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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/study/NCT03020160




Registration number
NCT03020160
Ethics application status
Date submitted
21/12/2016
Date registered
13/01/2017
Date last updated
11/01/2023

Titles & IDs
Public title
A Study to Evaluate the Efficacy, Safety, Pharmacokinetics, and Pharmacodynamics of Emicizumab Given Every 4 Weeks in Participants With Hemophilia A
Scientific title
A Multicenter, Open-Label, Phase III Study to Evaluate the Efficacy, Safety, Pharmacokinetics, and Pharmacodynamics of Emicizumab Given Every 4 Weeks (Q4W) in Patients With Hemophilia A
Secondary ID [1] 0 0
2016-001094-33
Secondary ID [2] 0 0
BO39182
Universal Trial Number (UTN)
Trial acronym
HAVEN 4
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
Description of intervention(s) / exposure
Treatment: Drugs - Emicizumab

Experimental: Emicizumab: PK Run-in Cohort - 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.

Experimental: Emicizumab: Expansion Cohort - 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.


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

Outcomes
Primary outcome [1] 0 0
Expansion Part: Annualized Bleeding Rate (ABR) for Treated Bleeds
Timepoint [1] 0 0
From Baseline to at least 24 weeks
Primary outcome [2] 0 0
Expansion Part: Annualized Bleeding Rate (ABR) for All Bleeds
Timepoint [2] 0 0
From Baseline to at least 24 weeks
Primary outcome [3] 0 0
Expansion Part: Annualized Bleeding Rate (ABR) for Treated Spontaneous Bleeds
Timepoint [3] 0 0
From Baseline to at least 24 weeks
Primary outcome [4] 0 0
Expansion Part: Annualized Bleeding Rate (ABR) for Treated Joint Bleeds
Timepoint [4] 0 0
From Baseline to at least 24 weeks
Primary outcome [5] 0 0
Expansion Part: Annualized Bleeding Rate (ABR) for Treated Target Joint Bleeds
Timepoint [5] 0 0
From Baseline to at least 24 weeks
Secondary outcome [1] 0 0
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)
Timepoint [1] 0 0
Baseline, Week 25
Secondary outcome [2] 0 0
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
Timepoint [2] 0 0
Baseline, Week 25
Secondary outcome [3] 0 0
Expansion Part: Change From Baseline to Week 25 in the Haem-A-QoL Questionnaire Physical Health Score for Adult Participants (=18 Years of Age)
Timepoint [3] 0 0
Baseline, Week 25
Secondary outcome [4] 0 0
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
Timepoint [4] 0 0
Baseline, Week 25
Secondary outcome [5] 0 0
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)
Timepoint [5] 0 0
Baseline, Week 25
Secondary outcome [6] 0 0
Expansion Part: Change From Baseline to Week 25 in the European Quality of Life-5 Dimensions-5 Levels (EQ-5D-5L) Questionnaire Visual Analogue Scale (VAS) Score
Timepoint [6] 0 0
Baseline, Week 25
Secondary outcome [7] 0 0
Expansion Part: Percentage of Participants With a Meaningful Improvement From Baseline to Week 25 in the EQ-5D-5L Questionnaire VAS Score
Timepoint [7] 0 0
Baseline, Week 25
Secondary outcome [8] 0 0
Expansion Part: Change From Baseline to Week 25 in the EQ-5D-5L Questionnaire Index Utility Score
Timepoint [8] 0 0
Baseline, Week 25
Secondary outcome [9] 0 0
Expansion Part: Percentage of Participants With a Meaningful Improvement From Baseline to Week 25 in the EQ-5D-5L Questionnaire Index Utility Score
Timepoint [9] 0 0
Baseline, Week 25
Secondary outcome [10] 0 0
Expansion Part: Proportion of Days Away From Work to Expected Days at Work in the Previous Four Weeks
Timepoint [10] 0 0
Predose at Baseline, Weeks 13 and 25
Secondary outcome [11] 0 0
Expansion Part: Proportion of Days Away From School to Expected Days at School in the Previous Four Weeks
Timepoint [11] 0 0
Predose at Baseline, Weeks 13 and 25
Secondary outcome [12] 0 0
Expansion Part: Number of Days Hospitalized
Timepoint [12] 0 0
From Baseline until at least 24 weeks of treatment (median [min-max] observation time: 25.57 [24.1-29.4] weeks)
Secondary outcome [13] 0 0
Expansion Part: Percentage of Participants Who Preferred Either the New Emicizumab Subcutaneous (SC) Treatment or Their Previous Hemophilia Intravenous (IV) Treatment, or Had No Preference, as Assessed Using the Emicizumab Preference Survey
Timepoint [13] 0 0
Predose at Week 17
Secondary outcome [14] 0 0
PK Run-In Part: Time to Reach Maximum Observed Plasma Concentration (Tmax) of Emicizumab
Timepoint [14] 0 0
