Severe Haemophilia A
Conditions
Brief summary
To compare the number of breakthrough bleeds under tailored prophylaxis with Human cell line recombinant factor FVIII (Human-cl rhFVIII) with the historical bleeding rate from patients who received Human-cl rhFVIII as on demand treatment.
Detailed description
There were 3 phases in this study: (1) An initial pharmacokinetic (PK) assessment in which participants received a single infusion of 60±5 IU/kg of Human-cl rhFVIII; blood samples were collected for 72 hours following the infusion. (2) Prophylactic Treatment-Phase I during which participants received infusions of 30-40 IU/kg of human-cl rhFVIII every other day or 3x/week for 1-3 months. (3) Prophylactic Treatment-Phase II during which the dose and dosing interval were determined individually from data gathered in the initial PK assessment. The maximum dosing interval with a dose of ≤ 60-80 IU/kg that maintains a trough level of ≥ 0.01 IU/mL was determined. Participants were treated for 6 months.
Interventions
BIOLOGICALHuman-cl rhFVIII
Human-cl rhFVIII was provided as a freeze-dried concentrate to be reconstituted in water for injection.
Sponsors
Octapharma
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
PREVENTION
Masking
NONE
Eligibility
Sex/Gender
MALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Severe haemophilia A (FVIII:C \< 1%) according to medical history. * Male patients ≥ 18 years old. * Previous treatment with a FVIII concentrate (regular prophylaxis with good compliance or on-demand treatment) for at least 150 exposure days (EDs). * Good documentation regarding dosing and bleeding frequency in the 6 months preceding study start. * Immunocompetence (CD4+ count \> 200/microliter). * HIV-negative, if positive, viral load \< 200 particles/microliter or \< 400,000 copies/mL. * Freely given written informed consent
Exclusion criteria
* Any coagulation disorder other than haemophilia A. * Present or past FVIII inhibitor activity (\> 0.6 Bethesda Unit \[BU\]) * Severe liver or kidney disease.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Annualized Number of Bleeding Episodes (BE) in Phase II | Beginning to the end of Phase II (6 months) | The annualized number of total BEs was calculated for each participant as follows: d\*y/t, where y = the number of BEs documented in Phase II, t = the number of treatment periods in days, and d = 365.25, the number of days per year. A bleeding episode (BE) was defined as any BE whether treated or not during Phase II of the study; BEs related to surgery were not included. This study was considered as showing efficacy if the annualized number of BEs was reduced by 50% compared to the number of BEs observed in study GENA-01 where patient where severe Hemophilia A patients were treated on-demand (NCT00989196). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Annualized Number of Spontaneous Bleeding Episodes (BE) in Phase II | Beginning to the end of Phase II (6 months) | The annualized number of spontaneous BEs was calculated for each participant as follows: d\*y/t, where y = the number of spontaneous BEs documented in Phase II, t = the number of treatment periods in days, and d = 365.25, the number of days per year. A spontaneous bleeding episode (BE) was defined as a BE whether treated or not during Phase II of the study. BEs related to surgery and BEs due to trauma or due to other causes were not included. |
| Annualized Number of Bleeding Episodes (BE) in Phase II in Participants With ≤ 2 Treatments/Week | Beginning to the end of Phase II (6 months) | The annualized number of BEs was calculated for each participant as follows: d\*y/t, where y = the number of BEs documented in Phase II, t = the number of treatment periods in days, and d = 365.25, the number of days per year. A bleeding episode (BE) was defined as a BE whether treated or not during Phase II of the study. BEs related to surgery were not included. |
| Median Dosing Interval During Individually Tailored Prophylaxis | Beginning to the end of Phase II (6 months) | The median time between 2 prophylactic doses of Human-cl rhFVIII in the prophylactic treatment phase II were determined per patient |
| Dosage Per Week in Phase II | Beginning to the end of Phase II (6 months) | The mean dosage per week during Phase II of the study are reported. |
Countries
Austria, Bulgaria, Germany, Hungary, Poland, Romania, Slovakia, United Kingdom
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Human-cl rhFVIII Up to 60-80 IU/kg of intravenous human-cl rhFVIII (human cell line recombinant Factor VIII) was administered at an individually determined dose and dose interval. | 66 |
| Total | 66 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Prophylactic Treatment-Phase II | investigator Error of Early Termination | 1 |
| Prophylactic Treatment-Phase II | Lost to Follow-up | 1 |
Baseline characteristics
| Characteristic | Human-cl rhFVIII |
|---|---|
| Age | 33.6 years STANDARD_DEVIATION 9.9 |
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 1 Participants |
| Age, Categorical Between 18 and 65 years | 65 Participants |
| BMI | 25.4 kg/m^2 STANDARD_DEVIATION 5.4 |
| Hemophilia Joint Health Score (HJHS) | 37.4 Units on a scale STANDARD_DEVIATION 25.3 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 65 Participants |
| Region of Enrollment Austria | 1 participants |
| Region of Enrollment Bulgaria | 31 participants |
| Region of Enrollment Germany | 4 participants |
| Region of Enrollment Hungary | 4 participants |
| Region of Enrollment Poland | 9 participants |
| Region of Enrollment Romania | 9 participants |
| Region of Enrollment Slovakia | 2 participants |
| Region of Enrollment United Kingdom | 6 participants |
| Sex: Female, Male Female | 0 Participants |
| Sex: Female, Male Male | 66 Participants |
| Weight | 80.5 kg STANDARD_DEVIATION 19.9 |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 24 / 66 |
| serious Total, serious adverse events | 5 / 66 |
Outcome results
Primary
Annualized Number of Bleeding Episodes (BE) in Phase II
The annualized number of total BEs was calculated for each participant as follows: d\*y/t, where y = the number of BEs documented in Phase II, t = the number of treatment periods in days, and d = 365.25, the number of days per year. A bleeding episode (BE) was defined as any BE whether treated or not during Phase II of the study; BEs related to surgery were not included. This study was considered as showing efficacy if the annualized number of BEs was reduced by 50% compared to the number of BEs observed in study GENA-01 where patient where severe Hemophilia A patients were treated on-demand (NCT00989196).
