A Study to Evaluate the Safety and Tolerability of Prophylactic Emicizumab in Hemophilia A Patients With Inhibitors

Phase 3CompletedNCT03191799

Hoffmann-La Roche195 enrolled

Overview

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.

Study Type

INTERVENTIONAL

Allocation

Purpose

TREATMENT

Masking

NONE

Enrollment

195

Conditions

Hemophilia A

Interventions

Emicizumab

Initial dosing will be 3 mg/kg/week subcutaneously for 4 weeks; Maintenance dosing will follow at 1.5 mg/kg/week subcutaneously for the remainder of the 2-year treatment period

Eligibility

Sex: ALLMin age: 12 Years

Medical Language ↔ Plain English

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 * Receipt of: Emicizumab in a prior investigational study; An investigational drug to treat or reduce the risk of hemophilic bleeds within five half-lives of last drug administration; A non-hemophilia-related investigational drug within last 30 days or five half-lives, whichever is shorter; or, Any concurrent investigational drug. * Pregnancy or lactation, or intent to become pregnant during the study * Positive serum pregnancy test result within 7 days prior to initiation of emicizumab (females only)

Locations (72)

Royal Prince Alfred Hospital; Haematology

Camperdown, New South Wales, Australia

Alfred Hospital

Melbourne, Victoria, Australia

Fiona Stanley Hospital

Murdoch, Western Australia, Australia

UZ Leuven Gasthuisberg

Leuven, Belgium

Centro de Hematologia E Hemoterapia Do Parana - Hemepar

Curitiba, Paraná, Brazil

Outcomes

Primary Outcomes

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

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

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

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

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

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 Body Temperature at Specified Timepoints

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.

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)

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)

Secondary Outcomes

Model-Based Annualized Bleed Rates (ABR) for Treated Bleeds, All Bleeds, Treated Joint Bleeds, Treated Target Joint Bleeds, and Treated Spontaneous Bleeds

The number of bleeds over the efficacy period was analyzed as an ABR using a negative binomial regression model. Treated bleeds: bleeds followed by a hemophilia medication reported to be a "Treatment for bleed". All bleeds: included both treated and non-treated bleeds. Treated joint bleeds: treated bleeds where bleed type was "joint bleed" accompanied by at least one of following symptoms: "increased swelling or warmth of the skin over the joint", "increasing pain" or "decreased range of motion or difficulty using the joint compared with baseline". Treated target joint bleeds: treated joint bleeds that occurred in a target joint, defined as a joint in which ≥3 treated joint bleeds occurred during the 24 weeks prior to study entry. Treated spontaneous bleeds: treated bleeds with no other known contributing factor such as trauma or procedure/surgery. For all bleed types, bleeds due to surgery/procedure were excluded. Bleeds occurring after dose up-titration have been excluded.

Time frame: 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

The number of bleeds over the efficacy period was calculated as: ABR = (number of bleeds/number of days during the efficacy period) x 365.25. Treated bleeds: bleeds followed by a hemophilia medication reported to be a "Treatment for bleed". All bleeds: included both treated and non-treated bleeds. Treated joint bleeds: treated bleeds where bleed type was "joint bleed" accompanied by at least one of following symptoms: "increased swelling or warmth of the skin over the joint", "increasing pain" or "decreased range of motion or difficulty using the joint compared with baseline". Treated target joint bleeds: treated joint bleeds that occurred in a target joint, defined as a joint in which ≥3 treated joint bleeds occurred during the 24 weeks prior to study entry. Treated spontaneous bleeds: treated bleeds with no other known contributing factor such as trauma or procedure/surgery. For all types, bleeds due to surgery/procedure and bleeds occurring after dose up-titration were excluded.

