Back to resultsA Study to Evaluate the Safety, Efficacy, Pharmacokinetics and Pharmacodynamics of Emicizumab in Participants With Mild or Moderate Hemophilia A Without FVIII Inhibitors (HAVEN 6)
Primary Purpose
Mild Hereditary Factor VIII Deficiency Disease Without Inhibitor, Moderate Hereditary Factor VIII Deficiency Disease Without Inhibitor, Hemophilia A
Status
Active
Phase
Phase 3
Locations
International
Study Type
Interventional
Intervention
Emicizumab
Sponsored by
About this trial
This is an interventional treatment trial for Mild Hereditary Factor VIII Deficiency Disease Without Inhibitor focused on measuring Mild Hemophilia A Without Factor VIII Inhibitors, Moderate Hemophilia A Without Factor VIII Inhibitors
Eligibility Criteria
Inclusion Criteria:
- Diagnosis of mild (FVIII level between >5% and <40%) or moderate (FVIII level between ≥1% and ≤5%) congenital Hemophilia A without FVIII inhibitors
- Weight ≥3 kilograms (kg)
- Need for prophylaxis based on investigator assessment
- A negative test for inhibitor (i.e., <0.6 Bethesda Units per milliliter [BU/mL]) within 8 weeks prior to enrollment
- No documented inhibitor (i.e., <0.6 BU/mL), FVIII half-life <6 hours, or FVIII recovery <66% in the last 5 years
- Documentation of the details of prophylactic or episodic FVIII treatment and of number of bleeding episodes for at least the last 24 weeks prior to enrollment
- Adequate hematologic hepatic and renal function
- For women of childbearing potential: agreement to remain abstinent or use contraception (as defined in the protocol) during the treatment period and for at least 24 weeks after the final dose of study drug
Exclusion Criteria:
- Inherited or acquired bleeding disorder other than mild or moderate congenital hemophilia A
- History of illicit drug or alcohol abuse within 48 weeks prior to screening, in the investigator's judgment
- Previous (within the last 12 months) or current treatment for thromboembolic disease or signs of thromboembolic disease
- Other conditions 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
- Planned surgery during the emicizumab loading dose phase (surgeries in participants on emicizumab from Week 5 onwards are allowed)
- Known HIV infection with CD4 counts <200 cells per microlitre (/μL)
- Concomitant disease, condition, significant abnormality on screening evaluation 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
- Receipt of any of the following: An investigational drug to treat or reduce the risk of hemophilic bleeds within 5 half-lives of last drug administration with the exception of prior emicizumab prophylaxis; A non-hemophilia-related investigational drug within last 30 days or 5 half-lives, whichever is shorter; or Any other investigational drug currently being administered or planned to be administered
- Inability to comply with the study protocol in the opinion of the investigator
- Pregnant or breastfeeding, or intending to become pregnant during the study (women of childbearing potential must have a negative serum pregnancy test result within 7 days prior to initiation of study drug)
Sites / Locations
- Childrens Hospital LA
- Hemophilia of Georgia Center for Bleeding & Clotting Disorders
- Children'S Healthcare of Atlanta
- Indiana Hemophilia & Thrombosis center
- University of Michigan, C.S. Mott Children's Hospital
- Washington Institute for Coagulation
- Cliniques Universitaires St-Luc
- UZ Leuven Gasthuisberg
- Kaye Edmonton Clinic
- Eastern Health - General Hospital
- Hopital Cardio-vasculaire Louis Pradel; Hemostase clinique
- CH de Bicetre; Centre de Traitement d' Hemophilie
- Groupe Hospitalier Necker Enfants Malades
- Universitätsklinikum Bonn; Institut für Experimentelle Hämatologie und Transfusionsmedizin
- Klinikum der Universität München, Campus Innenstadt; Hämostaseologische Ambulanz/Hämophiliezentrum
- Amsterdam UMC Location AMC
- Instytut Hematologii i Transfuzjologii; Klinika Zaburze? Hemostazy i Chorób Wewn?trznych
- Charlotte Maxeke Johannesburg Hospital; Haemophilia Comprehensive Care Center
- Hospital Universitario la Paz; Servicio de Hematologia
- Hospital Universitario Virgen del Rocio; Servicio de Hematologia
- Cardiff and Vale NHS Trust; Arthur Bloom Haemophilia Centre
- Royal Free Hospital; Haemophilia Centre
- Great Ormond street Hospital for Children NHS Foundation Trust; Haemophilia Centre
Arms of the Study
Arm 1
Arm Type
Experimental
Arm Label
Emicizumab
Arm Description
Participants with mild and moderate hemophilia A without factor VIII (FVIII) inhibitors will be enrolled to receive the emicizumab loading dose regimen followed by the participant's preference of one of 3 maintenance dose regimens.
Outcomes
Primary Outcome Measures
Model-Based Annualized Bleed Rate for Treated Bleeds
The number of treated bleeds over the efficacy period was estimated as an annualized bleed rate (ABR) using a negative binomial regression model, which accounts for different follow-up times. A treated bleed was 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.
Mean Calculated Annualized Bleed Rate for Treated Bleeds
The number of treated bleeds over the efficacy period is presented here as a calculated annualized bleed rate (ABR) that was annualized for each participant using the following formula: ABR = (number of bleeds/number of days during the efficacy period) x 365.25. A treated bleed was 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.
Median Calculated Annualized Bleed Rate for Treated Bleeds
The number of treated bleeds over the efficacy period is presented here as a calculated annualized bleed rate (ABR) that was annualized for each participant using the following formula: ABR = (number of bleeds/number of days during the efficacy period) x 365.25. A treated bleed was 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.
Secondary Outcome Measures
Model-Based Annualized Bleed Rate for All Bleeds
The number of all bleeds over the efficacy period was estimated as an annualized bleed rate (ABR) using a negative binomial regression model, which accounts for different follow-up times. 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 meant that 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. For non-treated bleeds, the 72-hour rule was implemented by calculating a treatment-free period of 72 hours from the bleed itself.
Mean Calculated Annualized Bleed Rate for All Bleeds
The number of all bleeds over the efficacy period is presented here as a calculated annualized bleed rate (ABR) that was annualized for each participant using the following formula: ABR = (number of bleeds/number of days during the efficacy period) x 365.25. 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 meant that 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. For non-treated bleeds, the 72-hour rule was implemented by calculating a treatment-free period of 72 hours from the bleed itself.
Median Calculated Annualized Bleed Rate for All Bleeds
The number of all bleeds over the efficacy period is presented here as a calculated annualized bleed rate (ABR) that was annualized for each participant using the following formula: ABR = (number of bleeds/number of days during the efficacy period) x 365.25. 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 meant that 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. For non-treated bleeds, the 72-hour rule was implemented by calculating a treatment-free period of 72 hours from the bleed itself.
Model-Based Annualized Bleed Rate for Treated Joint Bleeds
The number of treated joint bleeds over the efficacy period was estimated as an annualized bleed rate (ABR) using a negative binomial regression model, which accounts for different follow-up times. A treated joint bleed was defined as a bleed with type reported as "joint" based on 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, and the bleed 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.
