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Completed

NCT Number: NCT03315455

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

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.

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Key information

Conditions

Hemophilia A Blood Coagulation Disorders Blood Coagulation Disorders, Inherited Coagulation Protein Disorders Congenital, Hereditary, and Neonatal Diseases and Abnormalities Genetic Diseases, Inborn Hematologic Diseases Hemic and Lymphatic Diseases Hemorrhagic Disorders

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 3

Primary location

Beijing Children's Hospital, Capital Medical University, Beijing, China

Loading trial locations.

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

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

Treatment and study plan

Emicizumab

Drug

Emicizumab will be administered via subcutaneous (SC) injection, as described for each treatment arm.

Other names: Hemlibra, RO5534262, RG6013, ACE910

Primary outcomes

  1. Model-Based Annualized Bleeding Rate for Treated Bleeds

    Time frame: From Baseline to at least 24 weeks

    The number of treated bleeds over the efficacy period was estimated as an annualized bleeding rate (ABR) using a negative binomial regression model, which accounts for different follow-up times. A treated bleed was defined as a bleed that was directly followed by a hemophilia medication reported to be a "treatment for bleed". The 72-hour rule was implemented: two bleeds of the same type and at the same anatomical location were counted as one bleed if the second bleed occurred within 72 hours from the last treatment for the first bleed. Bleeds due to surgery/procedure were excluded.

  2. Mean Calculated Annualized Bleeding Rate for Treated Bleeds

    Time frame: From Baseline to at least 24 weeks

    The number of treated bleeds over the efficacy period is presented here as a calculated annualized bleeding rate (ABR) that was annualized for each participant using the following formula: ABR = (number of bleeds/number of days during the efficacy period) x 365.25. A treated bleed was defined as a bleed that was directly followed by a hemophilia medication reported to be a "treatment for bleed". The 72-hour rule was implemented: two bleeds of the same type and at the same anatomical location were counted as one bleed if the second bleed occurred within 72 hours from the last treatment for the first bleed. Bleeds due to surgery/procedure were excluded.

  3. Median Calculated Annualized Bleeding Rate for Treated Bleeds

    Time frame: From Baseline to at least 24 weeks

    The number of treated bleeds over the efficacy period is presented here as a calculated annualized bleeding rate (ABR) that was annualized for each participant using the following formula: ABR = (number of bleeds/number of days during the efficacy period) x 365.25. A treated bleed was defined as a bleed that was directly followed by a hemophilia medication reported to be a "treatment for bleed". The 72-hour rule was implemented: two bleeds of the same type and at the same anatomical location were counted as one bleed if the second bleed occurred within 72 hours from the last treatment for the first bleed. Bleeds due to surgery/procedure were excluded.

Secondary outcomes

  1. Model-Based Annualized Bleeding Rate for All Bleeds

    Time frame: From Baseline to at least 24 weeks

    The number of all bleeds over the efficacy period was estimated as an annualized bleeding rate (ABR) using a negative binomial regression model, which accounts for different follow-up times. In this outcome measure, all bleeds are included, irrespective of treatment with coagulation factors, with the following exception: bleeds due to surgery/procedure are excluded. As "all bleeds" comprises both treated and non-treated bleeds, the 72-hour rule was implemented separately for treated and non-treated bleeds. For treated bleeds, the 72-hour rule meant that two bleeds of the same type and at the same anatomical location were counted as one bleed if the second bleed occurred within 72 hours from the last treatment for the first bleed. For non-treated bleeds, the 72-hour rule was implemented by calculating a treatment-free period of 72 hours from the bleed itself.

  2. Mean Calculated Annualized Bleeding Rate for All Bleeds

    Time frame: From Baseline to at least 24 weeks

    The number of all bleeds over the efficacy period is presented here as a calculated annualized bleeding rate (ABR) that was annualized for each participant using the following formula: ABR = (number of bleeds/number of days during the efficacy period) x 365.25. In this outcome measure, all bleeds are included, irrespective of treatment with coagulation factors, with the following exception: bleeds due to surgery/procedure are excluded. As "all bleeds" comprises both treated and non-treated bleeds, the 72-hour rule was implemented separately for treated and non-treated bleeds. For treated bleeds, the 72-hour rule meant that two bleeds of the same type and at the same anatomical location were counted as one bleed if the second bleed occurred within 72 hours from the last treatment for the first bleed. For non-treated bleeds, the 72-hour rule was implemented by calculating a treatment-free period of 72 hours from the bleed itself.

