Hemophilia A
Conditions
Brief summary
This is a clinical study to investigate the pharmacokinetics, efficacy, safety and immunogenicity of human-cl rhFVIII, a newly developed human cell-line derived recombinant FVIII concentrate in previously treated patients with severe Hemophilia A.
Interventions
BIOLOGICALHuman-cl rhFVIII
50 IU/kg for PK dose
BIOLOGICALKogenate FS
50 IU/kg for PK dose
Sponsors
Octapharma
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
MALE
Age
12 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* Severe hemophilia A (FVIII:C \<= 1%) * Male subjects between 12 and 65 years of age * Body weight 25 kg to 110 kg * Previously treated with FVIII concentrate for at least 150 EDs
Exclusion criteria
* Other coagulation disorder than hemophilia A * Present or past FVIII inhibitor activity
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| The Area Under the Concentration Curve for Human-cl rhFVIII Compared to Kogenate FS | At baseline (prior to infusion), 0.25, 0.5, 0.75, 1, 3, 6, 9, 12, 24, 30 and 48 hours after the end of the infusion. | After the infusion of 50IU/kg bw of Human-cl rhFVIII and Kogenate FS respectively, FVIII activity levels were measured at various time points before and after the infusion. FVIII level results derived from the chromogenic FVIII assay were used to calculate the mean of the area under the curve normalized to the dose administered. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Plasma Concentration (Cmax) for Human-cl rhFVIII Compared to Kogenate FS | At baseline (prior to infusion), 0.25, 0.5, 0.75, 1, 3, 6, 9, 12, 24, 30 and 48 hours after the end of the infusion. | After the infusion of 50IU/kg bw of Human-cl rhFVIII and Kogenate FS respectively, FVIII activity levels were measured at various time points before and after the infusion. FVIII level results derived from the chromogenic FVIII assay were used to calculate the mean of the area under the curve normalized to the dose administered. |
| Time to Reach Maximum Plasma Concentration (Tmax) for Human-cl rhFVIII Compared to Kogenate FS | At baseline (prior to infusion), 0.25, 0.5, 0.75, 1, 3, 6, 9, 12, 24, 30 and 48 hours after the end of the infusion. | After the infusion of 50IU/kg bw of Human-cl rhFVIII and Kogenate FS respectively, FVIII activity levels were measured at various time points before and after the infusion. FVIII level results derived from the chromogenic FVIII assay were used to calculate the mean of the area under the curve normalized to the dose administered. |
| Mean Residence Time (MRT) for Human-cl rhFVIII Compared to Kogenate FS | At baseline (prior to infusion), 0.25, 0.5, 0.75, 1, 3, 6, 9, 12, 24, 30 and 48 hours after the end of the infusion. | After the infusion of 50IU/kg bw of Human-cl rhFVIII and Kogenate FS respectively, FVIII activity levels were measured at various time points before and after the infusion. FVIII level results derived from the chromogenic FVIII assay were used to calculate the mean of the area under the curve normalized to the dose administered. |
| Invivo Half-life (T1/2) for Human-cl rhFVIII Compared to Kogenate FS | At baseline (prior to infusion), 0.25, 0.5, 0.75, 1, 3, 6, 9, 12, 24, 30 and 48 hours after the end of the infusion. | After the infusion of 50IU/kg bw of Human-cl rhFVIII and Kogenate FS respectively, FVIII activity levels were measured at various time points before and after the infusion. FVIII level results derived from the chromogenic FVIII assay were used to calculate the mean of the area under the curve normalized to the dose administered. |
| Clearance (CL) for Human-cl rhFVIII Compared to Kogenate FS | At baseline (prior to infusion), 0.25, 0.5, 0.75, 1, 3, 6, 9, 12, 24, 30 and 48 hours after the end of the infusion. | After the infusion of 50IU/kg bw of Human-cl rhFVIII and Kogenate FS respectively, FVIII activity levels were measured at various time points before and after the infusion. FVIII level results derived from the chromogenic FVIII assay were used to calculate the mean of the area under the curve normalized to the dose administered. |
