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

• ClinicalTrials.gov Identifier: NCT00989196
• Recruitment Status: Completed
• First Posted: October 2, 2009
• Results First Posted: January 17, 2014
• Last Update Posted: October 8, 2019
• Sponsor: Octapharma
• Information provided by (Responsible Party): Octapharma

• Study Type: Interventional
• Study Design: Allocation: Randomized; Intervention Model: Crossover Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Hemophilia A
• Interventions: Biological: Human-cl rhFVIII; Biological: Kogenate FS
• Enrollment: 22

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.

Arm/Group Title	Human c1 rhFVIII First Crossover, Then Treatment	Kogenate First Crossover, Then Treatment
Arm/Group Description	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)	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)
Period Title: PK Crossover Period
Started	10	12
Completed	10	12
Not Completed	0	0
Period Title: Treatment Period
Started	10	12
Completed	9	12
Not Completed	1	0
Reason Not Completed
Lost to Follow-up	1	0

Baseline Characteristics

Arm/Group Title		Human cl rhFVIII
Arm/Group Description		Human-cl rhFVIII and Kogenate in cross-over design:50 IU/kg for PK dose
Overall Number of Baseline Participants		22
Baseline Analysis Population Description		[Not Specified]
Age, Categorical; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	22 participants
	<=18 years	2 9.1%
	Between 18 and 65 years	19 86.4%
	>=65 years	1 4.5%
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	22 participants
		39.6 (14.06)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	22 participants
	Female	0 0.0%
	Male	22 100.0%
Region of Enrollment; Measure Type: Number; Unit of measure: Participants	Number Analyzed	22 participants
United States		10
Bulgaria		6
Germany		6

Outcome Measures

1. Primary Outcome

Title	The Area Under the Concentration Curve for Human-cl rhFVIII Compared to Kogenate FS
Description	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.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Human cl rhFVIII	Kogenate FS
Arm/Group Description:	Human-cl rhFVIII 50 IU/kg for PK dose	Kogenate FS 50 IU/kg for PK dose
Overall Number of Participants Analyzed	22	22
Mean (Standard Deviation); Unit of Measure: h IU/mL (IU/kg)
	0.39 (0.14)	0.38 (0.09)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Human cl rhFVIII, Kogenate FS
	Comments	[Not Specified]
	Type of Statistical Test	Non-Inferiority or Equivalence (legacy)
	Comments	For the comparison of the PK profile of Human-cl rhFVIII with Kogenate, the 90% confidence intervals for the ratio or log-ratio of Human-cl rhFVIII over Kogenate for selected, dose independent or dose adjusted, PK parameters will be presented. In addition a formal statistical procedure will test whether the ratio of mean AUCs is within a 80 to 125% range to show bioequivalence.
Method of Estimation	Estimation Parameter	Ratio
	Estimated Value	0.98
	Confidence Interval	(2-Sided) 90%; 0.874 to 1.107
	Estimation Comments	[Not Specified]

2. Secondary Outcome

Title	Invivo Half-life (T1/2) for Human-cl rhFVIII Compared to Kogenate FS
Description	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.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Human cl rhFVIII	Kogenate FS
Arm/Group Description:	Human-cl rhFVIII 50 IU/kg for PK dose	Kogenate FS 50 IU/kg for PK dose
Overall Number of Participants Analyzed	22	22
Mean (Standard Deviation); Unit of Measure: hours
	14.73 (9.96)	16.14 (5.88)

3. Secondary Outcome

Title	Maximum Plasma Concentration (Cmax) for Human-cl rhFVIII Compared to Kogenate FS
Description	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.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Human cl rhFVIII	Kogenate FS
Arm/Group Description:	Human-cl rhFVIII 50 IU/kg for PK dose	Kogenate FS 50 IU/kg for PK dose
Overall Number of Participants Analyzed	22	22
Mean (Standard Deviation); Unit of Measure: IU/mL
	1.462 (0.223)	1.394 (0.2)

4. Secondary Outcome

Title	Time to Reach Maximum Plasma Concentration (Tmax) for Human-cl rhFVIII Compared to Kogenate FS
Description	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.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Human cl rhFVIII	Kogenate FS
Arm/Group Description:	Human-cl rhFVIII 50 IU/kg for PK dose	Kogenate FS 50 IU/kg for PK dose
Overall Number of Participants Analyzed	22	22
Mean (Standard Deviation); Unit of Measure: hours
	0.35 (0.23)	0.34 (0.2)

