A Multicenter, Open-Label, Phase III Study to Evaluate the Efficacy, Safety, Pharmacokinetics, and Pharmacodynamics of Emicizumab Given Every 4 Weeks (Q4W) in Patients With Hemophilia A
Overview
- Phase
- Phase 3
- Intervention
- Emicizumab
- Conditions
- Hemophilia A
- Sponsor
- Hoffmann-La Roche
- Enrollment
- 48
- Locations
- 17
- Primary Endpoint
- Expansion Part: Annualized Bleeding Rate (ABR) for Treated Bleeds
- Status
- Completed
- Last Updated
- 3 years ago
Overview
Brief Summary
This multicenter, open-label, non-randomized study will assess the efficacy, safety, pharmacokinetics, and pharmacodynamics of emicizumab administered at a dose of 6 milligrams per kilogram (mg/kg) every 4 weeks in participants with hemophilia A with or without inhibitors against factor VIII (FVIII). The study consists of 2 parts: a pharmacokinetic (PK) run-in part followed by an expansion part.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Body weight greater than or equal to (\>/=) 40 kilograms (kg) at screening
- •Diagnosis of severe congenital hemophilia A or hemophilia A with FVIII inhibitors
- •Participants using rFVIIa or willing to switch to recombinant activated factor VII (rFVIIa) as primary bypassing agent for the treatment of breakthrough bleeds
- •FVIII inhibitor test during screening with titer results available prior to first administration of study drug
- •Participants without FVIII inhibitors, that is with less than (\<) 0.6 Bethesda unit per milliliter \[BU/mL\];\< 1.0 BU/mL only for laboratories with an historical sensitivity cutoff for inhibitor detection of 1.0 BU/mL, who completed successful immune tolerance induction (ITI) must have done so at least 5 years before screening and must have no evidence of inhibitor recurrence (permanent or temporary) indicated by detection of an inhibitor greater than (\>) 0.6 BU/mL (\> 1.0 BU/mL only for laboratories with an historical sensitivity cutoff for inhibitor detection of 1.0 BU/mL) since ITI
- •Adequate hematologic, hepatic, and renal function
Exclusion Criteria
- •Inherited or acquired bleeding disorder other than hemophilia A
- •Ongoing or planned ITI therapy; participants in whom ITI has failed will be eligible with a 72-hour washout period prior to the first emicizumab administration
- •History of illicit drug or alcohol abuse within 48 weeks prior to screening, in the investigator's judgment
- •Participants who are at high risk for thrombotic microangiopathy (TMA) (for example, have a previous medical or family history of TMA), in the investigator's judgment
- •Previous (within the last 12 months) or current treatment for thromboembolic disease (with the exception of previous catheter-associated thrombosis for which anti-thrombotic treatment is not currently ongoing) or signs of thromboembolic disease
- •Other conditions (for example, certain autoimmune diseases) that may currently increase the risk of bleeding or thrombosis
- •History of clinically significant hypersensitivity associated with monoclonal antibody therapies or components of the emicizumab injection
- •Known HIV infection with cluster of differentiation (CD) 4 cells counts \<200 cells per microliter (cells/mcL)
- •Use of systemic immunomodulators (for example, interferon) at enrollment or planned use during the study, with the exception of anti-retroviral therapy
- •Concomitant disease, condition, significant abnormality on screening evaluations or laboratory tests, or treatment that could interfere with the conduct of the study, or that would, in the opinion of the investigator, pose an additional unacceptable risk in administering study drug to the participant
Arms & Interventions
Emicizumab: PK Run-in Cohort
Participants received emicizumab subcutaneously (SC) at a dose of 6 mg/kg once every 4 weeks, with no loading dose, for at least 24 weeks.
Intervention: Emicizumab
Emicizumab: Expansion Cohort
Participants received emicizumab subcutaneously (SC) at a loading dose of 3 mg/kg once every week for the first 4 weeks followed by a maintenance dose of 6 mg/kg emicizumab SC once every 4 weeks for at least 24 weeks.
