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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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Human-cl rhFVIII | Experimental |
| |
| Kogenate FS | Active Comparator |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Human-cl rhFVIII | Biological | 50 IU/kg for PK dose |
| |
| Measure | Description | Time Frame |
|---|---|---|
| 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. | 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. |
| Measure | Description | Time Frame |
|---|---|---|
| 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. |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Sigurd Knaub, PhD | Octapharma | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| UCLA Orthodpedic Hospital | Los Angeles | California | 90007 | United States | ||
| University of California, Davis |
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.
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
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| ID | Title | Description |
|---|---|---|
| FG000 | Human c1 rhFVIII First Crossover, Then Treatment | Participants were randomized to receive Human-cl rhFVIII (50 IU/kg bodyweight) first, then Kogenate FS (50 IU/kg bodyweight)second in the Crossover period. In the Treatment Period, participants received Kogenate (50 IU/kg bodyweight) |
| FG001 |
| Title | Milestones | Reasons Not Completed | |||||
|---|---|---|---|---|---|---|---|
| PK Crossover Period |
|
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| Kogenate FS |
| Biological |
50 IU/kg for PK dose |
|
| 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. |
| 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. | 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. |
| 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. | 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. |
| 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. | 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. |
| 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. | 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. |
| 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. | 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. |
| 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. | From 1st treatment after PK cycle 2 until study end. |
| 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). | 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 |
| Sacramento |
| California |
| 95817 |
| United States |
| University of Colorado | Denver | Colorado | 80045 | United States |
| Georgetown University | Washington D.C. | District of Columbia | 20057 | United States |
| RUSH University Medical Center | Chicago | Illinois | 60612 | United States |
| University of Medicine and Dentistry | New Brunswick | New Jersey | 08903 | United States |
| Prof. Lissitchkov | Sofia | Bulgaria |
| Medizinische Hochschule | Hanover | Lower Saxony | Germany |
| Vivantes Klinikum | Berlin | Germany |
| Kogenate First Crossover, Then Treatment |
Participants were randomized to receive Kogenate (50 IU/kg) first (14 days), then Human-cl rhFVIII (50 IU/kg bodyweight) second (14 days) in the Crossover period. In the Treatment Period, participants received Human-cl rhFVIII (50 IU/kg bodyweight) |
| COMPLETED |
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| NOT COMPLETED |
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| Treatment Period |
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| ID | Title | Description |
|---|---|---|
| BG000 | Human cl rhFVIII | Human-cl rhFVIII and Kogenate in cross-over design:50 IU/kg for PK dose |
| Units | Counts |
|---|---|
| Participants |
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| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes | |||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants | Participants |
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| Age, Continuous | Mean | Standard Deviation | years |
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| Sex: Female, Male | Count of Participants | Participants |
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| Region of Enrollment | Number | participants |
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| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 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. | Posted | Mean | Standard Deviation | h IU/mL (IU/kg) | 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. |
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| 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. | Posted | Mean | Standard Deviation | hours | 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. |
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| 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. | Posted | Mean | Standard Deviation | IU/mL | 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. |
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| 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. | Posted | Mean | Standard Deviation | hours | 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. |
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| 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. | Posted | Mean | Standard Deviation | hours | 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. |
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| 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. | Posted | Mean | Standard Deviation | mL/kg | 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. |
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| 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. | Posted | Mean | Standard Deviation | mL/h/kg | 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. |
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| 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. | Posted | Number | percentage of bleeding episodes | From 1st treatment after PK cycle 2 until study end. | Bleeding episodes | Bleeding episodes |
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| 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). | Posted | Number | participants | 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 |
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From 27 May 2010 to 18 September 2012 (study end)
All Adverse events were collected regardless of the intervention. Kogenate is a licensed product and the active ingredient is the same as for the investigational product Human cl rhFVIII. Therefore no distinction was made whether an AE occurred after Kogenate or after Human cl rhFVIII administration.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Human cl rhFVIII and Kogenate FS | All participants. Human-cl rhFVIII and Kogenate in cross-over design:50 IU/kg for PK period. After the PK period all participants received Human-cl rhFVIII in the treatment period. | 2 | 22 | 6 | 22 |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| HEPATIC CIRRHOSIS | Hepatobiliary disorders | MedDRA 15.1 | Non-systematic Assessment |
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| DEPRESSION SUICIDAL | Psychiatric disorders | Non-systematic Assessment |
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| HEPATIC ENCEPHALOPATHY | Nervous system disorders | Non-systematic Assessment |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Diarrhoea | Gastrointestinal disorders | Non-systematic Assessment |
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| Pyrexia | General disorders | Non-systematic Assessment |
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| Protein urine present | Metabolism and nutrition disorders | Non-systematic Assessment |
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Octapharma agreements may vary with individual investigators, but will not prohibit any investigator from publishing. Octapharma supports the publication of results from all centers of a multi-center trial but requests that reports based on single-site data not precede the primary publication of the entire clinical trial. Octapharma also reserves the right to review data prior to publishing and provide comments/changes within a certain time period.
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr. Sigurd Knaub | Octapharma AG | +41 554512141 | sigurd.knaub@octapharma.com |
| ID | Term |
|---|---|
| D006467 | Hemophilia A |
| ID | Term |
|---|---|
| D025861 | Blood Coagulation Disorders, Inherited |
| D001778 | Blood Coagulation Disorders |
| D006402 | Hematologic Diseases |
| D006425 | Hemic and Lymphatic Diseases |
| D020147 | Coagulation Protein Disorders |
| D006474 | Hemorrhagic Disorders |
| D030342 | Genetic Diseases, Inborn |
| D009358 | Congenital, Hereditary, and Neonatal Diseases and Abnormalities |
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| ID | Term |
|---|---|
| C078147 | F8 protein, human |
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| Germany |
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| Bleeding episodes |
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