Efficacy, Safety, and Pharmacokinetic Study of Prophylactic Emicizumab Versus No Prophylaxis in Hemophilia A Participants

Study Design & Population

Study type: Interventional
Phase: Phase 3
Interventions: Emicizumab (Drug)
Age: Pediatric, Adult, Older Adult
Sex: All
Sponsor: Hoffmann-La Roche
Primary completion: Aug 2022

Outcome Measures

Outcome	Result	p-value
PRIMARY Model-Based Annualized Bleeding Rate for Treated Bleeds	27.0; 1.0; 1.0; 1.2	<0.0001 sig
PRIMARY Mean Calculated Annualized Bleeding Rate for Treated Bleeds	43.7; 1.4; 1.5; 1.2	—
PRIMARY Median Calculated Annualized Bleeding Rate for Treated Bleeds	45.3; 0.0; 0.0; 0.0	—
SECONDARY Model-Based Annualized Bleeding Rate for All Bleeds	41.1; 1.9; 2.1; 3.8	<0.0001 sig
SECONDARY Mean Calculated Annualized Bleeding Rate for All Bleeds	53.0; 2.7; 3.1; 3.8	—
SECONDARY Median Calculated Annualized Bleeding Rate for All Bleeds	56.7; 1.5; 1.9; 2.1	—
SECONDARY Model-Based Annualized Bleeding Rate for Treated Spontaneous Bleeds	23.6; 0.4; 0.5; 0.6	<0.0001 sig
SECONDARY Mean Calculated Annualized Bleeding Rate for Treated Spontaneous Bleeds	30.9; 0.5; 0.6; 0.6	—
SECONDARY Median Calculated Annualized Bleeding Rate for Treated Spontaneous Bleeds	21.8; 0.0; 0.0; 0.0	—
SECONDARY Model-Based Annualized Bleeding Rate for Treated Joint Bleeds	17.7; 0.7; 0.6; 0.1	<0.0001 sig
SECONDARY Mean Calculated Annualized Bleeding Rate for Treated Joint Bleeds	25.5; 1.0; 0.8; 0.1	—
SECONDARY Median Calculated Annualized Bleeding Rate for Treated Joint Bleeds	10.9; 0.0; 0.0; 0.0	—
SECONDARY Model-Based Annualized Bleeding Rate for Treated Target Joint Bleeds	8.6; 0.4; 0.3; NA	<0.0001 sig
SECONDARY Mean Calculated Annualized Bleeding Rate for Treated Target Joint Bleeds	15.6; 0.7; 0.5; 0.0	—
SECONDARY Median Calculated Annualized Bleeding Rate for Treated Target Joint Bleeds	6.5; 0.0; 0.0; 0.0	—
SECONDARY Intra-Participant Comparison of the Calculated Annualized Bleeding Rate for Treated Bleeds With Emicizumab Prophylaxis On-Study Versus With Previous Episodic Therapy Pre-Study	13.02; 0.24	—
SECONDARY Intra-Participant Comparison of the Calculated Annualized Bleeding Rate for All Bleeds With Emicizumab Prophylaxis On-Study Versus With Previous Episodic Therapy Pre-Study	39.67; 2.04	—
SECONDARY Arms A, B, and C: Adjusted Mean Hemophilia A Quality of Life (Haem-A-QoL) Questionnaire Physical Health Domain Score at Week 25 in Participants ≥18 Years of Age	42.53; 27.85; 24.20	0.0515
SECONDARY Arms A, B, and C: Change From Baseline to Week 25 in Haem-A-QoL Questionnaire Physical Health Domain Score for Participants ≥18 Years of Age	51.25; 50.60; 42.14; -5.63; -20.20; -22.14	—
SECONDARY Arms A, B, and C: Adjusted Mean Haem-A-QoL Questionnaire Total Score at Week 25 in Participants ≥18 Years of Age	43.32; 37.26; 29.30	0.3281
SECONDARY Arms A, B, and C: Change From Baseline to Week 25 in Haem-A-QoL Questionnaire Total Score for Participants ≥18 Years of Age	42.05; 49.15; 46.59; -2.50; -10.14; -17.61	—
SECONDARY Arms A, B, and C: Hemophilia-Specific Quality of Life Short Form (Haemo-QoL-SF) Questionnaire Total Score at Baseline and Week 25 in Participants 12 to 17 Years of Age	44.7; 44.5; 35.7; 21.5; 32.9; 27.6	—
SECONDARY Arms A, B, and C: Adjusted Mean European Quality of Life 5-Dimensions-5 Levels Questionnaire (EQ-5D-5L) Questionnaire Visual Analog Scale (VAS) Score at Week 25	78.36; 81.82; 85.94	0.6165
SECONDARY Arms A, B, and C: Change From Baseline in EQ-5D-5L Questionnaire VAS Score at Week 25	84.50; 74.59; 78.96; -2.00; 4.82; 7.40	—
SECONDARY Arms A, B, and C: Adjusted Mean EQ-5D-5L Index Utility Score at Week 25	0.74; 0.79; 0.82	0.4890
SECONDARY Arms A, B, and C: Change From Baseline in EQ-5D-5L Index Utility Score at Week 25	0.76; 0.68; 0.75; 0.02; 0.08; 0.08	—
SECONDARY Arm D: Change From Baseline in Haemo-QoL-SF Questionnaire Physical Health and Total Scores at Week 25 in Participants 8 to 12 Years of Age	67.71; -53.75; 54.40; -23.86	—
SECONDARY Arm D: Caregiver-Reported Adapted Health-Related Quality of Life for Hemophilia Patients With Inhibitors (Adapted Inhib-QoL) Including Aspects of Caregiver Burden Questionnaire Transformed Total Score Over Time	51.04; 29.85; 11.29	—
SECONDARY Number of Participants With at Least One Adverse Event, Severity According to the World Health Organization (WHO) Toxicity Grading Scale, Primary Analysis of Randomized Comparison Arms	2; 25; 19; 2; 10; 6	—
SECONDARY Number of Participants With at Least One Adverse Event, Severity According to the World Health Organization (WHO) Toxicity Grading Scale, Final Analysis	29; 24; 14; 15; 5; 3	—
SECONDARY Number of Participants With at Least One Adverse Event Leading to Study Drug Discontinuation, Final Analysis	0; 0; 0; 0	—
SECONDARY Number of Participants With at Least One Systemic Hypersensitivity, Anaphylaxis, or Anaphylactoid Reaction, Severity According to the WHO Toxicity Grading Scale, Final Analysis	0; 1; 0; 0; 0; 1	—
SECONDARY Number of Participants With at Least One Thromboembolic Event, Severity According to the WHO Toxicity Grading Scale, Final Analysis	1; 0; 0; 0; 1; 0	—
SECONDARY Number of Participants With at Least One Thrombotic Microangiopathy, Severity According to the WHO Toxicity Grading Scale, Final Analysis	0; 0; 0; 0	—
SECONDARY Number of Participants With at Least One Injection-Site Reaction, Severity According to the WHO Toxicity Grading Scale, Final Analysis	4; 5; 0; 0; 3; 5	—
SECONDARY Number of Participants With Serum Chemistry Laboratory Abnormalities by Shift From Baseline to Highest WHO Grade Post-Baseline	0; 0; 1; 0; 0; 0	—
SECONDARY Number of Participants With Hematology Laboratory Abnormalities by Shift From Baseline to Highest WHO Grade Post-Baseline	2; 0; 0; 0; 1; 0	—
SECONDARY Change From Baseline in Body Temperature Over Time	36.48; 36.57; 36.45; 36.59; -0.04; -0.01	—
SECONDARY Change From Baseline in Pulse Rate Over Time	81.7; 78.9; 88.1; 94.1; 1.6; 3.5	—
SECONDARY Change From Baseline in Respiratory Rate Over Time	19.9; 19.5; 19.2; 20.4; 0.2; -0.1	—
SECONDARY Change From Baseline in Systolic Blood Pressure Over Time	123.6; 120.1; 124.9; 96.3; 1.7; 0.6	—
SECONDARY Change From Baseline in Diastolic Blood Pressure Over Time	82.6; 79.1; 82.4; 65.8; 1.1; 1.7	—
SECONDARY Number of Participants by Post-Baseline Anti-Emicizumab Antibody (ADA) Status	4; 4; 0; 0; 25; 23	—
SECONDARY Plasma Trough Concentration (Ctrough) of Emicizumab	12.5; 13.0; 13.9; 16.0; 22.9; 24.1	—