Mean Calculated Annualized Bleed Rate for Treated Joint Bleeds
The number of treated joint bleeds over the efficacy period is presented here as a calculated annualized bleed rate (ABR) that was annualized for each participant using the following formula: ABR = (number of bleeds/number of days during the efficacy period) x 365.25. A treated joint bleed was defined as a bleed with type reported as "joint" based on 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, and the bleed 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.
Median Calculated Annualized Bleed Rate for Treated Joint Bleeds
The number of treated joint bleeds over the efficacy period is presented here as a calculated annualized bleed rate (ABR) that was annualized for each participant using the following formula: ABR = (number of bleeds/number of days during the efficacy period) x 365.25. A treated joint bleed was defined as a bleed with type reported as "joint" based on 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, and the bleed 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.
Model-Based Annualized Bleed Rate for Treated Target Joint Bleeds
The number of treated target joint bleeds over the efficacy period was estimated as an annualized bleed rate (ABR) using a negative binomial regression model, which accounts for different follow-up times. A treated target joint bleed was 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 or an unresolved target joint (target joint that does not fulfil ≤2 bleeds into this joint within a consecutive 12-month period), and the bleed 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.
Mean Calculated Annualized Bleed Rate for Treated Target Joint Bleeds
The number of treated target joint bleeds over the efficacy period is presented here as a calculated annualized bleed rate (ABR) that was annualized for each participant using the following formula: ABR = (number of bleeds/number of days during the efficacy period) x 365.25. A treated target joint bleed was 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 or an unresolved target joint (target joint that does not fulfil ≤2 bleeds into this joint within a consecutive 12-month period), and the bleed 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.
Median Calculated Annualized Bleed Rate for Treated Target Joint Bleeds
The number of treated target joint bleeds over the efficacy period is presented here as a calculated annualized bleed rate (ABR) that was annualized for each participant using the following formula: ABR = (number of bleeds/number of days during the efficacy period) x 365.25. A treated target joint bleed was 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 or an unresolved target joint (target joint that does not fulfil ≤2 bleeds into this joint within a consecutive 12-month period), and the bleed 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.
Model-Based Annualized Bleed Rate for Treated Spontaneous Bleeds
The number of treated spontaneous bleeds over the efficacy period was estimated as an annualized bleed rate (ABR) using a negative binomial regression model, which accounts for different follow-up times. A treated spontaneous bleed was defined as a treated bleed (bleed directly followed by a hemophilia medication reported to be a "treatment for bleed") with no other known contributing factor such as trauma or procedure/surgery. 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.
Mean Calculated Annualized Bleed Rate for Treated Spontaneous Bleeds
The number of treated spontaneous bleeds over the efficacy period is presented here as a calculated annualized bleed rate (ABR) that was annualized for each participant using the following formula: ABR = (number of bleeds/number of days during the efficacy period) x 365.25. A treated spontaneous bleed was defined as a treated bleed (bleed directly followed by a hemophilia medication reported to be a "treatment for bleed") with no other known contributing factor such as trauma or procedure/surgery. 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.
Median Calculated Annualized Bleed Rate for Treated Spontaneous Bleeds
The number of treated spontaneous bleeds over the efficacy period is presented here as a calculated annualized bleed rate (ABR) that was annualized for each participant using the following formula: ABR = (number of bleeds/number of days during the efficacy period) x 365.25. A treated spontaneous bleed was defined as a treated bleed (bleed directly followed by a hemophilia medication reported to be a "treatment for bleed") with no other known contributing factor such as trauma or procedure/surgery. 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.
CATCH Questionnaire for Adult Participants: Change From Baseline in the Daily Activity Risk Perception and Impact Domain Scores Over Time
CATCH = Comprehensive Assessment Tool of Challenges in Hemophilia
CATCH Questionnaire for Adult Participants: Change From Baseline in the Social Activity Risk Perception and Impact Domain Scores Over Time
CATCH = Comprehensive Assessment Tool of Challenges in Hemophilia
CATCH Questionnaire for Adult Participants: Change From Baseline in the Recreational Activity Risk Perception and Impact Domain Scores Over Time
CATCH = Comprehensive Assessment Tool of Challenges in Hemophilia
CATCH Questionnaire for Adult Participants: Change From Baseline in the Work Impact Domain Score Over Time
CATCH = Comprehensive Assessment Tool of Challenges in Hemophilia
CATCH Questionnaire for Adult Participants: Change From Baseline in the Preoccupation Domain Score Over Time
CATCH = Comprehensive Assessment Tool of Challenges in Hemophilia
CATCH Questionnaire for Adult Participants: Change From Baseline in the Treatment Burden Domain Score Over Time
CATCH = Comprehensive Assessment Tool of Challenges in Hemophilia
CATCH Questionnaire for Adult Participants: Number of Participants by Responses to Their Level of Pain Associated With a Bleed Over Time
CATCH = Comprehensive Assessment Tool of Challenges in Hemophilia
CATCH Questionnaire for Adult Participants: Number of Participants by Responses to Their Level of Pain in Target Joints Over Time
CATCH = Comprehensive Assessment Tool of Challenges in Hemophilia
CATCH Questionnaire for Adult Participants: Number of Participants by Responses to Their Level of Pain at Its Worst Over Time
CATCH = Comprehensive Assessment Tool of Challenges in Hemophilia
CATCH Questionnaire for Adult Participants: Number of Participants by Responses to Their Level of Pain at Its Least Over Time
CATCH = Comprehensive Assessment Tool of Challenges in Hemophilia
CATCH Questionnaire for Adult Participants: Number of Participants by Responses to Their Level of Pain on Average Over Time
CATCH = Comprehensive Assessment Tool of Challenges in Hemophilia
CATCH Questionnaire for Pediatric Participants: Change From Baseline in the Daily Activity Risk Perception and Impact Domain Score Over Time
CATCH = Comprehensive Assessment Tool of Challenges in Hemophilia
CATCH Questionnaire for Pediatric Participants: Change From Baseline in the Social Activity Risk Perception and Impact Domain Score Over Time
CATCH = Comprehensive Assessment Tool of Challenges in Hemophilia
CATCH Questionnaire for Pediatric Participants: Change From Baseline in the Recreational Activity Risk Perception and Impact Domain Score Over Time
CATCH = Comprehensive Assessment Tool of Challenges in Hemophilia
CATCH Questionnaire for Pediatric Participants: Change From Baseline in the School Impact Domain Score Over Time
CATCH = Comprehensive Assessment Tool of Challenges in Hemophilia
CATCH Questionnaire for Pediatric Participants: Change From Baseline in the Preoccupation Domain Score Over Time
CATCH = Comprehensive Assessment Tool of Challenges in Hemophilia
CATCH Questionnaire for Pediatric Participants: Change From Baseline in the Treatment Burden Domain Score Over Time
CATCH = Comprehensive Assessment Tool of Challenges in Hemophilia
CATCH Questionnaire for Pediatric Participants: Number of Participants by Responses to Their Level of Pain Associated With a Bleed Over Time
CATCH = Comprehensive Assessment Tool of Challenges in Hemophilia
CATCH Questionnaire for Pediatric Participants: Number of Participants by Responses to Their Level of Pain at Its Worst Over Time
CATCH = Comprehensive Assessment Tool of Challenges in Hemophilia
CATCH Questionnaire for Caregivers: Change From Baseline in the Preoccupation Domain Score Over Time
CATCH = Comprehensive Assessment Tool of Challenges in Hemophilia
CATCH Questionnaire for Caregivers: Change From Baseline in the Treatment Burden Domain Score Over Time
CATCH = Comprehensive Assessment Tool of Challenges in Hemophilia
Percentage of Participants Who Prefer Emicizumab SC Treatment, Their Previous Hemophilia IV Treatment, or Have No Preference, as Assessed Through Use of the Emicizumab Preference Survey at Week 17
The Emicizumab Preference Survey is a fit-for-purpose questionnaire developed by the sponsor to record the participant's preference for treatment with subcutaneous (SC) emicizumab, intravenous (IV) factor VIIII (FVIII), or no preference. The 95% confidence intervals were calculated using the Pearson-Clopper method.
