Phase 3
Completed N=48
A Study to Evaluate the Efficacy, Safety, Pharmacokinetics, and Pharmacodynamics of Emicizumab Given Every 4 Weeks in Participants With Hemophilia A
Source: ClinicalTrials.gov NCT03020160 ↗Enrolled (actual)
48
Serious AEs
20.8%
Results posted
Dec 2018
Primary outcomePrimary: Expansion Part: Annualized Bleeding Rate (ABR) for Treated Bleeds — 2.4 treated bleed rate per year
◆ Published Evidence
Highly cited
383citations · ~55 / year
Efficacy, safety, and pharmacokinetics of emicizumab prophylaxis given every 4 weeks in people with haemophilia A (HAVEN 4): a multicentre, open-label, non-randomised phase 3 study.
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.
Linked Publications (2)
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Efficacy, safety, and pharmacokinetics of emicizumab prophylaxis given every 4 weeks in people with haemophilia A (HAVEN 4): a multicentre, open-label, non-randomised phase 3 study.
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Surgical outcomes in people with hemophilia A taking emicizumab prophylaxis: experience from the HAVEN 1-4 studies.
Outcome Measures
| Outcome | Result | p-value |
|---|---|---|
| PRIMARY Expansion Part: Annualized Bleeding Rate (ABR) for Treated Bleeds |
2.4 | — |
| PRIMARY Expansion Part: Annualized Bleeding Rate (ABR) for All Bleeds |
4.5 | — |
| PRIMARY Expansion Part: Annualized Bleeding Rate (ABR) for Treated Spontaneous Bleeds |
0.6 | — |
| PRIMARY Expansion Part: Annualized Bleeding Rate (ABR) for Treated Joint Bleeds |
1.7 | — |
| PRIMARY Expansion Part: Annualized Bleeding Rate (ABR) for Treated Target Joint Bleeds |
1.0 | — |
| SECONDARY 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) |
-13.62 | — |
| SECONDARY 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 |
67.6 | — |
| SECONDARY Expansion Part: Change From Baseline to Week 25 in the Haem-A-QoL Questionnaire Physical Health Score for Adult Participants (≥18 Years of Age) |
-15.14 | — |
| SECONDARY 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 |
67.6 | — |
| SECONDARY 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) |
-8.10 | — |
| SECONDARY 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 |
5.53 | — |
| SECONDARY Expansion Part: Percentage of Participants With a Meaningful Improvement From Baseline to Week 25 in the EQ-5D-5L Questionnaire VAS Score |
35.0 | — |
| SECONDARY Expansion Part: Change From Baseline to Week 25 in the EQ-5D-5L Questionnaire Index Utility Score |
0.06 | — |
| SECONDARY Expansion Part: Percentage of Participants With a Meaningful Improvement From Baseline to Week 25 in the EQ-5D-5L Questionnaire Index Utility Score |
47.5 | — |
| SECONDARY Expansion Part: Proportion of Days Away From Work to Expected Days at Work in the Previous Four Weeks |
0.05; 0.00; 0.01 | — |
| SECONDARY Expansion Part: Proportion of Days Away From School to Expected Days at School in the Previous Four Weeks |
0.12; 0.00; 0.03 | — |
| SECONDARY Expansion Part: Number of Days Hospitalized |
— | — |
| SECONDARY 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 |
100; 0.0; 0.0 | — |
| SECONDARY PK Run-In Part: Time to Reach Maximum Observed Plasma Concentration (Tmax) of Emicizumab |
6.95; 6.98 | — |
| SECONDARY PK Run-In Part: Maximum Observed Plasma Concentration (Cmax) of Emicizumab |
31.8; 62.7 | — |
| SECONDARY PK Run-In Part: Area Under the Plasma Concentration-Time Curve From Time Zero to End of Dosing Interval (AUC[0-tau]) of Emicizumab |
663; 1420 | — |
| SECONDARY PK Run-In Part: Area Under the Plasma Concentration-Time Curve From Time Zero to Extrapolated Infinite Time (AUC[0-inf]) of Emicizumab |
1490 | — |