| Efficacy of On-demand Treatment of Bleeding Episodes | From 1st treatment after PK cycle 2 until study end. | After each infusion of IMP and at the end of a BE, the following efficacy assessment is made by the subject (together with the Investigator in case of on-site treatment): Excellent: Abrupt pain relief and/or unequivocal improvement in objective signs of bleeding within approximately 8 hours after a single infusion. Good: Definite pain relief and/or improvement in signs of bleeding within approximately 8 - 12 hours after an infusion requiring up to 2 infusions for complete resolution. Moderate: Probable or slight beneficial effect within approximately 12 hours after the first infusion requiring more than two infusions for complete resolution. None: No improvement within 12 hours, or worsening of symptoms, requiring more than 2 infusions for complete resolution. The assessment was made at the end of a BE in case more than one infusion was needed. |
| Immunogenicity (Number of Patients That Developed an Inhibitor During the Course of the Study) | study entry, then immediately before both PK cycles, in the 48 hour sample of both PK cycles, after 10 to 15 EDs with human-cl rhFVIII, at the 3-month visit (± 2 weeks), then every 3 months (± 2 weeks) until study completion, and after >50 EDs (except for | Inhibitor activity was determined by the modified Bethesda assay (Nijmegen modification) at study entry, then immediately before both PK cycles, in the 48 hour sample of both PK cycles, after 10 to 15 EDs with human-cl rhFVIII, at the 3-month visit (± 2 weeks), then every 3 months (± 2 weeks) until study completion, and after \>50 EDs (except for some patients who may finish the study before they achieve 50 EDs), with human-cl rhFVIII (i.e. at the study completion visit). |
| Volume of Distribution at Steady State (Vss) for Human-cl rhFVIII Compared to Kogenate FS | At baseline (prior to infusion), 0.25, 0.5, 0.75, 1, 3, 6, 9, 12, 24, 30 and 48 hours after the end of the infusion. | After the infusion of 50IU/kg bw of Human-cl rhFVIII and Kogenate FS respectively, FVIII activity levels were measured at various time points before and after the infusion. FVIII level results derived from the chromogenic FVIII assay were used to calculate the mean of the area under the curve normalized to the dose administered. |
Countries
Bulgaria, Germany, United States
Participant flow
Recruitment details
The study was conducted at 6 centers in the USA, 2 centers in Germany and 1 center in Bulgaria. The first patient was included on May 27, 2010 and the last patient finished the study on September 18, 2012
Pre-assignment details
The patients started the study with a PK period. The PK period had a cross-over design (Kogenate vs Human cl rhFVIII) and subjects received either Kogenate first and Human cl rhFVIII second or vice versa. Once the PK measure had been done, the patient started the treatment period with Human cl rhFVIII only.
Participants by arm
| Arm | Count |
|---|---|
| Human cl rhFVIII Human-cl rhFVIII and Kogenate in cross-over design:50 IU/kg for PK dose | 22 |
| Total | 22 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Treatment Period | Lost to Follow-up | 1 | 0 |
Baseline characteristics
| Characteristic | Human cl rhFVIII |
|---|---|
| Age, Categorical <=18 years | 2 Participants |
| Age, Categorical >=65 years | 1 Participants |
| Age, Categorical Between 18 and 65 years | 19 Participants |
| Age, Continuous | 39.6 years STANDARD_DEVIATION 14.06 |
| Region of Enrollment Bulgaria | 6 participants |
| Region of Enrollment Germany | 6 participants |
| Region of Enrollment United States | 10 participants |
| Sex: Female, Male Female | 0 Participants |
| Sex: Female, Male Male | 22 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 6 / 22 |
| serious Total, serious adverse events | 2 / 22 |
Outcome results
Primary
The Area Under the Concentration Curve for Human-cl rhFVIII Compared to Kogenate FS
After the infusion of 50IU/kg bw of Human-cl rhFVIII and Kogenate FS respectively, FVIII activity levels were measured at various time points before and after the infusion. FVIII level results derived from the chromogenic FVIII assay were used to calculate the mean of the area under the curve normalized to the dose administered.