Percentage of Caregivers Who Prefer Emicizumab SC Treatment, Their Child's Previous Hemophilia IV Treatment, or Have No Preference, as Assessed Through Use of the Emicizumab Preference Survey at Week 17
The Emicizumab Preference Survey is a fit-for-purpose questionnaire developed by the sponsor to record the caregiver's preference for their child's treatment with subcutaneous (SC) emicizumab, intravenous (IV) factor VIIII (FVIII), or no preference. The 95% confidence intervals were calculated using the Pearson-Clopper method.
Hemophilia Joint Health Scores Over Time
Change From Baseline in Mean Daily Peak Activity Duration Over Time
For physical activity assessment, participants ≥5 years of age were instructed to wear the study accelerometry device on the wrist continuously (24 hours/day) every day for the designated 2-week periods during the study. A participant was considered to be compliant with the physical activity assessments if they wore the study device continuously (≥8 hours/day) every day for at least 8 days of each of the designated 2-week periods during the study. If this compliance criterion was not reached at a specific timepoint the participant was not included in the analysis of the designated 2-week periods where compliance was not reached. Daily measurements were averaged over the 14-days timepoint. Activity count was a measure of the acceleration measured by the device. The daily peak activity duration was defined as the sum of moderate to vigorous activity per day (in minutes).
Change From Baseline in Mean Daily Step Count Over Time
For physical activity assessment, participants ≥5 years of age were instructed to wear the study accelerometry device on the wrist continuously (24 hours/day) every day for the designated 2-week periods during the study. A participant was considered to be compliant with the physical activity assessments if they wore the study device continuously (≥8 hours/day) every day for at least 8 days of each of the designated 2-week periods during the study. If this compliance criterion was not reached at a specific timepoint the participant was not included in the analysis of the designated 2-week periods where compliance was not reached. Daily measurements were averaged over the 14-days timepoint. Activity count was a measure of the acceleration measured by the device.
Menstrual Bleed Questionnaire (MBQ) for Female Participants of Childbearing Potential: Change From Baseline in the MBQ Total Score Over Time
Menstrual Bleed Questionnaire (MBQ) for Female Participants of Childbearing Potential: Change From Baseline in the Heaviness Subscale Score Over Time
Menstrual Bleed Questionnaire (MBQ) for Female Participants of Childbearing Potential: Change From Baseline in the Quality of Life Subscale Score Over Time
Menstrual Bleed Questionnaire (MBQ) for Female Participants of Childbearing Potential: Change From Baseline in the Irregularity Subscale Score Over Time
Menstrual Bleed Questionnaire (MBQ) for Female Participants of Childbearing Potential: Change From Baseline in the Pain Subscale Score Over Time
Menstruation Diary With the Pictorial Blood Assessment Chart (PBAC) for Female Participants of Childbearing Potential: PBAC Scores Over Time
Number of Participants With at Least One Adverse Event by Severity, According to the World Health Organization (WHO) Toxicity Grading Scale
Number of Participants With Adverse Events Leading to Study Drug Discontinuation
Number of Participants With at Least One Thromboembolic Event
Number of Participants With at Least One Event of Thrombotic Microangiopathy
Number of Participants With at Least One Injection-Site Reaction by Severity, According to the WHO Toxicity Grading Scale
Number of Participants With at Least One Severe Hypersensitivity, Anaphylaxis, and Anaphylactoid Event
Number of Participants With at Least One Laboratory Abnormality
Laboratory parameters for hematology and blood chemistry will be measured and compared with a standard reference range. Values outside the standard reference range are considered abnormalities. Not every laboratory abnormality qualifies as an adverse event. A laboratory test result will be reported as an adverse event if it meets any of the following criteria: is accompanied by clinical symptoms; results in a change in study treatment or a medical intervention; or is clinically significant in the investigator's judgment.
Change From Baseline in Respiratory Rate Over Time
Change From Baseline in Pulse Rate Over Time
Change From Baseline in Body Temperature Over Time
Change From Baseline in Systolic Blood Pressure Over Time
Change From Baseline in Diastolic Blood Pressure Over Time
Change From Baseline in Electrocardiogram (ECG) Parameters Over Time: QT, QTcB, QTcF, RR, PR, and QRS Intervals
Change From Baseline in Heart Rate Over Time, as Measured by Electrocardiogram (ECG)
Plasma Trough Concentration (Ctrough) of Emicizumab Over Time
Number of Participants With Anti-Drug Antibodies Against Emicizumab at Baseline and Post-Baseline
Number of Participants Who Develop Anti-FVIII Inhibitors Over Time
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT04158648
Brief Title
A Study to Evaluate the Safety, Efficacy, Pharmacokinetics and Pharmacodynamics of Emicizumab in Participants With Mild or Moderate Hemophilia A Without FVIII Inhibitors
Acronym
HAVEN 6
Official Title
A Multicenter, Open-Label Study to Evaluate the Safety, Efficacy, Pharmacokinetics, and Pharmacodynamics of Emicizumab in Patients With Mild or Moderate Hemophilia A Without FVIII Inhibitors
Study Type
Interventional
2. Study Status
Record Verification Date
October 2023
Overall Recruitment Status
Active, not recruiting
Study Start Date
February 10, 2020 (Actual)
Primary Completion Date
October 30, 2021 (Actual)
Study Completion Date
October 30, 2024 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Hoffmann-La Roche
4. Oversight
Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No
5. Study Description
Brief Summary
This is a multicenter, open-label, single-arm study designed to evaluate the safety, efficacy, pharmacokinetics, and pharmacodynamics of emicizumab in participants with mild or moderate hemophilia A without inhibitors against factor VIII (FVIII).
