Clinical Trials/NCT03191799

NCT03191799

Completed

Phase 3

A Single-Arm, Multicenter Phase IIIB Clinical Trial to Evaluate the Safety and Tolerability of Prophylactic Emicizumab in Hemophilia A Patients With Inhibitors

Hoffmann-La Roche72 sites in 17 countries195 target enrollmentSeptember 5, 2017

ConditionsHemophilia A

InterventionsEmicizumab

DrugsEmicizumab

Overview

Phase: Phase 3
Intervention: Emicizumab
Conditions: Hemophilia A
Sponsor: Hoffmann-La Roche
Enrollment: 195
Locations: 72
Primary Endpoint: Change From Baseline in Body Weight at Specified Timepoints
Status: Completed
Last Updated: 4 years ago

Overview Investigators Eligibility Criteria Arms & Interventions Outcomes Sites Similar Trials

Overview

Brief Summary

This is a phase IIIb, single arm, open-label, multi-center study to evaluate the safety and tolerability of emicizumab in participants with congenital hemophilia A who have documented inhibitors against Factor VIII (FVIII) at enrollment. Approximately 200 participants, aged 12 or older, will be enrolled in this study and are expected to be enrolled at approximately 85 sites globally. Participants will receive an initial weekly dose of prophylactic emicizumab subcutaneously for 4 weeks, followed by a weekly maintenance dose subcutaneously for the remainder of the 2-year treatment period.

Registry

clinicaltrials.gov

Start Date

September 5, 2017

End Date

November 19, 2020

Last Updated

4 years ago

Study Type

Interventional

Study Design

Single Group

Sex

All

Investigators

Sponsor

Hoffmann-La Roche

Responsible Party

Sponsor

Eligibility Criteria

Inclusion Criteria

•As per investigator's judgement, a willingness and ability to comply with scheduled visits, treatment plans, laboratory tests, and other study procedures, including the patient-reported outcome (PRO) questionnaires and bleed diaries through the use of an electronic device or paper
•Aged 12 years or older at the time of informed consent
•Diagnosis of congenital hemophilia A with persistent inhibitors against FVIII
•Documented treatment with bypassing agents or FVIII concentrates in the last 6 months (on-demand or prophylaxis). Prophylaxis needs to be discontinued the latest by a day before starting emicizumab
•Adequate hematologic, hepatic, and renal function
•For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use a highly effective contraceptive method with a failure rate of \<1% per year during the treatment period and for at least five elimination half-lives (24 weeks) after the last dose of emicizumab

Exclusion Criteria

•Inherited or acquired bleeding disorder other than hemophilia A
•Ongoing (or plan to receive during the study) immune tolerance induction (ITI) therapy (prophylaxis regimens with FVIII and/or bypassing agents must be discontinued prior to enrollment). Patients receiving ITI therapy will be eligible following the completion of a 72-hour washout period prior to the first emicizumab administration
•History of illicit drug or alcohol abuse within 12 months prior to screening, as per the investigator's judgment
•High risk for thrombotic microangiopathy (TMA) (e.g., have a previous medical or family history of TMA), as per the investigator's judgment
•Previous (in the past 12 months) or current treatment for thromboembolic disease (with the exception of previous catheter-associated thrombosis for which antithrombotic treatment is not currently ongoing) or current signs of thromboembolic disease
•Other conditions (e.g., certain autoimmune diseases) that may increase the risk of bleeding or thrombosis
•History of clinically significant hypersensitivity reaction associated with monoclonal antibody therapies or components of the emicizumab injection
•Known human immunodeficiency virus (HIV) infection with CD4 count \<200 cells/μL within 6 months prior to screening
•Use of systemic immunomodulators (e.g., interferon or rituximab) at enrollment or planned use during the study, with the exception of antiretroviral therapy
•Concurrent disease, treatment, or abnormality in clinical laboratory tests that could interfere with the conduct of the study or that would, in the opinion of the investigator or Sponsor, preclude the patient's safe participation in and completion of the study or interpretation of the study results

Arms & Interventions

1.5 mg/kg Emicizumab QW

Participants will receive initial weekly doses of prophylactic emicizumab subcutaneously for 4 weeks, followed by maintenance doses consisting of half the initial dose, administered subcutaneously for the remainder of the 2-year treatment period

Intervention: Emicizumab

Outcomes

Primary Outcomes

Change From Baseline in Body Weight at Specified Timepoints

Time Frame: Baseline, Weeks 2, 3, and 5; Months 3, 6, 9, 12, and 18; and at Early Termination/Study Completion (up to 24 months)

Vital signs that were measured included body temperature, pulse and respiratory rates, systolic and diastolic blood pressure, and weight. On treatment days, measurement occurred prior to emicizumab administration.

