Hemophilia A With Inhibitors, Hemophilia B With Inhibitors
Conditions
Brief summary
The purpose of the study is to assess the safety, efficacy and pharmacokinetics of 2 separate dose regimens (75µg/kg and 225 µg/kg) of Coagulation Factor VIIa (Recombinant) for the treatment of bleeding episodes in hemophilia A or B patients with inhibitors to Factor VIII/IX
Detailed description
This was a global, multicenter, Phase III, prospective, open-label, randomized, crossover study. After obtaining informed consent and performance of screening procedures, patients who met all inclusion and exclusion criteria were randomized to one of two treatment regimens as follows: * 75 µg/kg treatment regimen * 225 µg/kg treatment regimen For each treatment regimen there were two phases: * Phase A (Initial phase) * Phase B (Treatment phase) The assigned treatment regimen was the dose administered in Phase A and was the starting dose in Phase B.
Interventions
BIOLOGICALCoagulation Factor VIIa (Recombinant)
A cross over design to assess the efficacy of 2 separate dose regimens (75µg/kg and 225 µg/kg) of Coagulation Factor VIIa (Recombinant) for the treatment of bleeding episodes in hemophilia A or B patients with inhibitors to Factor VIII/IX
Sponsors
Laboratoire français de Fractionnement et de Biotechnologies
rEVO Biologics
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
MALE
Age
12 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* be male with a diagnosis of congenital hemophilia A and/or B of any severity * have one of the following: * a positive inhibitor test Bethesda Unit (BU) ≥ 5 (as confirmed at screening by the institutional lab), OR * a BU\<5 but expected to have a high anamnestic response to FVIII or FIX, as demonstrated from the subject's medical history, precluding the use of Factor VIII or IX products to treat bleedings, OR * a BU\<5 but expected to be refractory to increased dosing of FVIII or FIX, as demonstrated from the subject's medical history, precluding the use of Factor VIII or IX products to treat bleedings * be 12 years or older, up to and including 75 years of age (NOTE: different age restrictions may apply per local regulation and/or ethical considerations) * have at least 3 bleeding episodes of any severity in the past 6 months be capable of understanding and willing to comply with the conditions of the protocol * have read, understood and provided written informed consent (patient and/or parent(s)/legal guardian(s) if \<18 years of age)
Exclusion criteria
* have any coagulation disorder other than hemophilia A or B * be immuno-suppressed (i.e., the patient should not be receiving systemic immunosuppressive medication, cluster of differentiation 4 (CD4) counts at screening should be \>200/µl) * have a known allergy or hypersensitivity to rabbits * have platelet count \<100,000/mL * have had within one month prior to first administration of the study drug in this study a major surgical procedure (e.g. orthopedic, abdominal) * have received an investigational drug within 30 days of the first study drug administration, or is expected to receive such drug during participation in this study * have a clinically relevant hepatic (AST and/or alanine aminotransferase (ALT) \>3 times the upper limit of normal) and/or renal impairment (creatinine \>2 times the upper limit of normal) * have a history of arterial and/or venous thromboembolic events (such as myocardial infarction, ischemic strokes, transient ischemic attacks, deep venous thrombosis or pulmonary embolism) within 2 years prior to first dose of study drug, or current New York Heart Association (NYHA) functional classification score of stage II -IV * have an active malignancy (those with non-melanoma skin cancer are allowed) * have any life-threatening disease or other disease or condition which, according to the investigator's judgment, could imply a potential hazard to the patient, interfere with the trial participation or trial outcome (e.g., a history of non-responsiveness to bypassing products).