  3. Median Calculated Annualized Bleeding Rate for All Bleeds

    Time frame: From Baseline to at least 24 weeks

    The number of all bleeds over the efficacy period is presented here as a calculated annualized bleeding rate (ABR) that was annualized for each participant using the following formula: ABR = (number of bleeds/number of days during the efficacy period) x 365.25. In this outcome measure, all bleeds are included, irrespective of treatment with coagulation factors, with the following exception: bleeds due to surgery/procedure are excluded. As "all bleeds" comprises both treated and non-treated bleeds, the 72-hour rule was implemented separately for treated and non-treated bleeds. For treated bleeds, the 72-hour rule meant that two bleeds of the same type and at the same anatomical location were counted as one bleed if the second bleed occurred within 72 hours from the last treatment for the first bleed. For non-treated bleeds, the 72-hour rule was implemented by calculating a treatment-free period of 72 hours from the bleed itself.

  4. Model-Based Annualized Bleeding Rate for Treated Spontaneous Bleeds

    Time frame: From Baseline to at least 24 weeks

    The number of treated spontaneous bleeds over the efficacy period was estimated as an annualized bleeding rate (ABR) using a negative binomial regression model, which accounts for different follow-up times. A treated spontaneous bleed was defined as a treated bleed (bleed directly followed by a hemophilia medication reported to be a "treatment for bleed") with no other known contributing factor such as trauma or procedure/surgery. The 72-hour rule was implemented: two bleeds of the same type and at the same anatomical location were counted as one bleed if the second bleed occurred within 72 hours from the last treatment for the first bleed. Bleeds due to surgery/procedure were excluded.

  5. Mean Calculated Annualized Bleeding Rate for Treated Spontaneous Bleeds

    Time frame: From Baseline to at least 24 weeks

    The number of treated spontaneous bleeds over the efficacy period is presented here as a calculated annualized bleeding rate (ABR) that was annualized for each participant using the following formula: ABR = (number of bleeds/number of days during the efficacy period) x 365.25. A treated spontaneous bleed was defined as a treated bleed (bleed directly followed by a hemophilia medication reported to be a "treatment for bleed") with no other known contributing factor such as trauma or procedure/surgery. The 72-hour rule was implemented: two bleeds of the same type and at the same anatomical location were counted as one bleed if the second bleed occurred within 72 hours from the last treatment for the first bleed. Bleeds due to surgery/procedure were excluded.

  6. Median Calculated Annualized Bleeding Rate for Treated Spontaneous Bleeds

    Time frame: From Baseline to at least 24 weeks

    The number of treated spontaneous bleeds over the efficacy period is presented here as a calculated annualized bleeding rate (ABR) that was annualized for each participant using the following formula: ABR = (number of bleeds/number of days during the efficacy period) x 365.25. A treated spontaneous bleed was defined as a treated bleed (bleed directly followed by a hemophilia medication reported to be a "treatment for bleed") with no other known contributing factor such as trauma or procedure/surgery. The 72-hour rule was implemented: two bleeds of the same type and at the same anatomical location were counted as one bleed if the second bleed occurred within 72 hours from the last treatment for the first bleed. Bleeds due to surgery/procedure were excluded.

  7. Model-Based Annualized Bleeding Rate for Treated Joint Bleeds

    Time frame: From Baseline to at least 24 weeks

    The number of treated joint bleeds over the efficacy period was estimated as an annualized bleeding rate (ABR) using a negative binomial regression model, which accounts for different follow-up times. A treated joint bleed was defined as a bleed with type reported as "joint" based on at least one of the following symptoms: increasing swelling or warmth of the skin over the joint and/or increasing pain, decreased range of motion, or difficulty using the joint compared with baseline, and the bleed was directly followed by a hemophilia medication reported to be a "treatment for bleed". The 72-hour rule was implemented: two bleeds of the same type and at the same anatomical location were counted as one bleed if the second bleed occurred within 72 hours from the last treatment for the first bleed. Bleeds due to surgery/procedure were excluded.

