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A Study to Evaluate the Efficacy, Safety, and Pharmacokinetics of Prophylactic Emicizumab Versus no Prophylaxis in Hemophilia A Participants With Inhibitors (HAVEN 1)

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ClinicalTrials.gov Identifier: NCT02622321
Recruitment Status : Active, not recruiting
First Posted : December 4, 2015
Results First Posted : November 24, 2017
Last Update Posted : March 15, 2018
Sponsor:
Collaborator:
Chugai Pharmaceutical
Information provided by (Responsible Party):
Hoffmann-La Roche

Brief 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 or greater than or equal to [>/=] 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).

Condition or disease Intervention/treatment Phase
Hemophilia A Drug: Emicizumab Drug: rFVIIa Drug: aPCC Phase 3

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 109 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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 With Inhibitors
Actual Study Start Date : November 18, 2015
Actual Primary Completion Date : October 25, 2016
Estimated Study Completion Date : December 31, 2019

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Hemophilia
Drug Information available for: Emicizumab
U.S. FDA Resources

Arm Intervention/treatment
Experimental: Arm A (Episodic Treatment): Emicizumab
Participants, who received episodic treatment with bypassing agents prior to study entry, will receive prophylactic emicizumab. Participants will continue to receive episodic bypassing agent therapy to treat breakthrough bleeds, with rFVIIa and/or activated prothrombin complex concentrate (aPCC).
Drug: Emicizumab
Emicizumab will be administered at a loading dose of 3 milligrams per kilogram per week (mg/kg/week) subcutaneously (SC) for the first 4 weeks followed by a maintenance dose of 1.5 mg/kg/week SC up to the end of study.
Other Name: ACE910; RO5534262
Drug: rFVIIa
Participants will continue to receive rFVIIa.
Other Name: NovoSeven®
Drug: aPCC
Participants will continue to receive aPCC.
Other Name: Factor Eight Inhibitor Bypassing Activity (FEIBA®)
Active Comparator: Arm B (Episodic Treatment): No Emicizumab
Participants, who received episodic treatment with bypassing agents prior to study entry, will not receive emicizumab prophylaxis. These participants will have the opportunity to switch to emicizumab prophylaxis after at least 24 weeks on-study. Participants will continue to receive bypassing agent therapy to treat breakthrough bleeds, with rFVIIa and/or aPCC.
Drug: Emicizumab
Emicizumab will be administered at a loading dose of 3 milligrams per kilogram per week (mg/kg/week) subcutaneously (SC) for the first 4 weeks followed by a maintenance dose of 1.5 mg/kg/week SC up to the end of study.
Other Name: ACE910; RO5534262
Drug: rFVIIa
Participants will continue to receive rFVIIa.
Other Name: NovoSeven®
Drug: aPCC
Participants will continue to receive aPCC.
Other Name: Factor Eight Inhibitor Bypassing Activity (FEIBA®)
Experimental: Arm C (Prophylactic Treatment): Emicizumab
Participants, who received prophylactic bypassing agents prior to study entry, will receive prophylactic emicizumab. Participants will continue to receive bypassing agent therapy to treat breakthrough bleeds, with rFVIIa and/or aPCC.
Drug: Emicizumab
Emicizumab will be administered at a loading dose of 3 milligrams per kilogram per week (mg/kg/week) subcutaneously (SC) for the first 4 weeks followed by a maintenance dose of 1.5 mg/kg/week SC up to the end of study.
Other Name: ACE910; RO5534262
Drug: rFVIIa
Participants will continue to receive rFVIIa.
Other Name: NovoSeven®
Drug: aPCC
Participants will continue to receive aPCC.
Other Name: Factor Eight Inhibitor Bypassing Activity (FEIBA®)
Experimental: Arm D (Episodic or Prophylactic Treatment): Emicizumab
Participants who received episodic bypassing agents while participating in Study BH29768 but were unable to enroll in Arms A or B, or participants who received prophylactic bypassing agents but were unable to enroll in Arm C, will be enrolled in this arm to receive prophylactic emicizumab. Participants will continue to receive bypassing agent therapy to treat breakthrough bleeds, with rFVIIa and/or aPCC.
Drug: Emicizumab
Emicizumab will be administered at a loading dose of 3 milligrams per kilogram per week (mg/kg/week) subcutaneously (SC) for the first 4 weeks followed by a maintenance dose of 1.5 mg/kg/week SC up to the end of study.
Other Name: ACE910; RO5534262
Drug: rFVIIa
Participants will continue to receive rFVIIa.
Other Name: NovoSeven®
Drug: aPCC
Participants will continue to receive aPCC.
Other Name: Factor Eight Inhibitor Bypassing Activity (FEIBA®)