Week 1 Day 1 predose (0 hours) and 8 hours postdose, and Week 1 Days 3 and 5, Week 2 Days 8 and 11, Week 3 Days 15 and 18, Week 4 Days 22 and 25, and Day 1 of Weeks 5, 21, 22, 23, 24, and 25
Secondary outcome [15] 0 0
PK Run-In Part: Maximum Observed Plasma Concentration (Cmax) of Emicizumab
Timepoint [15] 0 0
Week 1 Day 1 predose (0 hours) and 8 hours postdose, and Week 1 Days 3 and 5, Week 2 Days 8 and 11, Week 3 Days 15 and 18, Week 4 Days 22 and 25, and Day 1 of Weeks 5, 21, 22, 23, 24, and 25
Secondary outcome [16] 0 0
PK Run-In Part: Area Under the Plasma Concentration-Time Curve From Time Zero to End of Dosing Interval (AUC[0-tau]) of Emicizumab
Timepoint [16] 0 0
Week 1 Day 1 predose (0 hours) and 8 hours postdose, and Week 1 Days 3 and 5, Week 2 Days 8 and 11, Week 3 Days 15 and 18, Week 4 Days 22 and 25, and Day 1 of Weeks 5, 21, 22, 23, 24, and 25
Secondary outcome [17] 0 0
PK Run-In Part: Area Under the Plasma Concentration-Time Curve From Time Zero to Extrapolated Infinite Time (AUC[0-inf]) of Emicizumab
Timepoint [17] 0 0
Week 1 Day 1 predose (0 hours) and 8 hours postdose, and Week 1 Days 3 and 5, Week 2 Days 8 and 11, Week 3 Days 15 and 18, Week 4 Days 22 and 25, and Day 1 of Weeks 5, 21, 22, 23, 24, and 25
Secondary outcome [18] 0 0
PK Run-In Part: Apparent Plasma Terminal Half-Life (t1/2) of Emicizumab
Timepoint [18] 0 0
Week 1 Day 1 predose (0 hours) and 8 hours postdose, and Week 1 Days 3 and 5, Week 2 Days 8 and 11, Week 3 Days 15 and 18, Week 4 Days 22 and 25, and Day 1 of Weeks 5, 21, 22, 23, 24, and 25
Secondary outcome [19] 0 0
PK Run-In Part: Apparent Clearance (CL/F) of Emicizumab
Timepoint [19] 0 0
Week 1 Day 1 predose (0 hours) and 8 hours postdose, and Week 1 Days 3 and 5, Week 2 Days 8 and 11, Week 3 Days 15 and 18, Week 4 Days 22 and 25, and Day 1 of Weeks 5, 21, 22, 23, 24, and 25
Secondary outcome [20] 0 0
PK Run-In Part: Plasma Concentration of Emicizumab at Specified Timepoints
Timepoint [20] 0 0
Week 1 Day 1 predose and 8 hours postdose, and Week 1 Days 3 and 5, Week 2 Days 8 and 11, Week 3 Days 15 and 18, Week 4 Days 22 and 25, and Day 1 of Weeks 5, 6, 7, 8, 9, 11, 13, 15, 17, 19, 21, 22, 23, 24, and 25, and every 12 weeks thereafter to Week 265
Secondary outcome [21] 0 0
Expansion Part: Plasma Concentration of Emicizumab at Specified Timepoints
Timepoint [21] 0 0
Predose at Weeks 1, 2, 3, 4, 5, 9, 13, 17, 21, 25, 37, 49, 61, 73. 85, 97, 109, 121, 133, 145, 157, 169, 181, 193, 205, 217, 229, 241, and 253
Secondary outcome [22] 0 0
Number of Participants With at Least One Adverse Event
Timepoint [22] 0 0
From Baseline to study completion, dose up-titration, or change of dosing regimen, whichever occurred first (up to 5 years, 5 months)
Secondary outcome [23] 0 0
Number of Participants With at Least One Grade =3 Adverse Event
Timepoint [23] 0 0
From Baseline to study completion, dose up-titration, or change of dosing regimen, whichever occurred first (up to 5 years, 5 months)
Secondary outcome [24] 0 0
Number of Participants With at Least One Adverse Event Leading to Withdrawal From Treatment
Timepoint [24] 0 0
From Baseline to study completion, dose up-titration, or change of dosing regimen, whichever occurred first (up to 5 years, 5 months)
Secondary outcome [25] 0 0
Number of Participants With at Least One Adverse Event Related to Study Treatment
Timepoint [25] 0 0
From Baseline to study completion, dose up-titration, or change of dosing regimen, whichever occurred first (up to 5 years, 5 months)
Secondary outcome [26] 0 0
Number of Participants With at Least One Adverse Event of Changes From Baseline in Vital Signs
Timepoint [26] 0 0
From Baseline to study completion, dose up-titration, or change of dosing regimen, whichever occurred first (up to 5 years, 5 months)
Secondary outcome [27] 0 0
Number of Participants With at Least One Adverse Event of Changes From Baseline in Physical Examination Findings
Timepoint [27] 0 0
From Baseline to study completion, dose up-titration, or change of dosing regimen, whichever occurred first (up to 5 years, 5 months)
Secondary outcome [28] 0 0
Number of Participants With at Least One Shift in Clinical Laboratory Parameters From Baseline World Health Organization (WHO) Toxicity Scale Grade 0-2 to Post-Baseline WHO Grade 3 or 4
Timepoint [28] 0 0
From Baseline to study completion, dose up-titration, or change of dosing regimen, whichever occurred first (up to 5 years, 5 months)
Secondary outcome [29] 0 0
Number of Participants With at Least One Local Injection-Site Reaction
