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Phase 3 N=113 Randomized Treatment

A Study to Evaluate the Efficacy, Safety, and Pharmacokinetics of Prophylactic Emicizumab Versus no Prophylaxis in Hemophilia A Participants With Inhibitors

Hemophilia A

Enrolled (actual)
113
Serious AEs
23.8%
Results posted
Nov 2017
Primary outcome: Primary: Model-Based Annualized Bleed Rate (ABR) for Treated Bleeds, Arm A: Emicizumab Versus Arm B: No Prophylaxis — 2.9; 23.3 treated bleeds per year — p=<0.0001

Study Design & Population

Study type
Interventional
Phase
Phase 3
Interventions
Emicizumab (Drug); rFVIIa (Drug); aPCC (Drug)
Age
Pediatric, Adult, Older Adult · 12+ yrs
Sex
All
Sponsor
Hoffmann-La Roche
Primary completion
Oct 2016

Outcome Measures

OutcomeResultp-value
PRIMARY
Model-Based Annualized Bleed Rate (ABR) for Treated Bleeds, Arm A: Emicizumab Versus Arm B: No Prophylaxis
2.9; 23.3 <0.0001 sig
SECONDARY
Model-Based Annualized Bleed Rate (ABR) for All Bleeds, Arm A: Emicizumab Versus Arm B: No Prophylaxis
5.5; 28.3 <0.0001 sig
SECONDARY
Intra-Participant Comparison of the Model-Based Annualized Bleed Rate (ABR) for All Bleeds in Arm A: Emicizumab Versus Previous Episodic Bypassing Agents
4.1; 37.7 <0.0001 sig
SECONDARY
Intra-Participant Comparison of the Model-Based Annualized Bleed Rate (ABR) for Treated Bleeds in Arm A: Emicizumab Versus Previous Episodic Bypassing Agents
1.7; 21.6 <0.0001 sig
SECONDARY
Model-Based Annualized Bleed Rate (ABR) for Treated Joint Bleeds, Arm A: Emicizumab Versus Arm B: No Prophylaxis
0.8; 6.7 0.0050 sig
SECONDARY
Intra-Participant Comparison of the Model-Based Annualized Bleed Rate (ABR) for All Bleeds in Arm C: Emicizumab Versus Previous Prophylactic Bypassing Agents
5.5; 24.3 <0.0001 sig
SECONDARY
Intra-Participant Comparison of the Model-Based Annualized Bleed Rate (ABR) for Treated Bleeds in Arm C: Emicizumab Versus Previous Prophylactic Bypassing Agents
3.3; 15.7 0.0003 sig
SECONDARY
Model-Based Annualized Bleed Rate (ABR) for Treated Spontaneous Bleeds, Arm A: Emicizumab Versus Arm B: No Prophylaxis
1.3; 16.8 <0.0001 sig
SECONDARY
Model-Based Annualized Bleed Rate (ABR) for Treated Target Joint Bleeds, Arm A: Emicizumab Versus Arm B: No Prophylaxis
0.1; 3.0 0.0002 sig
SECONDARY
Mean Calculated Annualized Bleed Rates (ABR) for Treated Bleeds, All Bleeds, Treated Spontaneous Bleeds, Treated Joint Bleeds, and Treated Target Joint Bleeds, Arm A: Emicizumab Versus Arm B: No Prophylaxis
3.5; 26.2; 6.3; 30.8; 1.5; 18.1
SECONDARY
Median Calculated Annualized Bleed Rates (ABR) for Treated Bleeds, All Bleeds, Treated Spontaneous Bleeds, Treated Joint Bleeds, and Treated Target Joint Bleeds, Arm A: Emicizumab Versus Arm B: No Prophylaxis
0.0; 18.8; 2.0; 30.2; 0.0; 15.2
SECONDARY
Percentage of Participants With 0 Bleeds for Treated Bleeds, All Bleeds, Treated Spontaneous Bleeds, Treated Joint Bleeds, and Treated Target Joint Bleeds, Arm A: Emicizumab Versus Arm B: No Prophylaxis
62.9; 5.6; 37.1; 5.6; 68.6; 11.1
SECONDARY
Hemophilia-Specific Quality of Life (Haem-A-QoL) Questionnaire Physical Health Score at Week 25 in Adult Participants (>/=18 Years Old), Arm A: Emicizumab Versus Arm B: No Prophylaxis