Time frame: At baseline (prior to infusion), 0.25, 0.5, 0.75, 1, 3, 6, 9, 12, 24, 30 and 48 hours after the end of the infusion.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Human cl rhFVIII | The Area Under the Concentration Curve for Human-cl rhFVIII Compared to Kogenate FS | 0.39 h IU/mL (IU/kg) | Standard Deviation 0.14 |
| Kogenate FS | The Area Under the Concentration Curve for Human-cl rhFVIII Compared to Kogenate FS | 0.38 h IU/mL (IU/kg) | Standard Deviation 0.09 |
90% CI: [0.874, 1.107]
Secondary
Clearance (CL) for Human-cl rhFVIII Compared to Kogenate FS
After the infusion of 50IU/kg bw of Human-cl rhFVIII and Kogenate FS respectively, FVIII activity levels were measured at various time points before and after the infusion. FVIII level results derived from the chromogenic FVIII assay were used to calculate the mean of the area under the curve normalized to the dose administered.
Time frame: At baseline (prior to infusion), 0.25, 0.5, 0.75, 1, 3, 6, 9, 12, 24, 30 and 48 hours after the end of the infusion.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Human cl rhFVIII | Clearance (CL) for Human-cl rhFVIII Compared to Kogenate FS | 2.94 mL/h/kg | Standard Deviation 1.18 |
| Kogenate FS | Clearance (CL) for Human-cl rhFVIII Compared to Kogenate FS | 2.75 mL/h/kg | Standard Deviation 0.64 |
Secondary
Efficacy of On-demand Treatment of Bleeding Episodes
After each infusion of IMP and at the end of a BE, the following efficacy assessment is made by the subject (together with the Investigator in case of on-site treatment): Excellent: Abrupt pain relief and/or unequivocal improvement in objective signs of bleeding within approximately 8 hours after a single infusion. Good: Definite pain relief and/or improvement in signs of bleeding within approximately 8 - 12 hours after an infusion requiring up to 2 infusions for complete resolution. Moderate: Probable or slight beneficial effect within approximately 12 hours after the first infusion requiring more than two infusions for complete resolution. None: No improvement within 12 hours, or worsening of symptoms, requiring more than 2 infusions for complete resolution. The assessment was made at the end of a BE in case more than one infusion was needed.
Time frame: From 1st treatment after PK cycle 2 until study end.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Human cl rhFVIII | Efficacy of On-demand Treatment of Bleeding Episodes | Excellent | 60.3 percentage of bleeding episodes |
| Human cl rhFVIII | Efficacy of On-demand Treatment of Bleeding Episodes | Good | 34.1 percentage of bleeding episodes |
| Human cl rhFVIII | Efficacy of On-demand Treatment of Bleeding Episodes | Moderate | 5.5 percentage of bleeding episodes |
| Human cl rhFVIII | Efficacy of On-demand Treatment of Bleeding Episodes | None | 0 percentage of bleeding episodes |
Secondary
Immunogenicity (Number of Patients That Developed an Inhibitor During the Course of the Study)
Inhibitor activity was determined by the modified Bethesda assay (Nijmegen modification) at study entry, then immediately before both PK cycles, in the 48 hour sample of both PK cycles, after 10 to 15 EDs with human-cl rhFVIII, at the 3-month visit (± 2 weeks), then every 3 months (± 2 weeks) until study completion, and after \>50 EDs (except for some patients who may finish the study before they achieve 50 EDs), with human-cl rhFVIII (i.e. at the study completion visit).
Time frame: study entry, then immediately before both PK cycles, in the 48 hour sample of both PK cycles, after 10 to 15 EDs with human-cl rhFVIII, at the 3-month visit (± 2 weeks), then every 3 months (± 2 weeks) until study completion, and after >50 EDs (except for
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Human cl rhFVIII | Immunogenicity (Number of Patients That Developed an Inhibitor During the Course of the Study) | 0 participants |
Secondary
Invivo Half-life (T1/2) for Human-cl rhFVIII Compared to Kogenate FS
After the infusion of 50IU/kg bw of Human-cl rhFVIII and Kogenate FS respectively, FVIII activity levels were measured at various time points before and after the infusion. FVIII level results derived from the chromogenic FVIII assay were used to calculate the mean of the area under the curve normalized to the dose administered.
