Trial Outcomes & Findings for Prophylaxis Study of Recombinant Factor VIII Manufactured Protein-Free (rAHF-PFM) in Patients With Hemophilia A (NCT NCT00243386)

NCT ID: NCT00243386

Last Updated: 2021-05-19

Results Overview

Participants were Randomized to Receive 1 of the 2 Following Prophylaxis Regimens (Study Part 2): 1. Standard prophylaxis (20-40 IU/kg (every 48 ±6 hour), exact regimen determined by investigator) 2. PK-driven prophylaxis (20-80 IU/kg (every 72 ±6 hour), exact regimen determined by sponsor) Annualized bleed rates were transformed using the square root of the number of bleeding episodes observed (X = bleeds/year), X' = √(X + 0.5). This transformation was performed to stabilize the variance and align the sample distribution with the assumption of normality inherent in using the t-test.

• Recruitment status: COMPLETED
• Study phase: PHASE4
• Target enrollment: 82 participants
• Primary outcome timeframe: 12 months ±2 weeks
• Results posted on: 2021-05-19

Participant Flow

Participants were enrolled at 21 European and 9 United States clinical sites beginning January 2006 and completing in June 2010

82 participants were enrolled and screened. 7 were screen failures, 1 was withdrawn for non-compliance, and 1 requested withdrawal. Therefore, 73 of the 82 enrolled were exposed to investigational product in the first part of the study (on-demand treatment).

Participant milestones

Measure	All Study Participants Participants first underwent an open-label pharmacokinetic (PK) evaluation of rAHF-PFM. 48 hours after the initial PK study, a 6 month period of on-demand treatment was conducted (Part 1). After completing the on-demand treatment, participants were randomized to 1 of 2 prophylactic regimens for 12 months ±2 weeks (Part 2). The standard prophylactic regimen was dosed at 20 to 40 IU/kg every 48 ±6 hours, and the PK-driven prophylaxis regimen was dosed at 20 to 80 IU/kg every 72 ±6 hours.	PK-Driven Prophylaxis The PK-driven prophylaxis regimen was dosed at 20 to 80 IU/kg of rAHF-PFM every 72 ±6 hours	Standard Prophylaxis The standard prophylactic regimen was dosed at 20 to 40 IU/kg of rAHF-PFM every 48 ±6 hours
On-Demand Regimen (Study Part 1) STARTED	73	0	0
On-Demand Regimen (Study Part 1) COMPLETED	69	0	0
On-Demand Regimen (Study Part 1) NOT COMPLETED	4	0	0
End of Part 1, But Prior to Prophylaxis STARTED	69	0	0
End of Part 1, But Prior to Prophylaxis COMPLETED	66	0	0
End of Part 1, But Prior to Prophylaxis NOT COMPLETED	3	0	0
PK-Driven or Standard Prophylaxis STARTED	0	34	32
PK-Driven or Standard Prophylaxis COMPLETED	0	31	32
PK-Driven or Standard Prophylaxis NOT COMPLETED	0	3	0

Reasons for withdrawal

Measure	All Study Participants Participants first underwent an open-label pharmacokinetic (PK) evaluation of rAHF-PFM. 48 hours after the initial PK study, a 6 month period of on-demand treatment was conducted (Part 1). After completing the on-demand treatment, participants were randomized to 1 of 2 prophylactic regimens for 12 months ±2 weeks (Part 2). The standard prophylactic regimen was dosed at 20 to 40 IU/kg every 48 ±6 hours, and the PK-driven prophylaxis regimen was dosed at 20 to 80 IU/kg every 72 ±6 hours.	PK-Driven Prophylaxis The PK-driven prophylaxis regimen was dosed at 20 to 80 IU/kg of rAHF-PFM every 72 ±6 hours	Standard Prophylaxis The standard prophylactic regimen was dosed at 20 to 40 IU/kg of rAHF-PFM every 48 ±6 hours
On-Demand Regimen (Study Part 1) Withdrawal by Subject	1	0	0
On-Demand Regimen (Study Part 1) Lost to Follow-up	1	0	0
On-Demand Regimen (Study Part 1) Screen Failures	2	0	0
End of Part 1, But Prior to Prophylaxis Withdrawal by Subject	1	0	0
End of Part 1, But Prior to Prophylaxis Lost to Follow-up	1	0	0
End of Part 1, But Prior to Prophylaxis Withdrawn for Non-Compliance	1	0	0
PK-Driven or Standard Prophylaxis Withdrawn for Non-Compliance	0	2	0
PK-Driven or Standard Prophylaxis Lack of Efficacy	0	1	0

Baseline Characteristics

Prophylaxis Study of Recombinant Factor VIII Manufactured Protein-Free (rAHF-PFM) in Patients With Hemophilia A

Baseline characteristics by cohort

Measure	All Study Participants n=73 Participants Participants first underwent an open-label evaluation of rAHF-PFM PK. 48 hours after the initial PK study, a 6 month period of on-demand treatment was conducted (Part 1). After completing the on-demand treatment, participants were randomized to 1 of 2 prophylactic regimens for 12 months ±2 weeks (Part 2). The standard prophylactic regimen was dosed at 20 to 40 IU/kg every 48 ±6 hours, and the PK-driven prophylaxis regimen was dosed at 20 to 80 IU/kg every 72 ±6 hours.
Age, Continuous	26 years n=93 Participants
Sex: Female, Male Female	0 Participants n=93 Participants
Sex: Female, Male Male	73 Participants n=93 Participants

PRIMARY outcome

Timeframe: 12 months ±2 weeks

Population: Per Protocol

Participants were Randomized to Receive 1 of the 2 Following Prophylaxis Regimens (Study Part 2): 1. Standard prophylaxis (20-40 IU/kg (every 48 ±6 hour), exact regimen determined by investigator) 2. PK-driven prophylaxis (20-80 IU/kg (every 72 ±6 hour), exact regimen determined by sponsor) Annualized bleed rates were transformed using the square root of the number of bleeding episodes observed (X = bleeds/year), X' = √(X + 0.5). This transformation was performed to stabilize the variance and align the sample distribution with the assumption of normality inherent in using the t-test.

Outcome measures

Measure	PK-Driven Prophylaxis n=23 Participants PK-driven prophylaxis regimen dosed at 20 to 80 IU/kg every 72 ±6 hours	Standard Prophylaxis n=30 Participants Standard prophylaxis regimen dosed at 20 to 40 IU/kg every 48 ±6 hours	PK-Driven Prophylaxis 20-80 IU/kg (every 72 ± 6 hours), exact regimen to be determined by the sponsor	SAEs Outside of the 3 Treatment Arms Participants with SAEs that occurred after exposure to investigational product, but outside of the three treatment arms
Mean Transformed Annualized Bleed Rate Estimates From Each of the 1-year Prophylaxis Regimens	1.61 (bleeds/year)^(1/2) Standard Deviation 1.10	1.46 (bleeds/year)^(1/2) Standard Deviation 0.98	—	—

PRIMARY outcome

Timeframe: 12 months ±2 weeks

Population: Intent to treat

Participants were Randomized to Receive 1 of the 2 Following Prophylaxis Regimens (Part 2 of the study): 1. Standard prophylaxis- infusions every 48 ±6 hours, dosed at 20 to 40 IU/kg. 2. PK-driven prophylaxis- infusions every 72 ±6 hours dosed at 20 to 80 IU/kg.

