An Open-label Safety, Efficacy and Pharmacokinetic Study of a Recombinant FVIII Compared to Recombinant Human Antihemophilic FVIII in Patients With Severe Hemophilia A

• ClinicalTrials.gov Identifier: NCT01486927
• Recruitment Status: Completed
• First Posted: December 7, 2011
• Results First Posted: August 9, 2016
• Last Update Posted: August 9, 2016
• Sponsor: CSL Behring
• Information provided by (Responsible Party): CSL Behring

• Study Type: Interventional
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Hemophilia A
• Interventions: Biological: rVIII-SingleChain; Biological: Octocog alfa
• Enrollment: 175

Participant Flow

Recruitment Details	This multicenter, multinational study enrolled subjects at 54 participating study centers in the United States, Japan, Europe, Australia, Canada, Lebanon, Malaysia, Philippines, Russian Federation, South Africa, and Ukraine.
Pre-assignment Details	Screening took place 4 to 28 days prior to first dose of study product (rVIII-SingleChain). A total of 204 subjects were screened, 29 of these did not fulfill all eligibility criteria and were therefore screening failures. A total of 175 subjects were enrolled; 174 subjects were exposed to treatment with rVIII-SingleChain.

Arm/Group Title	Recombinant Factor VIII (rFVIII)
Arm/Group Description	In Part 1 of the study (a single-sequence crossover pharmacokinetic [PK] analysis), 27 subjects received a single injection of octocog alfa followed by a single injection of rVIII-SingleChain. Twenty-six of the 27 subjects from Part 1 then entered Part 2 of the study where they were assigned either to an on-demand or prophylaxis regimen with repeat injections of rVIII-SingleChain until they reached 50 exposure days (EDs). In Part 3 of the study, 148 additional subjects were enrolled and were assigned either to an on-demand or prophylaxis regimen with repeat injections of rVIII-SingleChain until they reached 50 EDs; 64 of these subjects participated in additional PK analyses. Overall, 174 subjects received rVIII-SingleChain as either on-demand or prophylaxis regimens, and 13 subjects participated in the surgical substudy.
Period Title: Overall Study
Started	174
Completed	161
Not Completed	13
Reason Not Completed
Knee surgery (prior to surgery substudy)	1
Physician Decision	1
50 Exposure days not reached	2
Withdrawal by Subject	8
Subject did not reach 6 mo of treatment	1

Baseline Characteristics

Arm/Group Title		Recombinant Factor VIII (rFVIII)
Arm/Group Description		In Part 1 of the study (a single-sequence crossover PK analysis), 27 subjects received a single injection of octocog alfa followed by a single injection of rVIII-SingleChain. Twenty-six of the 27 subjects from Part 1 then entered Part 2 of the study where they were assigned either to an on-demand or prophylaxis regimen with repeat injections of rVIII-SingleChain until they reached 50 EDs. In Part 3 of the study, 148 additional subjects were enrolled and were assigned either to an on-demand or prophylaxis regimen with repeat injections of rVIII-SingleChain until they reached 50 EDs; 64 of these subjects participated in additional PK analyses. Overall, 174 subjects received rVIII-SingleChain as either on-demand or prophylaxis regimens, and 13 subjects participated in the surgical substudy.
Overall Number of Baseline Participants		174
Baseline Analysis Population Description		[Not Specified]
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	174 participants
		31.3 (11.77)
Age, Customized; Measure Type: Number; Unit of measure: Participants	Number Analyzed	174 participants
Adolescents (12-17 years)		14
Adults (18-65 years)		160
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	174 participants
	Female	0 0.0%
	Male	174 100.0%
Type of FVIII product used before enrollment [1]; Measure Type: Number; Unit of measure: Participants	Number Analyzed	174 participants
Plasma-derived Product		83
Recombinant Product		91
		[1] Measure Description: Type of FVIII product used by the subjects before enrollment into the study. This could have been a plasma-derived FVIII product or a recombinant FVIII product.
Treatment modality of FVIII therapy before enrollment [1]; Measure Type: Number; Unit of measure: Participants	Number Analyzed	174 participants
Prophylaxis		82
On-demand		92
		[1] Measure Description: Treatment modality of FVIII therapy before enrollment, ie, routine prophylaxis or on-demand treatment. If a subject used both modalities, only the most recent one was counted.