  8. Mean Calculated Annualized Bleeding Rate for Treated Joint Bleeds

    Time frame: From Baseline to at least 24 weeks

    The number of treated joint bleeds over the efficacy period is presented here as a calculated annualized bleeding rate (ABR) that was annualized for each participant using the following formula: ABR = (number of bleeds/number of days during the efficacy period) x 365.25. A treated joint bleed was defined as a bleed with type reported as "joint" based on at least one of the following symptoms: increasing swelling or warmth of the skin over the joint and/or increasing pain, decreased range of motion, or difficulty using the joint compared with baseline, and the bleed was directly followed by a hemophilia medication reported to be a "treatment for bleed". The 72-hour rule was implemented: two bleeds of the same type and at the same anatomical location were counted as one bleed if the second bleed occurred within 72 hours from the last treatment for the first bleed. Bleeds due to surgery/procedure were excluded.

  9. Median Calculated Annualized Bleeding Rate for Treated Joint Bleeds

    Time frame: From Baseline to at least 24 weeks

    The number of treated joint bleeds over the efficacy period is presented here as a calculated annualized bleeding rate (ABR) that was annualized for each participant using the following formula: ABR = (number of bleeds/number of days during the efficacy period) x 365.25. A treated joint bleed was defined as a bleed with type reported as "joint" based on at least one of the following symptoms: increasing swelling or warmth of the skin over the joint and/or increasing pain, decreased range of motion, or difficulty using the joint compared with baseline, and the bleed was directly followed by a hemophilia medication reported to be a "treatment for bleed". The 72-hour rule was implemented: two bleeds of the same type and at the same anatomical location were counted as one bleed if the second bleed occurred within 72 hours from the last treatment for the first bleed. Bleeds due to surgery/procedure were excluded.

  10. Model-Based Annualized Bleeding Rate for Treated Target Joint Bleeds

    Time frame: From Baseline to at least 24 weeks

    The number of treated target joint bleeds over the efficacy period was estimated as an annualized bleeding rate (ABR) using a negative binomial regression model, which accounts for different follow-up times. A treated target joint bleed was defined as a joint bleed in a target joint, which is a joint location where at least 3 bleeds have occurred over the last 24 weeks prior to study entry or an unresolved target joint (target joint that does not fulfil ≤2 bleeds into this joint within a consecutive 12-month period), and the bleed was directly followed by a hemophilia medication reported to be a "treatment for bleed". The 72-hour rule was implemented: two bleeds of the same type and at the same anatomical location were counted as one bleed if the second bleed occurred within 72 hours from the last treatment for the first bleed. Bleeds due to surgery/procedure were excluded.

  11. Mean Calculated Annualized Bleeding Rate for Treated Target Joint Bleeds

    Time frame: From Baseline to at least 24 weeks

    The number of treated target joint bleeds over the efficacy period is presented here as a calculated annualized bleeding rate (ABR) that was annualized for each participant using the following formula: ABR = (number of bleeds/number of days during the efficacy period) x 365.25. A treated target joint bleed was defined as a joint bleed in a target joint, which is a joint location where at least 3 bleeds have occurred over the last 24 weeks prior to study entry or an unresolved target joint (target joint that does not fulfil ≤2 bleeds into this joint within a consecutive 12-month period), and the bleed was directly followed by a hemophilia medication reported to be a "treatment for bleed". The 72-hour rule was implemented: two bleeds of the same type and at the same anatomical location were counted as one bleed if the second bleed occurred within 72 hours from the last treatment for the first bleed. Bleeds due to surgery/procedure were excluded.

