Hemophilia A, Hemophilia B
Conditions
Keywords
with Factor VIII (FVIII) or Factor IX (FIX) inhibitors
Brief summary
The purpose of the study is to determine the efficacy and safety of rFVIIa BI as part of a six-month on-demand treatment regimen in hemophilia A or B subjects with inhibitors.
Interventions
BIOLOGICALRecombinant Factor VIIa BI (rFVIIa BI)
Administered approximately every 3 hours as an intravenous bolus injection on-demand
Sponsors
Baxalta now part of Shire
Study design
Allocation
RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
MALE
Age
12 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
Main Inclusion Criteria: * Participant is male with hemophilia A or B with inhibitors, with a high titer (≥5 Bethesda unit (BU)) or a historical high anamnestic response. * Participant is 12 to 65 years old at the time of screening. * Participant is currently using or has used bypassing agents for treatment of bleeding episodes. * Participant has an annualized bleed rate of 5 or more bleeding episodes per year on average over the 2 years prior to the Screening visit. * Participant has a Karnofsky Performance Score ≥60. * Participant is hepatitis C virus negative (HCV-) either by antibody testing or polymerase chain reaction (PCR); or hepatitis C virus positive (HCV+) with stable hepatic disease. * Participant is human immunodeficiency virus negative (HIV-) or HIV+ with stable disease, CD4+ count ≥200 cells/mm\^3 at screening. * Participant is willing and able to comply with the requirements of the protocol. Main
Exclusion criteria
* Participant is not willing to go on an on-demand treatment scheme. * Participant is positive for a FVII inhibitor at screening. * Participant has clinically symptomatic liver disease. * Participant has a platelet count \<100,000/µL. * The use of α-interferon with or without ribavirin is planned for an HCV-infected participant or the use of a protease inhibitor is planned for an HIV-infected participant. * Participants currently taking any of these medications for ≥30 days are eligible. * Participant has a known hypersensitivity to rFVIIa, hamster or murine proteins, or Tween 80. * Participant has a known history of being non-responsive to rFVIIa treatment of bleeding episodes. * Participant has a prior history of thromboembolic event or diagnosis of other diseases that may increase the participant's risk of thromboembolic complications. * Participant has participated in another clinical study involving an investigational product (IP) or investigational device within 30 days prior to enrollment or is scheduled to participate in another clinical study involving an IP or investigational device during the course of this study. * Participant is a family member or employee of the investigator. * Participant is scheduled for surgery during the study period.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Bleeding Episode With Treatment Success | within 12 hours of first dose | No additional hemostatic product required within 12 hours of first dose other than the prescribed dosing regimen. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Treatment Response for Each Bleeding Episode | within 24 hours of infusion | Participants rated the treatment of each bleeding episode. If treatment occurred under direct supervision of treating physician, the physician rated the response. Ratings based on a 4 point scale; EXCELLENT - full relief of pain and cessation of objective signs of bleeding (swelling, tenderness, decrease in range of motion \[for muscle bleeds\]) within 9 hours of treatment initiation. No additional infusion required to control bleeding, other than prescribed dosing regimen. GOOD - Substantial relief of pain and/or cessation of objective signs of bleeding within 9 hours of treatment initiation. No additional infusion required to control bleeding, other than prescribed dosing regimen. MODERATE - slight relief of pain and slight improvement of signs of bleeding within 9 hours of treatment initiation. Requires additional infusion beyond treatment regimen. NONE - No improvement or condition worsens. SUCCESSFUL = EXCELLENT or GOOD. |