Primary Outcome Measures :
  1. Arm A (Episodic Treatment): Emicizumab and Arm B (Episodic Treatment): No Emicizumab: Annualized Bleed Rate (ABR) for Treated Bleeds [ Time Frame: From Baseline up to clinical cut-off date (25 Oct 2016) (up to approximately 1 year) ]
    Number of treated bleeds over the efficacy period was assessed through ABR using a negative binomial (NB) regression model. Treated bleeds were defined as a bleed for which coagulation factors were administered. Bleeds due to surgery/procedure were excluded.


Secondary Outcome Measures :
  1. Arm A (Episodic Treatment): Emicizumab and Arm B (Episodic Treatment): No Emicizumab: ABR for All Bleeds [ Time Frame: From Baseline up to clinical cut-off date (25 Oct 2016) (up to approximately 1 year) ]
    Number of all bleeds over the efficacy period was assessed through ABR using an NB regression model. All bleeds included both treated (with coagulation factors) and not treated bleeds. Bleeds due to surgery/procedure were excluded.

  2. Arm A (Episodic Treatment): Emicizumab and Arm Anis: Episodic Bypassing Agents in NIS BH29768: ABR for All Bleeds [ Time Frame: For Arm Anis: up to 52 weeks before study entry (assessed retrospectively at baseline); for Arm A: From Baseline up to clinical cut-off date (25 Oct 2016) (up to approximately 1 year) ]
    Number of all bleeds over the efficacy period was assessed through ABR using an NB regression model. All bleeds included both treated (with coagulation factors) and not treated bleeds. Bleeds due to surgery/procedure were excluded. Intra-participant comparison of ABR of all bleeds prior to study entry, while receiving episodic bypassing agents during non-interventional study (NIS) BH29768 (NCT02476942) (Arm Anis), with ABR of all bleeds on emicizumab prophylaxis (in this study) (Arm A) was reported.

  3. Arm A (Episodic Treatment): Emicizumab and Arm Anis: Episodic Bypassing Agents in NIS BH29768: ABR for Treated Bleeds [ Time Frame: For Arm Anis: up to 52 weeks before study entry (assessed retrospectively at baseline); for Arm A: From Baseline up to clinical cut-off date (25 Oct 2016) (up to approximately 1 year) ]
    Number of treated bleeds over the efficacy period was assessed through ABR using an NB regression model. Treated bleeds were defined as a bleed for which coagulation factors were administered. Bleeds due to surgery/procedure were excluded. Intra-participant comparison of ABR of treated bleeds prior to study entry, while receiving episodic bypassing agents during NIS BH29768 (Arm Anis), with ABR of treated bleeds on emicizumab prophylaxis (in this study) (Arm A) was reported.

  4. Arm A (Episodic Treatment): Emicizumab and Arm B (Episodic Treatment): No Emicizumab: ABR for Treated Joint Bleeds [ Time Frame: From Baseline up to clinical cut-off date (25 Oct 2016) (up to approximately 1 year) ]
    Number of treated joint bleeds over the efficacy period was assessed through ABR using an NB regression model. Treated joint bleeds were defined as treated bleeds in a joint associated with unusual sensation (aura) in a joint, in combination with another symptom: unusual sensation, swelling/warmth, pain/decreased range of motion (RoM), difficulty moving the joint. Bleeds due to surgery/procedure were excluded.