Outcome Measures

1. Primary Outcome

Title	Treatment Success
Description	The investigator rated the efficacy of the treatment based on a 4-point rating scale "excellent, good, moderate or poor/no response". Efficacy ratings of "excellent" or "good" were considered treatment success for this end point; the percentage of bleeding events with a rating of excellent or good and the 95% confidence interval are presented. The denominator includes all treated bleeding events. The 95% confidence interval is based on a model to account for within-subject correlation.
Time Frame	Up to 24 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	rVIII-SingleChain On-demand	rVIII-SingleChain Prophylaxis	rVIII-SingleChain
Arm/Group Description:	The rVIII-SingleChain On-demand group consisted of all subjects in the efficacy population who received at least 1 dose rVIII-SingleChain as part of on-demand treatment during Parts 2 or 3 of the study. There were 27 subjects in the rVIII-SingleChain On-demand group.	The rVIII-SingleChain Prophylaxis group consisted of all subjects in the efficacy population who received at least 1 dose rVIII-SingleChain as part of routine prophylaxis treatment during Parts 2 or 3 of the study. There were 146 subjects in the rVIII-SingleChain Prophylaxis group.	The Efficacy population consisted of all subjects who received at least 1 dose of rVIII-SingleChain as part of either routine prophylaxis treatment or on-demand treatment during Parts 2 or 3 of the study. There were 173 subjects in the Efficacy population.
Overall Number of Participants Analyzed	27	146	173
Overall Number of Units Analyzed; Type of Units Analyzed: Number of treated bleeding events	590	258	848
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: % bleeding events successfully treated
	92.4; (87.8 to 95.3)	92.2; (86.3 to 95.8)	92.3; (88.9 to 94.8)

2. Primary Outcome

Title	Inhibitor Formation to FVIII
Description	Number of subjects who develop inhibitors to FVIII
Time Frame	Up to 24 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Recombinant Factor VIII (rFVIII)
Arm/Group Description:	In Part 1 of the study (a single-sequence crossover PK analysis), 27 subjects received a single injection of octocog alfa followed by a single injection of rVIII-SingleChain. Twenty-six of the 27 subjects from Part 1 then entered Part 2 of the study where they were assigned either to an on-demand or prophylaxis regimen with repeat injections of rVIII-SingleChain until they reached 50 EDs. In Part 3 of the study, 148 additional subjects were enrolled and were assigned either to an on-demand or prophylaxis regimen with repeat injections of rVIII-SingleChain until they reached 50 EDs; 64 of these subjects participated in additional PK analyses. Overall, 174 subjects received rVIII-SingleChain as either on-demand or prophylaxis regimens, and 13 subjects participated in the surgical substudy.
Overall Number of Participants Analyzed	174
Measure Type: Number; Unit of Measure: participants
	0

3. Primary Outcome

Title	Annualized Spontaneous Bleeding Rate
Description	The annualized spontaneous bleeding rate (AsBR) was derived for each subject as follows: 365.25*(number of spontaneous bleeding episodes requiring treatment) / (observed treatment period of interest).
Time Frame	Up to 24 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	rVIII-SingleChain On-demand	rVIII-SingleChain Prophylaxis
Arm/Group Description:	The rVIII-SingleChain On-demand group consisted of all subjects in the efficacy population who received at least 1 dose rVIII-SingleChain as part of on-demand treatment during Parts 2 or 3 of the study. There were 27 subjects in the rVIII-SingleChain On-demand group.	The rVIII-SingleChain Prophylaxis group consisted of all subjects in the efficacy population who received at least 1 dose rVIII-SingleChain as part of routine prophylaxis treatment during Parts 2 or 3 of the study. There were 146 subjects in the rVIII-SingleChain Prophylaxis group.
Overall Number of Participants Analyzed	27	146
Median (Inter-Quartile Range); Unit of Measure: Number of spontaneous bleeds per year
	11.73; (2.8 to 36.5)	0.00; (0.0 to 2.4)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	rVIII-SingleChain On-demand, rVIII-SingleChain Prophylaxis
	Comments	A test of the null hypothesis of no difference on AsBR between the 2 comparison groups was based on the Poisson Regression method. The corresponding prophylaxis/on-demand ratio with 95% confidence interval (CI) was calculated.
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	< 0.0001
	Comments	[Not Specified]
	Method	Poisson, regression
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Rate ratio
	Estimated Value	0.08
	Confidence Interval	(2-Sided) 95%; 0.07 to 0.10
	Estimation Comments	[Not Specified]