| Percentage of Clinical Responders (Sustained Bleeding Control) for All Acute Bleeding Episodes | 24 hours post infusion | Clinical responders defined as sustained bleeding control, (no additional hemostatic medication including rFVIIa BI required between 12 and 24 hours after first infusion of the successfully treated bleeding episode). |
| Safety and Tolerability of Treatment Regimens by Clinical Assessment of Percentage of Participants With Adverse Events (AEs) | 6 months (throughout study period) | Safety was determined by the number of AEs (both serious AEs \[SAEs\] and non-serious AEs \[nsAE\]). Tolerability was determined by the number of AEs related to rFVIIa BI (both SAEs and nsAEs) as determined by causality assessment of the AEs by the investigator. An AE was deemed Related if the investigator judged the AE to be possibly related or probably related to rFVIIa BI. The percentage of participants with AEs were presented by seriousness (SAE, nsAE), severity (Mild, Moderate or Severe) and causality (Related or Not Related to rFVIIa BI). |
| Safety and Tolerability of Treatment Regimens by Clinical Assessment of Adverse Events (AEs) | 6 months (throughout study period) | Safety was determined by the number of AEs (both serious AEs \[SAEs\] and non-serious AEs \[nsAE\]). Tolerability was determined by the number of AEs related to rFVIIa BI (both SAEs and nsAEs) as determined by causality assessment of the AEs by the investigator. An AE was deemed Related if the investigator judges the AE to be possibly related or probably related to rFVIIa BI. The percentage of AEs were presented by seriousness (SAE, nsAE), severity (Mild, Moderate or Severe) and causality (Related or Not Related \[to rFVIIa BI\]). |
| Percentage of Participants With Inhibitor Development to FVII | 6 months (throughout study period) | Development of rFVII inhibitors or FVIIa binding antibodies during the study. |
Countries
Japan, Poland, Romania, Russia, Serbia, Spain, Taiwan, Ukraine, United States
Participant flow
Recruitment details
Enrollment was conduced at 16 clinical sites from the following countries: Japan, Taiwan, Poland, Romania, Russian Federation, Serbia, Spain, Ukraine and the United States.
Pre-assignment details
40 participants provided informed consent and were screened for study participation, of which there was 1 screen failure. 39 participants (in pre-assignment period) were randomized where 1 participant withdrew after randomization but prior to treatment, therefore 38 participants were treated with recombinant activated factor VII BI (rFVIIa).
Participants by arm
| Arm | Count |
|---|---|
| Arm 1: up to 3 x 90 Micrograms/kg rFVIIa BI Bleeding episodes treated with up to 3 doses of 90 micrograms/kg of recombinant activated factor VII BI (rFVIIaBI) every 3 hours as on-demand intravenous bolus infusions. | 18 |
| Arm 2: 1 x 270 Micrograms/kg rFVIIa BI Bleeding episodes treated with 1 dose of 270 micrograms/kg of recombinant activated factor VII BI (rFVIIa BI) as on-demand intravenous bolus infusion. | 20 |
| Total | 38 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 1 | 1 |
| Overall Study | Withdrawal by Subject | 0 | 1 |
Baseline characteristics
| Characteristic | Arm 1: up to 3 x 90 Micrograms/kg rFVIIa BI | Arm 2: 1 x 270 Micrograms/kg rFVIIa BI | Total |
|---|---|---|---|
| Age, Continuous | 28 Years | 28 Years | 28 Years |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 18 Participants | 20 Participants | 38 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 4 / 18 | 2 / 20 |
| serious Total, serious adverse events | 2 / 18 | 2 / 20 |
Outcome results
Primary
Percentage of Bleeding Episode With Treatment Success
No additional hemostatic product required within 12 hours of first dose other than the prescribed dosing regimen.