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of Successfully Treated Mild/Moderate Bleeding Episodes | 12 hours after first administration of study drug | For the primary efficacy endpoint, successful treatment of a bleeding episode was defined as a combination of the following: * Good or Excellent response noted by the patient * Study drug treatment: No further treatment with study drug beyond timepoint for this bleeding episode * No other hemostatic treatment needed for this bleeding episode * No administration of blood products that would indicate continuation of bleeding beyond timepoint * No increase of pain beyond timepoint that could not otherwise be explained |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of Mild/Moderate Bleeding Episodes With Patient (Pt)-Reported Good or Excellent Responses at 12 Hours | at 12 hours | Based on Patient-Reported Good or Excellent responses as per the below descriptions: Good: Symptoms of bleed (e.g., swelling, tenderness, and decreased range of motion in the case of musculoskeletal haemorrhage) had largely been reduced by the treatment, but had not completely disappeared. Symptoms had improved enough to not require more infusions of the study drug. Excellent: Full relief of pain and cessation of objective signs of bleed (e.g., swelling, tenderness, and decreased range of motion in the case of musculoskeletal haemorrhage). No additional infusion of study drug was required. |
| Time to Assessment of a Good or Excellent Response of Mild/Moderate Bleeding Episodes by the Patient | Within 24 hours of Bleeding Episode | Categories of Response to Treatment are Described as Follows: None: No noticeable effect of the treatment on the bleed or worsening of patient's condition. Continuation of treatment with the study drug was needed. Moderate: Some effect of the treatment on the bleed was noticed, e.g., pain decreased or bleeding signs improved, but bleed continued and required continued treatment with the study drug. Good: Symptoms of bleed (e.g., swelling, tenderness, and decreased range of motion in the case of musculoskeletal haemorrhage) had largely been reduced by the treatment, but had not completely disappeared. Symptoms had improved enough to not require more infusions of the study drug. Excellent: Full relief of pain and cessation of objective signs of bleed (e.g., swelling, tenderness, and decreased range of motion in the case of musculoskeletal haemorrhage). No additional infusion of study drug was required. |
| Number of Administrations of Study Drug Per Mild/Moderate Bleeding Episode | Within 24 hours of Bleeding Episode | — |
| Total Amount of Study Drug Administered Per Mild/Moderate Bleeding Episode | Through study completion | — |
Countries
Belarus, Bulgaria, Georgia, Israel, Poland, Romania, Russia, Ukraine, United Kingdom, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| FVIIa 75 µg/kg First, Then 225 µg/kg Coagulation Factor VIIa (Recombinant): First Intervention (3 months), Second Intervention (3 months), continue cycle until end of study. | 13 |
| FVIIa 225 µg/kg First, Then 75 µg/kg Coagulation Factor VIIa (Recombinant): First Intervention (3 months), Second Intervention (3 months), continue cycle until end of study. | 14 |
| Total | 27 |
Baseline characteristics
| Characteristic | FVIIa 75 µg/kg First, Then 225 µg/kg | Total | FVIIa 225 µg/kg First, Then 75 µg/kg |
|---|---|---|---|
| Age, Categorical <=18 years | 2 Participants | 5 Participants | 3 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 11 Participants | 22 Participants | 11 Participants |
| Age, Continuous | 31.8 years STANDARD_DEVIATION 12.1 | 31.0 years STANDARD_DEVIATION 12.35 | 30.1 years STANDARD_DEVIATION 12.98 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 1 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 12 Participants | 26 Participants | 14 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 12 Participants | 25 Participants | 13 Participants |
| Region of Enrollment Bulgaria | 1 participants | 2 participants | 1 participants |
| Region of Enrollment Georgia | 1 participants | 2 participants | 1 participants |
| Region of Enrollment Poland | 1 participants | 1 participants | 0 participants |
| Region of Enrollment Russian Federation | 2 participants | 5 participants | 3 participants |
| Region of Enrollment Ukraine | 6 participants | 12 participants | 6 participants |
| Region of Enrollment United Kingdom | 0 participants | 1 participants | 1 participants |
| Region of Enrollment United States | 2 participants | 4 participants | 2 participants |
| Sex/Gender, Customized Male (n) | 13 participants | 27 participants | 14 participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 3 / 25 | 3 / 25 |
| serious Total, serious adverse events | 1 / 25 | 0 / 25 |
Outcome results
Primary
Proportion of Successfully Treated Mild/Moderate Bleeding Episodes