Overall Summary of the Number of Participants With Adverse Events, Severity Assessed According to the World Health Organization (WHO) Toxicity Grading Scale

Time Frame: From Baseline until study completion (up to 2 years)

Investigators sought information on adverse events (AEs) at each contact with participants. The WHO toxicity grading scale was used for assessing AE severity (i.e., intensity of an AE); any AEs not specifically listed in the WHO toxicity grading scale were assessed for severity according to the following grades: Grade 1 is mild; Grade 2 is moderate, Grade 3 is severe; Grade 4 is life-threatening; and Grade 5 is death. Regardless of severity, some AEs may have also met seriousness criteria. The terms "severe" and "serious" are not synonymous; severity and seriousness were independently assessed for each AE. aPCC = activated prothrombin complex concentrate

Adverse Events (AEs) Rates Per 100 Patient-Years for All-Grade AEs, Serious AEs, and Grade ≥3 AEs

Time Frame: From Baseline until study completion (up to 2 years)

Number of Participants by Hematology and Biochemistry Laboratory Parameter Test Results as Shifts From the WHO Toxicity Grade at Baseline to the Worst WHO Toxicity Grade Post-Baseline

Time Frame: Baseline, Weeks 2, 3, and 5; Months 3, 6, 9, 12, and 18; and at Early Termination/Study Completion (up to 24 months)

The World Health Organization (WHO) toxicity grading scale was used for determining the severity of laboratory abnormalities (i.e., test results outside of the reference range) for hematology and biochemistry parameters; Grade 0 is normal and Grades 1 to 4 represent worsening levels of the parameter outside of the normal range in the specified direction of the abnormality (high and low are above and below the range, respectively). Not every laboratory abnormality qualified as an adverse event (AE). A laboratory test result was reported as an AE if it met any of the following criteria: was accompanied by clinical symptoms; resulted in a change in study treatment; resulted in a medical intervention or a change in concomitant therapy; or was clinically significant in the investigator's judgment. Baseline was defined as the last available assessment prior to first receipt of study drug. Abs = absolute count; SGOT/AST = aspartate aminotransferase; SGPT/ALT = alanine aminotransferase

Change From Baseline in Body Temperature at Specified Timepoints

Time Frame: Baseline, Weeks 2, 3, and 5; Months 3, 6, 9, 12, and 18; and at Early Termination/Study Completion (up to 24 months)

Change From Baseline in Systolic Blood Pressure at Specified Timepoints

Time Frame: Baseline, Weeks 2, 3, and 5; Months 3, 6, 9, 12, and 18; and at Early Termination/Study Completion (up to 24 months)

Change From Baseline in Diastolic Blood Pressure at Specified Timepoints

Time Frame: Baseline, Weeks 2, 3, and 5; Months 3, 6, 9, 12, and 18; and at Early Termination/Study Completion (up to 24 months)

Change From Baseline in Pulse Rate at Specified Timepoints

Time Frame: Baseline, Weeks 2, 3, and 5; Months 3, 6, 9, 12, and 18; and at Early Termination/Study Completion (up to 24 months)

Change From Baseline in Respiratory Rate at Specified Timepoints

Time Frame: Baseline, Weeks 2, 3, and 5; Months 3, 6, 9, 12, and 18; and at Early Termination/Study Completion (up to 24 months)

