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

Hoffmann-La Roche41 sites in 10 countries73 target enrollmentFebruary 10, 2020

ConditionsMild Hereditary Factor VIII Deficiency Disease Without Inhibitor Moderate Hereditary Factor VIII Deficiency Disease Without Inhibitor Hemophilia A

InterventionsEmicizumab

DrugsEmicizumab

Overview

Phase: Phase 3
Intervention: Emicizumab
Conditions: Mild Hereditary Factor VIII Deficiency Disease Without Inhibitor
Sponsor: Hoffmann-La Roche
Enrollment: 73
Locations: 41
Primary Endpoint: Model-Based Annualized Bleed Rate for Treated Bleeds
Status: Completed
Last Updated: 3 months ago

Overview Investigators Eligibility Criteria Arms & Interventions Outcomes Sites Similar Trials

Overview

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).

Registry

clinicaltrials.gov

Start Date

February 10, 2020

End Date

December 19, 2025

Last Updated

3 months ago

Study Type

Interventional

Study Design

Single Group

Sex

All

Investigators

Sponsor

Hoffmann-La Roche

Responsible Party

Sponsor

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

Arms & Interventions

Emicizumab

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: Emicizumab

Outcomes

Primary Outcomes

Model-Based Annualized Bleed Rate for Treated Bleeds

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)

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

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)