Outcome measures

Measure	PK-Driven Prophylaxis n=34 Participants PK-driven prophylaxis regimen dosed at 20 to 80 IU/kg every 72 ±6 hours	Standard Prophylaxis n=32 Participants Standard prophylaxis regimen dosed at 20 to 40 IU/kg every 48 ±6 hours	PK-Driven Prophylaxis 20-80 IU/kg (every 72 ± 6 hours), exact regimen to be determined by the sponsor	SAEs Outside of the 3 Treatment Arms Participants with SAEs that occurred after exposure to investigational product, but outside of the three treatment arms
Median Annualized Bleed Rate Estimates From Each of the 1 Year Prophylaxis Regimens	2.01 Bleeds per year Interval 0.0 to 17.06	1.00 Bleeds per year Interval 0.0 to 25.87	—	—

SECONDARY outcome

Timeframe: On-demand 6 months (± 2 weeks); followed by Prophylaxis 12 months (± 2 weeks)

Population: Intent to treat

Annualized bleed rates were transformed using the square root of the number of bleeding episodes observed (X bleeds/year), X' = √(X + 0.5). This transformation was performed to stabilize the variance and align the sample distribution with the assumption of normality inherent in using the paired t-test. Mean Difference of Transformed Annualized Bleeding Rate (TABR) = (On-Demand Treatment TABR) - (Standard Prophylaxis Treatment TABR). Participants from the On-Demand portion of the study were subsequently randomized to either Standard Prophylaxis or PK-Driven Prophylaxis, (i.e the same participants were analyzed across the two measurement time periods).

Outcome measures

Measure	PK-Driven Prophylaxis n=32 Participants PK-driven prophylaxis regimen dosed at 20 to 80 IU/kg every 72 ±6 hours	Standard Prophylaxis Standard prophylaxis regimen dosed at 20 to 40 IU/kg every 48 ±6 hours	PK-Driven Prophylaxis 20-80 IU/kg (every 72 ± 6 hours), exact regimen to be determined by the sponsor	SAEs Outside of the 3 Treatment Arms Participants with SAEs that occurred after exposure to investigational product, but outside of the three treatment arms
Mean Difference of Transformed Annualized Bleeding Rate Between On-Demand and Standard Prophylaxis Treatment Regimens	5.29 (bleeds/year)^(1/2) Standard Deviation 1.46	—	—	—

SECONDARY outcome

Timeframe: On-demand 6 months (± 2 weeks); followed by Prophylaxis 12 months (± 2 weeks)

Population: Intent to treat

Annualized bleed rates were transformed using the square root of the number of bleeding episodes observed (X bleeds/year), X' = √(X + 0.5). This transformation was performed to stabilize the variance and align the sample distribution with the assumption of normality inherent in using the paired t-test. Mean Difference of Transformed Annualized Bleeding Rate (TABR) = (On-Demand Treatment TABR) - (PK-Driven Prophylaxis Treatment TABR) Participants from the On-Demand portion of the study were subsequently randomized to either Standard Prophylaxis or PK-Driven Prophylaxis, (i.e the same participants were analyzed across the two measurement time periods).

Outcome measures

Measure	PK-Driven Prophylaxis n=34 Participants PK-driven prophylaxis regimen dosed at 20 to 80 IU/kg every 72 ±6 hours	Standard Prophylaxis Standard prophylaxis regimen dosed at 20 to 40 IU/kg every 48 ±6 hours	PK-Driven Prophylaxis 20-80 IU/kg (every 72 ± 6 hours), exact regimen to be determined by the sponsor	SAEs Outside of the 3 Treatment Arms Participants with SAEs that occurred after exposure to investigational product, but outside of the three treatment arms
Mean Difference of Transformed Annualized Bleeding Rate Between On-Demand and PK-Driven Prophylaxis Treatment Regimens	5.00 (bleeds/year)^(1/2) Standard Deviation 1.85	—	—	—

SECONDARY outcome

Timeframe: On-demand 6 months (± 2 weeks); Prophylaxis 12 months (± 2 weeks)

Population: Intent to treat

Annualized bleed rates were transformed using the square root of the number of bleeding episodes observed (X bleeds/year), X' = √(X + 0.5). This transformation was performed to stabilize the variance and align the sample distribution with the assumption of normality inherent in using the paired t-test. Mean Difference of Transformed Annualized Bleeding Rate (TABR) = (On-Demand Treatment TABR) - (Any Prophylaxis Treatment TABR). Any Prophylaxis = Standard or PK-Driven Prophylaxis Participants from the On-Demand portion of the study were subsequently randomized to either Standard Prophylaxis or PK-Driven Prophylaxis, (i.e the same participants were analyzed across the two measurement time periods).

Outcome measures

Measure	PK-Driven Prophylaxis n=66 Participants PK-driven prophylaxis regimen dosed at 20 to 80 IU/kg every 72 ±6 hours	Standard Prophylaxis Standard prophylaxis regimen dosed at 20 to 40 IU/kg every 48 ±6 hours	PK-Driven Prophylaxis 20-80 IU/kg (every 72 ± 6 hours), exact regimen to be determined by the sponsor	SAEs Outside of the 3 Treatment Arms Participants with SAEs that occurred after exposure to investigational product, but outside of the three treatment arms
Mean Difference of Transformed Annualized Bleeding Rate Between On-Demand and Any Prophylaxis Treatment Regimens	5.14 (bleeds/year)^(1/2) Standard Deviation 1.66	—	—	—

SECONDARY outcome

Timeframe: 12 months ±2 weeks

Population: Intent to treat

Participants were Randomized to Receive 1 of the 2 Following Prophylaxis Regimens (Part 2 of the study): 1. Standard prophylaxis- infusions every 48 ±6 hours, dosed at 20 to 40 IU/kg. 2. PK-driven prophylaxis- infusions every 72 ±6 hours dosed at 20 to 80 IU/kg.

Outcome measures

Measure	PK-Driven Prophylaxis n=34 Participants PK-driven prophylaxis regimen dosed at 20 to 80 IU/kg every 72 ±6 hours	Standard Prophylaxis n=32 Participants Standard prophylaxis regimen dosed at 20 to 40 IU/kg every 48 ±6 hours	PK-Driven Prophylaxis 20-80 IU/kg (every 72 ± 6 hours), exact regimen to be determined by the sponsor	SAEs Outside of the 3 Treatment Arms Participants with SAEs that occurred after exposure to investigational product, but outside of the three treatment arms
Total Weight-Adjusted Dose of rAHF-PFM Used Per Year for Each Prophylaxis Arm	5197.8 IU/kg Interval 3268.4 to 8273.5	5768.2 IU/kg Interval 4728.0 to 6425.4	—	—

SECONDARY outcome

Timeframe: Throughout the study period (4 years and 5 months)

Population: Intent to Treat Efficacy Set

The number of bleeding episodes treated with 1, 2, 3, or ≥4 infusions of rAHF-PFM to achieve adequate hemostasis

Outcome measures

Measure	PK-Driven Prophylaxis n=62 Participants PK-driven prophylaxis regimen dosed at 20 to 80 IU/kg every 72 ±6 hours	Standard Prophylaxis n=13 Participants Standard prophylaxis regimen dosed at 20 to 40 IU/kg every 48 ±6 hours	PK-Driven Prophylaxis n=22 Participants 20-80 IU/kg (every 72 ± 6 hours), exact regimen to be determined by the sponsor	SAEs Outside of the 3 Treatment Arms Participants with SAEs that occurred after exposure to investigational product, but outside of the three treatment arms
Bleeding Episodes Treated With 1 to ≥4 Infusions 4 or more infusions (n = 21, 5, 5)	50 Bleeding episodes	9 Bleeding episodes	7 Bleeding episodes	—
Bleeding Episodes Treated With 1 to ≥4 Infusions 1 infusion (n = 62, 13, 22)	1168 Bleeding episodes	68 Bleeding episodes	90 Bleeding episodes	—
Bleeding Episodes Treated With 1 to ≥4 Infusions 2 infusions (n = 51, 6, 9)	277 Bleeding episodes	12 Bleeding episodes	37 Bleeding episodes	—
Bleeding Episodes Treated With 1 to ≥4 Infusions 3 infusions (n = 27, 2, 4)	128 Bleeding episodes	4 Bleeding episodes	5 Bleeding episodes	—