  12. Median Calculated Annualized Bleeding Rate for Treated Target Joint Bleeds

    Time frame: From Baseline to at least 24 weeks

    The number of treated target joint bleeds over the efficacy period is presented here as a calculated annualized bleeding rate (ABR) that was annualized for each participant using the following formula: ABR = (number of bleeds/number of days during the efficacy period) x 365.25. A treated target joint bleed was defined as a joint bleed in a target joint, which is a joint location where at least 3 bleeds have occurred over the last 24 weeks prior to study entry or an unresolved target joint (target joint that does not fulfil ≤2 bleeds into this joint within a consecutive 12-month period), and the bleed was directly followed by a hemophilia medication reported to be a "treatment for bleed". The 72-hour rule was implemented: two bleeds of the same type and at the same anatomical location were counted as one bleed if the second bleed occurred within 72 hours from the last treatment for the first bleed. Bleeds due to surgery/procedure were excluded.

  13. Intra-Participant Comparison of the Calculated Annualized Bleeding Rate for Treated Bleeds With Emicizumab Prophylaxis On-Study Versus With Previous Episodic Therapy Pre-Study

    Time frame: 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)

    This is an intra-participant comparison of the annualized bleeding rate (ABR) for treated bleeds pre-study versus on-study in the non-interventional study (NIS) population previously treated with episodic therapy in NIS BH29768. The number of treated bleeds over the efficacy period is presented here as a calculated ABR that was annualized for each participant using the following formula: ABR = (number of bleeds/number of days during the efficacy period) x 365.25. A treated bleed was defined as a bleed that was directly followed by a hemophilia medication reported to be a "treatment for bleed". The 72-hour rule was implemented: two bleeds of the same type and at the same anatomical location were counted as one bleed if the second bleed occurred within 72 hours from the last treatment for the first bleed. Bleeds due to surgery/procedure were excluded.

  14. Intra-Participant Comparison of the Calculated Annualized Bleeding Rate for All Bleeds With Emicizumab Prophylaxis On-Study Versus With Previous Episodic Therapy Pre-Study

    Time frame: 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)

    This is an intra-participant comparison of the annualized bleeding rate (ABR) for all bleeds pre-study versus on-study in the non-interventional study (NIS) population previously treated with episodic therapy in NIS BH29768. The ABR was calculated for each participant using the following formula: ABR = (number of bleeds/number of days during the efficacy period) x 365.25. All bleeds are included, irrespective of treatment with coagulation factors, with the following exception: bleeds due to surgery/procedure are excluded. "All bleeds" comprises both treated and non-treated bleeds, and the 72-hour rule was implemented separately for each type. For treated bleeds, the 72-hour rule meant that two bleeds of the same type and at the same anatomical location were counted as one bleed if the second bleed occurred within 72 hours from the last treatment for the first bleed. For non-treated bleeds, the 72-hour rule was calculated as a treatment-free period of 72 hours from the bleed itself.

  15. 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

    Time frame: Baseline and Week 25

    The Haem-A-QoL questionnaire has been developed and used in hemophilia A participants, assessing very specific aspects of dealing with hemophilia. The questionnaire consists of items pertaining to 10 domains: 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 ranges 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). The means were derived via an analysis of covariance (ANCOVA) model and have been adjusted for the following co-variates: baseline score, treatment group, and treatment by baseline interaction term.

  16. 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

    Time frame: Baseline and Week 25

    The Haem-A-QoL questionnaire has been developed and used in hemophilia A participants, assessing very specific aspects of dealing with hemophilia. The questionnaire consists of items pertaining to 10 domains: 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 ranges 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).

  17. Arms A, B, and C: Adjusted Mean Haem-A-QoL Questionnaire Total Score at Week 25 in Participants ≥18 Years of Age

    Time frame: Baseline and Week 25

    The Haem-A-QoL questionnaire has been developed and used in hemophilia A participants, assessing very specific aspects of dealing with hemophilia. The questionnaire consists of items pertaining to 10 domains: 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 ranges from 0 to 100 with lower scores reflective of better quality of life. Haem-A-QoL Total Score is the average of all domain scores and it ranges from 0 to 100, with lower scores reflective of better quality of life. The means were derived via an analysis of covariance (ANCOVA) model and have been adjusted for the following co-variates: baseline score, treatment group, and treatment by baseline interaction term.

