Clinical trial NCT03315455: Efficacy, Safety, and Pharmacokinetic Study of Prophylactic Emicizumab Versus No Prophylaxis in Hemophilia A Participants
Official title: A Randomized, Multicenter, Open-Label, Phase III Clinical Trial to Evaluate the Efficacy, Safety, and Pharmacokinetics of Prophylactic Emicizumab Versus No Prophylaxis in Hemophilia A Patients
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE3
Conditions: Hemophilia A
Lead sponsor: Hoffmann-La Roche
Sponsor class: INDUSTRY
First posted: 2017-10-20
Enrollment: 85
Sex: ALL
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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 (\<0.6 Bethesda unit per milliliter \[BU/mL\]) who completed successful immune tolerance induction (ITI) must have done so at least 5 years before screening and have no evidence of inhibitor recurrence (permanent or temporary)
* Documentation of the details of episodic therapy (FVIII or bypassing agents) and of number of bleeding episodes for at least the last 24 weeks and ≥5 bleeds in the last 24 weeks prior to study entry
* Adequate hematologic, hepatic, and renal function
* For women of child bearing potential: agreement to remain abstinent or use a protocol defined contraceptive measure during the treatment period and for at least 5 elimination half-lives (24 weeks) after the last dose of study drug

Inclusion Criteria for Arm D:

* Diagnosis of congenital hemophilia A of any severity and documented history of high-titer inhibitor (i.e., ≥5 BU/mL)
* Children \<12 years old at time of informed consent
* Body weight \>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/microliter (cells/mcL) within 24 weeks prior to screening. Participants with HIV infection who have CD4 \>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 risk, or would, in the opinion of the investigator, preclude the participant's safe participation in and completion of the study
* Pregnant or lactating, or intending to become pregnant during the study