SECONDARY outcome

Timeframe: On-demand 6 months (± 2 weeks); Prophylaxis 12 months (± 2 weeks)

Population: Hemostatic Efficacy Rating Analysis Set (Participants with bleeding episodes that were rated)

Number of rAHF-PFM-treated bleeding episodes with an assessment of hemostasis (4-point ordinal scale): Excellent: Full pain relief & bleeding cessation within ~8 hrs of 1 infusion. Additional infusions may have been given to maintain hemostasis; Good: Definite pain relief and/or improvement in bleeding within ~8 hrs after infusion. Possibly requires >1 infusion for complete resolution; Fair: Probable or slight relief of pain & slight improvement in bleeding within ~8 hrs after infusion. Requires >1 infusion for complete resolution; None: No improvement or condition worsens

Outcome measures

Measure	PK-Driven Prophylaxis n=70 Participants PK-driven prophylaxis regimen dosed at 20 to 80 IU/kg every 72 ±6 hours	Standard Prophylaxis n=18 Participants Standard prophylaxis regimen dosed at 20 to 40 IU/kg every 48 ±6 hours	PK-Driven Prophylaxis n=25 Participants 20-80 IU/kg (every 72 ± 6 hours), exact regimen to be determined by the sponsor	SAEs Outside of the 3 Treatment Arms Participants with SAEs that occurred after exposure to investigational product, but outside of the three treatment arms
Assessment of Hemostasis for Treatment of Bleeding Episodes Excellent	547 bleeding episodes	39 bleeding episodes	33 bleeding episodes	—
Assessment of Hemostasis for Treatment of Bleeding Episodes Good	943 bleeding episodes	38 bleeding episodes	75 bleeding episodes	—
Assessment of Hemostasis for Treatment of Bleeding Episodes Fair	167 bleeding episodes	16 bleeding episodes	11 bleeding episodes	—
Assessment of Hemostasis for Treatment of Bleeding Episodes None	3 bleeding episodes	0 bleeding episodes	20 bleeding episodes	—
Assessment of Hemostasis for Treatment of Bleeding Episodes Unknown	13 bleeding episodes	0 bleeding episodes	0 bleeding episodes	—

SECONDARY outcome

Timeframe: Pharmacokinetic evaluations: 30 minutes pre-infusion up to 48 hours post-infusion

Population: Intent to Treat Pharmacokinetic Analysis Set

Total AUC estimated by AUC 0-48h plus an area extrapolated from the log-linear regression model

Outcome measures

Measure	PK-Driven Prophylaxis n=65 Participants PK-driven prophylaxis regimen dosed at 20 to 80 IU/kg every 72 ±6 hours	Standard Prophylaxis n=6 Participants Standard prophylaxis regimen dosed at 20 to 40 IU/kg every 48 ±6 hours	PK-Driven Prophylaxis 20-80 IU/kg (every 72 ± 6 hours), exact regimen to be determined by the sponsor	SAEs Outside of the 3 Treatment Arms Participants with SAEs that occurred after exposure to investigational product, but outside of the three treatment arms
Total Area Under the Curve (AUC)	1334.45 IU*h/dL Standard Deviation 454.33	1061.26 IU*h/dL Standard Deviation 452.87	—	—

SECONDARY outcome

Timeframe: Pharmacokinetic evaluations: 30 minutes pre-infusion up to 48 hours post-infusion

Population: Intent to Treat Pharmacokinetic Analysis Set

Area under the factor VIII (FVIII) plasma concentration versus time curve (AUC) from 0 to 48 hours estimated using the linear trapezoidal method

Outcome measures

Measure	PK-Driven Prophylaxis n=65 Participants PK-driven prophylaxis regimen dosed at 20 to 80 IU/kg every 72 ±6 hours	Standard Prophylaxis n=6 Participants Standard prophylaxis regimen dosed at 20 to 40 IU/kg every 48 ±6 hours	PK-Driven Prophylaxis 20-80 IU/kg (every 72 ± 6 hours), exact regimen to be determined by the sponsor	SAEs Outside of the 3 Treatment Arms Participants with SAEs that occurred after exposure to investigational product, but outside of the three treatment arms
Area Under the Curve	1213.98 IU*h/dL Standard Deviation 323.96	966.68 IU*h/dL Standard Deviation 330.83	—	—

SECONDARY outcome

Timeframe: Within 1 hour post-infusion

Population: Intent to Treat Pharmacokinetic Analysis Set

Maximal Factor VIII Concentration After Infusion

Outcome measures

Measure	PK-Driven Prophylaxis n=65 Participants PK-driven prophylaxis regimen dosed at 20 to 80 IU/kg every 72 ±6 hours	Standard Prophylaxis n=6 Participants Standard prophylaxis regimen dosed at 20 to 40 IU/kg every 48 ±6 hours	PK-Driven Prophylaxis 20-80 IU/kg (every 72 ± 6 hours), exact regimen to be determined by the sponsor	SAEs Outside of the 3 Treatment Arms Participants with SAEs that occurred after exposure to investigational product, but outside of the three treatment arms
Maximum Plasma Concentration (C-max)	91.12 IU/dL Standard Deviation 20.15	74.47 IU/dL Standard Deviation 11.30	—	—

SECONDARY outcome

Timeframe: 30 minutes pre-infusion to 48 hours post-infusion

Population: Intent to Treat Pharmacokinetic Analysis Set

Change in factor VIII concentration from pre- to post-infusion at initial and termination study visits. Adjusted IR defined as: [Cmax (IU/dL) - pre-infusion FVIII (IU/dL)]/dose (IU/kg)

Outcome measures

Measure	PK-Driven Prophylaxis n=65 Participants PK-driven prophylaxis regimen dosed at 20 to 80 IU/kg every 72 ±6 hours	Standard Prophylaxis n=6 Participants Standard prophylaxis regimen dosed at 20 to 40 IU/kg every 48 ±6 hours	PK-Driven Prophylaxis 20-80 IU/kg (every 72 ± 6 hours), exact regimen to be determined by the sponsor	SAEs Outside of the 3 Treatment Arms Participants with SAEs that occurred after exposure to investigational product, but outside of the three treatment arms
Adjusted Incremental Recovery (IR)	1.81 IU/dL per IU/kg Standard Deviation 0.41	1.47 IU/dL per IU/kg Standard Deviation 0.27	—	—

SECONDARY outcome

Timeframe: Pharmacokinetic evaluations: 30 minutes pre-infusion up to 48 hours post-infusion

Population: Intent to Treat Pharmacokinetic Analysis Set

Computed from the regression slope in the terminal phase of the model. Terminal half life is the time it takes for the plasma concentration or the amount of drug in the body to be reduced by 50%.

Outcome measures

Measure	PK-Driven Prophylaxis n=65 Participants PK-driven prophylaxis regimen dosed at 20 to 80 IU/kg every 72 ±6 hours	Standard Prophylaxis n=6 Participants Standard prophylaxis regimen dosed at 20 to 40 IU/kg every 48 ±6 hours	PK-Driven Prophylaxis 20-80 IU/kg (every 72 ± 6 hours), exact regimen to be determined by the sponsor	SAEs Outside of the 3 Treatment Arms Participants with SAEs that occurred after exposure to investigational product, but outside of the three treatment arms
Terminal Half-life	13.91 hours Standard Deviation 5.07	14.66 hours Standard Deviation 5.21	—	—

SECONDARY outcome

Timeframe: Pharmacokinetic evaluations: 30 minutes pre-infusion up to 48 hours post-infusion