  5. Arm C (Prophylactic Treatment): Emicizumab and Arm Cnis: Prophylactic Bypassing Agents in NIS BH29768: ABR for All Bleeds [ Time Frame: For Arm Cnis: up to 52 weeks before study entry (assessed retrospectively at baseline); for Arm C: From Baseline up to clinical cut-off date (25 Oct 2016) (up to approximately 1 year) ]
    Number of all bleeds over the efficacy period was assessed through ABR using an NB regression model. All bleeds included both treated (with coagulation factors) and not treated bleeds. Bleeds due to surgery/procedure were excluded. Intra-participant comparison of ABR of all bleeds prior to study entry, while receiving prophylactic bypassing agents during NIS BH29768 (Arm Cnis), with ABR of all bleeds on emicizumab prophylaxis (in this study) (Arm C) was reported.

  6. Arm C (Prophylactic Treatment): Emicizumab and Arm Cnis: Prophylactic Bypassing Agents in NIS BH29768: ABR for Treated Bleeds [ Time Frame: For Arm Cnis: up to 52 weeks before study entry (assessed retrospectively at baseline); for Arm C: From Baseline up to clinical cut-off date (25 Oct 2016) (up to approximately 1 year) ]
    Number of treated bleeds over the efficacy period was assessed through ABR using an NB regression model. Treated bleeds were defined as a bleed for which coagulation factors were administered. Bleeds due to surgery/procedure were excluded. Intra-participant comparison of ABR of treated bleeds prior to study entry, while receiving prophylactic bypassing agents during NIS BH29768 (Arm Cnis), with ABR of treated bleeds on emicizumab prophylaxis (in this study) (Arm C) was reported.

  7. Arm A (Episodic Treatment): Emicizumab and Arm B (Episodic Treatment): No Emicizumab: ABR for Treated Spontaneous Bleeds [ Time Frame: From Baseline up to clinical cut-off date (25 Oct 2016) (up to approximately 1 year) ]
    Number of treated spontaneous bleeds over the efficacy period was assessed through ABR using an NB regression model. Treated spontaneous bleeds were defined as treated (with coagulation factors) bleeds with no known contributing factor (e.g., trauma, surgery).

  8. Arm A (Episodic Treatment): Emicizumab and Arm B (Episodic Treatment): No Emicizumab: ABR for Treated Target Joint Bleeds [ Time Frame: From Baseline up to clinical cut-off date (25 Oct 2016) (up to approximately 1 year) ]
    Number of treated target joint bleeds over the efficacy period was assessed through ABR using an NB regression model. Treated target joint bleeds included treated (with coagulation factors) joint bleeds in a target joint, defined as a joint in which greater than or equal to (>/=) 3 treated joint bleeds occurred during the last 24 weeks prior to study entry. Bleeds due to surgery/procedure are excluded.

  9. Arm A (Episodic Treatment): Emicizumab and Arm B (Episodic Treatment): No Emicizumab: Hemophilia-Specific Quality of Life (Haem-A-QoL) Questionnaire Physical Health Score in Adult Participants (>/=18 Years Old) [ Time Frame: Week 25 ]
    Haem-A-QoL questionnaire has been developed and used in hemophilia A participants. As a hemophilia-specific questionnaire, this measure assesses very specific aspects of dealing with hemophilia. This questionnaire consists of items pertaining to 10 domains specific to living with hemophilia. The 10 domains are: physical health, sports and leisure, school and work, dealing with hemophilia, family planning, feeling, relationships, treatment, view of yourself, and outlook for the future. The total score for each domain range from 0 to 100 with lower scores reflective of better quality of life. Physical Health domain score is reported (range 0 to 100, with lower scores reflective of better physical health).

  10. Arm A (Episodic Treatment): Emicizumab and Arm B (Episodic Treatment): No Emicizumab: Haem-A-QoL Questionnaire Total Score in Adult Participants (>/=18 Years Old) [ Time Frame: Week 25 ]
    Haem-A-QoL questionnaire has been developed and used in hemophilia A participants. As a hemophilia-specific questionnaire, this measure assesses very specific aspects of dealing with hemophilia. This questionnaire consists of items pertaining to 10 domains specific to living with hemophilia. The 10 domains are: physical health, sports and leisure, school and work, dealing with hemophilia, family planning, feeling, relationships, treatment, view of yourself, and outlook for the future. The total score for each domain range from 0 to 100 with lower scores reflective of better quality of life. Haem-A-QoL Questionnaire Total Score is the average of the all domain scores and range from 0 to 100, with lower scores reflective of better quality of life.