Intervention: Emicizumab
Outcomes
Primary Outcomes
Expansion Part: Annualized Bleeding Rate (ABR) for Treated Bleeds
Time Frame: From Baseline to at least 24 weeks
The number of treated bleeds over the efficacy period is presented as an annualized bleeding rate (ABR) that was analyzed using a negative binomial regression model with efficacy period as an offset to account for the difference in follow-up times. A bleed is considered a "treated bleed" if it is directly followed (i.e., no intervening bleed) by a hemophilia medication reported to be a "treatment for bleed", irrespective of time between treatment and the preceding bleed. A bleed and the first treatment thereafter and before a new bleed starts, are considered to be pairs, with the following exception: if multiple bleeds occur on the same calendar day, the subsequent treatment is considered to apply for each of these multiple bleeds. 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. Bleeds due to surgery/procedure are excluded.
Expansion Part: Annualized Bleeding Rate (ABR) for All Bleeds
Time Frame: From Baseline to at least 24 weeks
The number of all bleeds over the efficacy period is presented as an annualized bleeding rate (ABR) that was analyzed using a negative binomial regression model with efficacy period as an offset to account for the difference in follow-up times (i.e., the time that each participant stays in the study). 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 was implemented exactly as defined for the "treated bleeds" outcome measure. For non-treated bleeds, the 72-hour rule was implemented by calculating a treatment-free period of 72 hours from the bleed itself.
Expansion Part: Annualized Bleeding Rate (ABR) for Treated Spontaneous Bleeds
Time Frame: From Baseline to at least 24 weeks
The number of treated spontaneous bleeds over the efficacy period is presented as an annualized bleeding rate (ABR) that was analyzed using a negative binomial regression model with efficacy period as an offset to account for the difference in follow-up times (i.e., the time that each participant stays in the study). A bleed is classified as "spontaneous" if there is no other known contributing factor such as trauma or procedure/surgery. A "treated spontaneous bleed" is a spontaneous bleed that also fulfills the conditions of a treated bleed (see ABR for Treated Bleeds for the definition). Treated bleeds that fulfilled the 72-hour rule were included in the analysis of spontaneous bleeds. Bleeds due to surgery/procedure are excluded.
Expansion Part: Annualized Bleeding Rate (ABR) for Treated Joint Bleeds
Time Frame: From Baseline to at least 24 weeks
The number of treated joint bleeds over the efficacy period is presented as an annualized bleeding rate (ABR) that was analyzed using a negative binomial regression model with efficacy period as an offset to account for the difference in follow-up times (i.e., the time that each participant stays in the study). A "joint bleed" is defined as a bleed with type reported as "joint" and with 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. A "treated joint bleed" is a joint bleed that also fulfills the conditions of a treated bleed (see ABR for Treated Bleeds for the definition). Treated bleeds that fulfilled the 72-hour rule were included in the analysis of joint bleeds, excluding bleeds due to surgery/procedure.
Expansion Part: Annualized Bleeding Rate (ABR) for Treated Target Joint Bleeds
Time Frame: From Baseline to at least 24 weeks
The number of treated target joint bleeds over the efficacy period is presented as an annualized bleeding rate (ABR) that was analyzed using a negative binomial regression model with efficacy period as an offset to account for the difference in follow-up times (i.e., the time that each participant stays in the study). A "target joint bleed" is 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. A "treated target joint bleed" is a target joint bleed that also fulfills the conditions of a treated bleed (see ABR for Treated Bleeds for the definition). Bleeds due to surgery/procedure are excluded.