Timepoint [29] 0 0
From Baseline to study completion, dose up-titration, or change of dosing regimen, whichever occurred first (up to 5 years, 5 months)
Secondary outcome [30] 0 0
Number of Participants With at Least One Thromboembolic Event
Timepoint [30] 0 0
From Baseline to study completion, dose up-titration, or change of dosing regimen, whichever occurred first (up to 5 years, 5 months)
Secondary outcome [31] 0 0
Number of Participants With at Least One Thrombotic Microangiopathy
Timepoint [31] 0 0
From Baseline to study completion, dose up-titration, or change of dosing regimen, whichever occurred first (up to 5 years, 5 months)
Secondary outcome [32] 0 0
Number of Participants With at Least One Systemic Hypersensitivity, Anaphylaxis, or Anaphylactoid Reaction
Timepoint [32] 0 0
From Baseline to study completion, dose up-titration, or change of dosing regimen, whichever occurred first (up to 5 years, 5 months)
Secondary outcome [33] 0 0
Number of Participants With Anti-Drug Antibodies to Emicizumab at Any Time Post-Baseline During the Study
Timepoint [33] 0 0
Baseline, Weeks 5, 9, 13, 17, 21, and 25, and every 12 weeks thereafter until study completion (up to 5 years, 5 months)
Secondary outcome [34] 0 0
Number of Participants With De Novo Development of Anti-Factor VIII (FVIII) Antibodies
Timepoint [34] 0 0
Baseline, Weeks 9 and 17 (for non-inhibitor subjects only), Week 25, and every 12 weeks thereafter until study completion (up to 5 years, 5 months)
Secondary outcome [35] 0 0
Long-Term Efficacy of Emicizumab: Model-Based Annualized Bleeding Rates (ABR) for Treated Bleeds, All Bleeds, Treated Spontaneous Bleeds, Treated Joint Bleeds, and Treated Target Joint Bleeds
Timepoint [35] 0 0
From start of emicizumab treatment to study completion, dose up-titration, or change of dosing regimen (median [min-max] efficacy period for all emicizumab participants: 191.14 [28.0-264.4] weeks)
Secondary outcome [36] 0 0
Long-Term Efficacy of Emicizumab: Mean Calculated Annualized Bleeding Rates (ABR) for Treated Bleeds, All Bleeds, Treated Spontaneous Bleeds, Treated Joint Bleeds, and Treated Target Joint Bleeds
Timepoint [36] 0 0
From start of emicizumab treatment to study completion, dose up-titration, or change of dosing regimen (median [min-max] efficacy period for all emicizumab participants: 191.14 [28.0-264.4] weeks)
Secondary outcome [37] 0 0
Long-Term Efficacy of Emicizumab: Median Calculated Annualized Bleeding Rates (ABR) for Treated Bleeds, All Bleeds, Treated Spontaneous Bleeds, Treated Joint Bleeds, and Treated Target Joint Bleeds
Timepoint [37] 0 0
From start of emicizumab treatment to study completion, dose up-titration, or change of dosing regimen (median [min-max] efficacy period for all emicizumab participants: 191.14 [28.0-264.4] weeks)
Secondary outcome [38] 0 0
Long-Term Efficacy of Emicizumab: Mean Calculated Annualized Bleeding Rates (ABR) for Treated Bleeds Per 12-Week Intervals Over Time
Timepoint [38] 0 0
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, 229-240, 241-252, and 253-264 weeks
Secondary outcome [39] 0 0
Long-Term Efficacy of Emicizumab: Median Calculated Annualized Bleeding Rates (ABR) for Treated Bleeds Per 12-Week Intervals Over Time
Timepoint [39] 0 0
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, 229-240, 241-252, and 253-264 weeks
Secondary outcome [40] 0 0
Long-Term Efficacy of Emicizumab: Mean Calculated Annualized Bleeding Rates (ABR) for All Bleeds Per 12-Week Intervals Over Time
Timepoint [40] 0 0
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, 229-240, 241-252, and 253-264 weeks
Secondary outcome [41] 0 0
Long-Term Efficacy of Emicizumab: Median Calculated Annualized Bleeding Rates (ABR) for All Bleeds Per 12-Week Intervals Over Time
Timepoint [41] 0 0
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, 229-240, 241-252, and 253-264 weeks
Secondary outcome [42] 0 0
Long-Term Efficacy of Emicizumab: Mean Calculated Annualized Bleeding Rates (ABR) for Treated Spontaneous Bleeds Per 12-Week Intervals Over Time
Timepoint [42] 0 0
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, 229-240, 241-252, and 253-264 weeks
Secondary outcome [43] 0 0
Long-Term Efficacy of Emicizumab: Median Calculated Annualized Bleeding Rates (ABR) for Treated Spontaneous Bleeds Per 12-Week Intervals Over Time
Timepoint [43] 0 0
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, 229-240, 241-252, and 253-264 weeks