  18. Arms A, B, and C: Change From Baseline to Week 25 in Haem-A-QoL Questionnaire Total Score for Participants ≥18 Years of Age

    Time frame: Baseline and Week 25

    The Haem-A-QoL questionnaire has been developed and used in hemophilia A participants, assessing very specific aspects of dealing with hemophilia. The questionnaire consists of items pertaining to 10 domains: 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 ranges from 0 to 100 with lower scores reflective of better quality of life. Haem-A-QoL Total Score is the average of all domain scores and it ranges from 0 to 100, with lower scores reflective of better quality of life.

  19. 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

    Time frame: Baseline and Week 25

    The Haemo-QoL-SF contains 35 items covering nine dimensions considered relevant for the adolescent's (aged 12-17 years) health-related quality of life (HRQoL). Items are rated with five respective response options: never, seldom, sometimes, often, and always. The score ranges from 0 to 100, and a higher score is indicative of poorer HRQoL. According to the pre-specified statistical analysis plan, no statistical analyses were performed on the protocol-defined endpoints for the Haemo-QoL-SF due to the small number of adolescents randomized to Arms A, B and C.

  20. 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

    Time frame: Baseline and 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 VAS. The VAS 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. The means were derived via an analysis of covariance (ANCOVA) model and have been adjusted for the following co-variates: baseline score, treatment group, and treatment by baseline interaction term.

  21. Arms A, B, and C: Change From Baseline in EQ-5D-5L Questionnaire VAS Score at Week 25

    Time frame: Baseline and Week 25

    The European Quality of Life 5-Dimensions-5 Levels Questionnaire (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 VAS. The VAS 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.

  22. Arms A, B, and C: Adjusted Mean EQ-5D-5L Index Utility Score at Week 25

    Time frame: Baseline and Week 25

    The European Quality of Life 5-Dimensions-5 Levels Questionnaire (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 VAS. The EQ-5D-5L health state profile is designed to record the participant's current health state in 5 domains: mobility, selfcare, usual activities, pain/discomfort, and anxiety/depression. Responses from the five domains are used to calculate a single index utility score on a scale of 0 to 1, with higher scores reflective of better quality of life. The means were derived via an analysis of covariance (ANCOVA) model and have been adjusted for the following co-variates: baseline score, treatment group, and treatment by baseline interaction term.

  23. Arms A, B, and C: Change From Baseline in EQ-5D-5L Index Utility Score at Week 25

    Time frame: Baseline and Week 25

    The European Quality of Life 5-Dimensions-5 Levels Questionnaire (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 VAS. The EQ-5D-5L health state profile is designed to record the participant's current health state in 5 domains: mobility, selfcare, usual activities, pain/discomfort, and anxiety/depression. Responses from the five domains are used to calculate a single index utility score on a scale of 0 to 1, with higher scores reflective of better quality of life.

  24. 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

    Time frame: Baseline and Week 25

    The Hemophilia-Specific Quality of Life Short Form (Haemo-QoL-SF) questionnaire contains 35 items covering nine dimensions considered relevant for the children's health-related quality of life (HRQoL). Items are rated with five respective response options: never, seldom, sometimes, often, and always. The scores range from 0 to 100, and higher scores are indicative of poorer HRQoL.

  25. 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

    Time frame: Baseline (Week 1) and Weeks 13 and 25

    Proxy assessment of HRQoL and aspects of caregiver burden for all children, regardless of age, were collected using the Adapted Inhib-QoL with Aspects of Caregiver Burden questionnaire. The questionnaire comprises two parts. The first part asks the caregiver for his/her opinion on the child's HRQoL (proxy HRQoL). The second part asks the caregiver to rate how the child's situation is for them (i.e., the impact of the child's disease and treatment on the caregiver). Items are rated with 5 respective response options: never, seldom, sometimes, often, and all the time. Scores range from 0 to 100, with lower scores reflective of better HRQoL. A total score is calculated as the sum of all of the items in the scale.

