Trial Outcomes & Findings for Clinical Study to Investigate the Pharmacokinetics, Efficacy, Safety and Immunogenicity of a Recombinant FVIII in Patients With Severe Hemophilia A (NCT NCT00989196)

NCT ID: NCT00989196

Last Updated: 2019-10-08

Results Overview

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.

• Recruitment status: COMPLETED
• Study phase: PHASE2
• Target enrollment: 22 participants
• Primary outcome timeframe: 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.
• Results posted on: 2019-10-08

Participant Flow

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

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.

Participant milestones

Measure	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)	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)
PK Crossover Period STARTED	10	12
PK Crossover Period COMPLETED	10	12
PK Crossover Period NOT COMPLETED	0	0
Treatment Period STARTED	10	12
Treatment Period COMPLETED	9	12
Treatment Period NOT COMPLETED	1	0

Reasons for withdrawal

Measure	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)	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)
Treatment Period Lost to Follow-up	1	0

Baseline Characteristics

Clinical Study to Investigate the Pharmacokinetics, Efficacy, Safety and Immunogenicity of a Recombinant FVIII in Patients With Severe Hemophilia A

Baseline characteristics by cohort

Measure	Human cl rhFVIII n=22 Participants Human-cl rhFVIII and Kogenate in cross-over design:50 IU/kg for PK dose
Age, Categorical <=18 years	2 Participants n=5 Participants
Age, Categorical Between 18 and 65 years	19 Participants n=5 Participants
Age, Categorical >=65 years	1 Participants n=5 Participants
Age, Continuous	39.6 years STANDARD_DEVIATION 14.06 • n=5 Participants
Sex: Female, Male Female	0 Participants n=5 Participants
Sex: Female, Male Male	22 Participants n=5 Participants
Region of Enrollment United States	10 participants n=5 Participants
Region of Enrollment Bulgaria	6 participants n=5 Participants
Region of Enrollment Germany	6 participants n=5 Participants

PRIMARY outcome

Timeframe: 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.

Outcome measures

Measure	Human cl rhFVIII n=22 Participants Human-cl rhFVIII 50 IU/kg for PK dose	Kogenate FS n=22 Participants Kogenate FS 50 IU/kg for PK dose
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	0.38 h IU/mL (IU/kg) Standard Deviation 0.09

SECONDARY outcome

Timeframe: 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.

Outcome measures

Measure	Human cl rhFVIII n=22 Participants Human-cl rhFVIII 50 IU/kg for PK dose	Kogenate FS n=22 Participants Kogenate FS 50 IU/kg for PK dose
Invivo Half-life (T1/2) for Human-cl rhFVIII Compared to Kogenate FS	14.73 hours Standard Deviation 9.96	16.14 hours Standard Deviation 5.88

SECONDARY outcome

Timeframe: 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.

Outcome measures

Measure	Human cl rhFVIII n=22 Participants Human-cl rhFVIII 50 IU/kg for PK dose	Kogenate FS n=22 Participants Kogenate FS 50 IU/kg for PK dose
Maximum Plasma Concentration (Cmax) for Human-cl rhFVIII Compared to Kogenate FS	1.462 IU/mL Standard Deviation 0.223	1.394 IU/mL Standard Deviation 0.2

SECONDARY outcome

Timeframe: 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.

Outcome measures

Measure	Human cl rhFVIII n=22 Participants Human-cl rhFVIII 50 IU/kg for PK dose	Kogenate FS n=22 Participants Kogenate FS 50 IU/kg for PK dose
Time to Reach Maximum Plasma Concentration (Tmax) for Human-cl rhFVIII Compared to Kogenate FS	0.35 hours Standard Deviation 0.23	0.34 hours Standard Deviation 0.2

SECONDARY outcome

Timeframe: 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.

Outcome measures

Measure	Human cl rhFVIII n=22 Participants Human-cl rhFVIII 50 IU/kg for PK dose	Kogenate FS n=22 Participants Kogenate FS 50 IU/kg for PK dose
Mean Residence Time (MRT) for Human-cl rhFVIII Compared to Kogenate FS	19.45 hours Standard Deviation 12.02	20 hours Standard Deviation 5.61

SECONDARY outcome

Timeframe: 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.

Outcome measures

Measure	Human cl rhFVIII n=22 Participants Human-cl rhFVIII 50 IU/kg for PK dose	Kogenate FS n=22 Participants Kogenate FS 50 IU/kg for PK dose
Volume of Distribution at Steady State (Vss) for Human-cl rhFVIII Compared to Kogenate FS	49.58 mL/kg Standard Deviation 17.27	53.32 mL/kg Standard Deviation 13.57

SECONDARY outcome

Timeframe: 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.

Outcome measures

Measure	Human cl rhFVIII n=22 Participants Human-cl rhFVIII 50 IU/kg for PK dose	Kogenate FS n=22 Participants Kogenate FS 50 IU/kg for PK dose
Clearance (CL) for Human-cl rhFVIII Compared to Kogenate FS	2.94 mL/h/kg Standard Deviation 1.18	2.75 mL/h/kg Standard Deviation 0.64

SECONDARY outcome

Timeframe: 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.

Outcome measures

Measure	Human cl rhFVIII n=986 Bleeding episodes Human-cl rhFVIII 50 IU/kg for PK dose	Kogenate FS Kogenate FS 50 IU/kg for PK dose
Efficacy of On-demand Treatment of Bleeding Episodes Excellent	60.3 percentage of bleeding episodes	—
Efficacy of On-demand Treatment of Bleeding Episodes Good	34.1 percentage of bleeding episodes	—
Efficacy of On-demand Treatment of Bleeding Episodes Moderate	5.5 percentage of bleeding episodes	—
Efficacy of On-demand Treatment of Bleeding Episodes None	0 percentage of bleeding episodes	—

SECONDARY outcome

Timeframe: 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).

Outcome measures

Measure	Human cl rhFVIII n=22 Participants Human-cl rhFVIII 50 IU/kg for PK dose	Kogenate FS Kogenate FS 50 IU/kg for PK dose
Immunogenicity (Number of Patients That Developed an Inhibitor During the Course of the Study)	0 participants	—

Adverse Events

Human cl rhFVIII and Kogenate FS

Serious events: 2 serious events

Other events: 6 other events

Deaths: 0 deaths

Serious adverse events

Measure	Human cl rhFVIII and Kogenate FS n=22 participants at risk 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.
Hepatobiliary disorders HEPATIC CIRRHOSIS	4.5% 1/22 • Number of events 1 • 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.
Psychiatric disorders DEPRESSION SUICIDAL	4.5% 1/22 • Number of events 1 • 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.
Nervous system disorders HEPATIC ENCEPHALOPATHY	4.5% 1/22 • Number of events 1 • 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.

Other adverse events

Measure	Human cl rhFVIII and Kogenate FS n=22 participants at risk 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.
Gastrointestinal disorders Diarrhoea	9.1% 2/22 • Number of events 2 • 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.
General disorders Pyrexia	9.1% 2/22 • Number of events 2 • 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.
Metabolism and nutrition disorders Protein urine present	9.1% 2/22 • Number of events 2 • 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.

Additional Information

Dr. Sigurd Knaub

Octapharma AG

Phone: +41 554512141

Email: sigurd.knaub@octapharma.com

Results disclosure agreements

• Principal investigator is a sponsor employee 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.
• Publication restrictions are in place

Restriction type: OTHER