Time frame: Beginning to the end of Phase II (6 months)
Population: Prophylactic treatment population: All participants who received at least 1 dose of Human-cl rhFVIII in Phase II and had any data collected after treatment with Human-cl rhFVIII.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Human-cl rhFVIII | Annualized Number of Bleeding Episodes (BE) in Phase II | 3.05 Annualized number of bleeding episodes | Standard Deviation 13.43 |
Comparison: This study was considered as showing efficacy if the annualized number of bleeding episodes (BE) was reduced by 50% compared to the number of BEs observed in study GENA-01 (NCT00989196).p-value: <0.0595% CI: [2.56, 3.8]2-sided, 1-sample Poisson test
Secondary
Annualized Number of Bleeding Episodes (BE) in Phase II in Participants With ≤ 2 Treatments/Week
The annualized number of BEs was calculated for each participant as follows: d\*y/t, where y = the number of BEs documented in Phase II, t = the number of treatment periods in days, and d = 365.25, the number of days per year. A bleeding episode (BE) was defined as a BE whether treated or not during Phase II of the study. BEs related to surgery were not included.
Time frame: Beginning to the end of Phase II (6 months)
Population: Prophylactic treatment population: All participants who received at least 1 dose of Human-cl rhFVIII in Phase II and had any data collected after treatment with Human-cl rhFVIII. Only participants who received ≤ 2 treatments/week were included in the analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Human-cl rhFVIII | Annualized Number of Bleeding Episodes (BE) in Phase II in Participants With ≤ 2 Treatments/Week | 4.1 Annualized number of bleeding episodes | Standard Deviation 17.4 |
Secondary
Annualized Number of Spontaneous Bleeding Episodes (BE) in Phase II
The annualized number of spontaneous BEs was calculated for each participant as follows: d\*y/t, where y = the number of spontaneous BEs documented in Phase II, t = the number of treatment periods in days, and d = 365.25, the number of days per year. A spontaneous bleeding episode (BE) was defined as a BE whether treated or not during Phase II of the study. BEs related to surgery and BEs due to trauma or due to other causes were not included.
Time frame: Beginning to the end of Phase II (6 months)
Population: Prophylactic treatment population: All participants who received at least 1 dose of Human-cl rhFVIII in Phase II and had any data collected after treatment with Human-cl rhFVIII.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Human-cl rhFVIII | Annualized Number of Spontaneous Bleeding Episodes (BE) in Phase II | 1.84 Annualized number of bleeding episodes | Standard Deviation 8.81 |
Comparison: This study was considered as showing efficacy if the annualized number of spontaneous bleeding episodes (BE) was reduced by 50% compared to the number of spontaneous BEs observed in study GENA-01 (NCT00989196).p-value: <0.0595% CI: [1.46, 2.43]2-sided, 1-sample Poisson test
Secondary
Dosage Per Week in Phase II
The mean dosage per week during Phase II of the study are reported.
Time frame: Beginning to the end of Phase II (6 months)
Population: Prophylactic treatment population: All participants who received at least 1 dose of Human-cl rhFVIII in Phase II and had any data collected after treatment with Human-cl rhFVIII.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Human-cl rhFVIII | Dosage Per Week in Phase II | 97.7 IU/kg | Standard Deviation 23.1 |
Secondary
Median Dosing Interval During Individually Tailored Prophylaxis
The median time between 2 prophylactic doses of Human-cl rhFVIII in the prophylactic treatment phase II were determined per patient
Time frame: Beginning to the end of Phase II (6 months)
Population: Prophylactic treatment population: All participants who received at least 1 dose of Human-cl rhFVIII in Phase II and had any data collected after treatment with Human-cl rhFVIII.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Human-cl rhFVIII | Median Dosing Interval During Individually Tailored Prophylaxis | Beginning of Phase II | 83.1 Hours |
| Human-cl rhFVIII | Median Dosing Interval During Individually Tailored Prophylaxis | End of Phase II | 83.3 Hours |