  26. 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

    Time frame: From Baseline until primary cutoff date (at least 24 weeks): Arm C (Control) No Prophylaxis, median (range): 24.0 (23.9-28.0) weeks; Arms A & B Emicizumab, median (range): Arm A: 43.7 (28.1-60.3) weeks; Arm B: 46.1 (24.0-58.7) weeks

    The number of participants experiencing at least one adverse event (AE), including all non-serious and serious AEs, is reported here. According to the ICH guideline for Good Clinical Practice, an AE is any untoward medical occurrence in a clinical investigation subject administered a pharmaceutical product, regardless of causal attribution. The terms "severe" and "serious" are not synonymous. A serious AE is any AE that is a significant medical event meeting any of the standard criteria. Severity refers to the intensity of an AE (e.g., rated as mild, moderate, or severe, or according to the World Health Organization [WHO] toxicity grading scale); the event itself may be of relatively minor medical significance. Severity and seriousness were independently assessed by the investigator for each reported AE.

  27. Number of Participants With at Least One Adverse Event, Severity According to the World Health Organization (WHO) Toxicity Grading Scale, Final Analysis

    Time frame: From first dose of emicizumab until end of study: Arms A to C: up to 88 months; Arm D: up to 52.4 months

    The number of participants experiencing at least one adverse event (AE), including all non-serious and serious AEs, is reported here. According to the ICH guideline for Good Clinical Practice, an AE is any untoward medical occurrence in a clinical investigation subject administered a pharmaceutical product, regardless of causal attribution. The terms "severe" and "serious" are not synonymous. A serious AE is any AE that is a significant medical event meeting any of the standard criteria. Severity refers to the intensity of an AE (e.g., rated as mild, moderate, or severe, or according to the World Health Organization [WHO] toxicity grading scale); the event itself may be of relatively minor medical significance. Severity and seriousness were independently assessed by the investigator for each reported AE.

  28. Number of Participants With at Least One Adverse Event Leading to Study Drug Discontinuation, Final Analysis

    Time frame: From first dose of emicizumab until end of study: Arms A to C: up to 88 months; Arm D: up to 52.4 months

    According to the ICH guideline for Good Clinical Practice, an adverse event (AE) is any untoward medical occurrence in a clinical investigation subject administered a pharmaceutical product, regardless of causal attribution. The terms "severe" and "serious" are not synonymous. A serious AE is any AE that is a significant medical event meeting any of the standard criteria. Severity refers to the intensity of an AE (e.g., rated as 1 = mild, 2 = moderate, 3 = severe, or 4 = potentially life-threatening according to the World Health Organization [WHO] toxicity grading scale); the event itself may be of relatively minor medical significance. Severity and seriousness were independently assessed by the investigator for each reported AE.

  29. Number of Participants With at Least One Systemic Hypersensitivity, Anaphylaxis, or Anaphylactoid Reaction, Severity According to the WHO Toxicity Grading Scale, Final Analysis

    Time frame: From first dose of emicizumab until end of study: Arms A to C: up to 88 months; Arm D: up to 52.4 months

    According to the ICH guideline for Good Clinical Practice, an adverse event (AE) is any untoward medical occurrence in a clinical investigation subject administered a pharmaceutical product, regardless of causal attribution. The terms "severe" and "serious" are not synonymous. A serious AE is any AE that is a significant medical event meeting any of the standard criteria. Severity refers to the intensity of an AE (e.g., rated as 1 = mild, 2 = moderate, 3 = severe, or 4 = potentially life-threatening according to the World Health Organization [WHO] toxicity grading scale); the event itself may be of relatively minor medical significance. Severity and seriousness were independently assessed by the investigator for each reported AE.