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Mild Hereditary Factor VIII Deficiency Disease Without Inhibitor, Moderate Hereditary Factor VIII Deficiency Disease Without Inhibitor, Hemophilia A
Keywords
Mild Hemophilia A Without Factor VIII Inhibitors, Moderate Hemophilia A Without Factor VIII Inhibitors
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
73 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Emicizumab
Arm Type
Experimental
Arm Description
Participants with mild and moderate hemophilia A without factor VIII (FVIII) inhibitors will be enrolled to receive the emicizumab loading dose regimen followed by the participant's preference of one of 3 maintenance dose regimens.
Intervention Type
Drug
Intervention Name(s)
Emicizumab
Other Intervention Name(s)
Hemlibra, RO5534262, RG6013, ACE910
Intervention Description
Four loading doses of emicizumab 3 milligrams per kilogram of body weight (mg/kg) will be administered subcutaneously (SC) once a week (QW) for 4 weeks followed by participant's preference of one of the three following maintenance SC dose regimens: 1.5 mg/kg QW, 3 mg/kg once every 2 weeks (Q2W), or 6 mg/kg once every 4 weeks (Q4W).
Primary Outcome Measure Information:
Title
Model-Based Annualized Bleed Rate for Treated Bleeds
Description
The number of treated bleeds over the efficacy period was estimated as an annualized bleed rate (ABR) using a negative binomial regression model, which accounts for different follow-up times. A treated bleed was 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.
Time Frame
From the day of first emicizumab dose to at least 52 weeks of emicizumab treatment (median [range, min-max] efficacy period: 55.64 [8.6-89.9] weeks)
Title
Mean Calculated Annualized Bleed Rate for Treated Bleeds
Description
The number of treated bleeds over the efficacy period is presented here as a calculated annualized bleed rate (ABR) that was annualized for each participant using the following formula: ABR = (number of bleeds/number of days during the efficacy period) x 365.25. A treated bleed was 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.
Time Frame
From the day of first emicizumab dose to at least 52 weeks of emicizumab treatment (median [range, min-max] efficacy period: 55.64 [8.6-89.9] weeks)
Title
Median Calculated Annualized Bleed Rate for Treated Bleeds
Description
The number of treated bleeds over the efficacy period is presented here as a calculated annualized bleed rate (ABR) that was annualized for each participant using the following formula: ABR = (number of bleeds/number of days during the efficacy period) x 365.25. A treated bleed was 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.
Time Frame
From the day of first emicizumab dose to at least 52 weeks of emicizumab treatment (median [range, min-max] efficacy period: 55.64 [8.6-89.9] weeks)
Secondary Outcome Measure Information:
Title
Model-Based Annualized Bleed Rate for All Bleeds
Description
The number of all bleeds over the efficacy period was estimated as an annualized bleed rate (ABR) using a negative binomial regression model, which accounts for different follow-up times. 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 meant that 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. For non-treated bleeds, the 72-hour rule was implemented by calculating a treatment-free period of 72 hours from the bleed itself.
Time Frame
From the day of first emicizumab dose to at least 52 weeks of emicizumab treatment (median [range, min-max] efficacy period: 55.64 [8.6-89.9] weeks)
Title
Mean Calculated Annualized Bleed Rate for All Bleeds
Description
The number of all bleeds over the efficacy period is presented here as a calculated annualized bleed rate (ABR) that was annualized for each participant using the following formula: ABR = (number of bleeds/number of days during the efficacy period) x 365.25. 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 meant that 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. For non-treated bleeds, the 72-hour rule was implemented by calculating a treatment-free period of 72 hours from the bleed itself.
Time Frame
From the day of first emicizumab dose to at least 52 weeks of emicizumab treatment (median [range, min-max] efficacy period: 55.64 [8.6-89.9] weeks)
Title
Median Calculated Annualized Bleed Rate for All Bleeds
Description
The number of all bleeds over the efficacy period is presented here as a calculated annualized bleed rate (ABR) that was annualized for each participant using the following formula: ABR = (number of bleeds/number of days during the efficacy period) x 365.25. 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 meant that 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. For non-treated bleeds, the 72-hour rule was implemented by calculating a treatment-free period of 72 hours from the bleed itself.
Time Frame
From the day of first emicizumab dose to at least 52 weeks of emicizumab treatment (median [range, min-max] efficacy period: 55.64 [8.6-89.9] weeks)
Title
Model-Based Annualized Bleed Rate for Treated Joint Bleeds
Description
The number of treated joint bleeds over the efficacy period was estimated as an annualized bleed rate (ABR) using a negative binomial regression model, which accounts for different follow-up times. A treated joint bleed was defined as a bleed with type reported as "joint" based on 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, and the bleed 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.
Time Frame
From the day of first emicizumab dose to at least 52 weeks of emicizumab treatment (median [range, min-max] efficacy period: 55.64 [8.6-89.9] weeks)
Title
Mean Calculated Annualized Bleed Rate for Treated Joint Bleeds
Description
The number of treated joint bleeds over the efficacy period is presented here as a calculated annualized bleed rate (ABR) that was annualized for each participant using the following formula: ABR = (number of bleeds/number of days during the efficacy period) x 365.25. A treated joint bleed was defined as a bleed with type reported as "joint" based on 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, and the bleed 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.
Time Frame
From the day of first emicizumab dose to at least 52 weeks of emicizumab treatment (median [range, min-max] efficacy period: 55.64 [8.6-89.9] weeks)
Title
Median Calculated Annualized Bleed Rate for Treated Joint Bleeds
Description
The number of treated joint bleeds over the efficacy period is presented here as a calculated annualized bleed rate (ABR) that was annualized for each participant using the following formula: ABR = (number of bleeds/number of days during the efficacy period) x 365.25. A treated joint bleed was defined as a bleed with type reported as "joint" based on 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, and the bleed 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.
Time Frame
From the day of first emicizumab dose to at least 52 weeks of emicizumab treatment (median [range, min-max] efficacy period: 55.64 [8.6-89.9] weeks)
Title
Model-Based Annualized Bleed Rate for Treated Target Joint Bleeds
Description
The number of treated target joint bleeds over the efficacy period was estimated as an annualized bleed rate (ABR) using a negative binomial regression model, which accounts for different follow-up times. A treated target joint bleed was 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 or an unresolved target joint (target joint that does not fulfil ≤2 bleeds into this joint within a consecutive 12-month period), and the bleed 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.
Time Frame
From the day of first emicizumab dose to at least 52 weeks of emicizumab treatment (median [range, min-max] efficacy period: 55.64 [8.6-89.9] weeks)
Title
Mean Calculated Annualized Bleed Rate for Treated Target Joint Bleeds
Description
The number of treated target joint bleeds over the efficacy period is presented here as a calculated annualized bleed rate (ABR) that was annualized for each participant using the following formula: ABR = (number of bleeds/number of days during the efficacy period) x 365.25. A treated target joint bleed was 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 or an unresolved target joint (target joint that does not fulfil ≤2 bleeds into this joint within a consecutive 12-month period), and the bleed 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.