Secondary Outcomes
- Expansion Part: Percentage of Adult Participants (≥18 Years of Age) With a Clinically Meaningful Improvement From Baseline to Week 25 in the Haem-A-QoL Questionnaire Physical Health Score(Baseline, Week 25)
- Expansion Part: Change From Baseline to Week 25 in the Hemophilia A Quality of Life (Haem-A-QoL) Questionnaire Total Score for Adult Participants (≥18 Years of Age)(Baseline, Week 25)
- Expansion Part: Change From Baseline to Week 25 in the Haem-A-QoL Questionnaire Physical Health Score for Adult Participants (≥18 Years of Age)(Baseline, Week 25)
- Expansion Part: Proportion of Days Away From School to Expected Days at School in the Previous Four Weeks(Predose at Baseline, Weeks 13 and 25)
- PK Run-In Part: Apparent Clearance (CL/F) of Emicizumab(Week 1 Day 1 predose (0 hours) and 8 hours postdose, and Week 1 Days 3 and 5, Week 2 Days 8 and 11, Week 3 Days 15 and 18, Week 4 Days 22 and 25, and Day 1 of Weeks 5, 21, 22, 23, 24, and 25)
- PK Run-In Part: Plasma Concentration of Emicizumab at Specified Timepoints(Week 1 Day 1 predose and 8 hours postdose, and Week 1 Days 3 and 5, Week 2 Days 8 and 11, Week 3 Days 15 and 18, Week 4 Days 22 and 25, and Day 1 of Weeks 5, 6, 7, 8, 9, 11, 13, 15, 17, 19, 21, 22, 23, 24, and 25, and every 12 weeks thereafter to Week 265)
- Number of Participants With at Least One Local Injection-Site Reaction(From Baseline to study completion, dose up-titration, or change of dosing regimen, whichever occurred first (up to 5 years, 5 months))
- Number of Participants With at Least One Thromboembolic Event(From Baseline to study completion, dose up-titration, or change of dosing regimen, whichever occurred first (up to 5 years, 5 months))
- Expansion Part: Percentage of Adult Participants (≥18 Years of Age) With a Clinically Meaningful Improvement From Baseline to Week 25 in the Haem-A-QoL Questionnaire Total Score(Baseline, Week 25)
- PK Run-In Part: Maximum Observed Plasma Concentration (Cmax) of Emicizumab(Week 1 Day 1 predose (0 hours) and 8 hours postdose, and Week 1 Days 3 and 5, Week 2 Days 8 and 11, Week 3 Days 15 and 18, Week 4 Days 22 and 25, and Day 1 of Weeks 5, 21, 22, 23, 24, and 25)
- PK Run-In Part: Apparent Plasma Terminal Half-Life (t1/2) of Emicizumab(Week 1 Day 1 predose (0 hours) and 8 hours postdose, and Week 1 Days 3 and 5, Week 2 Days 8 and 11, Week 3 Days 15 and 18, Week 4 Days 22 and 25, and Day 1 of Weeks 5, 21, 22, 23, 24, and 25)
- Number of Participants With at Least One Adverse Event(From Baseline to study completion, dose up-titration, or change of dosing regimen, whichever occurred first (up to 5 years, 5 months))
- Number of Participants With at Least One Adverse Event of Changes From Baseline in Physical Examination Findings(From Baseline to study completion, dose up-titration, or change of dosing regimen, whichever occurred first (up to 5 years, 5 months))
- Expansion Part: Change From Baseline to Week 25 in the Hemophilia-Quality of Life-Short Form (Haemo-QoL-SF) Questionnaire Total Score for Adolescent Participants (12-17 Years of Age)(Baseline, Week 25)
- Expansion Part: Change From Baseline to Week 25 in the EQ-5D-5L Questionnaire Index Utility Score(Baseline, Week 25)
- PK Run-In Part: Area Under the Plasma Concentration-Time Curve From Time Zero to End of Dosing Interval (AUC[0-tau]) of Emicizumab(Week 1 Day 1 predose (0 hours) and 8 hours postdose, and Week 1 Days 3 and 5, Week 2 Days 8 and 11, Week 3 Days 15 and 18, Week 4 Days 22 and 25, and Day 1 of Weeks 5, 21, 22, 23, 24, and 25)