  30. Number of Participants With at Least One Thromboembolic Event, Severity According to the WHO Toxicity Grading Scale, Final Analysis

    Time frame: From first dose of emicizumab until end of study: Arms A to C: up to 88 months; Arm D: up to 52.4 months

    According to the ICH guideline for Good Clinical Practice, an adverse event (AE) is any untoward medical occurrence in a clinical investigation subject administered a pharmaceutical product, regardless of causal attribution. The terms "severe" and "serious" are not synonymous. A serious AE is any AE that is a significant medical event meeting any of the standard criteria. Severity refers to the intensity of an AE (e.g., rated as 1 = mild, 2 = moderate, 3 = severe, or 4 = potentially life-threatening according to the World Health Organization [WHO] toxicity grading scale); the event itself may be of relatively minor medical significance. Severity and seriousness were independently assessed by the investigator for each reported AE.

  31. Number of Participants With at Least One Thrombotic Microangiopathy, Severity According to the WHO Toxicity Grading Scale, Final Analysis

    Time frame: From first dose of emicizumab until end of study: Arms A to C: up to 88 months; Arm D: up to 52.4 months

    According to the ICH guideline for Good Clinical Practice, an adverse event (AE) is any untoward medical occurrence in a clinical investigation subject administered a pharmaceutical product, regardless of causal attribution. The terms "severe" and "serious" are not synonymous. A serious AE is any AE that is a significant medical event meeting any of the standard criteria. Severity refers to the intensity of an AE (e.g., rated as 1 = mild, 2 = moderate, 3 = severe, or 4 = potentially life-threatening according to the World Health Organization [WHO] toxicity grading scale); the event itself may be of relatively minor medical significance. Severity and seriousness were independently assessed by the investigator for each reported AE.

  32. Number of Participants With at Least One Injection-Site Reaction, Severity According to the WHO Toxicity Grading Scale, Final Analysis

    Time frame: From first dose of emicizumab until end of study: Arms A to C: up to 88 months; Arm D: up to 52.4 months

    According to the ICH guideline for Good Clinical Practice, an adverse event (AE) is any untoward medical occurrence in a clinical investigation subject administered a pharmaceutical product, regardless of causal attribution. The terms "severe" and "serious" are not synonymous. A serious AE is any AE that is a significant medical event meeting any of the standard criteria. Severity refers to the intensity of an AE (e.g., rated as 1 = mild, 2 = moderate, 3 = severe, or 4 = potentially life-threatening according to the World Health Organization [WHO] toxicity grading scale); the event itself may be of relatively minor medical significance. Severity and seriousness were independently assessed by the investigator for each reported AE.

  33. Number of Participants With Serum Chemistry Laboratory Abnormalities by Shift From Baseline to Highest WHO Grade Post-Baseline

    Time frame: From first dose of emicizumab until end of study: Arms A to C: up to 88 months; Arm D: up to 52.4 months

    The number of participants with abnormal shifts in laboratory chemistry parameters while on emicizumab throughout the study are provided below as shifts from baseline to the highest WHO grade post-baseline (1 = mild, 2 = moderate, 3 = severe, or 4 = potentially life-threatening). Not every laboratory abnormality qualifies as an adverse event. A laboratory test result must be reported as an adverse event if it meets any of the following criteria: Is accompanied by clinical symptoms; Results in a change in study treatment; Results in a medical intervention or a change in concomitant therapy; Is clinically significant in the investigator's judgment. It was the investigator's responsibility to review all laboratory findings. SGOT/AST = serum glutamic-oxaloacetic transaminase/aspartate aminotransferase; SGPT/ALT = serum glutamic-pyruvic transaminase/alanine aminotransferase

  34. Number of Participants With Hematology Laboratory Abnormalities by Shift From Baseline to Highest WHO Grade Post-Baseline

    Time frame: From first dose of emicizumab until end of study: Arms A to C: up to 88 months; Arm D: up to 52.4 months

    The number of participants with abnormal shifts in laboratory hematology parameters while on emicizumab throughout the study are provided below as shifts from baseline to the highest WHO grade post-baseline (1 = mild, 2 = moderate, 3 = severe, or 4 = potentially life-threatening). Not every laboratory abnormality qualifies as an adverse event. A laboratory test result must be reported as an adverse event if it meets any of the following criteria: Is accompanied by clinical symptoms; Results in a change in study treatment; Results in a medical intervention or a change in concomitant therapy; Is clinically significant in the investigator's judgment. It was the investigator's responsibility to review all laboratory findings.