Time Frame
From the day of first emicizumab dose to at least 52 weeks of emicizumab treatment (median [range, min-max] efficacy period: 55.64 [8.6-89.9] weeks)
Title
Median Calculated Annualized Bleed Rate for Treated Target Joint Bleeds
Description
The number of treated target joint bleeds over the efficacy period is presented here as a calculated annualized bleed rate (ABR) that was annualized for each participant using the following formula: ABR = (number of bleeds/number of days during the efficacy period) x 365.25. A treated target joint bleed was 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 or an unresolved target joint (target joint that does not fulfil ≤2 bleeds into this joint within a consecutive 12-month period), and the bleed 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.
Time Frame
From the day of first emicizumab dose to at least 52 weeks of emicizumab treatment (median [range, min-max] efficacy period: 55.64 [8.6-89.9] weeks)
Title
Model-Based Annualized Bleed Rate for Treated Spontaneous Bleeds
Description
The number of treated spontaneous bleeds over the efficacy period was estimated as an annualized bleed rate (ABR) using a negative binomial regression model, which accounts for different follow-up times. A treated spontaneous bleed was defined as a treated bleed (bleed directly followed by a hemophilia medication reported to be a "treatment for bleed") with no other known contributing factor such as trauma or procedure/surgery. 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.
Time Frame
From the day of first emicizumab dose to at least 52 weeks of emicizumab treatment (median [range, min-max] efficacy period: 55.64 [8.6-89.9] weeks)
Title
Mean Calculated Annualized Bleed Rate for Treated Spontaneous Bleeds
Description
The number of treated spontaneous bleeds over the efficacy period is presented here as a calculated annualized bleed rate (ABR) that was annualized for each participant using the following formula: ABR = (number of bleeds/number of days during the efficacy period) x 365.25. A treated spontaneous bleed was defined as a treated bleed (bleed directly followed by a hemophilia medication reported to be a "treatment for bleed") with no other known contributing factor such as trauma or procedure/surgery. 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.
Time Frame
From the day of first emicizumab dose to at least 52 weeks of emicizumab treatment (median [range, min-max] efficacy period: 55.64 [8.6-89.9] weeks)
Title
Median Calculated Annualized Bleed Rate for Treated Spontaneous Bleeds
Description
The number of treated spontaneous bleeds over the efficacy period is presented here as a calculated annualized bleed rate (ABR) that was annualized for each participant using the following formula: ABR = (number of bleeds/number of days during the efficacy period) x 365.25. A treated spontaneous bleed was defined as a treated bleed (bleed directly followed by a hemophilia medication reported to be a "treatment for bleed") with no other known contributing factor such as trauma or procedure/surgery. 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.
Time Frame
From the day of first emicizumab dose to at least 52 weeks of emicizumab treatment (median [range, min-max] efficacy period: 55.64 [8.6-89.9] weeks)
Title
CATCH Questionnaire for Adult Participants: Change From Baseline in the Daily Activity Risk Perception and Impact Domain Scores Over Time
Description
CATCH = Comprehensive Assessment Tool of Challenges in Hemophilia
Time Frame
Baseline (Week 1), Weeks 13, 25, 37 and 49, and every 12 weeks thereafter until Study Completion/Discontinuation Visit (up to approximately 48 months)
Title
CATCH Questionnaire for Adult Participants: Change From Baseline in the Social Activity Risk Perception and Impact Domain Scores Over Time
Description
CATCH = Comprehensive Assessment Tool of Challenges in Hemophilia
Time Frame
Baseline (Week 1), Weeks 13, 25, 37 and 49, and every 12 weeks thereafter until Study Completion/Discontinuation Visit (up to approximately 48 months)
Title
CATCH Questionnaire for Adult Participants: Change From Baseline in the Recreational Activity Risk Perception and Impact Domain Scores Over Time
Description
CATCH = Comprehensive Assessment Tool of Challenges in Hemophilia
Time Frame
Baseline (Week 1), Weeks 13, 25, 37 and 49, and every 12 weeks thereafter until Study Completion/Discontinuation Visit (up to approximately 48 months)
Title
CATCH Questionnaire for Adult Participants: Change From Baseline in the Work Impact Domain Score Over Time
Description
CATCH = Comprehensive Assessment Tool of Challenges in Hemophilia
Time Frame
Baseline (Week 1), Weeks 13, 25, 37 and 49, and every 12 weeks thereafter until Study Completion/Discontinuation Visit (up to approximately 48 months)
Title
CATCH Questionnaire for Adult Participants: Change From Baseline in the Preoccupation Domain Score Over Time
Description
CATCH = Comprehensive Assessment Tool of Challenges in Hemophilia
Time Frame
Baseline (Week 1), Weeks 13, 25, 37 and 49, and every 12 weeks thereafter until Study Completion/Discontinuation Visit (up to approximately 48 months)
Title
CATCH Questionnaire for Adult Participants: Change From Baseline in the Treatment Burden Domain Score Over Time
Description
CATCH = Comprehensive Assessment Tool of Challenges in Hemophilia
Time Frame
Baseline (Week 1), Weeks 13, 25, 37 and 49, and every 12 weeks thereafter until Study Completion/Discontinuation Visit (up to approximately 48 months)
Title
CATCH Questionnaire for Adult Participants: Number of Participants by Responses to Their Level of Pain Associated With a Bleed Over Time
Description
CATCH = Comprehensive Assessment Tool of Challenges in Hemophilia
Time Frame
Baseline (Week 1), Weeks 13, 25, 37 and 49, and every 12 weeks thereafter until Study Completion/Discontinuation Visit (up to approximately 48 months)
Title
CATCH Questionnaire for Adult Participants: Number of Participants by Responses to Their Level of Pain in Target Joints Over Time
Description
CATCH = Comprehensive Assessment Tool of Challenges in Hemophilia
Time Frame
Baseline (Week 1), Weeks 13, 25, 37 and 49, and every 12 weeks thereafter until Study Completion/Discontinuation Visit (up to approximately 48 months)
Title
CATCH Questionnaire for Adult Participants: Number of Participants by Responses to Their Level of Pain at Its Worst Over Time
Description
CATCH = Comprehensive Assessment Tool of Challenges in Hemophilia
Time Frame
Baseline (Week 1), Weeks 13, 25, 37 and 49, and every 12 weeks thereafter until Study Completion/Discontinuation Visit (up to approximately 48 months)
Title
CATCH Questionnaire for Adult Participants: Number of Participants by Responses to Their Level of Pain at Its Least Over Time
Description
CATCH = Comprehensive Assessment Tool of Challenges in Hemophilia
Time Frame
Baseline (Week 1), Weeks 13, 25, 37 and 49, and every 12 weeks thereafter until Study Completion/Discontinuation Visit (up to approximately 48 months)
Title
CATCH Questionnaire for Adult Participants: Number of Participants by Responses to Their Level of Pain on Average Over Time
Description