5. Secondary Outcome

Title	Mean Residence Time (MRT) for Human-cl rhFVIII Compared to Kogenate FS
Description	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.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Human cl rhFVIII	Kogenate FS
Arm/Group Description:	Human-cl rhFVIII 50 IU/kg for PK dose	Kogenate FS 50 IU/kg for PK dose
Overall Number of Participants Analyzed	22	22
Mean (Standard Deviation); Unit of Measure: hours
	19.45 (12.02)	20 (5.61)

6. Secondary Outcome

Title	Volume of Distribution at Steady State (Vss) for Human-cl rhFVIII Compared to Kogenate FS
Description	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.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Human cl rhFVIII	Kogenate FS
Arm/Group Description:	Human-cl rhFVIII 50 IU/kg for PK dose	Kogenate FS 50 IU/kg for PK dose
Overall Number of Participants Analyzed	22	22
Mean (Standard Deviation); Unit of Measure: mL/kg
	49.58 (17.27)	53.32 (13.57)

7. Secondary Outcome

Title	Clearance (CL) for Human-cl rhFVIII Compared to Kogenate FS
Description	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.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Human cl rhFVIII	Kogenate FS
Arm/Group Description:	Human-cl rhFVIII 50 IU/kg for PK dose	Kogenate FS 50 IU/kg for PK dose
Overall Number of Participants Analyzed	22	22
Mean (Standard Deviation); Unit of Measure: mL/h/kg
	2.94 (1.18)	2.75 (0.64)

8. Secondary Outcome

Title	Efficacy of On-demand Treatment of Bleeding Episodes
Description	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.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Human cl rhFVIII
Arm/Group Description:	Human-cl rhFVIII and Kogenate in cross-over design:50 IU/kg for PK dose
Overall Number of Participants Analyzed	22
Overall Number of Units Analyzed; Type of Units Analyzed: Bleeding episodes	986
Measure Type: Number; Unit of Measure: percentage of bleeding episodes
Excellent	60.3
Good	34.1
Moderate	5.5
None	0

9. Secondary Outcome

Title	Immunogenicity (Number of Patients That Developed an Inhibitor During the Course of the Study)
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Human cl rhFVIII
Arm/Group Description:	Human-cl rhFVIII and Kogenate in cross-over design:50 IU/kg for PK dose
Overall Number of Participants Analyzed	22
Measure Type: Number; Unit of Measure: participants
	0

Adverse Events

Time Frame	From 27 May 2010 to 18 September 2012 (study end)
Adverse Event Reporting Description	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.
Arm/Group Title	Human cl rhFVIII and Kogenate FS
Arm/Group Description	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.
All-Cause Mortality
	Human cl rhFVIII and Kogenate FS
	Affected / at Risk (%)
Total	--/--
Serious Adverse Events
	Human cl rhFVIII and Kogenate FS
	Affected / at Risk (%)	# Events
Total	2/22 (9.09%)
Hepatobiliary disorders
HEPATIC CIRRHOSIS * 1	1/22 (4.55%)	1
Nervous system disorders
HEPATIC ENCEPHALOPATHY *	1/22 (4.55%)	1
Psychiatric disorders
DEPRESSION SUICIDAL *	1/22 (4.55%)	1
* Indicates events were collected by non-systematic assessment; 1 Term from vocabulary, MedDRA 15.1
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Human cl rhFVIII and Kogenate FS
	Affected / at Risk (%)	# Events
Total	6/22 (27.27%)
Gastrointestinal disorders
Diarrhoea *	2/22 (9.09%)	2
General disorders
Pyrexia *	2/22 (9.09%)	2
Metabolism and nutrition disorders
Protein urine present *	2/22 (9.09%)	2
* Indicates events were collected by non-systematic assessment

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

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.

Results Point of Contact

• Name/Title: Dr. Sigurd Knaub
• Organization: Octapharma AG
• Phone: +41 554512141
• EMail: sigurd.knaub@octapharma.com

• Responsible Party: Octapharma
• ClinicalTrials.gov Identifier: NCT00989196
• Other Study ID Numbers: GENA-01
• First Submitted: September 30, 2009
• First Posted: October 2, 2009
• Results First Submitted: March 1, 2013
• Results First Posted: January 17, 2014
• Last Update Posted: October 8, 2019