For the primary efficacy endpoint, successful treatment of a bleeding episode was defined as a combination of the following: * Good or Excellent response noted by the patient * Study drug treatment: No further treatment with study drug beyond timepoint for this bleeding episode * No other hemostatic treatment needed for this bleeding episode * No administration of blood products that would indicate continuation of bleeding beyond timepoint * No increase of pain beyond timepoint that could not otherwise be explained
Time frame: 12 hours after first administration of study drug
Population: Treated Population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| FVIIa 75 µg/kg | Proportion of Successfully Treated Mild/Moderate Bleeding Episodes | .849 Proportion of Success of BEs |
| FVIIa 225µg/kg | Proportion of Successfully Treated Mild/Moderate Bleeding Episodes | .932 Proportion of Success of BEs |
Secondary
Number of Administrations of Study Drug Per Mild/Moderate Bleeding Episode
Time frame: Within 24 hours of Bleeding Episode
Population: Treated Population with non-missing measurements
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| FVIIa 75 µg/kg | Number of Administrations of Study Drug Per Mild/Moderate Bleeding Episode | 2.5 Number of Administrations of Study Drug | Standard Deviation 1.75 |
| FVIIa 225µg/kg | Number of Administrations of Study Drug Per Mild/Moderate Bleeding Episode | 1.4 Number of Administrations of Study Drug | Standard Deviation 0.96 |
Secondary
Proportion of Mild/Moderate Bleeding Episodes With Patient (Pt)-Reported Good or Excellent Responses at 12 Hours
Based on Patient-Reported Good or Excellent responses as per the below descriptions: Good: Symptoms of bleed (e.g., swelling, tenderness, and decreased range of motion in the case of musculoskeletal haemorrhage) had largely been reduced by the treatment, but had not completely disappeared. Symptoms had improved enough to not require more infusions of the study drug. Excellent: Full relief of pain and cessation of objective signs of bleed (e.g., swelling, tenderness, and decreased range of motion in the case of musculoskeletal haemorrhage). No additional infusion of study drug was required.
Time frame: at 12 hours
Population: Treated Population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| FVIIa 75 µg/kg | Proportion of Mild/Moderate Bleeding Episodes With Patient (Pt)-Reported Good or Excellent Responses at 12 Hours | 0.857 Pt-reported proportion success of BEs |
| FVIIa 225µg/kg | Proportion of Mild/Moderate Bleeding Episodes With Patient (Pt)-Reported Good or Excellent Responses at 12 Hours | 0.937 Pt-reported proportion success of BEs |
Secondary
Time to Assessment of a Good or Excellent Response of Mild/Moderate Bleeding Episodes by the Patient
Categories of Response to Treatment are Described as Follows: None: No noticeable effect of the treatment on the bleed or worsening of patient's condition. Continuation of treatment with the study drug was needed. Moderate: Some effect of the treatment on the bleed was noticed, e.g., pain decreased or bleeding signs improved, but bleed continued and required continued treatment with the study drug. Good: Symptoms of bleed (e.g., swelling, tenderness, and decreased range of motion in the case of musculoskeletal haemorrhage) had largely been reduced by the treatment, but had not completely disappeared. Symptoms had improved enough to not require more infusions of the study drug. Excellent: Full relief of pain and cessation of objective signs of bleed (e.g., swelling, tenderness, and decreased range of motion in the case of musculoskeletal haemorrhage). No additional infusion of study drug was required.
Time frame: Within 24 hours of Bleeding Episode
Population: Treated Population with non-missing measurements
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| FVIIa 75 µg/kg | Time to Assessment of a Good or Excellent Response of Mild/Moderate Bleeding Episodes by the Patient | 5.98 Hours |
| FVIIa 225µg/kg | Time to Assessment of a Good or Excellent Response of Mild/Moderate Bleeding Episodes by the Patient | 3.00 Hours |
Secondary
Total Amount of Study Drug Administered Per Mild/Moderate Bleeding Episode
Time frame: Through study completion
Population: Treated Population with non-missing measurements
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| FVIIa 75 µg/kg | Total Amount of Study Drug Administered Per Mild/Moderate Bleeding Episode | 187.868 µg/kg per bleeding episode | Standard Deviation 131.7982 |
| FVIIa 225µg/kg | Total Amount of Study Drug Administered Per Mild/Moderate Bleeding Episode | 252.963 µg/kg per bleeding episode | Standard Deviation 78.9732 |