Population: Intent to Treat Pharmacokinetic Analysis Set

Computed as the weight-adjusted dose divided by total AUC

Outcome measures

Measure	PK-Driven Prophylaxis n=65 Participants PK-driven prophylaxis regimen dosed at 20 to 80 IU/kg every 72 ±6 hours	Standard Prophylaxis n=6 Participants Standard prophylaxis regimen dosed at 20 to 40 IU/kg every 48 ±6 hours	PK-Driven Prophylaxis 20-80 IU/kg (every 72 ± 6 hours), exact regimen to be determined by the sponsor	SAEs Outside of the 3 Treatment Arms Participants with SAEs that occurred after exposure to investigational product, but outside of the three treatment arms
Weight-Adjusted Clearance	3.89 mL/(kg*h) Standard Deviation 1.21	5.17 mL/(kg*h) Standard Deviation 1.94	—	—

SECONDARY outcome

Timeframe: Pharmacokinetic evaluations: 30 minutes pre-infusion up to 48 hours post-infusion

Population: Intent to Treat Pharmacokinetic Analysis Set

Computed as total Area Under the Moment Curve (AUMC) divided by the total AUC

Outcome measures

Measure	PK-Driven Prophylaxis n=65 Participants PK-driven prophylaxis regimen dosed at 20 to 80 IU/kg every 72 ±6 hours	Standard Prophylaxis n=6 Participants Standard prophylaxis regimen dosed at 20 to 40 IU/kg every 48 ±6 hours	PK-Driven Prophylaxis 20-80 IU/kg (every 72 ± 6 hours), exact regimen to be determined by the sponsor	SAEs Outside of the 3 Treatment Arms Participants with SAEs that occurred after exposure to investigational product, but outside of the three treatment arms
Mean Residence Time	17.71 hours Standard Deviation 7.16	17.88 hours Standard Deviation 5.67	—	—

SECONDARY outcome

Timeframe: Pharmacokinetic evaluations: 30 minutes pre-infusion up to 48 hours post-infusion

Population: Intent to Treat Pharmacokinetic Analysis Set

Computed as weight-adjusted clearance * mean residence time

Outcome measures

Measure	PK-Driven Prophylaxis n=65 Participants PK-driven prophylaxis regimen dosed at 20 to 80 IU/kg every 72 ±6 hours	Standard Prophylaxis n=6 Participants Standard prophylaxis regimen dosed at 20 to 40 IU/kg every 48 ±6 hours	PK-Driven Prophylaxis 20-80 IU/kg (every 72 ± 6 hours), exact regimen to be determined by the sponsor	SAEs Outside of the 3 Treatment Arms Participants with SAEs that occurred after exposure to investigational product, but outside of the three treatment arms
Volume of Distribution at Steady State	0.65 dL/kg Standard Deviation 0.19	0.84 dL/kg Standard Deviation 0.19	—	—

SECONDARY outcome

Timeframe: Throughout study period (4 years and 5 months)

Population: Safety Analysis Set

Number of treated participants who developed factor VIII inhibitors

Outcome measures

Measure	PK-Driven Prophylaxis n=73 Participants PK-driven prophylaxis regimen dosed at 20 to 80 IU/kg every 72 ±6 hours	Standard Prophylaxis Standard prophylaxis regimen dosed at 20 to 40 IU/kg every 48 ±6 hours	PK-Driven Prophylaxis 20-80 IU/kg (every 72 ± 6 hours), exact regimen to be determined by the sponsor	SAEs Outside of the 3 Treatment Arms Participants with SAEs that occurred after exposure to investigational product, but outside of the three treatment arms
Factor VIII Inhibitor Development	0 Participants	—	—	—

SECONDARY outcome

Timeframe: Throughout study period (4 years and 5 months)

Population: Safety Analysis Set

Number of treated participants with AEs judged to be possibly or probably related to treatment with IP

Outcome measures

Measure	PK-Driven Prophylaxis n=73 Participants PK-driven prophylaxis regimen dosed at 20 to 80 IU/kg every 72 ±6 hours	Standard Prophylaxis Standard prophylaxis regimen dosed at 20 to 40 IU/kg every 48 ±6 hours	PK-Driven Prophylaxis 20-80 IU/kg (every 72 ± 6 hours), exact regimen to be determined by the sponsor	SAEs Outside of the 3 Treatment Arms Participants with SAEs that occurred after exposure to investigational product, but outside of the three treatment arms
Number of Participants With AEs Related to Investigational Product (IP)	4 Participants	—	—	—

SECONDARY outcome

Timeframe: Throughout study period (4 years and 5 months)

Population: Safety Analysis Set

Number of treated participants with 1 or more AE regardless of relatedness to IP

Outcome measures

Measure	PK-Driven Prophylaxis n=73 Participants PK-driven prophylaxis regimen dosed at 20 to 80 IU/kg every 72 ±6 hours	Standard Prophylaxis Standard prophylaxis regimen dosed at 20 to 40 IU/kg every 48 ±6 hours	PK-Driven Prophylaxis 20-80 IU/kg (every 72 ± 6 hours), exact regimen to be determined by the sponsor	SAEs Outside of the 3 Treatment Arms Participants with SAEs that occurred after exposure to investigational product, but outside of the three treatment arms
Number of Participants Who Reported ≥1 AE Regardless of Relatedness to Investigational Product (IP)	44 Participants	—	—	—

SECONDARY outcome

Timeframe: Throughout the study period (4 years and 5 months)

Population: Safety Analysis Set

Outcome measures

Measure	PK-Driven Prophylaxis n=72 Participants PK-driven prophylaxis regimen dosed at 20 to 80 IU/kg every 72 ±6 hours	Standard Prophylaxis n=32 Participants Standard prophylaxis regimen dosed at 20 to 40 IU/kg every 48 ±6 hours	PK-Driven Prophylaxis n=34 Participants 20-80 IU/kg (every 72 ± 6 hours), exact regimen to be determined by the sponsor	SAEs Outside of the 3 Treatment Arms Participants with SAEs that occurred after exposure to investigational product, but outside of the three treatment arms
Number of Participants Who Reported ≥1 AE Regardless of Relatedness to IP by Treatment Regimen	33 participants	15 participants	19 participants	—

SECONDARY outcome

Timeframe: Throughout the study period (4 years and 5 months)

Population: Safety Analysis Set

Outcome measures

Measure	PK-Driven Prophylaxis n=72 Participants PK-driven prophylaxis regimen dosed at 20 to 80 IU/kg every 72 ±6 hours	Standard Prophylaxis n=32 Participants Standard prophylaxis regimen dosed at 20 to 40 IU/kg every 48 ±6 hours	PK-Driven Prophylaxis n=34 Participants 20-80 IU/kg (every 72 ± 6 hours), exact regimen to be determined by the sponsor	SAEs Outside of the 3 Treatment Arms n=1 Participants Participants with SAEs that occurred after exposure to investigational product, but outside of the three treatment arms
Number of Participants With SAEs by Preferred MedDRA Term and Treatment Regimen NAUSEA	1 participants	0 participants	0 participants	0 participants
Number of Participants With SAEs by Preferred MedDRA Term and Treatment Regimen HAEMOPHILIC ARTHROPATHY	1 participants	0 participants	1 participants	0 participants
Number of Participants With SAEs by Preferred MedDRA Term and Treatment Regimen ABDOMINAL PAIN	1 participants	0 participants	0 participants	0 participants
Number of Participants With SAEs by Preferred MedDRA Term and Treatment Regimen TOOTH ABSCESS	1 participants	0 participants	0 participants	0 participants
Number of Participants With SAEs by Preferred MedDRA Term and Treatment Regimen JOINT DISLOCATION	1 participants	0 participants	0 participants	0 participants
Number of Participants With SAEs by Preferred MedDRA Term and Treatment Regimen SYNOVITIS	1 participants	0 participants	0 participants	0 participants
Number of Participants With SAEs by Preferred MedDRA Term and Treatment Regimen CALCULUS URINARY	1 participants	0 participants	0 participants	0 participants
Number of Participants With SAEs by Preferred MedDRA Term and Treatment Regimen HOSPITALIZATION	1 participants	0 participants	0 participants	0 participants
Number of Participants With SAEs by Preferred MedDRA Term and Treatment Regimen PULPITIS DENTAL	0 participants	1 participants	0 participants	0 participants
Number of Participants With SAEs by Preferred MedDRA Term and Treatment Regimen SOMNAMBULISM	0 participants	1 participants	0 participants	0 participants
Number of Participants With SAEs by Preferred MedDRA Term and Treatment Regimen FACTOR VIII INHIBITION (UNCONFIRMED)	0 participants	0 participants	1 participants	0 participants
Number of Participants With SAEs by Preferred MedDRA Term and Treatment Regimen APPENDICITIS	0 participants	0 participants	1 participants	0 participants
Number of Participants With SAEs by Preferred MedDRA Term and Treatment Regimen PAIN IN EXTREMITY	0 participants	0 participants	0 participants	1 participants