Time frame: 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)

Data from ClinicalTrials.gov

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Instituto Estadual de Hema

Rio de Janeiro, Rio de Janeiro, Brazil

Hospital das Clinicas - UNICAMP

Campinas, São Paulo, Brazil

Faculdade de Medicina de Ribeirão Preto - Universidade de Sao Paulo

Ribeirão Preto, São Paulo, Brazil

Kaye Edmonton Clinic

Edmonton, Alberta, Canada

CancerCare Manitoba; Neuro-Oncology

Winnipeg, Manitoba, Canada

...and 62 more locations

Median Calculated Annualized Bleed Rates (ABR) for Treated Bleeds, All Bleeds, Treated Joint Bleeds, Treated Target Joint Bleeds, and Treated Spontaneous Bleeds

Time frame: 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

Treated bleeds: bleeds followed by a hemophilia medication reported to be a "Treatment for bleed". Bleeds due to surgery/procedure were excluded. The 72-hour rule was implemented: two bleeds of the same type and at the same anatomical location are counted as one bleed if the second bleed occurs within 72 hours from the last treatment for the first bleed. Included data before up-titration only, for participants whose dose was up-titrated.

Time frame: 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

All bleeds: included both treated and non-treated bleeds. Bleeds due to surgery/procedure were excluded. The 72-hour rule was implemented: two bleeds of the same type and at the same anatomical location are counted as one bleed if the second bleed occurs within 72 hours from the last treatment for the first bleed. Included data before up-titration only, for participants whose dose was up-titrated.

Time frame: 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

Treated spontaneous bleeds: treated bleeds with no other known contributing factor such as trauma or procedure/surgery. Bleeds due to surgery/procedure were excluded. The 72-hour rule was implemented: two bleeds of the same type and at the same anatomical location are counted as one bleed if the second bleed occurs within 72 hours from the last treatment for the first bleed. Included data before up-titration only, for participants whose dose was up-titrated.

Time frame: 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

The number of bleeds over the efficacy period was calculated as an ABR for each participant using the following formula: ABR = (number of bleeds/number of days during the efficacy period) x 365.25. Treated bleeds: bleeds followed by a hemophilia medication reported to be a "Treatment for bleed". Bleeds due to surgery/procedure were excluded. The 72-hour rule was implemented: two bleeds of the same type and at the same anatomical location are counted as one bleed if the second bleed occurs within 72 hours from the last treatment for the first bleed. Included data before up-titration only, for participants whose dose was up-titrated.

Time frame: 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

The number of bleeds over the efficacy period was calculated as an ABR for each participant using the following formula: ABR = (number of bleeds/number of days during the efficacy period) x 365.25. All bleeds: included both treated and non-treated bleeds. Bleeds due to surgery/procedure were excluded. The 72-hour rule was implemented: two bleeds of the same type and at the same anatomical location are counted as one bleed if the second bleed occurs within 72 hours from the last treatment for the first bleed. Included data before up-titration only, for participants whose dose was up-titrated.

Time frame: 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

The number of bleeds over the efficacy period was calculated as an ABR for each participant using the following formula: ABR = (number of bleeds/number of days during the efficacy period) x 365.25. Treated spontaneous bleeds: treated bleeds with no other known contributing factor such as trauma or procedure/surgery. Bleeds due to surgery/procedure were excluded. The 72-hour rule was implemented: two bleeds of the same type and at the same anatomical location are counted as one bleed if the second bleed occurs within 72 hours from the last treatment for the first bleed. Included data before up-titration only, for participants whose dose was up-titrated.

Time frame: 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

The Haem-A-QoL questionnaire was designed for adult participants (greater than or equal to 18 years old) with hemophilia. It consists of 46 items comprising 10 domains: physical health, treatment, work and school, dealing with hemophilia, feelings, familly planning, future, partnerships and sexuality, sports and leisure, and view of yourself. Items are rated by participants with one of five response options: never, seldom, sometimes, often, and always; although, for some items there is also a 'not applicable' option. The Total Score is based on the scores for each domain and ranges from 0 to 100, with lower scores reflective of better quality of life.