  35. Change From Baseline in Body Temperature Over Time

    Time frame: Baseline and Weeks 5, 25, 49, and 73

    The data for Arm C are from the emicizumab prophylaxis period and are labelled to correspond to the visit schedule of the other study arms. For Arm C, this is relative to the point at which participants switched to start receiving emicizumab (after having completed 24 weeks of no prophylaxis).

  36. Change From Baseline in Pulse Rate Over Time

    Time frame: Baseline, Weeks 5, 25, 49, and 73

    The data for Arm C are from the emicizumab prophylaxis period and are labelled to correspond to the visit schedule of the other study arms. For Arm C, this is relative to the point at which participants switched to start receiving emicizumab (after having completed 24 weeks of no prophylaxis).

  37. Change From Baseline in Respiratory Rate Over Time

    Time frame: Baseline, Weeks 5, 25, 49, and 73

    The data for Arm C are from the emicizumab prophylaxis period and are labelled to correspond to the visit schedule of the other study arms. For Arm C, this is relative to the point at which participants switched to start receiving emicizumab (after having completed 24 weeks of no prophylaxis).

  38. Change From Baseline in Systolic Blood Pressure Over Time

    Time frame: Baseline, Weeks 5, 25, 49, and 73

    The data for Arm C are from the emicizumab prophylaxis period and are labelled to correspond to the visit schedule of the other study arms. For Arm C, this is relative to the point at which participants switched to start receiving emicizumab (after having completed 24 weeks of no prophylaxis).

  39. Change From Baseline in Diastolic Blood Pressure Over Time

    Time frame: Baseline, Weeks 5, 25, 49, and 73

    The data for Arm C are from the emicizumab prophylaxis period and are labelled to correspond to the visit schedule of the other study arms. For Arm C, this is relative to the point at which participants switched to start receiving emicizumab (after having completed 24 weeks of no prophylaxis).

  40. Number of Participants by Post-Baseline Anti-Emicizumab Antibody (ADA) Status

    Time frame: Samples taken at Baseline and at prespecified times post-baseline from first dose of emicizumab until data cutoff date, median (range) time of exposure to emicizumab: All Arms: 196.14 (20.1-222.1) weeks; Arm D only: 64.14 (61.1-67.3) weeks

    Participants were considered anti-drug antibody (ADA)-positive if they were ADA-negative at baseline but developed an ADA response following study drug administration, or if they were ADA-positive at baseline and the titer of one or more post-baseline samples was at least 4-fold greater than the titer of the baseline sample. Participants were considered ADA-negative if they were ADA-negative at baseline and all post-baseline samples were negative following drug administration, or if they were ADA-positive at baseline but did not have any post-baseline (following drug administration) samples with a titer that was at least 4-fold greater than the titer of the baseline sample.

  41. Plasma Trough Concentration (Ctrough) of Emicizumab

    Time frame: Arms A & D, QW (up to Week 49 for Arm D only): Weeks 2, 3, 4, 5, 7, 9, 13, 17, 21, 25, 33, 41, 49, 61, 73, 85, 97, 109, 121, and 133; Arms B & C, Q4W: Weeks 2, 3, 4, 5, 9, 13, 17, 21, 25, 37, 49, 61, 73, 85, 97, 109, 121, and 133

    The data for Arm C are from the emicizumab prophylaxis period and are labelled to correspond to the visit schedule of the other study arms. For Arm C, this is relative to the point at which participants switched to start receiving emicizumab (after having completed 24 weeks of no prophylaxis).

Sponsors and collaborators

Lead sponsor

Hoffmann-La Roche

Industry

Registry information

Official study 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

Acronym: HAVEN 5

Important dates

Study start
2018
Primary completion
2022
Study completion
2025
First posted
Oct 20, 2017
Registry last updated
Apr 1, 2026

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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