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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/show/NCT02622321




Registration number
NCT02622321
Ethics application status
Date submitted
2/12/2015
Date registered
4/12/2015
Date last updated
13/05/2020

Titles & IDs
Public title
A Study to Evaluate the Efficacy, Safety, and Pharmacokinetics of Prophylactic Emicizumab Versus no Prophylaxis in Hemophilia A Participants With Inhibitors
Scientific 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
Secondary ID [1] 0 0
2015-002866-21
Secondary ID [2] 0 0
BH29884
Universal Trial Number (UTN)
Trial acronym
HAVEN 1
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Hemophilia A 0 0
Condition category
Condition code
Blood 0 0 0 0
Clotting disorders
Human Genetics and Inherited Disorders 0 0 0 0
Other human genetics and inherited disorders

Intervention/exposure
Study type
Interventional(has expanded access)
Description of intervention(s) / exposure
Treatment: Drugs - Emicizumab
Treatment: Drugs - rFVIIa
Treatment: Drugs - aPCC

Experimental: Arm A (Episodic Treatment): Emicizumab - Participants, who received episodic treatment with bypassing agents prior to study entry, will receive prophylactic emicizumab. Participants will continue to receive episodic bypassing agent therapy to treat breakthrough bleeds, with rFVIIa and/or activated prothrombin complex concentrate (aPCC).

Active Comparator: Arm B (Episodic Treatment): No Emicizumab - Participants, who received episodic treatment with bypassing agents prior to study entry, will not receive emicizumab prophylaxis. These participants will have the opportunity to switch to emicizumab prophylaxis after at least 24 weeks on-study. Participants will continue to receive bypassing agent therapy to treat breakthrough bleeds, with rFVIIa and/or aPCC.

Experimental: Arm C (Prophylactic Treatment): Emicizumab - Participants, who received prophylactic bypassing agents prior to study entry, will receive prophylactic emicizumab. Participants will continue to receive bypassing agent therapy to treat breakthrough bleeds, with rFVIIa and/or aPCC.

Experimental: Arm D (Episodic or Prophylactic Treatment): Emicizumab - Participants who received episodic bypassing agents while participating in Study BH29768 but were unable to enroll in Arms A or B, or participants who received prophylactic bypassing agents but were unable to enroll in Arm C, will be enrolled in this arm to receive prophylactic emicizumab. Participants will continue to receive bypassing agent therapy to treat breakthrough bleeds, with rFVIIa and/or aPCC.


Treatment: Drugs: Emicizumab
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.

Treatment: Drugs: rFVIIa
Participants will continue to receive rFVIIa.

Treatment: Drugs: aPCC
Participants will continue to receive aPCC.

Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Arm A (Episodic Treatment): Emicizumab and Arm B (Episodic Treatment): No Emicizumab: Annualized Bleed Rate (ABR) for Treated Bleeds - Number of treated bleeds over the efficacy period was assessed through ABR using a negative binomial (NB) regression model. Treated bleeds were defined as a bleed for which coagulation factors were administered. Bleeds due to surgery/procedure were excluded.
Timepoint [1] 0 0
From Baseline up to clinical cut-off date (25 Oct 2016) (up to approximately 1 year)
Secondary outcome [1] 0 0
Arm A (Episodic Treatment): Emicizumab and Arm B (Episodic Treatment): No Emicizumab: ABR for All Bleeds - Number of all bleeds over the efficacy period was assessed through ABR using an NB regression model. All bleeds included both treated (with coagulation factors) and not treated bleeds. Bleeds due to surgery/procedure were excluded.
Timepoint [1] 0 0
From Baseline up to clinical cut-off date (25 Oct 2016) (up to approximately 1 year)
Secondary outcome [2] 0 0
Arm A (Episodic Treatment): Emicizumab and Arm Anis: Episodic Bypassing Agents in NIS BH29768: ABR for All Bleeds - Number of all bleeds over the efficacy period was assessed through ABR using an NB regression model. All bleeds included both treated (with coagulation factors) and not treated bleeds. Bleeds due to surgery/procedure were excluded. Intra-participant comparison of ABR of all bleeds prior to study entry, while receiving episodic bypassing agents during non-interventional study (NIS) BH29768 (NCT02476942) (Arm Anis), with ABR of all bleeds on emicizumab prophylaxis (in this study) (Arm A) was reported.
Timepoint [2] 0 0
For Arm Anis: up to 52 weeks before study entry (assessed retrospectively at baseline); for Arm A: From Baseline up to clinical cut-off date (25 Oct 2016) (up to approximately 1 year)
Secondary outcome [3] 0 0
Arm A (Episodic Treatment): Emicizumab and Arm Anis: Episodic Bypassing Agents in NIS BH29768: ABR for Treated Bleeds - Number of treated bleeds over the efficacy period was assessed through ABR using an NB regression model. Treated bleeds were defined as a bleed for which coagulation factors were administered. Bleeds due to surgery/procedure were excluded. Intra-participant comparison of ABR of treated bleeds prior to study entry, while receiving episodic bypassing agents during NIS BH29768 (Arm Anis), with ABR of treated bleeds on emicizumab prophylaxis (in this study) (Arm A) was reported.
Timepoint [3] 0 0
For Arm Anis: up to 52 weeks before study entry (assessed retrospectively at baseline); for Arm A: From Baseline up to clinical cut-off date (25 Oct 2016) (up to approximately 1 year)
Secondary outcome [4] 0 0
Arm A (Episodic Treatment): Emicizumab and Arm B (Episodic Treatment): No Emicizumab: ABR for Treated Joint Bleeds - Number of treated joint bleeds over the efficacy period was assessed through ABR using an NB regression model. Treated joint bleeds were defined as treated bleeds in a joint associated with unusual sensation (aura) in a joint, in combination with another symptom: unusual sensation, swelling/warmth, pain/decreased range of motion (RoM), difficulty moving the joint. Bleeds due to surgery/procedure were excluded.
Timepoint [4] 0 0
From Baseline up to clinical cut-off date (25 Oct 2016) (up to approximately 1 year)
Secondary outcome [5] 0 0
Arm C (Prophylactic Treatment): Emicizumab and Arm Cnis: Prophylactic Bypassing Agents in NIS BH29768: ABR for All Bleeds - Number of all bleeds over the efficacy period was assessed through ABR using an NB regression model. All bleeds included both treated (with coagulation factors) and not treated bleeds. Bleeds due to surgery/procedure were excluded. Intra-participant comparison of ABR of all bleeds prior to study entry, while receiving prophylactic bypassing agents during NIS BH29768 (Arm Cnis), with ABR of all bleeds on emicizumab prophylaxis (in this study) (Arm C) was reported.
Timepoint [5] 0 0
For Arm Cnis: up to 52 weeks before study entry (assessed retrospectively at baseline); for Arm C: From Baseline up to clinical cut-off date (25 Oct 2016) (up to approximately 1 year)
Secondary outcome [6] 0 0
Arm C (Prophylactic Treatment): Emicizumab and Arm Cnis: Prophylactic Bypassing Agents in NIS BH29768: ABR for Treated Bleeds - Number of treated bleeds over the efficacy period was assessed through ABR using an NB regression model. Treated bleeds were defined as a bleed for which coagulation factors were administered. Bleeds due to surgery/procedure were excluded. Intra-participant comparison of ABR of treated bleeds prior to study entry, while receiving prophylactic bypassing agents during NIS BH29768 (Arm Cnis), with ABR of treated bleeds on emicizumab prophylaxis (in this study) (Arm C) was reported.
Timepoint [6] 0 0
For Arm Cnis: up to 52 weeks before study entry (assessed retrospectively at baseline); for Arm C: From Baseline up to clinical cut-off date (25 Oct 2016) (up to approximately 1 year)
Secondary outcome [7] 0 0
Arm A (Episodic Treatment): Emicizumab and Arm B (Episodic Treatment): No Emicizumab: ABR for Treated Spontaneous Bleeds - Number of treated spontaneous bleeds over the efficacy period was assessed through ABR using an NB regression model. Treated spontaneous bleeds were defined as treated (with coagulation factors) bleeds with no known contributing factor (e.g., trauma, surgery).
Timepoint [7] 0 0
From Baseline up to clinical cut-off date (25 Oct 2016) (up to approximately 1 year)
Secondary outcome [8] 0 0
