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 or IX in 12 patients ( birth to \<6 years old), and 12 patients (≥6 years old to \<12 years old).
Detailed description
A Phase III Study on the Safety, Pharmacokinetics, and Efficacy of Coagulation Factor VIIa (Recombinant) in Congenital Hemophilia A or B Pediatric Patients from birth to \<12 years old with Inhibitors to Factor VIII or IX: PerSept 2
Interventions
BIOLOGICALCoagulation FVIIa (Recombinant)
A cross over design to assess the efficacy of 2 separate dose regimens (75 µg/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 or Factor IX
Sponsors
LFB USA, Inc.
Laboratoire français de Fractionnement et de Biotechnologies
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
MALE
Age
No minimum to 11 Years
Healthy volunteers
No
Inclusion criteria
* be male with a diagnosis of congenital hemophilia A or B of any severity * have one of the following: * a positive inhibitor test BU ≥5, OR * a Bethesda Unit (BU) \<5 but expected to have a high anamnestic response to FVIII or FIX, as demonstrated from the patient's medical history, precluding the use of factor VIII or IX products to treat bleeding episodes, OR * a BU \<5 but expected to be refractory to increased dosing of FVIII or FIX, as demonstrated from the patient's medical history, precluding the use of factor VIII or IX products to treat bleeding episodes * be aged from birth to \<12 years old * have experienced at least 3 bleeding episodes of any severity in the past 6 months * parents or legal guardians must be capable of understanding and be willing to comply with the conditions of the protocol * parents or legal guardians must have read, understood, and provided written informed consent
Exclusion criteria
* have any coagulation disorder other than hemophilia A or B * be immunosuppressed (i.e., the patient may not be receiving systemic immunosuppressive medication; cluster of differentiation 4 (CD4) counts at screening must be \>200/µL) * have a known allergy or hypersensitivity to rabbits * have platelet count \<100,000/mL * have had a major surgical procedure (e.g. orthopedic, abdominal) within 1 month prior to first administration of study drug * have received an investigational drug within 30 days of first study drug administration, or be expected to receive such drug during participation in this study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of Successfully Treated Bleeding Episodes (Mild/Moderate/Severe) Per EMA Definition | 12 hours after first administration of study drug | * Good or excellent response noted by the patient/caregiver for mild/moderate bleeding episodes; * Good or excellent response noted by the physician for severe bleeding episodes. |
| Proportion of Successfully Treated Mild/Moderate Bleeding Episodes Per FDA Requirement. | 12 hours after first administration of study drug | For the primary efficacy endpoint, successful treatment of mild/moderate bleeding episode was defined as meeting all of the following: * Good or excellent response noted by the patient/parent/legal guardian or other caregiver, depending on patient's age and maturity * Study drug treatment: No further treatment with LR769 beyond timepoint where a good or excellent response for this bleeding episode was noted * No other hemostatic treatment needed for this bleeding episode * No administration of blood products that would indicate continuation of bleeding beyond timepoint where a good or excellent response for this bleeding episode was noted * No increase of pain beyond timepoint where a good or excellent response for this bleeding episode was noted that could not be explained other than as continuation of bleeding |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to Patient Assessment of a Good or Excellent Response for Mild/Moderate Bleeding Episodes | 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. |
| Total Amount of Study Drug Administered Per Mild/Moderate Bleeding Episode | Within 24 hours of Bleeding Episode | The total amount of study drug administered in order to treat one mild/moderate bleeding episode. |
| Number of Administrations of Study Drug Per Mild/Moderate Bleeding Episode | Within 24 hours of Bleeding Episode | The number of study drug administrations with non-missing dose information in order to treat one mild/moderate bleeding episode. |
| Patient-Reported Good or Excellent Response for Mild/Moderate Bleeding Episodes | 12 hour after first administration of study drug | 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 hemorrhage) 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 hemorrhage). No additional infusion of study drug was required. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Mild/Moderate Bleeding Episodes With Successful Pain Relief | 12 hour after first administration of study drug | Successful pain relief was defined as a Visual Analogue Scale (VAS: 0-100; 0: no pain at all; 100: the worst pain ever possible) pain score at 12 hours after initial study drug administration that was less than the pain score at the start of treatment with study drug. |
Countries
Bulgaria, Czechia, Georgia, South Africa, Ukraine, 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), repeat sequence for entirety of study. | 12 |
| FVIIa: 225 µg/kg First, Then 75 µg/kg Coagulation Factor VIIa (Recombinant) : First Intervention (3 months), Second Intervention (3 months), repeat sequence for entirety of study. | 13 |
| Total | 25 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Physician Decision | 1 | 1 |
| Overall Study | Withdrawal by Subject | 0 | 2 |
Baseline characteristics
| Characteristic | FVIIa: 225 µg/kg First, Then 75 µg/kg | Total | FVIIa: 75 µg/kg First, Then 225 µg/kg |
|---|---|---|---|
| Age, Continuous | 4.8 years STANDARD_DEVIATION 3.63 | 4.9 years STANDARD_DEVIATION 3.28 | 4.9 years STANDARD_DEVIATION 3.02 |
| Age, Customized Age, Categorical >= 6 years to < 12 years old | 6 Participants | 12 Participants | 6 Participants |
| Age, Customized Age, Categorical Birth to < 6 years old | 7 Participants | 13 Participants | 6 Participants |
| Body Mass Index (BMI) | 17.35 kg/m^2 STANDARD_DEVIATION 3.842 | 17.53 kg/m^2 STANDARD_DEVIATION 3.209 | 17.74 kg/m^2 STANDARD_DEVIATION 2.505 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants | 3 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 11 Participants | 22 Participants | 11 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Height | 108.60 cm STANDARD_DEVIATION 25.904 | 106.49 cm STANDARD_DEVIATION 23.382 | 104.21 cm STANDARD_DEVIATION 21.21 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 3 Participants | 7 Participants | 4 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 | 10 Participants | 18 Participants | 8 Participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 13 Participants | 25 Participants | 12 Participants |
| Weight | 21.94 kg STANDARD_DEVIATION 13.391 | 20.88 kg STANDARD_DEVIATION 10.782 | 19.73 kg STANDARD_DEVIATION 7.432 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 23 | 0 / 25 |
| other Total, other adverse events | 12 / 23 | 15 / 25 |
| serious Total, serious adverse events | 0 / 23 | 2 / 25 |
Outcome results
Primary
Proportion of Successfully Treated Bleeding Episodes (Mild/Moderate/Severe) Per EMA Definition
* Good or excellent response noted by the patient/caregiver for mild/moderate bleeding episodes; * Good or excellent response noted by the physician for severe bleeding episodes.