Summary

This multicenter, open-label, Phase 3 study with randomized and non-randomized arms is designed to investigate the efficacy, safety, and pharmacokinetics of emicizumab in participants with hemophilia A regardless of factor VIII (FVIII) inhibitor status. Participants greater than or equal to (≥)12 years old who received episodic therapy with FVIII or bypassing agents prior to study entry and experienced at least 5 bleeds over the prior 24 weeks will be randomized in a 2:2:1 ratio to the following regimens: Arm A: Emicizumab prophylaxis at 3 milligrams per kilogram (mg/kg) once every week (QW) subcutaneously (SC) for 4 weeks, followed by 1.5 mg/kg QW SC; Arm B: Emicizumab prophylaxis at 3 mg/kg QW SC for 4 weeks, followed by 6 mg/kg once every 4 weeks (Q4W) SC; and Arm C: No prophylaxis (control arm). In addition, pediatric participants less than (<)12 years old with hemophilia A and FVIII inhibitors who received episodic therapy with bypassing agents prior to study entry will be enrolled to Arm D: Emicizumab prophylaxis at 3 mg/kg QW SC for 4 weeks, followed by 1.5 mg/kg QW SC.

Eligibility Criteria

Inclusion Criteria

Inclusion Criteria for Arms A, B, and C:

Diagnosis of severe congenital hemophilia A or hemophilia A with FVIII inhibitors
Aged 12 years or older at the time of informed consent
Body weight ≥40 kilograms (kg) at the time of screening
Participants without FVIII inhibitors ( 3 kg at time of informed consent
Requires treatment with bypassing agents
Adequate hematologic, hepatic, and renal function
For female participants who are of childbearing potential, follow the same contraception criteria as listed above for Arms A, B, and C

Exclusion Criteria

Exclusion Criteria for Arms A, B, and C:

Inherited or acquired bleeding disorder other than hemophilia A
At high risk for thrombotic microangiopathy, in the investigator's judgment
History of illicit drug or alcohol abuse within 48 weeks prior to screening, in 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 anti-thrombotic treatment is not currently ongoing) or signs of thromboembolic disease
Other conditions that may increase risk of bleeding or thrombosis
History of clinically significant hypersensitivity associated with monoclonal antibody therapies or components of the emicizumab injection
Known human immuno-deficiency virus (HIV) infection with cluster of differentiation 4 (CD4) count 200 cells/mcL and meet all other criteria are eligible
Use of systemic immunomodulators at enrollment or planned use during the study, with the exception of anti-retroviral therapy
Concurrent disease, treatment, or abnormality in clinical laboratory tests that could interfere with the conduct of the study, may pose additional risk, or would, in the opinion of the investigator, preclude the participant's safe participation in and completion of the study
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 concurrently, within last 30 days or 5 half-lives, whichever is shorter
Pregnant or lactating, or intending to become pregnant during the study

Exclusion Criteria for Arm D:

Inherited or acquired bleeding disorder other than hemophilia A
Ongoing (or plan to receive during the study) ITI therapy or prophylaxis treatment with FVIII
Previous (in the past 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 diseases that may increase risk of bleeding or thrombosis
History of clinically significant hypersensitivity associated with monoclonal antibody therapies or components of the emicizumab injection
Known infection with HIV, hepatitis B virus (HBV), or hepatitis C virus (HCV)
At high risk for thrombotic microangiopathy, in the investigator's judgment
Use of systemic immunomodulators at enrollment or planned use during the study
Planned surgery (excluding minor procedures such as tooth extraction or incision and drainage) during the study
Inability (or unwillingness by caregiver) to receive (allow receipt of) blood or blood products (or any standard-of-care treatment for a life-threatening condition)
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 concurrently, within last 30 days or 5 half-lives, whichever is shorter
Concurrent disease, treatment, or abnormality in clinical laboratory tests that could interfere with the conduct of the study, may pose additional r

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