Time frame: within 12 hours of first dose
Population: Full Analysis Dataset
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm 1: up to 3 x 90 Micrograms/kg rFVIIa BI | Percentage of Bleeding Episode With Treatment Success | 96.19 percent of bleeding episodes |
| Arm 2: 1 x 270 Micrograms/kg rFVIIa BI | Percentage of Bleeding Episode With Treatment Success | 79.30 percent of bleeding episodes |
Comparison: Equivalence test of successfully treated bleeding episodes (BEs) between or within treatment arms. Denoting the success rates in the two treatment groups by p1 and p2 , the null hypotheses of H01 : p1/p2 \< 0.83 and H02 : p1/p2 \> 1.20 was implicitly tested against the one-sided alternatives Ha1: 0.83 ≤ p1/p2 and Ha2 : p1/p2 ≤ 1.20, by comparing the 90% two-sided confidence interval (CI) of the ratio of success proportions to the equivalence region defined as \[0.83, 1.20\].90% CI: [1.15, 1.28]Ratio of success proportion
Secondary
Percentage of Clinical Responders (Sustained Bleeding Control) for All Acute Bleeding Episodes
Clinical responders defined as sustained bleeding control, (no additional hemostatic medication including rFVIIa BI required between 12 and 24 hours after first infusion of the successfully treated bleeding episode).
Time frame: 24 hours post infusion
Population: Full Analysis Dataset
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm 1: up to 3 x 90 Micrograms/kg rFVIIa BI | Percentage of Clinical Responders (Sustained Bleeding Control) for All Acute Bleeding Episodes | 93.43 percent of bleeding episodes |
| Arm 2: 1 x 270 Micrograms/kg rFVIIa BI | Percentage of Clinical Responders (Sustained Bleeding Control) for All Acute Bleeding Episodes | 76.17 percent of bleeding episodes |
Secondary
Percentage of Participants With Inhibitor Development to FVII
Development of rFVII inhibitors or FVIIa binding antibodies during the study.
Time frame: 6 months (throughout study period)
Population: Safety Analysis Dataset
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm 1: up to 3 x 90 Micrograms/kg rFVIIa BI | Percentage of Participants With Inhibitor Development to FVII | 0 percent of participants |
| Arm 2: 1 x 270 Micrograms/kg rFVIIa BI | Percentage of Participants With Inhibitor Development to FVII | 0 percent of participants |
Secondary
Safety and Tolerability of Treatment Regimens by Clinical Assessment of Adverse Events (AEs)
Safety was determined by the number of AEs (both serious AEs \[SAEs\] and non-serious AEs \[nsAE\]). Tolerability was determined by the number of AEs related to rFVIIa BI (both SAEs and nsAEs) as determined by causality assessment of the AEs by the investigator. An AE was deemed Related if the investigator judges the AE to be possibly related or probably related to rFVIIa BI. The percentage of AEs were presented by seriousness (SAE, nsAE), severity (Mild, Moderate or Severe) and causality (Related or Not Related \[to rFVIIa BI\]).
Time frame: 6 months (throughout study period)
Population: Safety Analysis Dataset
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Arm 1: up to 3 x 90 Micrograms/kg rFVIIa BI | Safety and Tolerability of Treatment Regimens by Clinical Assessment of Adverse Events (AEs) | SAE-Moderate-Unrelated | 6.7 percent of AEs |
| Arm 1: up to 3 x 90 Micrograms/kg rFVIIa BI | Safety and Tolerability of Treatment Regimens by Clinical Assessment of Adverse Events (AEs) | nsAE-Mild-Unrelated | 73.3 percent of AEs |
| Arm 1: up to 3 x 90 Micrograms/kg rFVIIa BI | Safety and Tolerability of Treatment Regimens by Clinical Assessment of Adverse Events (AEs) | SAE-Severe-Unrelated | 20.0 percent of AEs |