SECONDARY outcome

Timeframe: Throughout study period (4 years and 5 months)

Population: Safety Analysis Set

Outcome measures

Measure	PK-Driven Prophylaxis n=73 Participants PK-driven prophylaxis regimen dosed at 20 to 80 IU/kg every 72 ±6 hours	Standard Prophylaxis Standard prophylaxis regimen dosed at 20 to 40 IU/kg every 48 ±6 hours	PK-Driven Prophylaxis 20-80 IU/kg (every 72 ± 6 hours), exact regimen to be determined by the sponsor	SAEs Outside of the 3 Treatment Arms Participants with SAEs that occurred after exposure to investigational product, but outside of the three treatment arms
AEs With Onset ≤1 Hour Following the End of an Infusion, Regardless of Relatedness	39 Events	—	—	—

SECONDARY outcome

Timeframe: Throughout the study period (4 years and 5 months)

Population: Safety Analysis Set

This outcome is focused only on SEVERE SAEs and SEVERE non-SAEs

Outcome measures

Measure	PK-Driven Prophylaxis n=72 Participants PK-driven prophylaxis regimen dosed at 20 to 80 IU/kg every 72 ±6 hours	Standard Prophylaxis n=32 Participants Standard prophylaxis regimen dosed at 20 to 40 IU/kg every 48 ±6 hours	PK-Driven Prophylaxis n=34 Participants 20-80 IU/kg (every 72 ± 6 hours), exact regimen to be determined by the sponsor	SAEs Outside of the 3 Treatment Arms Participants with SAEs that occurred after exposure to investigational product, but outside of the three treatment arms
Number of Participants With Severe SAEs and Severe Non-SAEs by Preferred MedDRA Term and Treatment Regimen TOOTH ABSCESS (SAE)	1 participants	0 participants	0 participants	—
Number of Participants With Severe SAEs and Severe Non-SAEs by Preferred MedDRA Term and Treatment Regimen HAEMOPHILIC ARTHROPATHY (SAE)	0 participants	0 participants	1 participants	—
Number of Participants With Severe SAEs and Severe Non-SAEs by Preferred MedDRA Term and Treatment Regimen HAEMOPHILIC ARTHROPATHY (non-SAE)	1 participants	0 participants	1 participants	—
Number of Participants With Severe SAEs and Severe Non-SAEs by Preferred MedDRA Term and Treatment Regimen ABDOMINAL PAIN (non-SAE)	1 participants	0 participants	0 participants	—
Number of Participants With Severe SAEs and Severe Non-SAEs by Preferred MedDRA Term and Treatment Regimen ARTHRALGIA (non-SAE)	1 participants	0 participants	0 participants	—

SECONDARY outcome

Timeframe: Baseline

Population: Safety Analysis Set

Physical Functioning (PF); Role Limitation Due to Physical Health (RP); Bodily Pain (BP); General Health (GH); Vitality (VT); Social Functioning (SF); Role Limitation Due to Emotional Problems (RE); Mental Health (MH), Physical Component Score (PCS); Mental Component Score (MCS). Baseline SF-36v1 Scores, where data available. Scores range 0-100, higher scores represent better health. There is no total overall score; scoring is done for subscores and summary scores. The raw data from the SF-36 items were transformed to norm based scores for each of the 8 HRQoL/SF-36 health domain scores.

Outcome measures

Measure	PK-Driven Prophylaxis n=71 Participants PK-driven prophylaxis regimen dosed at 20 to 80 IU/kg every 72 ±6 hours	Standard Prophylaxis Standard prophylaxis regimen dosed at 20 to 40 IU/kg every 48 ±6 hours	PK-Driven Prophylaxis 20-80 IU/kg (every 72 ± 6 hours), exact regimen to be determined by the sponsor	SAEs Outside of the 3 Treatment Arms Participants with SAEs that occurred after exposure to investigational product, but outside of the three treatment arms
Baseline Health-related Quality of Life (HRQoL) Scores: PF, RP, BP, GH, VT, SF, RE, MH, PCS, and MCS Physical Functioning (PF)	44.56 Scores on a scale Interval 17.29 to 57.14	—	—	—
Baseline Health-related Quality of Life (HRQoL) Scores: PF, RP, BP, GH, VT, SF, RE, MH, PCS, and MCS Role-Physical (RP)	42.10 Scores on a scale Interval 27.95 to 56.24	—	—	—
Baseline Health-related Quality of Life (HRQoL) Scores: PF, RP, BP, GH, VT, SF, RE, MH, PCS, and MCS Bodily Pain (BP)	46.48 Scores on a scale Interval 25.07 to 62.75	—	—	—
Baseline Health-related Quality of Life (HRQoL) Scores: PF, RP, BP, GH, VT, SF, RE, MH, PCS, and MCS General Health (GH)	43.87 Scores on a scale Interval 19.52 to 64.0	—	—	—
Baseline Health-related Quality of Life (HRQoL) Scores: PF, RP, BP, GH, VT, SF, RE, MH, PCS, and MCS Vitality (VT)	51.42 Scores on a scale Interval 25.39 to 67.2	—	—	—
Baseline Health-related Quality of Life (HRQoL) Scores: PF, RP, BP, GH, VT, SF, RE, MH, PCS, and MCS Social Functioning (SF)	46.28 Scores on a scale Interval 19.14 to 57.14	—	—	—
Baseline Health-related Quality of Life (HRQoL) Scores: PF, RP, BP, GH, VT, SF, RE, MH, PCS, and MCS Role-Emotional (RE)	55.34 Scores on a scale Interval 23.74 to 55.34	—	—	—
Baseline Health-related Quality of Life (HRQoL) Scores: PF, RP, BP, GH, VT, SF, RE, MH, PCS, and MCS Mental Health (MH)	50.44 Scores on a scale Interval 20.91 to 64.07	—	—	—
Baseline Health-related Quality of Life (HRQoL) Scores: PF, RP, BP, GH, VT, SF, RE, MH, PCS, and MCS Physical Component Score (PCS)	42.32 Scores on a scale Interval 20.1 to 67.67	—	—	—
Baseline Health-related Quality of Life (HRQoL) Scores: PF, RP, BP, GH, VT, SF, RE, MH, PCS, and MCS Mental Component Score (MCS)	52.65 Scores on a scale Interval 22.56 to 68.1	—	—	—

SECONDARY outcome

Timeframe: End of on-demand treatment period (6 months) and at study termination (approximately 18 months)

Population: Pharmacoeconomic Analysis Set

Physical Functioning (PF); Role Limitation Due to Physical Health (RP); Bodily Pain (BP); General Health (GH); Vitality (VT); Social Functioning (SF); Role Limitation Due to Emotional Problems (RE); Mental Health (MH), Physical Component Score (PCS); Mental Component Score (MCS). Baseline SF-36v1 Scores, where data available. Scores range 0-100, higher scores represent better health. There is no total overall score; scoring is done for subscores and summary scores. The raw data from the SF-36 items were transformed to norm based scores for each of the 8 HRQoL/SF-36 health domain scores.