Secondary Outcomes

Model-Based Annualized Bleed Rates (ABR) for Treated Bleeds, All Bleeds, Treated Joint Bleeds, Treated Target Joint Bleeds, and Treated Spontaneous Bleeds(From first dose of emicizumab until dose up-titration or withdrawal from treatment (median [min-max] efficacy period: 103.14 [1.1-108.3] weeks))
Mean Calculated Annualized Bleed Rates (ABR) for Treated Bleeds, All Bleeds, Treated Joint Bleeds, Treated Target Joint Bleeds, and Treated Spontaneous Bleeds(From first dose of emicizumab until dose up-titration or withdrawal from treatment (median [min-max] efficacy period: 103.14 [1.1-108.3] weeks))
Median Calculated Annualized Bleed Rates (ABR) for Treated Bleeds, All Bleeds, Treated Joint Bleeds, Treated Target Joint Bleeds, and Treated Spontaneous Bleeds(From first dose of emicizumab until dose up-titration or withdrawal from treatment (median [min-max] efficacy period: 103.14 [1.1-108.3] weeks))
Percentage of Participants by the Categorized Number of Bleeds for Treated Bleeds(From first dose of emicizumab until dose up-titration or withdrawal from treatment (median [min-max] efficacy period: 103.14 [1.1-108.3] weeks))
Percentage of Participants by the Categorized Number of Bleeds for All Bleeds(From first dose of emicizumab until dose up-titration or withdrawal from treatment (median [min-max] efficacy period: 103.14 [1.1-108.3] weeks))
Percentage of Participants by the Categorized Number of Bleeds for Treated Spontaneous Bleeds(From first dose of emicizumab until dose up-titration or withdrawal from treatment (median [min-max] efficacy period: 103.14 [1.1-108.3] weeks))
Percentage of Participants by the Categorized Calculated Annualized Bleed Rates (ABR) for Treated Bleeds(From first dose of emicizumab until dose up-titration or withdrawal from treatment (median [min-max] efficacy period: 103.14 [1.1-108.3] weeks))
Percentage of Participants by the Categorized Calculated Annualized Bleed Rates (ABR) for All Bleeds(From first dose of emicizumab until dose up-titration or withdrawal from treatment (median [min-max] efficacy period: 103.14 [1.1-108.3] weeks))
Percentage of Participants by the Categorized Calculated Annualized Bleed Rates (ABR) for Treated Spontaneous Bleeds(From first dose of emicizumab until dose up-titration or withdrawal from treatment (median [min-max] efficacy period: 103.14 [1.1-108.3] weeks))
Change From Baseline in the Hemophilia Adult Quality of Life (Haem-A-QoL) Questionnaire Total Score at Specified Timepoints, Adult Participants(Baseline (Week 1), 3, 6, 12, and 18 months, and at Early Termination or Study Completion (up to 24 months))
Percentage of Participants With an Improvement From Baseline Greater Than the Responder Threshold for the Hemophilia Adult Quality of Life (Haem-A-QoL) Questionnaire Total Score at Specified Timepoints(At 3, 6, 12, and 18 months)
Change From Baseline in the Hemophilia Adult Quality of Life (Haem-A-QoL) Questionnaire Physical Health Domain Score at Specified Timepoints, Adult Participants(Baseline (Week 1), 3, 6, 12, and 18 months, and at Early Termination or Study Completion (up to 24 months))
Percentage of Participants With an Improvement From Baseline Greater Than the Responder Threshold for the Hemophilia Adult Quality of Life (Haem-A-QoL) Questionnaire Physical Health Domain Score at Specified Timepoints(At 3, 6, 12, and 18 months)
Change From Baseline in the Hemophilia Adult Quality of Life (Haem-A-QoL) Questionnaire Treatment Domain Score at Specified Timepoints, Adult Participants(Baseline (Week 1), 3, 6, 12, and 18 months, and at Early Termination or Study Completion (up to 24 months))
Change From Baseline in the Hemophilia Adult Quality of Life (Haem-A-QoL) Questionnaire Work and School Domain Score at Specified Timepoints, Adult Participants(Baseline (Week 1), 3, 6, 12, and 18 months, and at Early Termination or Study Completion (up to 24 months))
Change From Baseline in the Hemophilia Adult Quality of Life (Haem-A-QoL) Questionnaire Dealing With Hemophilia Domain Score at Specified Timepoints, Adult Participants(Baseline (Week 1), 3, 6, 12, and 18 months, and at Early Termination or Study Completion (up to 24 months))
Change From Baseline in the Hemophilia Adult Quality of Life (Haem-A-QoL) Questionnaire Feelings Domain Score at Specified Timepoints, Adult Participants(Baseline (Week 1), 3, 6, 12, and 18 months, and at Early Termination or Study Completion (up to 24 months))
Change From Baseline in the Hemophilia Adult Quality of Life (Haem-A-QoL) Questionnaire Family Planning Domain Score at Specified Timepoints, Adult Participants(Baseline (Week 1), 3, 6, 12, and 18 months, and at Early Termination or Study Completion (up to 24 months))
Change From Baseline in the Hemophilia Adult Quality of Life (Haem-A-QoL) Questionnaire Future Domain Score at Specified Timepoints, Adult Participants(Baseline (Week 1), 3, 6, 12, and 18 months, and at Early Termination or Study Completion (up to 24 months))