| Arm 1: up to 3 x 90 Micrograms/kg rFVIIa BI | Safety and Tolerability of Treatment Regimens by Clinical Assessment of Adverse Events (AEs) | nsAE-Moderate-Unrelated | 0 percent of AEs |
| Arm 1: up to 3 x 90 Micrograms/kg rFVIIa BI | Safety and Tolerability of Treatment Regimens by Clinical Assessment of Adverse Events (AEs) | SAE-Severe-Related | 0 percent of AEs |
| Arm 2: 1 x 270 Micrograms/kg rFVIIa BI | Safety and Tolerability of Treatment Regimens by Clinical Assessment of Adverse Events (AEs) | nsAE-Moderate-Unrelated | 18.8 percent of AEs |
| Arm 2: 1 x 270 Micrograms/kg rFVIIa BI | Safety and Tolerability of Treatment Regimens by Clinical Assessment of Adverse Events (AEs) | SAE-Severe-Unrelated | 0 percent of AEs |
| Arm 2: 1 x 270 Micrograms/kg rFVIIa BI | Safety and Tolerability of Treatment Regimens by Clinical Assessment of Adverse Events (AEs) | SAE-Severe-Related | 12.5 percent of AEs |
| Arm 2: 1 x 270 Micrograms/kg rFVIIa BI | Safety and Tolerability of Treatment Regimens by Clinical Assessment of Adverse Events (AEs) | nsAE-Mild-Unrelated | 62.5 percent of AEs |
| Arm 2: 1 x 270 Micrograms/kg rFVIIa BI | Safety and Tolerability of Treatment Regimens by Clinical Assessment of Adverse Events (AEs) | SAE-Moderate-Unrelated | 6.3 percent of AEs |
Secondary
Safety and Tolerability of Treatment Regimens by Clinical Assessment of Percentage of Participants With Adverse Events (AEs)
Safety was determined by the number of AEs (both serious AEs \[SAEs\] and non-serious AEs \[nsAE\]). Tolerability was determined by the number of AEs related to rFVIIa BI (both SAEs and nsAEs) as determined by causality assessment of the AEs by the investigator. An AE was deemed Related if the investigator judged the AE to be possibly related or probably related to rFVIIa BI. The percentage of participants with AEs were presented by seriousness (SAE, nsAE), severity (Mild, Moderate or Severe) and causality (Related or Not Related to rFVIIa BI).
Time frame: 6 months (throughout study period)
Population: Safety Analysis Dataset
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Arm 1: up to 3 x 90 Micrograms/kg rFVIIa BI | Safety and Tolerability of Treatment Regimens by Clinical Assessment of Percentage of Participants With Adverse Events (AEs) | SAE-Severe-Unrelated | 11.1 percent of participants with AEs |
| Arm 1: up to 3 x 90 Micrograms/kg rFVIIa BI | Safety and Tolerability of Treatment Regimens by Clinical Assessment of Percentage of Participants With Adverse Events (AEs) | nsAE-Mild-Unrelated | 22.2 percent of participants with AEs |
| Arm 1: up to 3 x 90 Micrograms/kg rFVIIa BI | Safety and Tolerability of Treatment Regimens by Clinical Assessment of Percentage of Participants With Adverse Events (AEs) | SAE-Severe-Related | 0 percent of participants with AEs |
| Arm 1: up to 3 x 90 Micrograms/kg rFVIIa BI | Safety and Tolerability of Treatment Regimens by Clinical Assessment of Percentage of Participants With Adverse Events (AEs) | nsAE-Moderate-Unrelated | 0 percent of participants with AEs |
| Arm 1: up to 3 x 90 Micrograms/kg rFVIIa BI | Safety and Tolerability of Treatment Regimens by Clinical Assessment of Percentage of Participants With Adverse Events (AEs) | SAE-Moderate-Unrelated | 5.6 percent of participants with AEs |
| Arm 2: 1 x 270 Micrograms/kg rFVIIa BI | Safety and Tolerability of Treatment Regimens by Clinical Assessment of Percentage of Participants With Adverse Events (AEs) | nsAE-Moderate-Unrelated | 15.0 percent of participants with AEs |