  11. Arm A (Episodic Treatment): Emicizumab and Arm B (Episodic Treatment): No Emicizumab: European Quality of Life-5 Dimensions-5 Levels (EQ-5D-5L) Visual Analog Scale Score [ Time Frame: Week 25 ]
    EQ-5D-5L is a standardized, participant-rated questionnaire to assess health-related quality of life. The EQ-5D-5L includes 2 components: the EQ-5D-5L health state profile (descriptive system) and the EQ-5D-5L Visual Analog Scale. The Visual Analogue Scale is designed to rate the participant's current health state on a scale from 0 to 100, where 0 represents the worst imaginable health state and 100 represents the best imaginable health state.

  12. Arm A (Episodic Treatment): Emicizumab and Arm B (Episodic Treatment): No Emicizumab: EQ-5D-5L Index Utility Score [ Time Frame: Week 25 ]
    EQ-5D-5L is a standardized, participant-rated questionnaire to assess health-related quality of life. The EQ-5D-5L includes 2 components: the EQ-5D-5L health state profile (descriptive system) and the EQ-5D-5L Visual Analog Scale. The EQ-5D-5L health state profile is designed to record the participant's current health state in 5 domains: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Responses from the five domains are used to calculate a single utility index value ranging from 1 to 5, where 1 indicates better health state (no problems) and 5 indicates worst health state (confined to bed).

  13. Arm A (Episodic Treatment): Emicizumab and Arm B (Episodic Treatment): No Emicizumab: Hemophilia-Specific Quality of Life - Short Form (Haemo-Qol-SF) Questionnaire Total Score in Adolescents Participants (12-17 Years Old) [ Time Frame: Week 25 ]
    The Haemo-QoL-SF contains 35 items, which cover nine domains considered relevant for the children's health-related quality of life (physical health, feelings, view of yourself, family, friends, other people, sports and school, dealing with hemophilia and treatment). Items are rated with five respective response options: never, seldom, sometimes, often, and always. Haemo-QoL-SF total score range from 0 to 100, where lower scores reflect better health-related quality of life. Data for this outcome was to be analyzed only if >3 participant (in each arm) have available data.

  14. Percentage of Participants With Anti-Emicizumab Antibodies [ Time Frame: Baseline up to approximately 1 year ]
  15. Plasma Trough Concentration of Emicizumab [ Time Frame: Arm A: Pre-dose (0 hour [hr]) on Weeks 1-5, 7, 9, 13, 17, 21, 25, 33, 41, 49; Arm B: Pre-dose (0 hr) on Weeks 25-29, 31, 33, 37, 41; Arm C: Pre-dose (0 hr) on Weeks 1-5, 7, 9, 13, 17, 21, 25, 33, 41; Arm D: Pre-dose (0 hr) on Weeks 1-5, 7, 9, 13 ]
    Plasma concentrations of emicizumab were analyzed using a validated Enzyme Linked Immunosorbent Assay (ELISA). The lower limit of quantification (LLOQ) was 100 nanograms per milliliter (ng/mL).



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Ages Eligible for Study:   12 Years and older   (Child, Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02622321


  Show 46 Study Locations
Sponsors and Collaborators
Hoffmann-La Roche
Chugai Pharmaceutical
Investigators
Study Director: Clinical Trials Hoffmann-La Roche

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Hoffmann-La Roche
ClinicalTrials.gov Identifier: NCT02622321     History of Changes
Other Study ID Numbers: BH29884
2015-002866-21 ( EudraCT Number )
First Posted: December 4, 2015    Key Record Dates
Results First Posted: November 24, 2017
Last Update Posted: March 15, 2018
Last Verified: February 2018

Additional relevant MeSH terms:
Hemophilia A
Blood Coagulation Disorders, Inherited
Blood Coagulation Disorders
Hematologic Diseases
Coagulation Protein Disorders
Hemorrhagic Disorders
Genetic Diseases, Inborn
Feiba
Factor VIII
Antibodies, Bispecific
Coagulants
Immunologic Factors
Physiological Effects of Drugs