Outcome measures

Measure	PK-Driven Prophylaxis n=63 Participants PK-driven prophylaxis regimen dosed at 20 to 80 IU/kg every 72 ±6 hours	Standard Prophylaxis n=31 Participants Standard prophylaxis regimen dosed at 20 to 40 IU/kg every 48 ±6 hours	PK-Driven Prophylaxis n=34 Participants 20-80 IU/kg (every 72 ± 6 hours), exact regimen to be determined by the sponsor	SAEs Outside of the 3 Treatment Arms n=65 Participants Participants with SAEs that occurred after exposure to investigational product, but outside of the three treatment arms
Health-related Quality of Life (HRQoL) Scores: PF, RP, BP, GH, VT, SF, RE, MH, PCS, and MCS at the End of Treatment Regimens Bodily Pain (BP)	46.5 Scores on a scale Interval 29.4 to 62.8	51.6 Scores on a scale Interval 19.9 to 62.8	51.6 Scores on a scale Interval 29.4 to 62.8	51.6 Scores on a scale Interval 19.9 to 62.8
Health-related Quality of Life (HRQoL) Scores: PF, RP, BP, GH, VT, SF, RE, MH, PCS, and MCS at the End of Treatment Regimens General Health (GH)	43.9 Scores on a scale Interval 19.5 to 64.0	48.6 Scores on a scale Interval 19.5 to 64.0	46.2 Scores on a scale Interval 29.8 to 60.3	48.6 Scores on a scale Interval 19.5 to 64.0
Health-related Quality of Life (HRQoL) Scores: PF, RP, BP, GH, VT, SF, RE, MH, PCS, and MCS at the End of Treatment Regimens Mental Component Score (MCS), On-Demand n=62	54.9 Scores on a scale Interval 22.8 to 69.9	56.1 Scores on a scale Interval 13.3 to 69.6	54.5 Scores on a scale Interval 11.4 to 62.5	55.0 Scores on a scale Interval 11.4 to 69.6
Health-related Quality of Life (HRQoL) Scores: PF, RP, BP, GH, VT, SF, RE, MH, PCS, and MCS at the End of Treatment Regimens Mental Health (MH), On-Demand n=62	51.6 Scores on a scale Interval 14.1 to 64.1	50.4 Scores on a scale Interval 20.9 to 64.1	52.7 Scores on a scale Interval 7.3 to 64.1	50.4 Scores on a scale Interval 7.3 to 64.1
Health-related Quality of Life (HRQoL) Scores: PF, RP, BP, GH, VT, SF, RE, MH, PCS, and MCS at the End of Treatment Regimens Physical Component Score (PCS), On-Demand n=62	44.0 Scores on a scale Interval 16.1 to 61.2	50.2 Scores on a scale Interval 17.6 to 68.8	47.3 Scores on a scale Interval 25.3 to 62.3	47.8 Scores on a scale Interval 17.6 to 68.8
Health-related Quality of Life (HRQoL) Scores: PF, RP, BP, GH, VT, SF, RE, MH, PCS, and MCS at the End of Treatment Regimens Physical Functioning (PF), On-Demand n=62	48.8 Scores on a scale Interval 17.3 to 57.1	46.7 Scores on a scale Interval 21.5 to 57.1	46.7 Scores on a scale Interval 17.3 to 57.1	46.7 Scores on a scale Interval 17.3 to 57.1
Health-related Quality of Life (HRQoL) Scores: PF, RP, BP, GH, VT, SF, RE, MH, PCS, and MCS at the End of Treatment Regimens Role Emotional (RE)	55.3 Scores on a scale Interval 23.7 to 55.3	55.3 Scores on a scale Interval 23.7 to 55.3	55.3 Scores on a scale Interval 23.7 to 55.3	55.3 Scores on a scale Interval 23.7 to 55.3
Health-related Quality of Life (HRQoL) Scores: PF, RP, BP, GH, VT, SF, RE, MH, PCS, and MCS at the End of Treatment Regimens Role Physical (RP)	49.2 Scores on a scale Interval 28.0 to 56.2	56.2 Scores on a scale Interval 28.0 to 56.2	56.2 Scores on a scale Interval 28.0 to 56.2	56.2 Scores on a scale Interval 28.0 to 56.2
Health-related Quality of Life (HRQoL) Scores: PF, RP, BP, GH, VT, SF, RE, MH, PCS, and MCS at the End of Treatment Regimens Social Functioning (SF)	46.3 Scores on a scale Interval 30.0 to 57.1	51.7 Scores on a scale Interval 24.6 to 57.1	51.7 Scores on a scale Interval 13.7 to 57.1	51.7 Scores on a scale Interval 13.7 to 57.1
Health-related Quality of Life (HRQoL) Scores: PF, RP, BP, GH, VT, SF, RE, MH, PCS, and MCS at the End of Treatment Regimens Vitality (VT)	53.8 Scores on a scale Interval 32.5 to 70.4	56.2 Scores on a scale Interval 27.8 to 70.4	56.2 Scores on a scale Interval 23.0 to 68.0	56.2 Scores on a scale Interval 23.0 to 70.4

SECONDARY outcome

Timeframe: End of on-demand treatment period (6 months) and at study termination (approximately 18 months)

Population: Pharmacoeconomic Analysis Set ≥14 Years and Older

Differences in health domain scores = (End of on-demand treatment) - (End of prophylaxis regimen). A negative value for the median difference equates to a larger domain score for the prophylaxis regimen Physical Functioning (PF); Role Limitation Due to Physical Health (RP); Bodily Pain (BP); General Health (GH); Vitality (VT); Social Functioning (SF); Role Limitation Due to Emotional Problems (RE); Mental Health (MH), Physical Component Score (PCS); Mental Component Score (MCS). Scores range 0-100, higher scores represent better health. There is no total overall score; scoring is done for subscores and summary scores. The raw data from the SF-36 items were transformed to norm based scores for each of the 8 HRQoL/SF-36 health domain scores.

Outcome measures

Measure	PK-Driven Prophylaxis n=27 Participants PK-driven prophylaxis regimen dosed at 20 to 80 IU/kg every 72 ±6 hours	Standard Prophylaxis n=30 Participants Standard prophylaxis regimen dosed at 20 to 40 IU/kg every 48 ±6 hours	PK-Driven Prophylaxis n=57 Participants 20-80 IU/kg (every 72 ± 6 hours), exact regimen to be determined by the sponsor	SAEs Outside of the 3 Treatment Arms Participants with SAEs that occurred after exposure to investigational product, but outside of the three treatment arms
HRQoL Scores Change From On-Demand Treatment Regimen Period Through Prophylaxis Period Physical Functioning (PF)	0.00 Scores on a scale Interval -10.48 to 14.68	-2.10 Scores on a scale Interval -18.88 to 20.97	-2.10 Scores on a scale Interval -18.88 to 20.97	—
HRQoL Scores Change From On-Demand Treatment Regimen Period Through Prophylaxis Period Role Physical (RP)	0.00 Scores on a scale Interval -28.29 to 21.21	0.00 Scores on a scale Interval -28.29 to 28.29	0.00 Scores on a scale Interval -28.29 to 28.29	—
HRQoL Scores Change From On-Demand Treatment Regimen Period Through Prophylaxis Period Bodily Pain (BP)	0.00 Scores on a scale Interval -29.55 to 17.55	-4.29 Scores on a scale Interval -25.27 to 13.28	0.00 Scores on a scale Interval -29.55 to 17.55	—
HRQoL Scores Change From On-Demand Treatment Regimen Period Through Prophylaxis Period General Health (GH)	-3.74 Scores on a scale Interval -29.55 to 17.55	-2.34 Scores on a scale Interval -21.07 to 18.73	-2.34 Scores on a scale Interval -20.13 to 17.79	—
HRQoL Scores Change From On-Demand Treatment Regimen Period Through Prophylaxis Period Vitality (VT)	0.00 Scores on a scale Interval -9.47 to 23.67	0.00 Scores on a scale Interval -16.57 to 30.77	0.00 Scores on a scale Interval -16.57 to 30.77	—
HRQoL Scores Change From On-Demand Treatment Regimen Period Through Prophylaxis Period Social Functioning (SF)	0.00 Scores on a scale Interval -21.72 to 16.29	0.00 Scores on a scale Interval -16.29 to 16.29	0.00 Scores on a scale Interval -21.72 to 16.29	—
HRQoL Scores Change From On-Demand Treatment Regimen Period Through Prophylaxis Period Role Emotional (RE)	0.00 Scores on a scale Interval -10.53 to 31.6	0.00 Scores on a scale Interval -31.6 to 21.07	0.00 Scores on a scale Interval -31.6 to 31.6	—
HRQoL Scores Change From On-Demand Treatment Regimen Period Through Prophylaxis Period Mental Health (MH)	0.00 Scores on a scale Interval -13.63 to 15.9	-1.13 Scores on a scale Interval -40.9 to 34.08	0.00 Scores on a scale Interval -40.9 to 34.08	—
HRQoL Scores Change From On-Demand Treatment Regimen Period Through Prophylaxis Period Physical Component Score (PCS)	-2.55 Scores on a scale Interval -20.22 to 8.69	-3.14 Scores on a scale Interval -16.78 to 19.7	-2.76 Scores on a scale Interval -20.22 to 19.7	—
HRQoL Scores Change From On-Demand Treatment Regimen Period Through Prophylaxis Period Mental Component Score (MCS)	1.52 Scores on a scale Interval -8.31 to 21.64	0.79 Scores on a scale Interval -35.25 to 24.56	1.30 Scores on a scale Interval -35.25 to 24.56	—