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

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 Outcomes

Model-Based Annualized Bleed Rate for Treated Joint Bleeds(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))
Median Calculated Annualized Bleed Rate for Treated Joint Bleeds(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))
Model-Based Annualized Bleed Rate for Treated Target Joint Bleeds(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))
Mean Calculated Annualized Bleed Rate for Treated Target Joint Bleeds(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))
Median Calculated Annualized Bleed Rate for All Bleeds(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))
Model-Based Annualized Bleed Rate for All Bleeds(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))
Mean Calculated Annualized Bleed Rate for All Bleeds(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))
CATCH Questionnaire for Adult Participants: Change From Baseline in the Work Impact Domain Score Over Time(Baseline (Week 1), Weeks 13, 25, 37 and 49, and every 12 weeks thereafter until Study Completion/Discontinuation Visit (up to approximately 48 months))
CATCH Questionnaire for Adult Participants: Change From Baseline in the Preoccupation Domain Score Over Time(Baseline (Week 1), Weeks 13, 25, 37 and 49, and every 12 weeks thereafter until Study Completion/Discontinuation Visit (up to approximately 48 months))
Mean Calculated Annualized Bleed Rate for Treated Joint Bleeds(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))
CATCH Questionnaire for Adult Participants: Number of Participants by Responses to Their Level of Pain at Its Worst Over Time(Baseline (Week 1), Weeks 13, 25, 37 and 49, and every 12 weeks thereafter until Study Completion/Discontinuation Visit (up to approximately 48 months))
Median Calculated Annualized Bleed Rate for Treated Spontaneous Bleeds(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))
CATCH Questionnaire for Adult Participants: Change From Baseline in the Daily Activity Risk Perception and Impact Domain Scores Over Time(Baseline (Week 1), Weeks 13, 25, 37 and 49, and every 12 weeks thereafter until Study Completion/Discontinuation Visit (up to approximately 48 months))
CATCH Questionnaire for Adult Participants: Change From Baseline in the Recreational Activity Risk Perception and Impact Domain Scores Over Time(Baseline (Week 1), Weeks 13, 25, 37 and 49, and every 12 weeks thereafter until Study Completion/Discontinuation Visit (up to approximately 48 months))
Median Calculated Annualized Bleed Rate for Treated Target Joint Bleeds(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))
Model-Based Annualized Bleed Rate for Treated Spontaneous Bleeds(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))
CATCH Questionnaire for Adult Participants: Number of Participants by Responses to Their Level of Pain at Its Least Over Time(Baseline (Week 1), Weeks 13, 25, 37 and 49, and every 12 weeks thereafter until Study Completion/Discontinuation Visit (up to approximately 48 months))
Mean Calculated Annualized Bleed Rate for Treated Spontaneous Bleeds(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))
CATCH Questionnaire for Adult Participants: Change From Baseline in the Social Activity Risk Perception and Impact Domain Scores Over Time(Baseline (Week 1), Weeks 13, 25, 37 and 49, and every 12 weeks thereafter until Study Completion/Discontinuation Visit (up to approximately 48 months))
CATCH Questionnaire for Adult Participants: Change From Baseline in the Treatment Burden Domain Score Over Time(Baseline (Week 1), Weeks 13, 25, 37 and 49, and every 12 weeks thereafter until Study Completion/Discontinuation Visit (up to approximately 48 months))
CATCH Questionnaire for Adult Participants: Number of Participants by Responses to Their Level of Pain Associated With a Bleed Over Time(Baseline (Week 1), Weeks 13, 25, 37 and 49, and every 12 weeks thereafter until Study Completion/Discontinuation Visit (up to approximately 48 months))
CATCH Questionnaire for Adult Participants: Number of Participants by Responses to Their Level of Pain in Target Joints Over Time(Baseline (Week 1), Weeks 13, 25, 37 and 49, and every 12 weeks thereafter until Study Completion/Discontinuation Visit (up to approximately 48 months))
CATCH Questionnaire for Adult Participants: Number of Participants by Responses to Their Level of Pain on Average Over Time(Baseline (Week 1), Weeks 13, 25, 37 and 49, and every 12 weeks thereafter until Study Completion/Discontinuation Visit (up to approximately 48 months))
CATCH Questionnaire for Pediatric Participants: Change From Baseline in the Social Activity Risk Perception and Impact Domain Score Over Time(Baseline (Week 1), Weeks 13, 25, 37 and 49, and every 12 weeks thereafter until Study Completion/Discontinuation Visit (up to approximately 48 months))
CATCH Questionnaire for Pediatric Participants: Change From Baseline in the School Impact Domain Score Over Time(Baseline (Week 1), Weeks 13, 25, 37 and 49, and every 12 weeks thereafter until Study Completion/Discontinuation Visit (up to approximately 48 months))
CATCH Questionnaire for Pediatric Participants: Change From Baseline in the Treatment Burden Domain Score Over Time(Baseline (Week 1), Weeks 13, 25, 37 and 49, and every 12 weeks thereafter until Study Completion/Discontinuation Visit (up to approximately 48 months))
CATCH Questionnaire for Pediatric Participants: Change From Baseline in the Daily Activity Risk Perception and Impact Domain Score Over Time(Baseline (Week 1), Weeks 13, 25, 37 and 49, and every 12 weeks thereafter until Study Completion/Discontinuation Visit (up to approximately 48 months))
CATCH Questionnaire for Pediatric Participants: Change From Baseline in the Recreational Activity Risk Perception and Impact Domain Score Over Time(Baseline (Week 1), Weeks 13, 25, 37 and 49, and every 12 weeks thereafter until Study Completion/Discontinuation Visit (up to approximately 48 months))