Arm A (Episodic Treatment): Emicizumab and Arm B (Episodic Treatment): No Emicizumab: ABR for Treated Target Joint Bleeds - Number of treated target joint bleeds over the efficacy period was assessed through ABR using an NB regression model. Treated target joint bleeds included treated (with coagulation factors) joint bleeds in a target joint, defined as a joint in which greater than or equal to (>/=) 3 treated joint bleeds occurred during the last 24 weeks prior to study entry. Bleeds due to surgery/procedure are excluded.
Timepoint [8] 0 0
From Baseline up to clinical cut-off date (25 Oct 2016) (up to approximately 1 year)
Secondary outcome [9] 0 0
Arm A (Episodic Treatment): Emicizumab and Arm B (Episodic Treatment): No Emicizumab: Hemophilia-Specific Quality of Life (Haem-A-QoL) Questionnaire Physical Health Score in Adult Participants (>/=18 Years Old) - Haem-A-QoL questionnaire has been developed and used in hemophilia A participants. As a hemophilia-specific questionnaire, this measure assesses very specific aspects of dealing with hemophilia. This questionnaire consists of items pertaining to 10 domains specific to living with hemophilia. The 10 domains are: physical health, sports and leisure, school and work, dealing with hemophilia, family planning, feeling, relationships, treatment, view of yourself, and outlook for the future. The total score for each domain range from 0 to 100 with lower scores reflective of better quality of life. Physical Health domain score is reported (range 0 to 100, with lower scores reflective of better physical health).
Timepoint [9] 0 0
Week 25
Secondary outcome [10] 0 0
Arm A (Episodic Treatment): Emicizumab and Arm B (Episodic Treatment): No Emicizumab: Haem-A-QoL Questionnaire Total Score in Adult Participants (>/=18 Years Old) - Haem-A-QoL questionnaire has been developed and used in hemophilia A participants. As a hemophilia-specific questionnaire, this measure assesses very specific aspects of dealing with hemophilia. This questionnaire consists of items pertaining to 10 domains specific to living with hemophilia. The 10 domains are: physical health, sports and leisure, school and work, dealing with hemophilia, family planning, feeling, relationships, treatment, view of yourself, and outlook for the future. The total score for each domain range from 0 to 100 with lower scores reflective of better quality of life. Haem-A-QoL Questionnaire Total Score is the average of the all domain scores and range from 0 to 100, with lower scores reflective of better quality of life.
Timepoint [10] 0 0
Week 25
Secondary outcome [11] 0 0
Arm A (Episodic Treatment): Emicizumab and Arm B (Episodic Treatment): No Emicizumab: European Quality of Life-5 Dimensions-5 Levels (EQ-5D-5L) Visual Analog Scale Score - EQ-5D-5L is a standardized, participant-rated questionnaire to assess health-related quality of life. The EQ-5D-5L includes 2 components: the EQ-5D-5L health state profile (descriptive system) and the EQ-5D-5L Visual Analog Scale. The Visual Analogue Scale is designed to rate the participant's current health state on a scale from 0 to 100, where 0 represents the worst imaginable health state and 100 represents the best imaginable health state.
Timepoint [11] 0 0
Week 25
Secondary outcome [12] 0 0
Arm A (Episodic Treatment): Emicizumab and Arm B (Episodic Treatment): No Emicizumab: EQ-5D-5L Index Utility Score - EQ-5D-5L is a standardized, participant-rated questionnaire to assess health-related quality of life. The EQ-5D-5L includes 2 components: the EQ-5D-5L health state profile (descriptive system) and the EQ-5D-5L Visual Analog Scale. The EQ-5D-5L health state profile is designed to record the participant's current health state in 5 domains: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Responses from the five domains are used to calculate a single utility index value ranging from 1 to 5, where 1 indicates better health state (no problems) and 5 indicates worst health state (confined to bed).
Timepoint [12] 0 0
Week 25
Secondary outcome [13] 0 0
Arm A (Episodic Treatment): Emicizumab and Arm B (Episodic Treatment): No Emicizumab: Hemophilia-Specific Quality of Life - Short Form (Haemo-Qol-SF) Questionnaire Total Score in Adolescents Participants (12-17 Years Old) - The Haemo-QoL-SF contains 35 items, which cover nine domains considered relevant for the children's health-related quality of life (physical health, feelings, view of yourself, family, friends, other people, sports and school, dealing with hemophilia and treatment). Items are rated with five respective response options: never, seldom, sometimes, often, and always. Haemo-QoL-SF total score range from 0 to 100, where lower scores reflect better health-related quality of life. Data for this outcome was to be analyzed only if >3 participant (in each arm) have available data.
Timepoint [13] 0 0
Week 25
Secondary outcome [14] 0 0
Percentage of Participants With Anti-Emicizumab Antibodies
Timepoint [14] 0 0
Baseline up to approximately 1 year
Secondary outcome [15] 0 0
Plasma Trough Concentration of Emicizumab - Plasma concentrations of emicizumab were analyzed using a validated Enzyme Linked Immunosorbent Assay (ELISA). The lower limit of quantification (LLOQ) was 100 nanograms per milliliter (ng/mL).
Timepoint [15] 0 0
Arm A: Pre-dose (0 hour [hr]) on Weeks 1-5, 7, 9, 13, 17, 21, 25, 33, 41, 49; Arm B: Pre-dose (0 hr) on Weeks 25-29, 31, 33, 37, 41; Arm C: Pre-dose (0 hr) on Weeks 1-5, 7, 9, 13, 17, 21, 25, 33, 41; Arm D: Pre-dose (0 hr) on Weeks 1-5, 7, 9, 13