4. Primary Outcome

Title	Treatment Success During the Peri-operative Surgical Sub-study
Description	Subjects received rVIII-SingleChain before and during surgery based on the type of surgery and the clinical status of the subject. The investigator rated the efficacy of the treatment based on a 4-point surgical treatment rating scale of "excellent, good, moderate or poor/no response". Efficacy ratings of "excellent" or "good" were considered treatment success for this end point. The rate of success, defined as the percentage of surgeries with a rating of excellent or good for hemostatic efficacy on the surgical treatment scale is presented for the Surgical Population, based on the total number of surgeries (N=16) as denominator.
Time Frame	From the start of surgery through the post-operative recovery (generally up to 14 days after surgery)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	rVIII-SingleChain Surgical
Arm/Group Description:	The rVIII-SingleChain Surgical group included all subjects enrolled in the surgical sub-study who received at least 1 dose of rVIII-SingleChain during the surgical sub-study. There were 13 subjects in the rVIII-SingleChain Surgical group.
Overall Number of Participants Analyzed	13
Measure Type: Number; Unit of Measure: % of surgeries with successful treatment
	100

5. Secondary Outcome

Title	AUC0-∞ (Part 1)
Description	AUC0-∞ (AUC from 0 extrapolated to infinity) of a single infusion of octocog alfa and rVIII-SingleChain without correction for subject's predose plasma FVIII activity. FVIII activity values for octocog alfa are dose-adjusted for chromogenic potency.
Time Frame	Before infusion and at up to 10 time points within 72 hours of infusion

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	PK Population (Part 1)
Arm/Group Description:	The PK population (Part 1) consisted of subjects who had received 1 dose of 50 IU/kg of rVIII-SingleChain and for whom a sufficient number of analyzable PK samples were obtained to permit the evaluation of the PK profile. In the Part 1 PK analysis, these subjects also received 1 dose of 50 IU/kg octocog alfa. There were 27 subjects in the PK population (Part 1).
Overall Number of Participants Analyzed	27
Mean (Standard Deviation); Unit of Measure: IU*h/dL
Octocog alfa	1550 (552)
rVIII-SingleChain	2090 (650)

6. Secondary Outcome

Title	Cmax (Part 1)
Description	Cmax of a single infusion of octocog alfa and rVIII-SingleChain with correction for subject's predose plasma FVIII activity. FVIII activity values for octocog alfa are dose-adjusted for chromogenic potency.
Time Frame	Before infusion and at up to 10 time points within 72 hours of infusion

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	PK Population (Part 1)
Arm/Group Description:	The PK population (Part 1) consisted of subjects who had received 1 dose of 50 IU/kg of rVIII-SingleChain and for whom a sufficient number of analyzable PK samples were obtained to permit the evaluation of the PK profile. In the Part 1 PK analysis, these subjects also received 1 dose of 50 IU/kg octocog alfa. There were 27 subjects in the PK population (Part 1).
Overall Number of Participants Analyzed	27
Mean (Standard Deviation); Unit of Measure: IU/dL
Octocog alfa	116 (18.1)
rVIII-SingleChain	113 (17.4)