| SECONDARY PK Run-In Part: Apparent Plasma Terminal Half-Life (t1/2) of Emicizumab |
29.5 | — |
| SECONDARY PK Run-In Part: Apparent Clearance (CL/F) of Emicizumab |
10.7; 11.1 | — |
| SECONDARY PK Run-In Part: Plasma Concentration of Emicizumab at Specified Timepoints |
NA; 7.0; 20.6; 26.5; 29.4; 27.7 | — |
| SECONDARY Expansion Part: Plasma Concentration of Emicizumab at Specified Timepoints |
NA; 16.0; 29.8; 41.3; 48.8; 40.4 | — |
| SECONDARY Number of Participants With at Least One Adverse Event |
7; 39; 2; 8 | — |
| SECONDARY Number of Participants With at Least One Grade ≥3 Adverse Event |
2; 7 | — |
| SECONDARY Number of Participants With at Least One Adverse Event Leading to Withdrawal From Treatment |
0; 0 | — |
| SECONDARY Number of Participants With at Least One Adverse Event Related to Study Treatment |
2; 14; 1; 9; 0; 1 | — |
| SECONDARY Number of Participants With at Least One Adverse Event of Changes From Baseline in Vital Signs |
2; 4; 1; 4; 0; 1 | — |
| SECONDARY Number of Participants With at Least One Adverse Event of Changes From Baseline in Physical Examination Findings |
0; 0 | — |
| SECONDARY 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 |
0; 1; 0; 1; 0; 2 | — |
| SECONDARY Number of Participants With at Least One Local Injection-Site Reaction |
1; 9 | — |
| SECONDARY Number of Participants With at Least One Thromboembolic Event |
0; 0 | — |
| SECONDARY Number of Participants With at Least One Thrombotic Microangiopathy |
0; 0 | — |
| SECONDARY Number of Participants With at Least One Systemic Hypersensitivity, Anaphylaxis, or Anaphylactoid Reaction |
0; 0 | — |
| SECONDARY Number of Participants With Anti-Drug Antibodies to Emicizumab at Any Time Post-Baseline During the Study |
1; 1 | — |
| SECONDARY Number of Participants With De Novo Development of Anti-Factor VIII (FVIII) Antibodies |
0; 0 | — |
| SECONDARY 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 |
1.9; 2.9; 0.5; 1.2; 0.5 | — |
| SECONDARY 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 |
2.0; 3.0; 0.7; 1.3; 0.6 | — |
| SECONDARY 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 |
0.6; 1.2; 0.0; 0.3; 0.0 | — |
| SECONDARY Long-Term Efficacy of Emicizumab: Mean Calculated Annualized Bleeding Rates (ABR) for Treated Bleeds Per 12-Week Intervals Over Time |
2.3; 2.5; 1.5; 1.9; 1.3; 2.7 | — |
| SECONDARY Long-Term Efficacy of Emicizumab: Median Calculated Annualized Bleeding Rates (ABR) for Treated Bleeds Per 12-Week Intervals Over Time |
0.0; 0.0; 0.0; 0.0; 0.0; 0.0 | — |
| SECONDARY Long-Term Efficacy of Emicizumab: Mean Calculated Annualized Bleeding Rates (ABR) for All Bleeds Per 12-Week Intervals Over Time |
5.1; 4.0; 3.1; 2.5; 2.2; 3.5 | — |
| SECONDARY Long-Term Efficacy of Emicizumab: Median Calculated Annualized Bleeding Rates (ABR) for All Bleeds Per 12-Week Intervals Over Time |
0.0; 4.3; 0.0; 0.0; 0.0; 0.0 | — |
| SECONDARY Long-Term Efficacy of Emicizumab: Mean Calculated Annualized Bleeding Rates (ABR) for Treated Spontaneous Bleeds Per 12-Week Intervals Over Time |
0.4; 1.0; 0.1; 0.0; 0.3; 0.2 | — |
| SECONDARY Long-Term Efficacy of Emicizumab: Median Calculated Annualized Bleeding Rates (ABR) for Treated Spontaneous Bleeds Per 12-Week Intervals Over Time |
0.0; 0.0; 0.0; 0.0; 0.0; 0.0 | — |
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 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
- Pregnancy or lactation or intention to become pregnant during the study
- Women with a positive serum pregnancy test result within 7 days prior to initiation of study drug
Data sourced from ClinicalTrials.gov (NCT03020160) and the linked publication. 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. Informational only — not medical advice.