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 Bleeding Episodes (Mild/Moderate/Severe) Per EMA Definition | 0.667 Proportion of successfully treated BEs |
| FVIIa 225µg/kg | Proportion of Successfully Treated Bleeding Episodes (Mild/Moderate/Severe) Per EMA Definition | 0.625 Proportion of successfully treated BEs |
Primary
Proportion of Successfully Treated Mild/Moderate Bleeding Episodes Per FDA Requirement.
For the primary efficacy endpoint, successful treatment of mild/moderate bleeding episode was defined as meeting all of the following: * Good or excellent response noted by the patient/parent/legal guardian or other caregiver, depending on patient's age and maturity * Study drug treatment: No further treatment with LR769 beyond timepoint where a good or excellent response for this bleeding episode was noted * No other hemostatic treatment needed for this bleeding episode * No administration of blood products that would indicate continuation of bleeding beyond timepoint where a good or excellent response for this bleeding episode was noted * No increase of pain beyond timepoint where a good or excellent response for this bleeding episode was noted that could not be explained other than as continuation of bleeding
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 Per FDA Requirement. | 0.654 Proportion of successfully treated BEs |
| FVIIa 225µg/kg | Proportion of Successfully Treated Mild/Moderate Bleeding Episodes Per FDA Requirement. | 0.603 Proportion of successfully treated BEs |
Secondary
Number of Administrations of Study Drug Per Mild/Moderate Bleeding Episode
The number of study drug administrations with non-missing dose information in order to treat one mild/moderate bleeding episode.
Time frame: Within 24 hours of Bleeding Episode
Population: Treated Population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| FVIIa 75 µg/kg | Number of Administrations of Study Drug Per Mild/Moderate Bleeding Episode | 3.6 Administrations of Study Drug | Standard Deviation 2.27 |
| FVIIa 225µg/kg | Number of Administrations of Study Drug Per Mild/Moderate Bleeding Episode | 2.6 Administrations of Study Drug | Standard Deviation 2.48 |
Secondary
Patient-Reported Good or Excellent Response for Mild/Moderate Bleeding Episodes
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 hemorrhage) 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 hemorrhage). No additional infusion of study drug was required.
Time frame: 12 hour after first administration of study drug
Population: Treated Population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| FVIIa 75 µg/kg | Patient-Reported Good or Excellent Response for Mild/Moderate Bleeding Episodes | 0.667 Proportion of successfully treated BEs |
| FVIIa 225µg/kg | Patient-Reported Good or Excellent Response for Mild/Moderate Bleeding Episodes | 0.629 Proportion of successfully treated BEs |
Secondary
Time to Patient Assessment of a Good or Excellent Response for Mild/Moderate Bleeding Episodes
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 Patient Assessment of a Good or Excellent Response for Mild/Moderate Bleeding Episodes | 9.00 Hours |
| FVIIa 225µg/kg | Time to Patient Assessment of a Good or Excellent Response for Mild/Moderate Bleeding Episodes | 12.00 Hours |
Secondary
Total Amount of Study Drug Administered Per Mild/Moderate Bleeding Episode
The total amount of study drug administered in order to treat one 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 | Total Amount of Study Drug Administered Per Mild/Moderate Bleeding Episode | 6.733 mL per bleeding episode | Standard Deviation 6.3693 |
| FVIIa 225µg/kg | Total Amount of Study Drug Administered Per Mild/Moderate Bleeding Episode | 8.287 mL per bleeding episode | Standard Deviation 5.6531 |
Other Pre-specified
Mild/Moderate Bleeding Episodes With Successful Pain Relief
Successful pain relief was defined as a Visual Analogue Scale (VAS: 0-100; 0: no pain at all; 100: the worst pain ever possible) pain score at 12 hours after initial study drug administration that was less than the pain score at the start of treatment with study drug.
Time frame: 12 hour after first administration of study drug
Population: Treated Population
| Arm | Measure | Value (COUNT_OF_UNITS) |
|---|---|---|
| FVIIa 75 µg/kg | Mild/Moderate Bleeding Episodes With Successful Pain Relief | 220 Bleeding Episodes (BEs) |
| FVIIa 225µg/kg | Mild/Moderate Bleeding Episodes With Successful Pain Relief | 275 Bleeding Episodes (BEs) |