7. Secondary Outcome

Title	Tmax (Part 1)
Description	Tmax = time of Cmax (with correction for subject's predose plasma FVIII activity) after a single infusion of octocog alfa and rVIII-SingleChain.
Time Frame	Before infusion and at up to 10 time points within 72 hours of infusion

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	PK Population (Part 1)
Arm/Group Description:	The PK population (Part 1) consisted of subjects who had received 1 dose of 50 IU/kg of rVIII-SingleChain and for whom a sufficient number of analyzable PK samples were obtained to permit the evaluation of the PK profile. In the Part 1 PK analysis, these subjects also received 1 dose of 50 IU/kg octocog alfa. There were 27 subjects in the PK population (Part 1).
Overall Number of Participants Analyzed	27
Median (Full Range); Unit of Measure: hours
Octocog alfa	0.583; (0.450 to 0.800)
rVIII-SingleChain	0.683; (0.467 to 1.25)

8. Secondary Outcome

Title	Half-life (t1/2) (Part 1)
Description	Half-life (t1/2) of a single infusion of octocog alfa and rVIII-SingleChain without correction for subject's predose plasma FVIII activity.
Time Frame	Before infusion and at up to 10 time points within 72 hours of infusion.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	PK Population (Part 1)
Arm/Group Description:	The PK population (Part 1) consisted of subjects who had received 1 dose of 50 IU/kg of rVIII-SingleChain and for whom a sufficient number of analyzable PK samples were obtained to permit the evaluation of the PK profile. In the Part 1 PK analysis, these subjects also received 1 dose of 50 IU/kg octocog alfa. There were 27 subjects in the PK population (Part 1).
Overall Number of Participants Analyzed	27
Mean (Standard Deviation); Unit of Measure: hours
Octocog alfa	13.3 (4.36)
rVIII-SingleChain	14.5 (3.77)

9. Secondary Outcome

Title	Mean Residence Time (MRT) (Part 1)
Description	Mean residence time (MRT) of a single infusion of octocog alfa and rVIII-SingleChain without correction for subject's predose plasma FVIII activity.
Time Frame	Before infusion and at up to 10 time points within 72 hours of infusion

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	PK Population (Part 1)
Arm/Group Description:	The PK population (Part 1) consisted of subjects who had received 1 dose of 50 IU/kg of rVIII-SingleChain and for whom a sufficient number of analyzable PK samples were obtained to permit the evaluation of the PK profile. In the Part 1 PK analysis, these subjects also received 1 dose of 50 IU/kg octocog alfa. There were 27 subjects in the PK population (Part 1).
Overall Number of Participants Analyzed	27
Mean (Standard Deviation); Unit of Measure: hours
Octocog alfa	17.1 (5.57)
rVIII-SingleChain	20.4 (5.49)

10. Secondary Outcome

Title	Clearance (Cl) (Part 1)
Description	Clearance (Cl) of a single infusion of octocog alfa and rVIII-SingleChain without correction for subject's predose plasma FVIII activity. FVIII activity values for octocog alfa are dose-adjusted for chromogenic potency.
Time Frame	Before infusion and at up to 10 time points within 72 hours of infusion

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	PK Population (Part 1)
Arm/Group Description:	The PK population (Part 1) consisted of subjects who had received 1 dose of 50 IU/kg of rVIII-SingleChain and for whom a sufficient number of analyzable PK samples were obtained to permit the evaluation of the PK profile. In the Part 1 PK analysis, these subjects also received 1 dose of 50 IU/kg octocog alfa. There were 27 subjects in the PK population (Part 1).
Overall Number of Participants Analyzed	27
Mean (Standard Deviation); Unit of Measure: mL/h/kg
Octocog alfa	3.68 (1.41)
rVIII-SingleChain	2.64 (0.846)

11. Secondary Outcome

Title	Volume of Distribution at Steady-state (Vss) (Part 1)
Description	Volume of distribution at steady-state (Vss) of a single infusion of octocog alfa and rVIII-SingleChain without correction for subject's predose plasma FVIII activity. FVIII activity values for octocog alfa are dose-adjusted for chromogenic potency.
Time Frame	Before infusion and at up to 10 time points within 72 hours of infusion