CATCH Questionnaire for Pediatric Participants: Change From Baseline in the Preoccupation Domain Score Over Time(Baseline (Week 1), Weeks 13, 25, 37 and 49, and every 12 weeks thereafter until Study Completion/Discontinuation Visit (up to approximately 48 months))
CATCH Questionnaire for Caregivers: Change From Baseline in the Preoccupation Domain Score Over Time(Baseline (Week 1), Weeks 13, 25, 37 and 49, and every 12 weeks thereafter until Study Completion/Discontinuation Visit (up to approximately 48 months))
Hemophilia Joint Health Scores Over Time(Days -7 to -1, Weeks 25, 49, and every 24 weeks thereafter until Study Completion/Discontinuation Visit (up to approximately 48 months))
Menstrual Bleed Questionnaire (MBQ) for Female Participants of Childbearing Potential: Change From Baseline in the MBQ Total Score Over Time(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))
Menstrual Bleed Questionnaire (MBQ) for Female Participants of Childbearing Potential: Change From Baseline in the Heaviness Subscale Score Over Time(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))
Menstrual Bleed Questionnaire (MBQ) for Female Participants of Childbearing Potential: Change From Baseline in the Irregularity Subscale Score Over Time(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))
CATCH Questionnaire for Pediatric Participants: Number of Participants by Responses to Their Level of Pain Associated With a Bleed Over Time(Baseline (Week 1), Weeks 13, 25, 37 and 49, and every 12 weeks thereafter until Study Completion/Discontinuation Visit (up to approximately 48 months))
CATCH Questionnaire for Pediatric Participants: Number of Participants by Responses to Their Level of Pain at Its Worst Over Time(Baseline (Week 1), Weeks 13, 25, 37 and 49, and every 12 weeks thereafter until Study Completion/Discontinuation Visit (up to approximately 48 months))
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(Week 17)
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(Week 17)
CATCH Questionnaire for Caregivers: Change From Baseline in the Treatment Burden Domain Score Over Time(Baseline (Week 1), Weeks 13, 25, 37 and 49, and every 12 weeks thereafter until Study Completion/Discontinuation Visit (up to approximately 48 months))
Change From Baseline in Mean Daily Peak Activity Duration Over Time(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))
Menstrual Bleed Questionnaire (MBQ) for Female Participants of Childbearing Potential: Change From Baseline in the Quality of Life Subscale Score Over Time(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))
Number of Participants With at Least One Thromboembolic Event(From Screening (Day -28 to -1) to Study Completion/Discontinuation Visit (up to approximately 48 months))
Change From Baseline in Mean Daily Step Count Over Time(Baseline (Weeks 1-2) and Weeks 13 (Weeks 12-13), 25 (Weeks 24-25), 37 (Weeks 36-37), and 49 (Weeks 48-49))
Number of Participants With Adverse Events Leading to Study Drug Discontinuation(From Screening (Day -28 to -1) to Study Completion/Discontinuation Visit (up to approximately 48 months))
Number of Participants With at Least One Severe Hypersensitivity, Anaphylaxis, and Anaphylactoid Event(From Screening (Day -28 to -1) to Study Completion/Discontinuation Visit (up to approximately 48 months))
Change From Baseline in Respiratory Rate Over Time(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))
Change From Baseline in Diastolic Blood Pressure Over Time(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))
Menstrual Bleed Questionnaire (MBQ) for Female Participants of Childbearing Potential: Change From Baseline in the Pain Subscale Score Over Time(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))
Menstruation Diary With the Pictorial Blood Assessment Chart (PBAC) for Female Participants of Childbearing Potential: PBAC Scores Over Time(Baseline (Day 1) and monthly (on days of menstruation) until Study Completion (up to approximately 48 months))
Number of Participants With at Least One Adverse Event by Severity, According to the World Health Organization (WHO) Toxicity Grading Scale(From Screening (Day -28 to -1) to Study Completion/Discontinuation Visit (up to approximately 48 months))
Number of Participants With at Least One Laboratory Abnormality(From Screening (Day -28 to -1) to Study Completion/Discontinuation Visit (up to approximately 48 months))
Change From Baseline in Body Temperature Over Time(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))
Change From Baseline in Systolic Blood Pressure Over Time(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))
Change From Baseline in Heart Rate Over Time, as Measured by Electrocardiogram (ECG)(Baseline, Weeks 5, 25, and 49, and every 12 weeks thereafter until Study Completion/Discontinuation Visit (up to approximately 48 months))
Number of Participants With at Least One Event of Thrombotic Microangiopathy(From Screening (Day -28 to -1) to Study Completion/Discontinuation Visit (up to approximately 48 months))
Number of Participants With at Least One Injection-Site Reaction by Severity, According to the WHO Toxicity Grading Scale(From Screening (Day -28 to -1) to Study Completion/Discontinuation Visit (up to approximately 48 months))
Change From Baseline in Pulse Rate Over Time(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))
Change From Baseline in Electrocardiogram (ECG) Parameters Over Time: QT, QTcB, QTcF, RR, PR, and QRS Intervals(Baseline, Weeks 5, 25, and 49, and every 12 weeks thereafter until Study Completion/Discontinuation Visit (up to approximately 48 months))
Plasma Trough Concentration (Ctrough) of Emicizumab Over Time(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))
Number of Participants With Anti-Drug Antibodies Against Emicizumab at Baseline and Post-Baseline(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))
Number of Participants Who Develop Anti-FVIII Inhibitors Over Time(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))