CATCH = Comprehensive Assessment Tool of Challenges in Hemophilia
Time Frame
Baseline (Week 1), Weeks 13, 25, 37 and 49, and every 12 weeks thereafter until Study Completion/Discontinuation Visit (up to approximately 48 months)
Title
CATCH Questionnaire for Pediatric Participants: Change From Baseline in the Daily Activity Risk Perception and Impact Domain Score Over Time
Description
CATCH = Comprehensive Assessment Tool of Challenges in Hemophilia
Time Frame
Baseline (Week 1), Weeks 13, 25, 37 and 49, and every 12 weeks thereafter until Study Completion/Discontinuation Visit (up to approximately 48 months)
Title
CATCH Questionnaire for Pediatric Participants: Change From Baseline in the Social Activity Risk Perception and Impact Domain Score Over Time
Description
CATCH = Comprehensive Assessment Tool of Challenges in Hemophilia
Time Frame
Baseline (Week 1), Weeks 13, 25, 37 and 49, and every 12 weeks thereafter until Study Completion/Discontinuation Visit (up to approximately 48 months)
Title
CATCH Questionnaire for Pediatric Participants: Change From Baseline in the Recreational Activity Risk Perception and Impact Domain Score Over Time
Description
CATCH = Comprehensive Assessment Tool of Challenges in Hemophilia
Time Frame
Baseline (Week 1), Weeks 13, 25, 37 and 49, and every 12 weeks thereafter until Study Completion/Discontinuation Visit (up to approximately 48 months)
Title
CATCH Questionnaire for Pediatric Participants: Change From Baseline in the School Impact Domain Score Over Time
Description
CATCH = Comprehensive Assessment Tool of Challenges in Hemophilia
Time Frame
Baseline (Week 1), Weeks 13, 25, 37 and 49, and every 12 weeks thereafter until Study Completion/Discontinuation Visit (up to approximately 48 months)
Title
CATCH Questionnaire for Pediatric Participants: Change From Baseline in the Preoccupation Domain Score Over Time
Description
CATCH = Comprehensive Assessment Tool of Challenges in Hemophilia
Time Frame
Baseline (Week 1), Weeks 13, 25, 37 and 49, and every 12 weeks thereafter until Study Completion/Discontinuation Visit (up to approximately 48 months)
Title
CATCH Questionnaire for Pediatric Participants: Change From Baseline in the Treatment Burden Domain Score Over Time
Description
CATCH = Comprehensive Assessment Tool of Challenges in Hemophilia
Time Frame
Baseline (Week 1), Weeks 13, 25, 37 and 49, and every 12 weeks thereafter until Study Completion/Discontinuation Visit (up to approximately 48 months)
Title
CATCH Questionnaire for Pediatric Participants: Number of Participants by Responses to Their Level of Pain Associated With a Bleed Over Time
Description
CATCH = Comprehensive Assessment Tool of Challenges in Hemophilia
Time Frame
Baseline (Week 1), Weeks 13, 25, 37 and 49, and every 12 weeks thereafter until Study Completion/Discontinuation Visit (up to approximately 48 months)
Title
CATCH Questionnaire for Pediatric Participants: Number of Participants by Responses to Their Level of Pain at Its Worst Over Time
Description
CATCH = Comprehensive Assessment Tool of Challenges in Hemophilia
Time Frame
Baseline (Week 1), Weeks 13, 25, 37 and 49, and every 12 weeks thereafter until Study Completion/Discontinuation Visit (up to approximately 48 months)
Title
CATCH Questionnaire for Caregivers: Change From Baseline in the Preoccupation Domain Score Over Time
Description
CATCH = Comprehensive Assessment Tool of Challenges in Hemophilia
Time Frame
Baseline (Week 1), Weeks 13, 25, 37 and 49, and every 12 weeks thereafter until Study Completion/Discontinuation Visit (up to approximately 48 months)
Title
CATCH Questionnaire for Caregivers: Change From Baseline in the Treatment Burden Domain Score Over Time
Description
CATCH = Comprehensive Assessment Tool of Challenges in Hemophilia
Time Frame
Baseline (Week 1), Weeks 13, 25, 37 and 49, and every 12 weeks thereafter until Study Completion/Discontinuation Visit (up to approximately 48 months)
Title
Percentage of Participants Who Prefer Emicizumab SC Treatment, Their Previous Hemophilia IV Treatment, or Have No Preference, as Assessed Through Use of the Emicizumab Preference Survey at Week 17
Description
The Emicizumab Preference Survey is a fit-for-purpose questionnaire developed by the sponsor to record the participant's preference for treatment with subcutaneous (SC) emicizumab, intravenous (IV) factor VIIII (FVIII), or no preference. The 95% confidence intervals were calculated using the Pearson-Clopper method.
Time Frame
Week 17
Title
Percentage of Caregivers Who Prefer Emicizumab SC Treatment, Their Child's Previous Hemophilia IV Treatment, or Have No Preference, as Assessed Through Use of the Emicizumab Preference Survey at Week 17
Description
The Emicizumab Preference Survey is a fit-for-purpose questionnaire developed by the sponsor to record the caregiver's preference for their child's treatment with subcutaneous (SC) emicizumab, intravenous (IV) factor VIIII (FVIII), or no preference. The 95% confidence intervals were calculated using the Pearson-Clopper method.
Time Frame
Week 17
Title
Hemophilia Joint Health Scores Over Time
Time Frame
Days -7 to -1, Weeks 25, 49, and every 24 weeks thereafter until Study Completion/Discontinuation Visit (up to approximately 48 months)
Title
Change From Baseline in Mean Daily Peak Activity Duration Over Time
Description
For physical activity assessment, participants ≥5 years of age were instructed to wear the study accelerometry device on the wrist continuously (24 hours/day) every day for the designated 2-week periods during the study. A participant was considered to be compliant with the physical activity assessments if they wore the study device continuously (≥8 hours/day) every day for at least 8 days of each of the designated 2-week periods during the study. If this compliance criterion was not reached at a specific timepoint the participant was not included in the analysis of the designated 2-week periods where compliance was not reached. Daily measurements were averaged over the 14-days timepoint. Activity count was a measure of the acceleration measured by the device. The daily peak activity duration was defined as the sum of moderate to vigorous activity per day (in minutes).
Time Frame
Baseline (Weeks 1-2) and Weeks 13 (Weeks 12-13 period), 25 (Weeks 24-25 period), 37 (Weeks 36-37 period), and 49 (Weeks 48-49 period)
Title
Change From Baseline in Mean Daily Step Count Over Time
Description
For physical activity assessment, participants ≥5 years of age were instructed to wear the study accelerometry device on the wrist continuously (24 hours/day) every day for the designated 2-week periods during the study. A participant was considered to be compliant with the physical activity assessments if they wore the study device continuously (≥8 hours/day) every day for at least 8 days of each of the designated 2-week periods during the study. If this compliance criterion was not reached at a specific timepoint the participant was not included in the analysis of the designated 2-week periods where compliance was not reached. Daily measurements were averaged over the 14-days timepoint. Activity count was a measure of the acceleration measured by the device.