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	PK Population (Part 1)
Arm/Group Description:	The PK population (Part 1) consisted of subjects who had received 1 dose of 50 IU/kg of rVIII-SingleChain and for whom a sufficient number of analyzable PK samples were obtained to permit the evaluation of the PK profile. In the Part 1 PK analysis, these subjects also received 1 dose of 50 IU/kg octocog alfa. There were 27 subjects in the PK population (Part 1).
Overall Number of Participants Analyzed	27
Mean (Standard Deviation); Unit of Measure: mL/kg
Octocog alfa	57.1 (11.3)
rVIII-SingleChain	50.0 (7.51)

12. Secondary Outcome

Title	Incremental Recovery (Part 1)
Description	Incremental recovery of a single infusion of octocog alfa and rVIII-SingleChain with correction for subject's predose plasma FVIII activity. FVIII activity values for octocog alfa are dose-adjusted for chromogenic potency.
Time Frame	At 30 minutes after infusion

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	PK Population (Part 1)
Arm/Group Description:	The PK population (Part 1) consisted of subjects who had received 1 dose of 50 IU/kg of rVIII-SingleChain and for whom a sufficient number of analyzable PK samples were obtained to permit the evaluation of the PK profile. In the Part 1 PK analysis, these subjects also received 1 dose of 50 IU/kg octocog alfa. There were 27 subjects in the PK population (Part 1).
Overall Number of Participants Analyzed	27
Mean (Standard Deviation); Unit of Measure: [IU/dL]/[IU/kg]
Octocog alfa	2.32 (0.381)
rVIII-SingleChain	2.24 (0.357)

13. Secondary Outcome

Title	Annualized Bleeding Rate for Total Bleeds and Traumatic Bleeds
Description	The annualized bleeding rate was derived for each subject as follows: 365.25*(number of bleeding episodes requiring treatment) / (observed treatment period of interest).
Time Frame	Up to 24 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	rVIII-SingleChain On-demand	rVIII-SingleChain Prophylaxis
Arm/Group Description:	The rVIII-SingleChain On-demand group consisted of all subjects in the efficacy population who received at least 1 dose rVIII-SingleChain as part of on-demand treatment during Parts 2 or 3 of the study. There were 27 subjects in the rVIII-SingleChain On-demand group.	The rVIII-SingleChain Prophylaxis group consisted of all subjects in the efficacy population who received at least 1 dose rVIII-SingleChain as part of routine prophylaxis treatment during Parts 2 or 3 of the study. There were 146 subjects in the rVIII-SingleChain Prophylaxis group.
Overall Number of Participants Analyzed	27	146
Median (Inter-Quartile Range); Unit of Measure: Number of bleeds per year
Total Bleeds	19.64; (6.2 to 46.5)	1.14; (0.0 to 4.2)
Traumatic Bleeds	3.12; (0.0 to 8.4)	0.00; (0.0 to 0.9)

14. Secondary Outcome

Title	Proportion of Bleeding Episodes Requiring 1, 2, 3 or > 3 Infusions of rVIII-SingleChain to Achieve Hemostasis
Description	Percentage of bleeding episodes requiring 1, 2, 3 or > 3 infusions of rVIII-SingleChain to achieve hemostasis. The denominator includes all treated bleeding episodes.
Time Frame	During the study (up to 24 months; assessed at Months 1, 2, 3, 4, 5, 6, 9, 12, 15, 18, 21 and 24)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	rVIII-SingleChain On-demand	rVIII-SingleChain Prophylaxis	rVIII-SingleChain
Arm/Group Description:	The rVIII-SingleChain On-demand group consisted of all subjects in the efficacy population who received at least 1 dose rVIII-SingleChain as part of on-demand treatment during Parts 2 or 3 of the study. There were 27 subjects in the rVIII-SingleChain On-demand group.	The rVIII-SingleChain Prophylaxis group consisted of all subjects in the efficacy population who received at least 1 dose rVIII-SingleChain as part of routine prophylaxis treatment during Parts 2 or 3 of the study. There were 146 subjects in the rVIII-SingleChain Prophylaxis group.	The Efficacy population consisted of all subjects who received at least one dose of rVIII-SingleChain as part of either routine prophylaxis treatment or on-demand treatment during Parts 2 or 3 of the study. There were 173 subjects in the Efficacy population.
Overall Number of Participants Analyzed	27	146	173
Overall Number of Units Analyzed; Type of Units Analyzed: Treated bleeding episodes	590	258	848
Measure Type: Number; Unit of Measure: Percentage of bleeding episodes
Requiring 1 infusion for hemostasis	82.7	76.7	80.9
Requiring 2 infusions for hemostasis	12.0	14.0	12.6
Requiring 3 infusions for hemostasis	3.22	3.88	3.42
Requiring >3 infusions for hemostasis	2.03	5.43	3.07

