's Hospital Los Angeles
state: California
city: Santa Monica
country: United States
facility: Santa Monica Oncology Center
state: California
city: Aurora
country: United States
facility: University of Colorado Denver, Children's Hospital
state: Colorado
city: Atlanta
country: United States
facility: Winship Cancer Institute
state: Georgia
city: Boston
country: United States
facility: Boston Childrens Hospital
state: Massachusetts
city: Detroit
country: United States
facility: Children's Hospital of Michigan; Pediatrics
state: Michigan
city: New York
country: United States
facility: Cornell Univ Medical College; Hematology-Oncolog
state: New York
city: Portland
country: United States
facility: Oregon Health & Science Uni ; Dept of Pediatrics
state: Oregon
city: Hershey
country: United States
facility: Pennsylvania State Hershey Medical Center; Division of Hematology/Oncology, H046
state: Pennsylvania
city: Houston
country: United States
facility: Univ of TX Health Science Ctr; Gulf States Hemo and Throm Ctr
state: Texas
city: Seattle
country: United States
facility: Bloodworks Northwest (formerly Puget Sound Blood Center); Hemophilia
state: Washington
city: Camperdown
country: Australia
facility: Royal Prince Alfred Hospital; Haematology
state: New South Wales
city: Melbourne
country: Australia
facility: The Alfred Hospital, Melbourne; Thrombosis and Haemostasis Unit
state: Victoria
city: San Jose
country: Costa Rica
facility: ICIC
city: Bron
country: France
facility: Hopital Cardio-vasculaire Louis Pradel; Hemostase clinique
city: Le Kremlin Bicetre
country: France
facility: CH de Bicetre; Centre de Traitement d' Hemophilie
city: Lille
country: France
facility: Hopital Cardiologique; Hematologie B
city: Paris
country: France
facility: Groupe Hospitalier Necker Enfants Malades
city: Bonn
country: Germany
facility: Universitätsklinikum Bonn; Institut für Experimentelle Hämatologie und Transfusionsmedizin
city: Hamburg
country: Germany
facility: CTC North GmbH & Co. KG am Universitätsklinikum Hamburg-Eppendorf
city: Mörfelden-Walldorf
country: Germany
facility: Hämophilie-Zentrum Rhein Main GmbH
city: Milano
country: Italy
facility: IRCCS Ca' Granda Ospedale Maggiore Policlinico; Centro Emofilia e Trombosi "Angelo Bianchi e Bonomi"
state: Lombardia
city: Firenze
country: Italy
facility: AOU Careggi; SOD Malattie Emorragiche
state: Toscana
city: Aichi
country: Japan
facility: Nagoya University Hospital
city: Hiroshima
country: Japan
facility: Hiroshima University Hospital
city: Hyogo
country: Japan
facility: Hyogo College of Medicine Hospital
city: Kanagawa
country: Japan
facility: St. Marianna University School of Medicine Hospital
city: Kitakyushu-shi
country: Japan
facility: Hospital of the University of Occupational and Environmental Health,Japan
city: Nara
country: Japan
facility: Nara Medical University Hospital
city: Tokyo
country: Japan
facility: Tokyo Medical University Hospital
city: Seoul
country: Korea, Republic of
facility: Severance Hospital
city: Auckland
country: New Zealand
facility: Auckland City Hospital; Auckland Haemophilia Centre
city: Gdansk
country: Poland
facility: Uniwersyteckie Centrum Kliniczne; Klinika Hematologii i Transplantologii
city: Lublin
country: Poland
facility: SPSK Nr1 Klinika Hematoo&Transpl.Szpiku
city: Poznań
country: Poland
facility: ALVAMED Lekarskie Gabinety Specjalistyczne
city: Warsaw
country: Poland
facility: Instytut Hematologii i Transfuzjologii; Klinika Zaburzeń Hemostazy i Chorób Wewnętrznych
city: Johannesburg
country: South Africa
facility: Charlotte Maxeke Johannesburg Hospital; Haemophilia Comprehensive Care Center
city: Madrid
country: Spain
facility: Hospital Universitario la Paz; Servicio de Hematologia
city: Sevilla
country: Spain
facility: Hospital Universitario Virgen del Rocio; Servicio de Hematologia
city: Valencia
country: Spain
facility: Hospital Universitario la Fe; Servicio de Hematologia
city: Taipei City
country: Taiwan
facility: National Taiwan Uni Hospital
city: Cardiff
country: United Kingdom
facility: Cardiff and Vale NHS Trust
city: London
country: United Kingdom
facility: St Thomas' Hospital; Haemostasis & Thromboisis Centre
city: Oxford
country: United Kingdom
facility: Oxford University Hospitals NHS Trust - Churchill Hospital
Study officials:
affiliation: Hoffmann-La Roche
name: Clinical Trials
role: STUDY_DIRECTOR
References:
citation: 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.
citation: 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.