Time Frame
Baseline (Weeks 1-2) and Weeks 13 (Weeks 12-13), 25 (Weeks 24-25), 37 (Weeks 36-37), and 49 (Weeks 48-49)
Title
Menstrual Bleed Questionnaire (MBQ) for Female Participants of Childbearing Potential: Change From Baseline in the MBQ Total Score Over Time
Time Frame
Baseline (Week 1), Weeks 5, 9, 13, 17, 21, 25, 29, 33, 37, 41, 45, 49, and every 4 weeks thereafter until Study Completion (up to approximately 48 months)
Title
Menstrual Bleed Questionnaire (MBQ) for Female Participants of Childbearing Potential: Change From Baseline in the Heaviness Subscale Score Over Time
Time Frame
Baseline (Week 1), Weeks 5, 9, 13, 17, 21, 25, 29, 33, 37, 41, 45, 49, and every 4 weeks thereafter until Study Completion (up to approximately 48 months)
Title
Menstrual Bleed Questionnaire (MBQ) for Female Participants of Childbearing Potential: Change From Baseline in the Quality of Life Subscale Score Over Time
Time Frame
Baseline (Week 1), Weeks 5, 9, 13, 17, 21, 25, 29, 33, 37, 41, 45, 49, and every 4 weeks thereafter until Study Completion (up to approximately 48 months)
Title
Menstrual Bleed Questionnaire (MBQ) for Female Participants of Childbearing Potential: Change From Baseline in the Irregularity Subscale Score Over Time
Time Frame
Baseline (Week 1), Weeks 5, 9, 13, 17, 21, 25, 29, 33, 37, 41, 45, 49, and every 4 weeks thereafter until Study Completion (up to approximately 48 months)
Title
Menstrual Bleed Questionnaire (MBQ) for Female Participants of Childbearing Potential: Change From Baseline in the Pain Subscale Score Over Time
Time Frame
Baseline (Week 1), Weeks 5, 9, 13, 17, 21, 25, 29, 33, 37, 41, 45, 49, and every 4 weeks thereafter until Study Completion (up to approximately 48 months)
Title
Menstruation Diary With the Pictorial Blood Assessment Chart (PBAC) for Female Participants of Childbearing Potential: PBAC Scores Over Time
Time Frame
Baseline (Day 1) and monthly (on days of menstruation) until Study Completion (up to approximately 48 months)
Title
Number of Participants With at Least One Adverse Event by Severity, According to the World Health Organization (WHO) Toxicity Grading Scale
Time Frame
From Screening (Day -28 to -1) to Study Completion/Discontinuation Visit (up to approximately 48 months)
Title
Number of Participants With Adverse Events Leading to Study Drug Discontinuation
Time Frame
From Screening (Day -28 to -1) to Study Completion/Discontinuation Visit (up to approximately 48 months)
Title
Number of Participants With at Least One Thromboembolic Event
Time Frame
From Screening (Day -28 to -1) to Study Completion/Discontinuation Visit (up to approximately 48 months)
Title
Number of Participants With at Least One Event of Thrombotic Microangiopathy
Time Frame
From Screening (Day -28 to -1) to Study Completion/Discontinuation Visit (up to approximately 48 months)
Title
Number of Participants With at Least One Injection-Site Reaction by Severity, According to the WHO Toxicity Grading Scale
Time Frame
From Screening (Day -28 to -1) to Study Completion/Discontinuation Visit (up to approximately 48 months)
Title
Number of Participants With at Least One Severe Hypersensitivity, Anaphylaxis, and Anaphylactoid Event
Time Frame
From Screening (Day -28 to -1) to Study Completion/Discontinuation Visit (up to approximately 48 months)
Title
Number of Participants With at Least One Laboratory Abnormality
Description
Laboratory parameters for hematology and blood chemistry will be measured and compared with a standard reference range. Values outside the standard reference range are considered abnormalities. Not every laboratory abnormality qualifies as an adverse event. A laboratory test result will be reported as an adverse event if it meets any of the following criteria: is accompanied by clinical symptoms; results in a change in study treatment or a medical intervention; or is clinically significant in the investigator's judgment.
Time Frame
From Screening (Day -28 to -1) to Study Completion/Discontinuation Visit (up to approximately 48 months)
Title
Change From Baseline in Respiratory Rate Over Time
Time Frame
Baseline, Weeks 1, 2, 3, 4, 5, 9, 13, 17, 21, 25, 29, 33, 37, 41, 45, and 49, and every 12 weeks thereafter until Study Completion/Discontinuation Visit (up to approximately 48 months)
Title
Change From Baseline in Pulse Rate Over Time
Time Frame
Baseline, Weeks 1, 2, 3, 4, 5, 9, 13, 17, 21, 25, 29, 33, 37, 41, 45, and 49, and every 12 weeks thereafter until Study Completion/Discontinuation Visit (up to approximately 48 months)
Title
Change From Baseline in Body Temperature Over Time
Time Frame
Baseline, Weeks 1, 2, 3, 4, 5, 9, 13, 17, 21, 25, 29, 33, 37, 41, 45, and 49, and every 12 weeks thereafter until Study Completion/Discontinuation Visit (up to approximately 48 months)
Title
Change From Baseline in Systolic Blood Pressure Over Time
Time Frame
Baseline, Weeks 1, 2, 3, 4, 5, 9, 13, 17, 21, 25, 29, 33, 37, 41, 45, and 49, and every 12 weeks thereafter until Study Completion/Discontinuation Visit (up to approximately 48 months)
Title
Change From Baseline in Diastolic Blood Pressure Over Time
Time Frame
Baseline, Weeks 1, 2, 3, 4, 5, 9, 13, 17, 21, 25, 29, 33, 37, 41, 45, and 49, and every 12 weeks thereafter until Study Completion/Discontinuation Visit (up to approximately 48 months)
Title
Change From Baseline in Electrocardiogram (ECG) Parameters Over Time: QT, QTcB, QTcF, RR, PR, and QRS Intervals
Time Frame
Baseline, Weeks 5, 25, and 49, and every 12 weeks thereafter until Study Completion/Discontinuation Visit (up to approximately 48 months)
Title
Change From Baseline in Heart Rate Over Time, as Measured by Electrocardiogram (ECG)
Time Frame
Baseline, Weeks 5, 25, and 49, and every 12 weeks thereafter until Study Completion/Discontinuation Visit (up to approximately 48 months)
Title
Plasma Trough Concentration (Ctrough) of Emicizumab Over Time
Time Frame
Pre-dose at Weeks 1, 2, 3, 4, 5, 9, 13, 17, 21, 25, 29, 33, 37, 41, 45, and 49, and every 12 weeks thereafter until study completion/discontinuation (up to approximately 48 months)
Title
Number of Participants With Anti-Drug Antibodies Against Emicizumab at Baseline and Post-Baseline
Time Frame
Pre-dose at Baseline (Week 1) and Weeks 5, 13, 25, 33, 41, and 49, and every 12 weeks thereafter until study completion/discontinuation (up to approximately 48 months)
Title
Number of Participants Who Develop Anti-FVIII Inhibitors Over Time
Time Frame