15. Other Pre-specified Outcome

Title	Incremental Recovery (Part 3)
Description	Incremental recovery of an initial and repeat infusion of rVIII-SingleChain with correction for subject's predose plasma FVIII activity.
Time Frame	At 30 minutes after infusion

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	rVIII-SingleChain PK Population (Part 3)
Arm/Group Description:	The rVIII-SingleChain PK population (Part 3) consisted of subjects who received rVIII-SingleChain during Part 3 of the study (initial and repeat dose) and for whom a sufficient number of analyzable PK samples were obtained to permit the evaluation of the PK profile. In Part 3, 64 subjects participated in the initial PK, of whom 30 also participated in the repeat PK.
Overall Number of Participants Analyzed	63
Mean (Standard Deviation); Unit of Measure: [IU/dL]/[IU/kg]
Initial, n = 63	1.85 (0.404)
Repeat, n = 29	1.99 (0.352)

16. Other Pre-specified Outcome

Title	Volume of Distribution at Steady-state (Vss) (Part 3)
Description	Volume of distribution at steady-state (Vss) of an initial and repeat infusion of rVIII-SingleChain without correction for subject's predose plasma FVIII activity.
Time Frame	Before infusion and at up to 12 time points within 96 hours of infusion.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	rVIII-SingleChain PK Population (Part 3)
Arm/Group Description:	The rVIII-SingleChain PK population (Part 3) consisted of subjects who received rVIII-SingleChain during Part 3 of the study (initial and repeat dose) and for whom a sufficient number of analyzable PK samples were obtained to permit the evaluation of the PK profile. In Part 3, 64 subjects participated in the initial PK, of whom 30 also participated in the repeat PK.
Overall Number of Participants Analyzed	64
Mean (Standard Deviation); Unit of Measure: mL/kg
Initial, n = 64	59.5 (14.2)
Repeat, n = 30	53.1 (8.74)

17. Other Pre-specified Outcome

Title	Clearance (Cl) (Part 3)
Description	Clearance (Cl) of an initial and repeat infusion of rVIII-SingleChain without correction for subject's predose plasma FVIII activity.
Time Frame	Before infusion and at up to 12 time points within 96 hours of infusion.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	rVIII-SingleChain PK Population (Part 3)
Arm/Group Description:	The rVIII-SingleChain PK population (Part 3) consisted of subjects who received rVIII-SingleChain during Part 3 of the study (initial and repeat dose) and for whom a sufficient number of analyzable PK samples were obtained to permit the evaluation of the PK profile. In Part 3, 64 subjects participated in the initial PK, of whom 30 also participated in the repeat PK.
Overall Number of Participants Analyzed	64
Mean (Standard Deviation); Unit of Measure: mL/h/kg
Initial, n = 64	3.15 (1.21)
Repeat, n = 30	3.05 (1.1)