30.19; 57.14 0.0029 sig
SECONDARY
Haem-A-QoL Questionnaire Total Score at Week 25 in Adult Participants (>/=18 Years Old), Arm A: Emicizumab Versus Arm B: No Prophylaxis
26.465; 47.504 0.0019 sig
SECONDARY
European Quality of Life-5 Dimensions-5 Levels (EQ-5D-5L) Visual Analog Scale Score at Week 25, Arm A: Emicizumab Versus Arm B: No Prophylaxis
83.8; 76.4 0.0171 sig
SECONDARY
EQ-5D-5L Index Utility Score at Week 25, Arm A: Emicizumab Versus Arm B: No Prophylaxis
0.83; 0.60 0.0014 sig
SECONDARY
Hemophilia-Specific Quality of Life - Short Form (Haemo-Qol-SF) Questionnaire Total Score at Baseline and Week 25 in Adolescent Participants (12-17 Years Old)
34.643; 37.143; 30.000; 30.714; 33.095; 30.000
SECONDARY
Long-Term Efficacy of Emicizumab: Model-Based Annualized Bleed Rates (ABR) for Treated Bleeds, All Bleeds, Treated Spontaneous Bleeds, Treated Joint Bleeds, and Treated Target Joint Bleeds, All Enrolled Participants
1.9; 0.6; 3.2; 1.5; 2.4; 3.5
SECONDARY
Long-Term Efficacy of Emicizumab: Mean Calculated Annualized Bleed Rates (ABR) for Treated Bleeds, All Bleeds, Treated Spontaneous Bleeds, Treated Joint Bleeds, and Treated Target Joint Bleeds, All Enrolled Participants
2.9; 0.6; 3.3; 1.6; 2.6; 4.8
SECONDARY
Long-Term Efficacy of Emicizumab: Median Calculated Annualized Bleed Rates (ABR) for Treated Bleeds, All Bleeds, Treated Spontaneous Bleeds, Treated Joint Bleeds, and Treated Target Joint Bleeds, All Enrolled Participants
0.3; 0.0; 0.0; 0.0; 0.0; 1.9
SECONDARY
Long-Term Efficacy of Emicizumab: Mean Calculated Annualized Bleed Rates (ABR) for Treated Bleeds Per 12-Week Intervals Over Time, All Enrolled Participants
3.9; 2.2; 0.9; 0.3; 0.4; 0.5
SECONDARY
Long-Term Efficacy of Emicizumab: Median Calculated Annualized Bleed Rates (ABR) for Treated Bleeds Per 12-Week Intervals Over Time, All Enrolled Participants
0.0; 0.0; 0.0; 0.0; 0.0; 0.0
SECONDARY
Long-Term Efficacy of Emicizumab: Mean Calculated Annualized Bleed Rates (ABR) for All Bleeds Per 12-Week Intervals Over Time, All Enrolled Participants
6.2; 3.4; 1.5; 1.4; 1.1; 1.0
SECONDARY
Long-Term Efficacy of Emicizumab: Median Calculated Annualized Bleed Rates (ABR) for All Bleeds Per 12-Week Intervals Over Time, All Enrolled Participants
0.0; 0.0; 0.0; 0.0; 0.0; 0.0
SECONDARY
Long-Term Efficacy of Emicizumab: Mean Calculated Annualized Bleed Rates (ABR) for Treated Spontaneous Bleeds Per 12-Week Intervals Over Time, All Enrolled Participants
2.2; 1.3; 0.4; 0.2; 0.1; 0.2
SECONDARY
Long-Term Efficacy of Emicizumab: Median Calculated Annualized Bleed Rates (ABR) for Treated Spontaneous Bleeds Per 12-Week Intervals Over Time, All Enrolled Participants
0.0; 0.0; 0.0; 0.0; 0.0; 0.0
SECONDARY
Safety Summary of the Overall Number and Percentage of Participants With at Least One Adverse Event, Severity Assessed According to the WHO Toxicity Grading Scale
34; 9; 15; 46; 9; 0
SECONDARY
Number of Participants Testing Negative or Positive for the Presence of Anti-Drug Antibodies (ADAs), Including Neutralizing ADAs, During the Study
33; 18; 47; 11; 33; 17
SECONDARY
Plasma Trough Concentrations of Emicizumab at Specified Timepoints
NA; NA; NA; NA; NA; 16.2