Screening (Day -28 to -1) and Weeks 1, 13, 25, 37, and 49, and every 12 weeks thereafter until study completion/discontinuation (up to approximately 48 months)
10. Eligibility
Sex
All
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
Diagnosis of mild (FVIII level between >5% and <40%) or moderate (FVIII level between ≥1% and ≤5%) congenital Hemophilia A without FVIII inhibitors
Weight ≥3 kilograms (kg)
Need for prophylaxis based on investigator assessment
A negative test for inhibitor (i.e., <0.6 Bethesda Units per milliliter [BU/mL]) within 8 weeks prior to enrollment
No documented inhibitor (i.e., <0.6 BU/mL), FVIII half-life <6 hours, or FVIII recovery <66% in the last 5 years
Documentation of the details of prophylactic or episodic FVIII treatment and of number of bleeding episodes for at least the last 24 weeks prior to enrollment
Adequate hematologic hepatic and renal function
For women of childbearing potential: agreement to remain abstinent or use contraception (as defined in the protocol) during the treatment period and for at least 24 weeks after the final dose of study drug
Exclusion Criteria:
Inherited or acquired bleeding disorder other than mild or moderate congenital hemophilia A
History of illicit drug or alcohol abuse within 48 weeks prior to screening, in the investigator's judgment
Previous (within the last 12 months) or current treatment for thromboembolic disease or signs of thromboembolic disease
Other conditions 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
Planned surgery during the emicizumab loading dose phase (surgeries in participants on emicizumab from Week 5 onwards are allowed)
Known HIV infection with CD4 counts <200 cells per microlitre (/μL)
Concomitant disease, condition, significant abnormality on screening evaluation 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
Receipt of any of the following: An investigational drug to treat or reduce the risk of hemophilic bleeds within 5 half-lives of last drug administration with the exception of prior emicizumab prophylaxis; A non-hemophilia-related investigational drug within last 30 days or 5 half-lives, whichever is shorter; or Any other investigational drug currently being administered or planned to be administered
Inability to comply with the study protocol in the opinion of the investigator
Pregnant or breastfeeding, or intending to become pregnant during the study (women of childbearing potential must have a negative serum pregnancy test result within 7 days prior to initiation of study drug)
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Clinical Trials
Organizational Affiliation
Hoffmann-La Roche
Official's Role
Study Director
Facility Information:
Facility Name
Childrens Hospital LA
City
Los Angeles
State/Province
California
ZIP/Postal Code
90027
Country
United States
Facility Name
Hemophilia of Georgia Center for Bleeding & Clotting Disorders
City
Atlanta
State/Province
Georgia
ZIP/Postal Code
30308
Country
United States
Facility Name
Children'S Healthcare of Atlanta
City
Atlanta
State/Province
Georgia
ZIP/Postal Code
30322
Country
United States
Facility Name
Indiana Hemophilia & Thrombosis center
City
Indianapolis
State/Province
Indiana
ZIP/Postal Code
46260
Country
United States
Facility Name
University of Michigan, C.S. Mott Children's Hospital
City
Ann Arbor
State/Province
Michigan
ZIP/Postal Code
48109
Country
United States
Facility Name
Washington Institute for Coagulation
City
Seattle
State/Province
Washington
ZIP/Postal Code
98101
Country
United States
Facility Name
Cliniques Universitaires St-Luc
City
Bruxelles
ZIP/Postal Code
1200
Country
Belgium
Facility Name
UZ Leuven Gasthuisberg
City
Leuven
ZIP/Postal Code
3000
Country
Belgium
Facility Name
Kaye Edmonton Clinic
City
Edmonton
State/Province
Alberta
ZIP/Postal Code
T6G 2V2
Country
Canada
Facility Name
Eastern Health - General Hospital
City
St. John's
State/Province
Newfoundland and Labrador
ZIP/Postal Code
A1B 3V6
Country
Canada
Facility Name
Hopital Cardio-vasculaire Louis Pradel; Hemostase clinique
City
Bron
ZIP/Postal Code
69677
Country
France
Facility Name
CH de Bicetre; Centre de Traitement d' Hemophilie
City
Le Kremlin Bicetre
ZIP/Postal Code
94275
Country
France
Facility Name
Groupe Hospitalier Necker Enfants Malades
City
Paris
ZIP/Postal Code
75015
Country
France
Facility Name
Universitätsklinikum Bonn; Institut für Experimentelle Hämatologie und Transfusionsmedizin
City
Bonn
ZIP/Postal Code
53127
Country
Germany
Facility Name
Klinikum der Universität München, Campus Innenstadt; Hämostaseologische Ambulanz/Hämophiliezentrum
City
München
ZIP/Postal Code
80336
Country
Germany
Facility Name
Amsterdam UMC Location AMC
City
Amsterdam
ZIP/Postal Code
1105 AZ
Country
Netherlands
Facility Name
Instytut Hematologii i Transfuzjologii; Klinika Zaburze? Hemostazy i Chorób Wewn?trznych
City
Warsaw
ZIP/Postal Code
02-776
Country
Poland
Facility Name
Charlotte Maxeke Johannesburg Hospital; Haemophilia Comprehensive Care Center
City
Johannesburg
ZIP/Postal Code
2193
Country
South Africa
Facility Name
Hospital Universitario la Paz; Servicio de Hematologia
City
Madrid
ZIP/Postal Code
28046
Country
Spain
Facility Name
Hospital Universitario Virgen del Rocio; Servicio de Hematologia
City
Sevilla
ZIP/Postal Code
41013
Country
Spain
Facility Name
Cardiff and Vale NHS Trust; Arthur Bloom Haemophilia Centre
City
Cardiff
ZIP/Postal Code
CF14 4XW
Country
United Kingdom
Facility Name
Royal Free Hospital; Haemophilia Centre
City
London
ZIP/Postal Code
NW3 2QG
Country
United Kingdom
Facility Name
Great Ormond street Hospital for Children NHS Foundation Trust; Haemophilia Centre
City
London
ZIP/Postal Code
WC1N 3HR
Country
United Kingdom
12. IPD Sharing Statement
Plan to Share IPD
Yes
IPD Sharing Plan Description
Qualified researchers may request access to individual patient level data through the request platform (www.vivli.org). Further details on Roche's criteria for eligible studies are available here (https://vivli.org/ourmember/roche/).
For further details on Roche's Global Policy on Sharing of Clinical Study Information and how to request access to related clinical study documents, see here (https://www.roche.com/innovation/process/clinical-trials/data-sharing/).
Learn more about this trial
A Study to Evaluate the Safety, Efficacy, Pharmacokinetics and Pharmacodynamics of Emicizumab in Participants With Mild or Moderate Hemophilia A Without FVIII Inhibitors
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