18. Other Pre-specified Outcome

Title	Mean Residence Time (MRT) (Part 3)
Description	Mean residence time (MRT) of an initial and repeat infusion of rVIII-SingleChain without correction for subject's predose plasma FVIII activity.
Time Frame	Before infusion and at up to 12 time points within 96 hours of infusion.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	rVIII-SingleChain PK Population (Part 3)
Arm/Group Description:	The rVIII-SingleChain PK population (Part 3) consisted of subjects who received rVIII-SingleChain during Part 3 of the study (initial and repeat dose) and for whom a sufficient number of analyzable PK samples were obtained to permit the evaluation of the PK profile. In Part 3, 64 subjects participated in the initial PK, of whom 30 also participated in the repeat PK.
Overall Number of Participants Analyzed	64
Mean (Standard Deviation); Unit of Measure: hours
Initial, n = 64	20.3 (5.36)
Repeat, n = 30	18.9 (5.39)

19. Other Pre-specified Outcome

Title	Half-life (t1/2) (Part 3)
Description	Half-life (t1/2) of an initial and repeat infusion of rVIII-SingleChain without correction for subject's predose plasma FVIII activity.
Time Frame	Before infusion and at up to 12 time points within 96 hours of infusion.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	rVIII-SingleChain PK Population (Part 3)
Arm/Group Description:	The rVIII-SingleChain PK population (Part 3) consisted of subjects who received rVIII-SingleChain during Part 3 of the study (initial and repeat dose) and for whom a sufficient number of analyzable PK samples were obtained to permit the evaluation of the PK profile. In Part 3, 64 subjects participated in the initial PK, of whom 30 also participated in the repeat PK.
Overall Number of Participants Analyzed	64
Mean (Standard Deviation); Unit of Measure: hours
Initial, n = 64	14.1 (3.82)
Repeat, n = 30	12.9 (3.7)

20. Other Pre-specified Outcome

Title	Tmax (Part 3)
Description	Tmax = time of Cmax (with correction for subject's predose plasma FVIII activity) after an initial and repeat infusion of rVIII-SingleChain.
Time Frame	Before infusion and at up to 12 time points within 96 hours of infusion.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	rVIII-SingleChain PK Population (Part 3)
Arm/Group Description:	The rVIII-SingleChain PK population (Part 3) consisted of subjects who received rVIII-SingleChain during Part 3 of the study (initial and repeat dose) and for whom a sufficient number of analyzable PK samples were obtained to permit the evaluation of the PK profile. In Part 3, 64 subjects participated in the initial PK, of whom 30 also participated in the repeat PK.
Overall Number of Participants Analyzed	63
Median (Full Range); Unit of Measure: hours
Initial, n = 63	0.333; (0.117 to 1.22)
Repeat, n = 29	0.317; (0.117 to 0.667)

21. Other Pre-specified Outcome

Title	Cmax (Part 3)
Description	Cmax of an initial and repeat infusion of rVIII-SingleChain with correction for subject's predose plasma FVIII activity.
Time Frame	Before infusion and at up to 12 time points within 96 hours of infusion

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	rVIII-SingleChain PK Population (Part 3)
Arm/Group Description:	The rVIII-SingleChain PK population (Part 3) consisted of subjects who received rVIII-SingleChain during Part 3 of the study (initial and repeat dose) and for whom a sufficient number of analyzable PK samples were obtained to permit the evaluation of the PK profile. In Part 3, 64 subjects participated in the initial PK, of whom 30 also participated in the repeat PK.
Overall Number of Participants Analyzed	63
Mean (Standard Deviation); Unit of Measure: IU/dL
Initial, n = 63	99.9 (19.9)
Repeat, n = 29	108 (18.5)

22. Other Pre-specified Outcome

Title	AUC0-∞ (Part 3)
Description	AUC0-∞ (AUC from 0 extrapolated to infinity) of an initial and repeat infusion of rVIII-SingleChain without correction for subject's predose plasma FVIII activity.
Time Frame	Before infusion and at up to 12 time points within 96 hours of infusion