Summary

This multicenter, open-label study will evaluate the safety, efficacy and pharmacokinetics of prophylactic emicizumab treatment in participants previously treated with episodic or prophylactic bypassing agents. Episodic bypassing agent participants will be randomized in a 2:1 fashion to receive emicizumab prophylaxis (Arm A) versus no prophylaxis (Arm B) and will be stratified across Arms A and B according to the number of bleeds they experienced over the last 24 weeks prior to study entry (less than [ /=] 9 bleeds); Arm B participants will have the opportunity to switch to emicizumab prophylaxis after at least 24 weeks on-study. Prophylactic bypassing agent participants will switch to emicizumab prophylaxis (Arm C) from the start of the trial; enrollment will be extended for 24 weeks after the last participant has enrolled in Arms A or B or until approximately 50 participants have enrolled in Arm C, whichever occurs first. Episodic bypassing agent participants who previously participated in the non-interventional study BH29768 (NCT02476942) who were unable to enroll in Arms A or B, or participants on prophylactic bypassing agents who were unable to enroll in Arm C, prior to their closure will have the opportunity to enroll in Arm D. Like participants in Arms A and C, Arm D participants will receive emicizumab prophylaxis from the start of the trial. All participants will continue to receive episodic bypassing agent therapy to treat breakthrough bleeds, preferably with recombinant activated factor VII (rFVIIa).

Eligibility Criteria

Inclusion Criteria

  • Body weight >/= 40 kilograms (kg) at the time of screening
  • Diagnosis of congenital hemophilia A of any severity and documented history of high-titer inhibitor ( that is [i.e.], >/= 5 Bethesda Units [BU])
  • Documentation of treatment with episodic or prophylactic bypassing agents for at least the last 24 weeks
  • >/= 6 bleeds in the last 24 weeks prior to screening (if on an episodic bypassing agent regimen) or >/=2 bleeds in the last 24 weeks prior to screening (if on a prophylactic bypassing agent regimen)
  • Adequate hematologic, hepatic and renal function
  • For women who are not postmenopausal or surgically sterile: agreement to remain abstinent or use single or combined highly effective contraceptive methods

Exclusion Criteria

  • Participants with inherited or acquired bleeding disorder other than hemophilia A
  • Participants with ongoing (or plan to receive during the study) immune tolerance induction therapy or prophylaxis with Factor VIII (FVIII), with the exception of participants who have received a treatment regimen of FVIII prophylaxis with concurrent bypassing agent prophylaxis
  • 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
  • Participants with other conditions (for example [e.g.], certain autoimmune diseases) that may increase the risk of bleeding or thrombosis
  • History of clinically significant hypersensitivity associated with monoclonal antibody therapies or components of the emicizumab injection
  • Known human immunodeficiency virus (HIV) infection with cluster of differentiation 4 (CD4) count < 200 cells per microliter (cells/mcL) within 24 weeks prior to screening
  • Use of systemic immunomodulators (e.g., interferon or rituximab) at enrolment or planned use during the study, with the exception of antiretroviral therapy
  • Participants who are at high risk for thrombotic microangiopathy (TMA; e.g., have a previous medical or family history of TMA), in the investigator's judgment
  • 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 participant's safe participation in and completion of the study or interpretation of the study results
  • Planned surgery (excluding minor procedures such as tooth extraction or incision and drainage) during the study
  • Receipt of emicizumab in a prior investigational study; An investigational drug to treat or reduce the risk of hemophilic bleeds within 5 half-lives of last drug administration; A non-hemophilia-related investigational drug within last 30 days or 5 half-lives, whichever is shorter; An investigational drug concurrently
  • Unwillingness to use highly effective contraception methods for the specified duration in the protocol (females only, unless required otherwise by the local health authority)
  • Clinically significant abnormality on screening evaluations or laboratory tests that, in the opinion of the investigator, may pose an additional risk in administering study drug to the participant
  • Pregnancy or lactation, or intent to become pregnant during the study
View full record on ClinicalTrials.gov →

Data sourced from ClinicalTrials.gov (NCT02622321). Outcome figures and adverse-event rates are extracted automatically from the registry's posted results and are provided for clinician reference, not as a substitute for the primary publication.

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