SECONDARY outcome

Timeframe: End of on-demand treatment period (6 months) and at study termination (approximately 18 months)

Population: Pharmacoeconomic analysis set for participants ≥14 years of age

Change = (End of on-demand treatment) - (End of prophylaxis regimen). A negative value for the median difference equates to a larger domain score for the prophylaxis regimen. Scores range 0-100, higher scores represent better health. There is no total overall score; scoring is done for subscores and summary scores. The raw data from the SF-36 items were transformed to norm based scores.

Outcome measures

Measure	PK-Driven Prophylaxis n=57 Participants PK-driven prophylaxis regimen dosed at 20 to 80 IU/kg every 72 ±6 hours	Standard Prophylaxis Standard prophylaxis regimen dosed at 20 to 40 IU/kg every 48 ±6 hours	PK-Driven Prophylaxis 20-80 IU/kg (every 72 ± 6 hours), exact regimen to be determined by the sponsor	SAEs Outside of the 3 Treatment Arms Participants with SAEs that occurred after exposure to investigational product, but outside of the three treatment arms
Bodily Pain HRQoL Scores Change From On-Demand Period Through Prophylaxis Period	0.00 Scores on a scale Interval -29.55 to 17.55	—	—	—

SECONDARY outcome

Timeframe: End of on-demand treatment period (6 months) and at study termination (approximately 18 months)

Population: Pharmacoeconomic analysis set for participants ≥14 years of age

Change = (End of on-demand treatment) - (End of prophylaxis regimen) A negative value for the median difference equates to a larger domain score for the prophylaxis regimen. Scores range 0-100, higher scores represent better health. There is no total overall score; scoring is done for subscores and summary scores. The raw data from the SF-36 items were transformed to norm based scores.

Outcome measures

Measure	PK-Driven Prophylaxis n=57 Participants PK-driven prophylaxis regimen dosed at 20 to 80 IU/kg every 72 ±6 hours	Standard Prophylaxis Standard prophylaxis regimen dosed at 20 to 40 IU/kg every 48 ±6 hours	PK-Driven Prophylaxis 20-80 IU/kg (every 72 ± 6 hours), exact regimen to be determined by the sponsor	SAEs Outside of the 3 Treatment Arms Participants with SAEs that occurred after exposure to investigational product, but outside of the three treatment arms
Physical Component Scores (PCS) HRQoL Scores Change From On-Demand Period Through Prophylaxis Period	-2.76 Scores on a scale Interval -20.22 to 19.7	—	—	—

POST_HOC outcome

Timeframe: On-demand 6 months (± 2 weeks); Prophylaxis 12 months (± 2 weeks)

Population: Per-Protocol Efficacy Analysis Set

Bleed rates (number of bleeding episodes per subject) were annualized to account for the varying number of days a subject may have actually been on each regimen.

Outcome measures

Measure	PK-Driven Prophylaxis n=53 Participants PK-driven prophylaxis regimen dosed at 20 to 80 IU/kg every 72 ±6 hours	Standard Prophylaxis n=30 Participants Standard prophylaxis regimen dosed at 20 to 40 IU/kg every 48 ±6 hours	PK-Driven Prophylaxis n=23 Participants 20-80 IU/kg (every 72 ± 6 hours), exact regimen to be determined by the sponsor	SAEs Outside of the 3 Treatment Arms n=53 Participants Participants with SAEs that occurred after exposure to investigational product, but outside of the three treatment arms
Median (IQR) Annualized Bleed Rates	43.98 Bleeding episodes Interval 35.73 to 56.53	0.99 Bleeding episodes Interval 0.0 to 2.14	1.00 Bleeding episodes Interval 0.0 to 4.08	1.00 Bleeding episodes Interval 0.0 to 4.07