Eligibility
Key inclusion criteria
* 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
Minimum age
12 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
* 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

Study design
Purpose of the study
Prevention
Allocation to intervention
Non-randomised 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
Completed
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
30/01/2017
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
29/06/2022
Sample size
Target
Accrual to date
Final
48
Recruitment in Australia
Recruitment state(s)
QLD,SA
Recruitment hospital [1] 0 0
Royal Brisbane Hospital; Clinical Haematology - Brisbane
Recruitment hospital [2] 0 0
Royal Adelaide Hospital; Haematology Clinical Trials - Adelaide
Recruitment postcode(s) [1] 0 0
4029 - Brisbane
Recruitment postcode(s) [2] 0 0
5000 - Adelaide
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
Indiana
Country [3] 0 0
United States of America
State/province [3] 0 0
Michigan
Country [4] 0 0
United States of America
State/province [4] 0 0
North Carolina
Country [5] 0 0
Belgium
State/province [5] 0 0
Bruxelles
Country [6] 0 0
Belgium
State/province [6] 0 0
Leuven
Country [7] 0 0
Japan
State/province [7] 0 0
Hokkaido
Country [8] 0 0
Japan
State/province [8] 0 0
Nara
Country [9] 0 0
Japan
State/province [9] 0 0
Tokyo
Country [10] 0 0
Poland
State/province [10] 0 0
Warsaw
Country [11] 0 0
Poland
State/province [11] 0 0
Wroclaw
Country [12] 0 0
Spain
State/province [12] 0 0
Madrid
Country [13] 0 0
Spain
State/province [13] 0 0
Sevilla
Country [14] 0 0
Spain
State/province [14] 0 0
Valencia

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
Trial website
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

No information has been provided regarding IPD availability


What supporting documents are/will be available?




Results publications and other study-related documents

No documents have been uploaded by study researchers.

Results are available at https://clinicaltrials.gov/study/NCT03020160