Eligibility
Key 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
Minimum age
12 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key 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

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 3
Type of endpoint(s)
Statistical methods / analysis

Recruitment
Recruitment status
Active, not recruiting
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW,VIC
Recruitment hospital [1] 0 0
Royal Prince Alfred Hospital; Haematology - Camperdown
Recruitment hospital [2] 0 0
The Alfred Hospital, Melbourne; Thrombosis and Haemostasis Unit - Melbourne
Recruitment postcode(s) [1] 0 0
2050 - Camperdown
Recruitment postcode(s) [2] 0 0
3004 - Melbourne
Recruitment outside Australia
Country [1] 0 0
United States of America
State/province [1] 0 0
California
Country [2] 0 0
United States of America
State/province [2] 0 0
Colorado
Country [3] 0 0
United States of America
State/province [3] 0 0
Georgia
Country [4] 0 0
United States of America
State/province [4] 0 0
Massachusetts
Country [5] 0 0
United States of America
State/province [5] 0 0
Michigan
Country [6] 0 0
United States of America
State/province [6] 0 0
New York
Country [7] 0 0
United States of America
State/province [7] 0 0
Oregon
Country [8] 0 0
United States of America
State/province [8] 0 0
Pennsylvania
Country [9] 0 0
United States of America
State/province [9] 0 0
Texas
Country [10] 0 0
United States of America
State/province [10] 0 0
Washington
Country [11] 0 0
Costa Rica
State/province [11] 0 0
San Jose
Country [12] 0 0
France
State/province [12] 0 0
Bron
Country [13] 0 0
France
State/province [13] 0 0
Le Kremlin Bicetre
Country [14] 0 0
France
State/province [14] 0 0
Lille
Country [15] 0 0
France
State/province [15] 0 0
Paris
Country [16] 0 0
Germany
State/province [16] 0 0
Bonn
Country [17] 0 0
Germany
State/province [17] 0 0
Hamburg
Country [18] 0 0
Germany
State/province [18] 0 0
Mörfelden-Walldorf
Country [19] 0 0
Italy
State/province [19] 0 0
Lombardia
Country [20] 0 0
Italy
State/province [20] 0 0
Toscana
Country [21] 0 0
Japan
State/province [21] 0 0
Aichi
Country [22] 0 0
Japan
State/province [22] 0 0
Hiroshima
Country [23] 0 0
Japan
State/province [23] 0 0
Hyogo
Country [24] 0 0
Japan
State/province [24] 0 0
Kanagawa
Country [25] 0 0
Japan
State/province [25] 0 0
Kitakyushu-shi
Country [26] 0 0
Japan
State/province [26] 0 0
Nara
Country [27] 0 0
Japan
State/province [27] 0 0
Tokyo
Country [28] 0 0
Korea, Republic of
State/province [28] 0 0
Seoul
Country [29] 0 0
New Zealand
State/province [29] 0 0
Auckland
Country [30] 0 0
Poland
State/province [30] 0 0
Gdansk
Country [31] 0 0
Poland
State/province [31] 0 0
Lublin
Country [32] 0 0
Poland
State/province [32] 0 0
Poznan
Country [33] 0 0
Poland
State/province [33] 0 0
Warsaw
Country [34] 0 0
South Africa
State/province [34] 0 0
Johannesburg
Country [35] 0 0
Spain
State/province [35] 0 0
Madrid
Country [36] 0 0
Spain
State/province [36] 0 0
Sevilla
Country [37] 0 0
Spain
State/province [37] 0 0
Valencia
Country [38] 0 0
Taiwan
State/province [38] 0 0
Taipei City
Country [39] 0 0
United Kingdom
State/province [39] 0 0
Cardiff
Country [40] 0 0
United Kingdom
State/province [40] 0 0
London
Country [41] 0 0
United Kingdom
State/province [41] 0 0
Oxford

Funding & Sponsors
Primary sponsor type
Commercial sector/Industry
Name
Hoffmann-La Roche
Address
Country
Other collaborator category [1] 0 0
Commercial sector/Industry
Name [1] 0 0
Chugai Pharmaceutical
Address [1] 0 0
Country [1] 0 0

Ethics approval
Ethics application status

Summary
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).
Trial website
https://clinicaltrials.gov/show/NCT02622321
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Clinical Trials
Address 0 0
Hoffmann-La Roche
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries

Summary results
Other publications