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	rVIII-SingleChain PK Population (Part 3)
Arm/Group Description:	The rVIII-SingleChain PK population (Part 3) consisted of subjects who received rVIII-SingleChain during Part 3 of the study (initial and repeat dose) and for whom a sufficient number of analyzable PK samples were obtained to permit the evaluation of the PK profile. In Part 3, 64 subjects participated in the initial PK, of whom 30 also participated in the repeat PK.
Overall Number of Participants Analyzed	64
Mean (Standard Deviation); Unit of Measure: IU*h/dL
Initial, n = 64	1830 (640)
Repeat, n = 30	1880 (649)

Adverse Events

Time Frame	For the duration of the study, approximately 2 years, 10 months.
Adverse Event Reporting Description	The Safety Population comprised all subjects treated with rVIII-SingleChain. A total of 14592 rVIII-SingleChain infusions were administered to 174 subjects during the study.
Arm/Group Title	Safety Population
Arm/Group Description	The Safety Population comprised all subjects treated with rVIII-SingleChain.
All-Cause Mortality
	Safety Population
	Affected / at Risk (%)
Total	--/--
Serious Adverse Events
	Safety Population
	Affected / at Risk (%)	# Events
Total	8/174 (4.60%)
Blood and lymphatic system disorders
Anaemia † 1	1/174 (0.57%)	1
Thrombocytopenia † 1	1/174 (0.57%)	1
Gastrointestinal disorders
Varices oesophageal † 1	1/174 (0.57%)	1
Immune system disorders
Hypersensitivity † 1	1/174 (0.57%)	1
Infections and infestations
Postoperative wound infection † 1	1/174 (0.57%)	1
Viral infection † 1	1/174 (0.57%)	1
Injury, poisoning and procedural complications
Ankle fracture † 1	1/174 (0.57%)	1
Investigations
Blood uric acid increased † 1	1/174 (0.57%)	1
Psychiatric disorders
Suicidal ideation † 1	1/174 (0.57%)	1
Respiratory, thoracic and mediastinal disorders
Tonsillar haemorrhage † 1	1/174 (0.57%)	1
† Indicates events were collected by systematic assessment; 1 Term from vocabulary, MedDRA (14.1)
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Safety Population
	Affected / at Risk (%)	# Events
Total	45/174 (25.86%)
Infections and infestations
Nasopharyngitis † 1	18/174 (10.34%)	22
Musculoskeletal and connective tissue disorders
Arthralgia † 1	20/174 (11.49%)	22
Nervous system disorders
Headache † 1	13/174 (7.47%)	14
† Indicates events were collected by systematic assessment; 1 Term from vocabulary, MedDRA (14.1)

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.

CSL agreements and restrictions on publishing may vary with individual investigators; however, CSL will not prohibit any investigator from publishing. CSL supports the publication of results from all centers of a multi-center trial and generally requires that reports based on single-site data not precede the primary publication of the entire clinical trial.

Results Point of Contact

• Name/Title: Clinical Trial Disclosure Manager
• Organization: CSL Behring
• Phone: Use email contact
• EMail: clinicaltrials@cslbehring.com

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Mahlangu J, Kuliczkowski K, Karim FA, Stasyshyn O, Kosinova MV, Lepatan LM, Skotnicki A, Boggio LN, Klamroth R, Oldenburg J, Hellmann A, Santagostino E, Baker RI, Fischer K, Gill JC, P'Ng S, Chowdary P, Escobar MA, Khayat CD, Rusen L, Bensen-Kennedy D, Blackman N, Limsakun T, Veldman A, St Ledger K, Pabinger I; AFFINITY Investigators. Efficacy and safety of rVIII-SingleChain: results of a phase 1/3 multicenter clinical trial in severe hemophilia A. Blood. 2016 Aug 4;128(5):630-7. doi: 10.1182/blood-2016-01-687434. Epub 2016 Jun 21.

• Responsible Party: CSL Behring
• ClinicalTrials.gov Identifier: NCT01486927
• Other Study ID Numbers: CSL627_1001; 2011-002393-23 ( EudraCT Number )
• First Submitted: November 19, 2011
• First Posted: December 7, 2011
• Results First Submitted: June 24, 2016
• Results First Posted: August 9, 2016
• Last Update Posted: August 9, 2016