- Expansion Part: Plasma Concentration of Emicizumab at Specified Timepoints(Predose at Weeks 1, 2, 3, 4, 5, 9, 13, 17, 21, 25, 37, 49, 61, 73. 85, 97, 109, 121, 133, 145, 157, 169, 181, 193, 205, 217, 229, 241, and 253)
- Number of Participants With at Least One Grade ≥3 Adverse Event(From Baseline to study completion, dose up-titration, or change of dosing regimen, whichever occurred first (up to 5 years, 5 months))
- Expansion Part: Change From Baseline to Week 25 in the European Quality of Life-5 Dimensions-5 Levels (EQ-5D-5L) Questionnaire Visual Analogue Scale (VAS) Score(Baseline, Week 25)
- PK Run-In Part: Time to Reach Maximum Observed Plasma Concentration (Tmax) of Emicizumab(Week 1 Day 1 predose (0 hours) and 8 hours postdose, and Week 1 Days 3 and 5, Week 2 Days 8 and 11, Week 3 Days 15 and 18, Week 4 Days 22 and 25, and Day 1 of Weeks 5, 21, 22, 23, 24, and 25)
- PK Run-In Part: Area Under the Plasma Concentration-Time Curve From Time Zero to Extrapolated Infinite Time (AUC[0-inf]) of Emicizumab(Week 1 Day 1 predose (0 hours) and 8 hours postdose, and Week 1 Days 3 and 5, Week 2 Days 8 and 11, Week 3 Days 15 and 18, Week 4 Days 22 and 25, and Day 1 of Weeks 5, 21, 22, 23, 24, and 25)
- Number of Participants With De Novo Development of Anti-Factor VIII (FVIII) Antibodies(Baseline, Weeks 9 and 17 (for non-inhibitor subjects only), Week 25, and every 12 weeks thereafter until study completion (up to 5 years, 5 months))
- Long-Term Efficacy of Emicizumab: Median Calculated Annualized Bleeding Rates (ABR) for Treated Bleeds, All Bleeds, Treated Spontaneous Bleeds, Treated Joint Bleeds, and Treated Target Joint Bleeds(From start of emicizumab treatment to study completion, dose up-titration, or change of dosing regimen (median [min-max] efficacy period for all emicizumab participants: 191.14 [28.0-264.4] weeks))
- Long-Term Efficacy of Emicizumab: Median Calculated Annualized Bleeding Rates (ABR) for Treated Bleeds Per 12-Week Intervals Over Time(1-12, 13-24, 25-36, 37-48, 49-60, 61-72, 73-84, 85-96, 97-108, 109-120, 121-132, 133-144, 145-156, 157-168, 169-180, 181-192, 193-204, 205-216, 217-228, 229-240, 241-252, and 253-264 weeks)
- Expansion Part: Percentage of Participants With a Meaningful Improvement From Baseline to Week 25 in the EQ-5D-5L Questionnaire VAS Score(Baseline, Week 25)
- Expansion Part: Percentage of Participants With a Meaningful Improvement From Baseline to Week 25 in the EQ-5D-5L Questionnaire Index Utility Score(Baseline, Week 25)
- Expansion Part: Proportion of Days Away From Work to Expected Days at Work in the Previous Four Weeks(Predose at Baseline, Weeks 13 and 25)
- Expansion Part: Number of Days Hospitalized(From Baseline until at least 24 weeks of treatment (median [min-max] observation time: 25.57 [24.1-29.4] weeks))
- Expansion Part: Percentage of Participants Who Preferred Either the New Emicizumab Subcutaneous (SC) Treatment or Their Previous Hemophilia Intravenous (IV) Treatment, or Had No Preference, as Assessed Using the Emicizumab Preference Survey(Predose at Week 17)
- Number of Participants With at Least One Adverse Event Leading to Withdrawal From Treatment(From Baseline to study completion, dose up-titration, or change of dosing regimen, whichever occurred first (up to 5 years, 5 months))
- Number of Participants With at Least One Adverse Event of Changes From Baseline in Vital Signs(From Baseline to study completion, dose up-titration, or change of dosing regimen, whichever occurred first (up to 5 years, 5 months))