Change From Baseline in the Hemophilia Adult Quality of Life (Haem-A-QoL) Questionnaire Partnership and Sexuality Domain Score at Specified Timepoints, Adult Participants(Baseline (Week 1), 3, 6, 12, and 18 months, and at Early Termination or Study Completion (up to 24 months))
Change From Baseline in the Hemophilia Adult Quality of Life (Haem-A-QoL) Questionnaire Sports and Leisure Domain Score at Specified Timepoints, Adult Participants(Baseline (Week 1), 3, 6, 12, and 18 months, and at Early Termination or Study Completion (up to 24 months))
Change From Baseline in the Hemophilia Adult Quality of Life (Haem-A-QoL) Questionnaire View of Yourself Domain Score at Specified Timepoints, Adult Participants(Baseline (Week 1), 3, 6, 12, and 18 months, and at Early Termination or Study Completion (up to 24 months))
Change From Baseline in the Hemophilia Quality of Life Short Form (Haemo-QoL-SF) Questionnaire Total Score at Specified Timepoints, Adolescent Participants(Baseline (Week 1), 3, 6, 12, and 18 months, and at Early Termination or Study Completion (up to 24 months))
Percentage of Participants Who Preferred the New Emicizumab Treatment or the Old Hemophilia Treatment, or Without Treatment Preference, as Assessed by the EmiPref Questionnaire(Month 3)
Percentage of Participants With an Improvement From Baseline Greater Than the Responder Threshold for the Hemophilia Quality of Life Short Form (Haemo-QoL-SF) Questionnaire Total Score at Specified Timepoints(At 3, 6, 12, and 18 months)
Change From Baseline in the Hemophilia Quality of Life Short Form (Haemo-QoL-SF) Questionnaire Physical Health Domain Score at Specified Timepoints, Adolescent Participants(Baseline (Week 1), 3, 6, 12, and 18 months, and at Early Termination or Study Completion (up to 24 months))
Percentage of Participants With an Improvement From Baseline Greater Than the Responder Threshold for the Hemophilia Quality of Life Short Form (Haemo-QoL-SF) Questionnaire Physical Health Domain Score at Specified Timepoints(At 3, 6, 12, and 18 months)
Change From Baseline in the Hemophilia Quality of Life Short Form (Haemo-QoL-SF) Questionnaire Treatment Domain Score at Specified Timepoints, Adolescent Participants(Baseline (Week 1), 3, 6, 12, and 18 months, and at Early Termination or Study Completion (up to 24 months))
Change From Baseline in the Hemophilia Quality of Life Short Form (Haemo-QoL-SF) Questionnaire Sports and School Domain Score at Specified Timepoints, Adolescent Participants(Baseline (Week 1), 3, 6, 12, and 18 months, and at Early Termination or Study Completion (up to 24 months))
Change From Baseline in the Hemophilia Quality of Life Short Form (Haemo-QoL-SF) Questionnaire Dealing With Hemophilia Domain Score at Specified Timepoints, Adolescent Participants(Baseline (Week 1), 3, 6, 12, and 18 months, and at Early Termination or Study Completion (up to 24 months))
Change From Baseline in the Hemophilia Quality of Life Short Form (Haemo-QoL-SF) Questionnaire Feelings Domain Score at Specified Timepoints, Adolescent Participants(Baseline (Week 1), 3, 6, 12, and 18 months, and at Early Termination or Study Completion (up to 24 months))
Change From Baseline in the Hemophilia Quality of Life Short Form (Haemo-QoL-SF) Questionnaire Family Domain Score at Specified Timepoints, Adolescent Participants(Baseline (Week 1), 3, 6, 12, and 18 months, and at Early Termination or Study Completion (up to 24 months))
Change From Baseline in the Hemophilia Quality of Life Short Form (Haemo-QoL-SF) Questionnaire Friends Domain Score at Specified Timepoints, Adolescent Participants(Baseline (Week 1), 3, 6, 12, and 18 months, and at Early Termination or Study Completion (up to 24 months))
Change From Baseline in the Hemophilia Quality of Life Short Form (Haemo-QoL-SF) Questionnaire Other People Domain Score at Specified Timepoints, Adolescent Participants(Baseline (Week 1), 3, 6, 12, and 18 months, and at Early Termination or Study Completion (up to 24 months))
Change From Baseline in the Hemophilia Quality of Life Short Form (Haemo-QoL-SF) Questionnaire View of Yourself Domain Score at Specified Timepoints, Adolescent Participants(Baseline (Week 1), 3, 6, 12, and 18 months, and at Early Termination or Study Completion (up to 24 months))
Change From Baseline in the EuroQoL Five-Dimension-Five Levels Questionnaire (EQ-5D-5L) Index Utility Score at Specified Timepoints(Baseline (Week 1), 3, 6, 12, and 18 months, and at Early Termination or Study Completion (up to 24 months))
Change From Baseline in the EuroQoL Five-Dimension-Five Levels Questionnaire (EQ-5D-5L) Quality-of-Life Visual Analogue Scale (VAS) Score at Specified Timepoints(Baseline (Week 1), 3, 6, 12, and 18 months, and at Early Termination or Study Completion (up to 24 months))
Number and Percentage of Participants With Anti-Drug Antibodies (ADAs) Against Emicizumab at Anytime Post-Baseline(Baseline (Week 1), Week 5, and at 3, 6, 9, 12, and 18 months, and at early termination/study completion (up to 24 months))
Mean Trough Plasma Concentrations of Emicizumab at Specified Timepoints(Pre-dose at Weeks 2, 3, and 5, Months 3, 6, 12, and 18, and at treatment discontinuation (up to 2 years))