| Arm 2: 1 x 270 Micrograms/kg rFVIIa BI | Safety and Tolerability of Treatment Regimens by Clinical Assessment of Percentage of Participants With Adverse Events (AEs) | SAE-Moderate-Unrelated | 5.0 percent of participants with AEs |
| Arm 2: 1 x 270 Micrograms/kg rFVIIa BI | Safety and Tolerability of Treatment Regimens by Clinical Assessment of Percentage of Participants With Adverse Events (AEs) | SAE-Severe-Unrelated | 0 percent of participants with AEs |
| Arm 2: 1 x 270 Micrograms/kg rFVIIa BI | Safety and Tolerability of Treatment Regimens by Clinical Assessment of Percentage of Participants With Adverse Events (AEs) | SAE-Severe-Related | 5.0 percent of participants with AEs |
| Arm 2: 1 x 270 Micrograms/kg rFVIIa BI | Safety and Tolerability of Treatment Regimens by Clinical Assessment of Percentage of Participants With Adverse Events (AEs) | nsAE-Mild-Unrelated | 30.0 percent of participants with AEs |
Secondary
Treatment Response for Each Bleeding Episode
Participants rated the treatment of each bleeding episode. If treatment occurred under direct supervision of treating physician, the physician rated the response. Ratings based on a 4 point scale; EXCELLENT - full relief of pain and cessation of objective signs of bleeding (swelling, tenderness, decrease in range of motion \[for muscle bleeds\]) within 9 hours of treatment initiation. No additional infusion required to control bleeding, other than prescribed dosing regimen. GOOD - Substantial relief of pain and/or cessation of objective signs of bleeding within 9 hours of treatment initiation. No additional infusion required to control bleeding, other than prescribed dosing regimen. MODERATE - slight relief of pain and slight improvement of signs of bleeding within 9 hours of treatment initiation. Requires additional infusion beyond treatment regimen. NONE - No improvement or condition worsens. SUCCESSFUL = EXCELLENT or GOOD.
Time frame: within 24 hours of infusion
Population: Full Analysis Dataset
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Arm 1: up to 3 x 90 Micrograms/kg rFVIIa BI | Treatment Response for Each Bleeding Episode | Good | 53.29 percent of bleeding episodes |
| Arm 1: up to 3 x 90 Micrograms/kg rFVIIa BI | Treatment Response for Each Bleeding Episode | No Assessment Available | 0 percent of bleeding episodes |
| Arm 1: up to 3 x 90 Micrograms/kg rFVIIa BI | Treatment Response for Each Bleeding Episode | Moderate | 9.69 percent of bleeding episodes |
| Arm 1: up to 3 x 90 Micrograms/kg rFVIIa BI | Treatment Response for Each Bleeding Episode | Excellent | 34.60 percent of bleeding episodes |
| Arm 1: up to 3 x 90 Micrograms/kg rFVIIa BI | Treatment Response for Each Bleeding Episode | None | 2.42 percent of bleeding episodes |
| Arm 1: up to 3 x 90 Micrograms/kg rFVIIa BI | Treatment Response for Each Bleeding Episode | Successful | 87.89 percent of bleeding episodes |
| Arm 2: 1 x 270 Micrograms/kg rFVIIa BI | Treatment Response for Each Bleeding Episode | None | 1.95 percent of bleeding episodes |
| Arm 2: 1 x 270 Micrograms/kg rFVIIa BI | Treatment Response for Each Bleeding Episode | Successful | 79.30 percent of bleeding episodes |
| Arm 2: 1 x 270 Micrograms/kg rFVIIa BI | Treatment Response for Each Bleeding Episode | Excellent | 36.72 percent of bleeding episodes |
| Arm 2: 1 x 270 Micrograms/kg rFVIIa BI | Treatment Response for Each Bleeding Episode | Good | 42.58 percent of bleeding episodes |
| Arm 2: 1 x 270 Micrograms/kg rFVIIa BI | Treatment Response for Each Bleeding Episode | No Assessment Available | 0.39 percent of bleeding episodes |
| Arm 2: 1 x 270 Micrograms/kg rFVIIa BI | Treatment Response for Each Bleeding Episode | Moderate | 18.36 percent of bleeding episodes |