- Number of Participants With at Least One Adverse Event Related to Study Treatment(From Baseline to study completion, dose up-titration, or change of dosing regimen, whichever occurred first (up to 5 years, 5 months))
- Number of Participants With at Least One Shift in Clinical Laboratory Parameters From Baseline World Health Organization (WHO) Toxicity Scale Grade 0-2 to Post-Baseline WHO Grade 3 or 4(From Baseline to study completion, dose up-titration, or change of dosing regimen, whichever occurred first (up to 5 years, 5 months))
- Number of Participants With at Least One Thrombotic Microangiopathy(From Baseline to study completion, dose up-titration, or change of dosing regimen, whichever occurred first (up to 5 years, 5 months))
- Long-Term Efficacy of Emicizumab: Mean Calculated Annualized Bleeding Rates (ABR) for Treated Bleeds, All Bleeds, Treated Spontaneous Bleeds, Treated Joint Bleeds, and Treated Target Joint Bleeds(From start of emicizumab treatment to study completion, dose up-titration, or change of dosing regimen (median [min-max] efficacy period for all emicizumab participants: 191.14 [28.0-264.4] weeks))
- Long-Term Efficacy of Emicizumab: Mean Calculated Annualized Bleeding Rates (ABR) for Treated Bleeds Per 12-Week Intervals Over Time(1-12, 13-24, 25-36, 37-48, 49-60, 61-72, 73-84, 85-96, 97-108, 109-120, 121-132, 133-144, 145-156, 157-168, 169-180, 181-192, 193-204, 205-216, 217-228, 229-240, 241-252, and 253-264 weeks)
- Long-Term Efficacy of Emicizumab: Median Calculated Annualized Bleeding Rates (ABR) for All Bleeds Per 12-Week Intervals Over Time(1-12, 13-24, 25-36, 37-48, 49-60, 61-72, 73-84, 85-96, 97-108, 109-120, 121-132, 133-144, 145-156, 157-168, 169-180, 181-192, 193-204, 205-216, 217-228, 229-240, 241-252, and 253-264 weeks)
- Number of Participants With at Least One Systemic Hypersensitivity, Anaphylaxis, or Anaphylactoid Reaction(From Baseline to study completion, dose up-titration, or change of dosing regimen, whichever occurred first (up to 5 years, 5 months))
- Long-Term Efficacy of Emicizumab: Median Calculated Annualized Bleeding Rates (ABR) for Treated Spontaneous Bleeds Per 12-Week Intervals Over Time(1-12, 13-24, 25-36, 37-48, 49-60, 61-72, 73-84, 85-96, 97-108, 109-120, 121-132, 133-144, 145-156, 157-168, 169-180, 181-192, 193-204, 205-216, 217-228, 229-240, 241-252, and 253-264 weeks)
- Number of Participants With Anti-Drug Antibodies to Emicizumab at Any Time Post-Baseline During the Study(Baseline, Weeks 5, 9, 13, 17, 21, and 25, and every 12 weeks thereafter until study completion (up to 5 years, 5 months))
- Long-Term Efficacy of Emicizumab: Model-Based Annualized Bleeding Rates (ABR) for Treated Bleeds, All Bleeds, Treated Spontaneous Bleeds, Treated Joint Bleeds, and Treated Target Joint Bleeds(From start of emicizumab treatment to study completion, dose up-titration, or change of dosing regimen (median [min-max] efficacy period for all emicizumab participants: 191.14 [28.0-264.4] weeks))
- Long-Term Efficacy of Emicizumab: Mean Calculated Annualized Bleeding Rates (ABR) for All Bleeds Per 12-Week Intervals Over Time(1-12, 13-24, 25-36, 37-48, 49-60, 61-72, 73-84, 85-96, 97-108, 109-120, 121-132, 133-144, 145-156, 157-168, 169-180, 181-192, 193-204, 205-216, 217-228, 229-240, 241-252, and 253-264 weeks)
- Long-Term Efficacy of Emicizumab: Mean Calculated Annualized Bleeding Rates (ABR) for Treated Spontaneous Bleeds Per 12-Week Intervals Over Time(1-12, 13-24, 25-36, 37-48, 49-60, 61-72, 73-84, 85-96, 97-108, 109-120, 121-132, 133-144, 145-156, 157-168, 169-180, 181-192, 193-204, 205-216, 217-228, 229-240, 241-252, and 253-264 weeks)