Time frame: At baseline (prior to infusion), 0.25, 0.5, 0.75, 1, 3, 6, 9, 12, 24, 30 and 48 hours after the end of the infusion.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Human cl rhFVIII | Invivo Half-life (T1/2) for Human-cl rhFVIII Compared to Kogenate FS | 14.73 hours | Standard Deviation 9.96 |
| Kogenate FS | Invivo Half-life (T1/2) for Human-cl rhFVIII Compared to Kogenate FS | 16.14 hours | Standard Deviation 5.88 |
Secondary
Maximum Plasma Concentration (Cmax) for Human-cl rhFVIII Compared to Kogenate FS
After the infusion of 50IU/kg bw of Human-cl rhFVIII and Kogenate FS respectively, FVIII activity levels were measured at various time points before and after the infusion. FVIII level results derived from the chromogenic FVIII assay were used to calculate the mean of the area under the curve normalized to the dose administered.
Time frame: At baseline (prior to infusion), 0.25, 0.5, 0.75, 1, 3, 6, 9, 12, 24, 30 and 48 hours after the end of the infusion.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Human cl rhFVIII | Maximum Plasma Concentration (Cmax) for Human-cl rhFVIII Compared to Kogenate FS | 1.462 IU/mL | Standard Deviation 0.223 |
| Kogenate FS | Maximum Plasma Concentration (Cmax) for Human-cl rhFVIII Compared to Kogenate FS | 1.394 IU/mL | Standard Deviation 0.2 |
Secondary
Mean Residence Time (MRT) for Human-cl rhFVIII Compared to Kogenate FS
After the infusion of 50IU/kg bw of Human-cl rhFVIII and Kogenate FS respectively, FVIII activity levels were measured at various time points before and after the infusion. FVIII level results derived from the chromogenic FVIII assay were used to calculate the mean of the area under the curve normalized to the dose administered.
Time frame: At baseline (prior to infusion), 0.25, 0.5, 0.75, 1, 3, 6, 9, 12, 24, 30 and 48 hours after the end of the infusion.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Human cl rhFVIII | Mean Residence Time (MRT) for Human-cl rhFVIII Compared to Kogenate FS | 19.45 hours | Standard Deviation 12.02 |
| Kogenate FS | Mean Residence Time (MRT) for Human-cl rhFVIII Compared to Kogenate FS | 20 hours | Standard Deviation 5.61 |
Secondary
Time to Reach Maximum Plasma Concentration (Tmax) for Human-cl rhFVIII Compared to Kogenate FS
After the infusion of 50IU/kg bw of Human-cl rhFVIII and Kogenate FS respectively, FVIII activity levels were measured at various time points before and after the infusion. FVIII level results derived from the chromogenic FVIII assay were used to calculate the mean of the area under the curve normalized to the dose administered.
Time frame: At baseline (prior to infusion), 0.25, 0.5, 0.75, 1, 3, 6, 9, 12, 24, 30 and 48 hours after the end of the infusion.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Human cl rhFVIII | Time to Reach Maximum Plasma Concentration (Tmax) for Human-cl rhFVIII Compared to Kogenate FS | 0.35 hours | Standard Deviation 0.23 |
| Kogenate FS | Time to Reach Maximum Plasma Concentration (Tmax) for Human-cl rhFVIII Compared to Kogenate FS | 0.34 hours | Standard Deviation 0.2 |
Secondary
Volume of Distribution at Steady State (Vss) for Human-cl rhFVIII Compared to Kogenate FS
After the infusion of 50IU/kg bw of Human-cl rhFVIII and Kogenate FS respectively, FVIII activity levels were measured at various time points before and after the infusion. FVIII level results derived from the chromogenic FVIII assay were used to calculate the mean of the area under the curve normalized to the dose administered.
Time frame: At baseline (prior to infusion), 0.25, 0.5, 0.75, 1, 3, 6, 9, 12, 24, 30 and 48 hours after the end of the infusion.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Human cl rhFVIII | Volume of Distribution at Steady State (Vss) for Human-cl rhFVIII Compared to Kogenate FS | 49.58 mL/kg | Standard Deviation 17.27 |
| Kogenate FS | Volume of Distribution at Steady State (Vss) for Human-cl rhFVIII Compared to Kogenate FS | 53.32 mL/kg | Standard Deviation 13.57 |