Adverse Events

On-Demand

Serious events: 7 serious events

Other events: 18 other events

Deaths: 0 deaths

Standard Prophylaxis

Serious events: 2 serious events

Other events: 4 other events

Deaths: 0 deaths

PK-Driven Prophylaxis

Serious events: 3 serious events

Other events: 7 other events

Deaths: 0 deaths

SAEs Outside of the 3 Treatment Arms

Serious events: 1 serious events

Other events: 0 other events

Deaths: 0 deaths

Serious adverse events

Measure	On-Demand n=73 participants at risk On-demand: rAHF-PFM was to be used for the treatment of bleeding episodes according to the severity and type of episode by the protocol-recommended dosing until the episode resolved: superficial (10-20 IU/kg every 12-14 hours), minor joint (20-40 IU/kg every 12-14 hours), deep muscle (30-60 IU/kg every 12-14 hours), major joint or life-threatening (60-100 IU/kg every 8-12 hours), genitourinary, GI, and intracranial (60-100 IU/kg every 8-12 hours)	Standard Prophylaxis n=32 participants at risk Standard prophylaxis regimen dosed at 20 to 40 IU/kg (every 48 ±6 hours), exact regimen to be determined by the investigator	PK-Driven Prophylaxis n=34 participants at risk PK-driven prophylaxis regimen dosed at 20 to 80 IU/kg (every 72 ±6 hours) exact regimen to be determined by the sponsor	SAEs Outside of the 3 Treatment Arms n=1 participants at risk Participants with SAEs that occurred after exposure to investigational product, but outside of the three treatment arms
Gastrointestinal disorders ABDOMINAL PAIN	1.4% 1/73 • Number of events 1 • Throughout the study period (4 years and 5 months)	0.00% 0/32 • Throughout the study period (4 years and 5 months)	0.00% 0/34 • Throughout the study period (4 years and 5 months)	0.00% 0/1 • Throughout the study period (4 years and 5 months)
Gastrointestinal disorders NAUSEA	1.4% 1/73 • Number of events 1 • Throughout the study period (4 years and 5 months)	0.00% 0/32 • Throughout the study period (4 years and 5 months)	0.00% 0/34 • Throughout the study period (4 years and 5 months)	0.00% 0/1 • Throughout the study period (4 years and 5 months)
Infections and infestations TOOTH ABSCESS	1.4% 1/73 • Number of events 1 • Throughout the study period (4 years and 5 months)	0.00% 0/32 • Throughout the study period (4 years and 5 months)	0.00% 0/34 • Throughout the study period (4 years and 5 months)	0.00% 0/1 • Throughout the study period (4 years and 5 months)
Injury, poisoning and procedural complications JOINT DISLOCATION	1.4% 1/73 • Number of events 1 • Throughout the study period (4 years and 5 months)	0.00% 0/32 • Throughout the study period (4 years and 5 months)	0.00% 0/34 • Throughout the study period (4 years and 5 months)	0.00% 0/1 • Throughout the study period (4 years and 5 months)
Musculoskeletal and connective tissue disorders HAEMOPHILIC ARTHROPATHY	1.4% 1/73 • Number of events 1 • Throughout the study period (4 years and 5 months)	0.00% 0/32 • Throughout the study period (4 years and 5 months)	2.9% 1/34 • Number of events 1 • Throughout the study period (4 years and 5 months)	0.00% 0/1 • Throughout the study period (4 years and 5 months)
Musculoskeletal and connective tissue disorders SYNOVITIS	1.4% 1/73 • Number of events 1 • Throughout the study period (4 years and 5 months)	0.00% 0/32 • Throughout the study period (4 years and 5 months)	0.00% 0/34 • Throughout the study period (4 years and 5 months)	0.00% 0/1 • Throughout the study period (4 years and 5 months)
Renal and urinary disorders CALCULUS URINARY	1.4% 1/73 • Number of events 1 • Throughout the study period (4 years and 5 months)	0.00% 0/32 • Throughout the study period (4 years and 5 months)	0.00% 0/34 • Throughout the study period (4 years and 5 months)	0.00% 0/1 • Throughout the study period (4 years and 5 months)
Surgical and medical procedures HOSPITALIZATION	1.4% 1/73 • Number of events 1 • Throughout the study period (4 years and 5 months)	0.00% 0/32 • Throughout the study period (4 years and 5 months)	0.00% 0/34 • Throughout the study period (4 years and 5 months)	0.00% 0/1 • Throughout the study period (4 years and 5 months)
Infections and infestations PULPITIS DENTAL	0.00% 0/73 • Throughout the study period (4 years and 5 months)	3.1% 1/32 • Number of events 1 • Throughout the study period (4 years and 5 months)	0.00% 0/34 • Throughout the study period (4 years and 5 months)	0.00% 0/1 • Throughout the study period (4 years and 5 months)
Psychiatric disorders SOMNAMBULISM	0.00% 0/73 • Throughout the study period (4 years and 5 months)	3.1% 1/32 • Number of events 1 • Throughout the study period (4 years and 5 months)	0.00% 0/34 • Throughout the study period (4 years and 5 months)	0.00% 0/1 • Throughout the study period (4 years and 5 months)
Blood and lymphatic system disorders FACTOR VIII INHIBITION	0.00% 0/73 • Throughout the study period (4 years and 5 months)	0.00% 0/32 • Throughout the study period (4 years and 5 months)	2.9% 1/34 • Number of events 1 • Throughout the study period (4 years and 5 months)	0.00% 0/1 • Throughout the study period (4 years and 5 months)
Infections and infestations APPENDICITIS	0.00% 0/73 • Throughout the study period (4 years and 5 months)	0.00% 0/32 • Throughout the study period (4 years and 5 months)	2.9% 1/34 • Number of events 1 • Throughout the study period (4 years and 5 months)	0.00% 0/1 • Throughout the study period (4 years and 5 months)
Musculoskeletal and connective tissue disorders PAIN IN EXTREMITY	0.00% 0/73 • Throughout the study period (4 years and 5 months)	0.00% 0/32 • Throughout the study period (4 years and 5 months)	0.00% 0/34 • Throughout the study period (4 years and 5 months)	100.0% 1/1 • Number of events 1 • Throughout the study period (4 years and 5 months)

Other adverse events

Measure	On-Demand n=73 participants at risk On-demand: rAHF-PFM was to be used for the treatment of bleeding episodes according to the severity and type of episode by the protocol-recommended dosing until the episode resolved: superficial (10-20 IU/kg every 12-14 hours), minor joint (20-40 IU/kg every 12-14 hours), deep muscle (30-60 IU/kg every 12-14 hours), major joint or life-threatening (60-100 IU/kg every 8-12 hours), genitourinary, GI, and intracranial (60-100 IU/kg every 8-12 hours)	Standard Prophylaxis n=32 participants at risk Standard prophylaxis regimen dosed at 20 to 40 IU/kg (every 48 ±6 hours), exact regimen to be determined by the investigator	PK-Driven Prophylaxis n=34 participants at risk PK-driven prophylaxis regimen dosed at 20 to 80 IU/kg (every 72 ±6 hours) exact regimen to be determined by the sponsor	SAEs Outside of the 3 Treatment Arms n=1 participants at risk Participants with SAEs that occurred after exposure to investigational product, but outside of the three treatment arms
Gastrointestinal disorders DIARRHOEA	5.5% 4/73 • Number of events 4 • Throughout the study period (4 years and 5 months)	0.00% 0/32 • Throughout the study period (4 years and 5 months)	0.00% 0/34 • Throughout the study period (4 years and 5 months)	0.00% 0/1 • Throughout the study period (4 years and 5 months)
Gastrointestinal disorders IRRITABLE BOWEL SYNDROME	0.00% 0/73 • Throughout the study period (4 years and 5 months)	0.00% 0/32 • Throughout the study period (4 years and 5 months)	5.9% 2/34 • Number of events 4 • Throughout the study period (4 years and 5 months)	0.00% 0/1 • Throughout the study period (4 years and 5 months)
Infections and infestations NASOPHARYNGITIS	8.2% 6/73 • Number of events 7 • Throughout the study period (4 years and 5 months)	0.00% 0/32 • Throughout the study period (4 years and 5 months)	0.00% 0/34 • Throughout the study period (4 years and 5 months)	0.00% 0/1 • Throughout the study period (4 years and 5 months)
Infections and infestations UPPER RESPIRATORY TRACT INFECTION	5.5% 4/73 • Number of events 4 • Throughout the study period (4 years and 5 months)	0.00% 0/32 • Throughout the study period (4 years and 5 months)	5.9% 2/34 • Number of events 2 • Throughout the study period (4 years and 5 months)	0.00% 0/1 • Throughout the study period (4 years and 5 months)
Musculoskeletal and connective tissue disorders ARTHRALGIA	0.00% 0/73 • Throughout the study period (4 years and 5 months)	6.2% 2/32 • Number of events 3 • Throughout the study period (4 years and 5 months)	0.00% 0/34 • Throughout the study period (4 years and 5 months)	0.00% 0/1 • Throughout the study period (4 years and 5 months)
Nervous system disorders HEADACHE	5.5% 4/73 • Number of events 6 • Throughout the study period (4 years and 5 months)	0.00% 0/32 • Throughout the study period (4 years and 5 months)	8.8% 3/34 • Number of events 5 • Throughout the study period (4 years and 5 months)	0.00% 0/1 • Throughout the study period (4 years and 5 months)
Respiratory, thoracic and mediastinal disorders COUGH	0.00% 0/73 • Throughout the study period (4 years and 5 months)	6.2% 2/32 • Number of events 2 • Throughout the study period (4 years and 5 months)	0.00% 0/34 • Throughout the study period (4 years and 5 months)	0.00% 0/1 • Throughout the study period (4 years and 5 months)

Additional Information

Study Director

Shire

Phone: +1 866 842 5335

Email: ClinicalTransparency@shire.com

Results disclosure agreements

• Principal investigator is a sponsor employee Baxter's agreements with PIs may vary per requirements of the individual PI, but contain common elements. For this study, PIs are restricted from independently publishing results until the earlier of the primary multicenter publication or ≤2 years after study completion. Baxter requires a review of results communications (e.g., for confidential information) ≥60 days prior to submission or communication. Baxter may request an additional delay of ≤60 days (e.g., intellectual property protection)
• Publication restrictions are in place

Restriction type: OTHER