Primary outcomes:
measure: Model-Based Annualized Bleeding Rate for Treated Bleeds
timeFrame: From Baseline to at least 24 weeks
measure: Mean Calculated Annualized Bleeding Rate for Treated Bleeds
timeFrame: From Baseline to at least 24 weeks
measure: Median Calculated Annualized Bleeding Rate for Treated Bleeds
timeFrame: From Baseline to at least 24 weeks
Secondary outcomes:
measure: Model-Based Annualized Bleeding Rate for All Bleeds
timeFrame: From Baseline to at least 24 weeks
measure: Mean Calculated Annualized Bleeding Rate for All Bleeds
timeFrame: From Baseline to at least 24 weeks
measure: Median Calculated Annualized Bleeding Rate for All Bleeds
timeFrame: From Baseline to at least 24 weeks
measure: Model-Based Annualized Bleeding Rate for Treated Spontaneous Bleeds
timeFrame: From Baseline to at least 24 weeks
measure: Mean Calculated Annualized Bleeding Rate for Treated Spontaneous Bleeds
timeFrame: From Baseline to at least 24 weeks
measure: Median Calculated Annualized Bleeding Rate for Treated Spontaneous Bleeds
timeFrame: From Baseline to at least 24 weeks
measure: Model-Based Annualized Bleeding Rate for Treated Joint Bleeds
timeFrame: From Baseline to at least 24 weeks
measure: Mean Calculated Annualized Bleeding Rate for Treated Joint Bleeds
timeFrame: From Baseline to at least 24 weeks
measure: Median Calculated Annualized Bleeding Rate for Treated Joint Bleeds
timeFrame: From Baseline to at least 24 weeks
measure: Model-Based Annualized Bleeding Rate for Treated Target Joint Bleeds
timeFrame: From Baseline to at least 24 weeks
measure: Mean Calculated Annualized Bleeding Rate for Treated Target Joint Bleeds
timeFrame: From Baseline to at least 24 weeks
measure: Median Calculated Annualized Bleeding Rate for Treated Target Joint Bleeds
timeFrame: From Baseline to at least 24 weeks
measure: Intra-Participant Comparison of the Calculated Annualized Bleeding Rate for Treated Bleeds With Emicizumab Prophylaxis On-Study Versus With Previous Episodic Therapy Pre-Study
timeFrame: Efficacy periods: At least 24 weeks prior to study entry (mean [min-max] for A+B NIS-Previous Episodic Therapy: 183 [169-221] days); and From Baseline to at least 24 weeks on study (mean [min-max] for A+B NIS-Emicizumab: 363 [324-422] days)
measure: Intra-Participant Comparison of the Calculated Annualized Bleeding Rate for All Bleeds With Emicizumab Prophylaxis On-Study Versus With Previous Episodic Therapy Pre-Study
timeFrame: Efficacy periods: At least 24 weeks prior to study entry (mean [min-max] for A+B NIS-Previous Episodic Therapy: 183 [169-221] days); and From Baseline to at least 24 weeks on study (mean [min-max] for A+B NIS-Emicizumab: 363 [324-422] days)
measure: 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
timeFrame: Baseline and Week 25
measure: 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
timeFrame: Baseline and Week 25
measure: Arms A, B, and C: Adjusted Mean Haem-A-QoL Questionnaire Total Score at Week 25 in Participants ≥18 Years of Age
timeFrame: Baseline and Week 25
measure: Arms A, B, and C: Change From Baseline to Week 25 in Haem-A-QoL Questionnaire Total Score for Participants ≥18 Years of Age
timeFrame: Baseline and Week 25
measure: 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
timeFrame: Baseline and Week 25
measure: 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
timeFrame: Baseline and Week 25
measure: Arms A, B, and C: Change From Baseline in EQ-5D-5L Questionnaire VAS Score at Week 25
timeFrame: Baseline and Week 25
measure: Arms A, B, and C: Adjusted Mean EQ-5D-5L Index Utility Score at Week 25
timeFrame: Baseline and Week 25
measure: Arms A, B, and C: Change From Baseline in EQ-5D-5L Index Utility Score at Week 25
timeFrame: Baseline and Week 25
measure: 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
timeFrame: Baseline and Week 25
measure: Arm D: Change From Baseline in the Caregiver-Reported Adapted Health-Related Quality of Life for Hemophilia Patients With Inhibitors (Adapted Inhib-QoL) Including Aspects of Caregiver Burden Questionnaire Score Over Time
timeFrame: Baseline (Week 1) and Weeks 17, 29, 37, and 49, every 12 weeks during extension phase, and study completion (up to 48 months)
measure: Number of Participants With Adverse Events by Severity, According to the World Health Organization (WHO) Toxicity Grading Scale
timeFrame: From Baseline until end of study (up to 85 months)
measure: Number of Participants With Adverse Events Leading to Study Drug Discontinuation
timeFrame: From Baseline until end of study (up to 85 months)
measure: Number of Participants With Thromboembolic Events by Severity, According to the WHO Toxicity Grading Scale
timeFrame: From Baseline until end of study (up to 85 months)
measure: Number of Participants With Thrombotic Microangiopathy by Severity, According to the WHO Toxicity Grading Scale
timeFrame: From Baseline until end of study (up to 85 months)
measure: Number of Participants With Injection-Site Reactions by Severity, According to the WHO Toxicity Grading Scale
timeFrame: From Baseline until end of study (up to 85 months)
measure: Number of Participants With Severe Hypersensitivity, Anaphylaxis, or Anaphylactoid Reactions
timeFrame: From Baseline until end of study (up to 85 months)
measure: Number of Participants With Serum Chemistry Laboratory Abnormalities by Highest WHO Grade Post-Baseline, According to the WHO Toxicity Grading Scale
timeFrame: From Baseline until end of study (up to 85 months)
measure: Number of Participants With Hematology Laboratory Abnormalities by Highest WHO Grade Post-Baseline, According to the WHO Toxicity Grading Scale
timeFrame: From Baseline until end of study (up to 85 months)
measure: Change From Baseline in Body Temperature Over Time
timeFrame: Baseline, Weeks 5, 25, 49, and at study completion (up to 85 months)
measure: Change From Baseline in Pulse Rate Over Time
timeFrame: Baseline, Weeks 5, 25, 49, and at study completion (up to 85 months)
measure: Change From Baseline in Respiratory Rate Over Time
timeFrame: Baseline, Weeks 5, 25, 49, and at study completion (up to 85 months)
measure: Change From Baseline in Systolic Blood Pressure Over Time
timeFrame: Baseline, Weeks 5, 25, 49, and at study completion (up to 85 months)
measure: Change From Baseline in Diastolic Blood Pressure Over Time
timeFrame: Baseline, Weeks 5, 25, 49, and at study completion (up to 85 months)
measure: Number of Participants With Anti-Emicizumab Antibodies
timeFrame: QW: Pre-dose at Weeks 1, 5, 9, 13, 17, 21, 25, 33, 41, 49, and every 12 weeks thereafter until study completion; Q4W: Pre-dose at Weeks 1, 5, 9, 13, 17, 21, 25, and every 12 weeks thereafter until study completion (up to 85 months)
measure: Plasma Trough Concentration (Ctrough) of Emicizumab
timeFrame: QW: Predose at Weeks 1, 2, 3, 4, 5, 7, 9, 13, 17, 21, 25, 33, 41, 49, and every 12 weeks thereafter to study completion; Q4W: Predose at Weeks 1, 2, 3, 4, 5, 7, 9, 13, 17, 21, 25, and every 12 weeks thereafter to study completion (up to 85 months)
Other outcomes:
Locations:
city: Beijing City
country: China
facility: Beijing Children's Hospital, Capital Medical University
city: Beijing
country: China
facility: Peking Union Medical College Hospital
city: Changsha
country: China
facility: Xiangya Hospital of Centre-South University
city: Guangdong Province Guangzhou City
country: China
facility: Southern Medical University Nanfang Hospital
city: Shanghai City
country: China
facility: Ruijin Hospital Shanghai Jiaotong University School of Medicine
city: Tianjin
country: China
facility: Tianjin Institute of Hematology & Blood Diseases Hospital
city: Wuhan
country: China
facility: Xiehe Hospital, Tongji Medical College Huazhong University of Science & Technology
city: Wuhan
country: China
facility: Tongji Hosp, Tongji Med. Col, Huazhong Univ. of Sci. & Tech
city: Hong kong
country: Hong Kong
facility: Queen Mary Hospital
city: Shatin
country: Hong Kong
facility: Prince of Wales Hospital
city: Penang
country: Malaysia
facility: Penang General Hospital
city: Sabah
country: Malaysia
facility: Queen Elizabeth Hospital
city: Bangkok
country: Thailand
facility: Ramathibodi Hospital
Study officials:
affiliation: Hoffmann-La Roche
name: Clinical Trials
role: STUDY_DIRECTOR
References: