Hemophilia A
Conditions
Brief summary
The primary purpose of this randomized, two-arm parallel clinical study in 66 previously treated patients with severe or moderately severe hemophilia A is to compare the rate of bleeding episodes for standard prophylaxis (20-40 IU/kg every 48 ± 6 hours; actual dose determined by the investigator) with that of alternate prophylaxis (20-80 IU/kg every 72 + 6 hours; actual dose determined by Baxter utilizing an algorithm and the patient's pharmacokinetic data). The rates of bleeding episodes for the on-demand regimen and the prophylaxis regimens will also be compared for the cross-over portion of the study. Enrolled patients will be treated originally on demand for a period of 6 months and then they will be randomized into one of the prophylaxis arms. Prophylactic treatment will last for a period of 12 months +/- 2 weeks.
Interventions
Standard prophylaxis: 20-40 IU/kg every 48+/-6 hours, actual dose determined by investigator
Sponsors
Baxalta now part of Shire
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
7 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* The subject has severe or moderately severe hemophilia A as defined by a baseline factor VIII level \<= 2% of normal, as tested at screening * The subject has a documented history of at least 150 exposure days to factor VIII concentrates (either plasma-derived or recombinant) * The subject is within 7 to 65 years of age * The subject has a Karnofsky performance score \> (greater than) 60 * The subject is human immunodeficiency virus negative (HIV-) or is HIV+ with a CD4 count \>= 400 cells/mm³ (CD4 count determined at screening, if necessary) * The subject has been on a documented on-demand treatment regimen for at least 12 months immediately prior to enrollment * The subject has a documented history (e.g. in medical charts or dispensing information, or signed investigator statement) of at least 8 joint hemorrhages in the 12 months immediately prior to enrollment * The subject resides within the coverage area of the mobile compliance device; coverage area will be determined at screening * The subject or the subject's legally authorized representative has provided written informed consent
Exclusion criteria
* The subject has a known hypersensitivity to factor VIII concentrates or mouse or hamster proteins * The subject has a history of factor VIII inhibitors with a titer \>= 0.6 BU (by Bethesda or Nijmegen assay) at any time prior to screening * The subject has a detectable factor VIII inhibitor at screening, with a titer \>= 0.4 BU (by Nijmegen Assay) in the central laboratory * The subject has severe chronic liver disease as evidenced by, but not limited to, any of the following: International Normalized Ratio (INR) \> 1.4, hypoalbuminemia, portal vein hypertension including presence of otherwise unexplained splenomegaly and history of esophageal varices. * The subject has been diagnosed with an inherited or acquired hemostatic defect other than hemophilia A (e.g., qualitative platelet defect or von Willebrand's Disease) * The subject has been treated during the last sixty (60) days prior to or is being treated at screening/enrollment with an immunomodulating drug. * The subject has participated in another investigational study within thirty (30) days of enrollment * The subject has previously participated in a clinical study with rAHF-PFM * The subject's clinical condition may require a major surgery (defined as moderate to critical risk and perioperative blood loss ≥ 500 mL) during the period of the subject's participation in the study * The subject is female of childbearing potential with a positive pregnancy test
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Mean Transformed Annualized Bleed Rate Estimates From Each of the 1-year Prophylaxis Regimens | 12 months ±2 weeks | 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. |
| Median Annualized Bleed Rate Estimates From Each of the 1 Year Prophylaxis Regimens | 12 months ±2 weeks | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Volume of Distribution at Steady State | Pharmacokinetic evaluations: 30 minutes pre-infusion up to 48 hours post-infusion | Computed as weight-adjusted clearance \* mean residence time |
| Mean Difference of Transformed Annualized Bleeding Rate Between On-Demand and Standard Prophylaxis Treatment Regimens | On-demand 6 months (± 2 weeks); followed by Prophylaxis 12 months (± 2 weeks) | 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). |
| Mean Difference of Transformed Annualized Bleeding Rate Between On-Demand and PK-Driven Prophylaxis Treatment Regimens | On-demand 6 months (± 2 weeks); followed by Prophylaxis 12 months (± 2 weeks) | 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). |
| Mean Difference of Transformed Annualized Bleeding Rate Between On-Demand and Any Prophylaxis Treatment Regimens | On-demand 6 months (± 2 weeks); Prophylaxis 12 months (± 2 weeks) | 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). |
| Total Weight-Adjusted Dose of rAHF-PFM Used Per Year for Each Prophylaxis Arm | 12 months ±2 weeks | 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. |
| Bleeding Episodes Treated With 1 to ≥4 Infusions | Throughout the study period (4 years and 5 months) | The number of bleeding episodes treated with 1, 2, 3, or ≥4 infusions of rAHF-PFM to achieve adequate hemostasis |
| Assessment of Hemostasis for Treatment of Bleeding Episodes | On-demand 6 months (± 2 weeks); Prophylaxis 12 months (± 2 weeks) | 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 |
| Total Area Under the Curve (AUC) | Pharmacokinetic evaluations: 30 minutes pre-infusion up to 48 hours post-infusion | Total AUC estimated by AUC 0-48h plus an area extrapolated from the log-linear regression model |
| Area Under the Curve | Pharmacokinetic evaluations: 30 minutes pre-infusion up to 48 hours post-infusion | Area under the factor VIII (FVIII) plasma concentration versus time curve (AUC) from 0 to 48 hours estimated using the linear trapezoidal method |
| Maximum Plasma Concentration (C-max) | Within 1 hour post-infusion | Maximal Factor VIII Concentration After Infusion |
| Adjusted Incremental Recovery (IR) | 30 minutes pre-infusion to 48 hours post-infusion | 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) |
| Terminal Half-life | Pharmacokinetic evaluations: 30 minutes pre-infusion up to 48 hours post-infusion | 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%. |
| Weight-Adjusted Clearance | Pharmacokinetic evaluations: 30 minutes pre-infusion up to 48 hours post-infusion | Computed as the weight-adjusted dose divided by total AUC |
| Number of Participants With AEs Related to Investigational Product (IP) | Throughout study period (4 years and 5 months) | Number of treated participants with AEs judged to be possibly or probably related to treatment with IP |
| Number of Participants Who Reported ≥1 AE Regardless of Relatedness to Investigational Product (IP) | Throughout study period (4 years and 5 months) | Number of treated participants with 1 or more AE regardless of relatedness to IP |
| Number of Participants Who Reported ≥1 AE Regardless of Relatedness to IP by Treatment Regimen | Throughout the study period (4 years and 5 months) | — |
| Number of Participants With SAEs by Preferred MedDRA Term and Treatment Regimen | Throughout the study period (4 years and 5 months) | — |
| AEs With Onset ≤1 Hour Following the End of an Infusion, Regardless of Relatedness | Throughout study period (4 years and 5 months) | — |
| Number of Participants With Severe SAEs and Severe Non-SAEs by Preferred MedDRA Term and Treatment Regimen | Throughout the study period (4 years and 5 months) | This outcome is focused only on SEVERE SAEs and SEVERE non-SAEs |
| Baseline Health-related Quality of Life (HRQoL) Scores: PF, RP, BP, GH, VT, SF, RE, MH, PCS, and MCS | Baseline | 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. |
| Health-related Quality of Life (HRQoL) Scores: PF, RP, BP, GH, VT, SF, RE, MH, PCS, and MCS at the End of Treatment Regimens | End of on-demand treatment period (6 months) and at study termination (approximately 18 months) | 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. |
| HRQoL Scores Change From On-Demand Treatment Regimen Period Through Prophylaxis Period | End of on-demand treatment period (6 months) and at study termination (approximately 18 months) | 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. |
| Bodily Pain HRQoL Scores Change From On-Demand Period Through Prophylaxis Period | End of on-demand treatment period (6 months) and at study termination (approximately 18 months) | 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. |
| Physical Component Scores (PCS) HRQoL Scores Change From On-Demand Period Through Prophylaxis Period | End of on-demand treatment period (6 months) and at study termination (approximately 18 months) | 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. |
| Factor VIII Inhibitor Development | Throughout study period (4 years and 5 months) | Number of treated participants who developed factor VIII inhibitors |
| Mean Residence Time | Pharmacokinetic evaluations: 30 minutes pre-infusion up to 48 hours post-infusion | Computed as total Area Under the Moment Curve (AUMC) divided by the total AUC |
Countries
Austria, Czechia, Greece, Hungary, Italy, Poland, Russia, Slovenia, United Kingdom, United States
Participant flow
Recruitment details
Participants were enrolled at 21 European and 9 United States clinical sites beginning January 2006 and completing in June 2010
Pre-assignment details
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).
Participants by arm
| Arm | Count |
|---|---|
| All Study 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. | 73 |
| Total | 73 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| End of Part 1, But Prior to Prophylaxis | Lost to Follow-up | 1 | 0 | 0 |
| End of Part 1, But Prior to Prophylaxis | Withdrawal by Subject | 1 | 0 | 0 |
| End of Part 1, But Prior to Prophylaxis | Withdrawn for Non-Compliance | 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 |
| On-Demand Regimen (Study Part 1) | Withdrawal by Subject | 1 | 0 | 0 |
| PK-Driven or Standard Prophylaxis | Lack of Efficacy | 0 | 1 | 0 |
| PK-Driven or Standard Prophylaxis | Withdrawn for Non-Compliance | 0 | 2 | 0 |
Baseline characteristics
| Characteristic | All Study Participants |
|---|---|
| Age, Continuous | 26 years |
| Sex: Female, Male Female | 0 Participants |
| Sex: Female, Male Male | 73 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 18 / 73 | 4 / 32 | 7 / 34 | 0 / 1 |
| serious Total, serious adverse events | 7 / 73 | 2 / 32 | 3 / 34 | 1 / 1 |
Outcome results
Primary
Mean Transformed Annualized Bleed Rate Estimates From Each of the 1-year Prophylaxis Regimens
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.
Time frame: 12 months ±2 weeks
Population: Per Protocol
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| PK-Driven Prophylaxis | Mean Transformed Annualized Bleed Rate Estimates From Each of the 1-year Prophylaxis Regimens | 1.61 (bleeds/year)^(1/2) | Standard Deviation 1.1 |
| Standard Prophylaxis | Mean Transformed Annualized Bleed Rate Estimates From Each of the 1-year Prophylaxis Regimens | 1.46 (bleeds/year)^(1/2) | Standard Deviation 0.98 |
Comparison: A t-test was used to compare the means of the transformed data. The null-hypothesis tested was H0: X'A(PK-driven prophylaxis) - X'B (standard prophylaxis) = 0 (i.e., no difference for treatment under the 2 prophylactic regimens. X' = (ABR+0.5)\^(1/2)p-value: 0.6016t-test, 2 sided
Primary
Median Annualized Bleed Rate Estimates From Each of the 1 Year Prophylaxis Regimens
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.
Time frame: 12 months ±2 weeks
Population: Intent to treat
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| PK-Driven Prophylaxis | Median Annualized Bleed Rate Estimates From Each of the 1 Year Prophylaxis Regimens | 2.01 Bleeds per year |
| Standard Prophylaxis | Median Annualized Bleed Rate Estimates From Each of the 1 Year Prophylaxis Regimens | 1.00 Bleeds per year |
p-value: 0.1467Wilcoxon-Rank Sum (Mann-Whitney)
Secondary
Adjusted Incremental Recovery (IR)
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)
Time frame: 30 minutes pre-infusion to 48 hours post-infusion
Population: Intent to Treat Pharmacokinetic Analysis Set
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| PK-Driven Prophylaxis | Adjusted Incremental Recovery (IR) | 1.81 IU/dL per IU/kg | Standard Deviation 0.41 |
| Standard Prophylaxis | Adjusted Incremental Recovery (IR) | 1.47 IU/dL per IU/kg | Standard Deviation 0.27 |
Secondary
AEs With Onset ≤1 Hour Following the End of an Infusion, Regardless of Relatedness
Time frame: Throughout study period (4 years and 5 months)
Population: Safety Analysis Set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| PK-Driven Prophylaxis | AEs With Onset ≤1 Hour Following the End of an Infusion, Regardless of Relatedness | 39 Events |
Secondary
Area Under the Curve
Area under the factor VIII (FVIII) plasma concentration versus time curve (AUC) from 0 to 48 hours estimated using the linear trapezoidal method
Time frame: Pharmacokinetic evaluations: 30 minutes pre-infusion up to 48 hours post-infusion
Population: Intent to Treat Pharmacokinetic Analysis Set
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| PK-Driven Prophylaxis | Area Under the Curve | 1213.98 IU*h/dL | Standard Deviation 323.96 |
| Standard Prophylaxis | Area Under the Curve | 966.68 IU*h/dL | Standard Deviation 330.83 |
Secondary
Assessment of Hemostasis for Treatment of Bleeding Episodes
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
Time frame: On-demand 6 months (± 2 weeks); Prophylaxis 12 months (± 2 weeks)
Population: Hemostatic Efficacy Rating Analysis Set (Participants with bleeding episodes that were rated)
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| PK-Driven Prophylaxis | Assessment of Hemostasis for Treatment of Bleeding Episodes | Unknown | 13 bleeding episodes |
| PK-Driven Prophylaxis | Assessment of Hemostasis for Treatment of Bleeding Episodes | None | 3 bleeding episodes |
| PK-Driven Prophylaxis | Assessment of Hemostasis for Treatment of Bleeding Episodes | Excellent | 547 bleeding episodes |
| PK-Driven Prophylaxis | Assessment of Hemostasis for Treatment of Bleeding Episodes | Good | 943 bleeding episodes |
| PK-Driven Prophylaxis | Assessment of Hemostasis for Treatment of Bleeding Episodes | Fair | 167 bleeding episodes |
| Standard Prophylaxis | Assessment of Hemostasis for Treatment of Bleeding Episodes | Good | 38 bleeding episodes |
| Standard Prophylaxis | Assessment of Hemostasis for Treatment of Bleeding Episodes | Fair | 16 bleeding episodes |
| Standard Prophylaxis | Assessment of Hemostasis for Treatment of Bleeding Episodes | Unknown | 0 bleeding episodes |
| Standard Prophylaxis | Assessment of Hemostasis for Treatment of Bleeding Episodes | Excellent | 39 bleeding episodes |
| Standard Prophylaxis | Assessment of Hemostasis for Treatment of Bleeding Episodes | None | 0 bleeding episodes |
| PK-Driven Prophylaxis | Assessment of Hemostasis for Treatment of Bleeding Episodes | Unknown | 0 bleeding episodes |
| PK-Driven Prophylaxis | Assessment of Hemostasis for Treatment of Bleeding Episodes | None | 20 bleeding episodes |
| PK-Driven Prophylaxis | Assessment of Hemostasis for Treatment of Bleeding Episodes | Excellent | 33 bleeding episodes |
| PK-Driven Prophylaxis | Assessment of Hemostasis for Treatment of Bleeding Episodes | Good | 75 bleeding episodes |
| PK-Driven Prophylaxis | Assessment of Hemostasis for Treatment of Bleeding Episodes | Fair | 11 bleeding episodes |
Secondary
Baseline Health-related Quality of Life (HRQoL) Scores: PF, RP, BP, GH, VT, SF, RE, MH, PCS, and MCS
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.
Time frame: Baseline
Population: Safety Analysis Set
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| PK-Driven Prophylaxis | 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 |
| PK-Driven Prophylaxis | 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 |
| PK-Driven Prophylaxis | 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 |
| PK-Driven Prophylaxis | 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 |
| PK-Driven Prophylaxis | 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 |
| PK-Driven Prophylaxis | 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 |
| PK-Driven Prophylaxis | 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 |
| PK-Driven Prophylaxis | 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 |
| PK-Driven Prophylaxis | 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 |
| PK-Driven Prophylaxis | 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 |
Secondary
Bleeding Episodes Treated With 1 to ≥4 Infusions
The number of bleeding episodes treated with 1, 2, 3, or ≥4 infusions of rAHF-PFM to achieve adequate hemostasis
Time frame: Throughout the study period (4 years and 5 months)
Population: Intent to Treat Efficacy Set
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| PK-Driven Prophylaxis | Bleeding Episodes Treated With 1 to ≥4 Infusions | 2 infusions (n = 51, 6, 9) | 277 Bleeding episodes |
| PK-Driven Prophylaxis | Bleeding Episodes Treated With 1 to ≥4 Infusions | 4 or more infusions (n = 21, 5, 5) | 50 Bleeding episodes |
| PK-Driven Prophylaxis | Bleeding Episodes Treated With 1 to ≥4 Infusions | 3 infusions (n = 27, 2, 4) | 128 Bleeding episodes |
| PK-Driven Prophylaxis | Bleeding Episodes Treated With 1 to ≥4 Infusions | 1 infusion (n = 62, 13, 22) | 1168 Bleeding episodes |
| Standard Prophylaxis | Bleeding Episodes Treated With 1 to ≥4 Infusions | 3 infusions (n = 27, 2, 4) | 4 Bleeding episodes |
| Standard Prophylaxis | Bleeding Episodes Treated With 1 to ≥4 Infusions | 4 or more infusions (n = 21, 5, 5) | 9 Bleeding episodes |
| Standard Prophylaxis | Bleeding Episodes Treated With 1 to ≥4 Infusions | 2 infusions (n = 51, 6, 9) | 12 Bleeding episodes |
| Standard Prophylaxis | Bleeding Episodes Treated With 1 to ≥4 Infusions | 1 infusion (n = 62, 13, 22) | 68 Bleeding episodes |
| PK-Driven Prophylaxis | Bleeding Episodes Treated With 1 to ≥4 Infusions | 4 or more infusions (n = 21, 5, 5) | 7 Bleeding episodes |
| PK-Driven Prophylaxis | Bleeding Episodes Treated With 1 to ≥4 Infusions | 1 infusion (n = 62, 13, 22) | 90 Bleeding episodes |
| PK-Driven Prophylaxis | Bleeding Episodes Treated With 1 to ≥4 Infusions | 3 infusions (n = 27, 2, 4) | 5 Bleeding episodes |
| PK-Driven Prophylaxis | Bleeding Episodes Treated With 1 to ≥4 Infusions | 2 infusions (n = 51, 6, 9) | 37 Bleeding episodes |
Secondary
Bodily Pain HRQoL Scores Change From On-Demand Period Through Prophylaxis Period
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.
Time frame: 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
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| PK-Driven Prophylaxis | Bodily Pain HRQoL Scores Change From On-Demand Period Through Prophylaxis Period | 0.00 Scores on a scale |
p-value: 0.0007Wilcoxon signed-rank test
Secondary
Factor VIII Inhibitor Development
Number of treated participants who developed factor VIII inhibitors
Time frame: Throughout study period (4 years and 5 months)
Population: Safety Analysis Set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| PK-Driven Prophylaxis | Factor VIII Inhibitor Development | 0 Participants |
Secondary
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); 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.
Time frame: End of on-demand treatment period (6 months) and at study termination (approximately 18 months)
Population: Pharmacoeconomic Analysis Set
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| PK-Driven Prophylaxis | 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 |
| PK-Driven Prophylaxis | 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 |
| PK-Driven Prophylaxis | 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 |
| PK-Driven Prophylaxis | 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 |
| PK-Driven Prophylaxis | 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 |
| PK-Driven Prophylaxis | 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 |
| PK-Driven Prophylaxis | 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 |
| PK-Driven Prophylaxis | 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 |
| PK-Driven Prophylaxis | 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 |
| PK-Driven Prophylaxis | 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 |
| Standard Prophylaxis | 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 | 56.1 Scores on a scale |
| Standard Prophylaxis | 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) | 51.7 Scores on a scale |
| Standard Prophylaxis | 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 | 50.4 Scores on a scale |
| Standard Prophylaxis | 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 | 50.2 Scores on a scale |
| Standard Prophylaxis | 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 | 46.7 Scores on a scale |
| Standard Prophylaxis | 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 |
| Standard Prophylaxis | 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) | 56.2 Scores on a scale |
| Standard Prophylaxis | 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) | 56.2 Scores on a scale |
| Standard Prophylaxis | 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) | 51.6 Scores on a scale |
| Standard Prophylaxis | 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) | 48.6 Scores on a scale |
| PK-Driven Prophylaxis | 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) | 56.2 Scores on a scale |
| PK-Driven Prophylaxis | 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 |
| PK-Driven Prophylaxis | 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) | 56.2 Scores on a scale |
| PK-Driven Prophylaxis | 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) | 51.6 Scores on a scale |
| PK-Driven Prophylaxis | 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 | 52.7 Scores on a scale |
| PK-Driven Prophylaxis | 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 | 46.7 Scores on a scale |
| PK-Driven Prophylaxis | 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) | 51.7 Scores on a scale |
| PK-Driven Prophylaxis | 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) | 46.2 Scores on a scale |
| PK-Driven Prophylaxis | 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 | 47.3 Scores on a scale |
| PK-Driven Prophylaxis | 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 | 54.5 Scores on a scale |
| SAEs Outside of the 3 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 | Physical Component Score (PCS), On-Demand n=62 | 47.8 Scores on a scale |
| SAEs Outside of the 3 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 | Role Physical (RP) | 56.2 Scores on a scale |
| SAEs Outside of the 3 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 | Physical Functioning (PF), On-Demand n=62 | 46.7 Scores on a scale |
| SAEs Outside of the 3 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 | Vitality (VT) | 56.2 Scores on a scale |
| SAEs Outside of the 3 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 | Role Emotional (RE) | 55.3 Scores on a scale |
| SAEs Outside of the 3 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 | General Health (GH) | 48.6 Scores on a scale |
| SAEs Outside of the 3 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 | Mental Component Score (MCS), On-Demand n=62 | 55.0 Scores on a scale |
| SAEs Outside of the 3 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 | Mental Health (MH), On-Demand n=62 | 50.4 Scores on a scale |
| SAEs Outside of the 3 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) | 51.6 Scores on a scale |
| SAEs Outside of the 3 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 | Social Functioning (SF) | 51.7 Scores on a scale |
Secondary
HRQoL Scores Change From On-Demand Treatment Regimen Period Through Prophylaxis Period
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.
Time frame: End of on-demand treatment period (6 months) and at study termination (approximately 18 months)
Population: Pharmacoeconomic Analysis Set ≥14 Years and Older
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| PK-Driven Prophylaxis | HRQoL Scores Change From On-Demand Treatment Regimen Period Through Prophylaxis Period | Mental Component Score (MCS) | 1.52 Scores on a scale |
| PK-Driven Prophylaxis | HRQoL Scores Change From On-Demand Treatment Regimen Period Through Prophylaxis Period | Role Emotional (RE) | 0.00 Scores on a scale |
| PK-Driven Prophylaxis | HRQoL Scores Change From On-Demand Treatment Regimen Period Through Prophylaxis Period | Vitality (VT) | 0.00 Scores on a scale |
| PK-Driven Prophylaxis | HRQoL Scores Change From On-Demand Treatment Regimen Period Through Prophylaxis Period | Role Physical (RP) | 0.00 Scores on a scale |
| PK-Driven Prophylaxis | HRQoL Scores Change From On-Demand Treatment Regimen Period Through Prophylaxis Period | Social Functioning (SF) | 0.00 Scores on a scale |
| PK-Driven Prophylaxis | HRQoL Scores Change From On-Demand Treatment Regimen Period Through Prophylaxis Period | Physical Functioning (PF) | 0.00 Scores on a scale |
| PK-Driven Prophylaxis | HRQoL Scores Change From On-Demand Treatment Regimen Period Through Prophylaxis Period | Physical Component Score (PCS) | -2.55 Scores on a scale |
| PK-Driven Prophylaxis | HRQoL Scores Change From On-Demand Treatment Regimen Period Through Prophylaxis Period | Bodily Pain (BP) | 0.00 Scores on a scale |
| PK-Driven Prophylaxis | HRQoL Scores Change From On-Demand Treatment Regimen Period Through Prophylaxis Period | Mental Health (MH) | 0.00 Scores on a scale |
| PK-Driven Prophylaxis | HRQoL Scores Change From On-Demand Treatment Regimen Period Through Prophylaxis Period | General Health (GH) | -3.74 Scores on a scale |
| Standard Prophylaxis | HRQoL Scores Change From On-Demand Treatment Regimen Period Through Prophylaxis Period | Bodily Pain (BP) | -4.29 Scores on a scale |
| Standard Prophylaxis | HRQoL Scores Change From On-Demand Treatment Regimen Period Through Prophylaxis Period | Physical Functioning (PF) | -2.10 Scores on a scale |
| Standard Prophylaxis | HRQoL Scores Change From On-Demand Treatment Regimen Period Through Prophylaxis Period | Role Physical (RP) | 0.00 Scores on a scale |
| Standard Prophylaxis | HRQoL Scores Change From On-Demand Treatment Regimen Period Through Prophylaxis Period | General Health (GH) | -2.34 Scores on a scale |
| Standard Prophylaxis | HRQoL Scores Change From On-Demand Treatment Regimen Period Through Prophylaxis Period | Vitality (VT) | 0.00 Scores on a scale |
| Standard Prophylaxis | HRQoL Scores Change From On-Demand Treatment Regimen Period Through Prophylaxis Period | Social Functioning (SF) | 0.00 Scores on a scale |
| Standard Prophylaxis | HRQoL Scores Change From On-Demand Treatment Regimen Period Through Prophylaxis Period | Role Emotional (RE) | 0.00 Scores on a scale |
| Standard Prophylaxis | HRQoL Scores Change From On-Demand Treatment Regimen Period Through Prophylaxis Period | Mental Health (MH) | -1.13 Scores on a scale |
| Standard Prophylaxis | HRQoL Scores Change From On-Demand Treatment Regimen Period Through Prophylaxis Period | Physical Component Score (PCS) | -3.14 Scores on a scale |
| Standard Prophylaxis | HRQoL Scores Change From On-Demand Treatment Regimen Period Through Prophylaxis Period | Mental Component Score (MCS) | 0.79 Scores on a scale |
| PK-Driven Prophylaxis | HRQoL Scores Change From On-Demand Treatment Regimen Period Through Prophylaxis Period | Role Emotional (RE) | 0.00 Scores on a scale |
| PK-Driven Prophylaxis | HRQoL Scores Change From On-Demand Treatment Regimen Period Through Prophylaxis Period | Bodily Pain (BP) | 0.00 Scores on a scale |
| PK-Driven Prophylaxis | HRQoL Scores Change From On-Demand Treatment Regimen Period Through Prophylaxis Period | Physical Functioning (PF) | -2.10 Scores on a scale |
| PK-Driven Prophylaxis | HRQoL Scores Change From On-Demand Treatment Regimen Period Through Prophylaxis Period | Mental Health (MH) | 0.00 Scores on a scale |
| PK-Driven Prophylaxis | HRQoL Scores Change From On-Demand Treatment Regimen Period Through Prophylaxis Period | Role Physical (RP) | 0.00 Scores on a scale |
| PK-Driven Prophylaxis | HRQoL Scores Change From On-Demand Treatment Regimen Period Through Prophylaxis Period | Vitality (VT) | 0.00 Scores on a scale |
| PK-Driven Prophylaxis | HRQoL Scores Change From On-Demand Treatment Regimen Period Through Prophylaxis Period | Mental Component Score (MCS) | 1.30 Scores on a scale |
| PK-Driven Prophylaxis | HRQoL Scores Change From On-Demand Treatment Regimen Period Through Prophylaxis Period | Social Functioning (SF) | 0.00 Scores on a scale |
| PK-Driven Prophylaxis | HRQoL Scores Change From On-Demand Treatment Regimen Period Through Prophylaxis Period | General Health (GH) | -2.34 Scores on a scale |
| PK-Driven Prophylaxis | HRQoL Scores Change From On-Demand Treatment Regimen Period Through Prophylaxis Period | Physical Component Score (PCS) | -2.76 Scores on a scale |
Secondary
Maximum Plasma Concentration (C-max)
Maximal Factor VIII Concentration After Infusion
Time frame: Within 1 hour post-infusion
Population: Intent to Treat Pharmacokinetic Analysis Set
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| PK-Driven Prophylaxis | Maximum Plasma Concentration (C-max) | 91.12 IU/dL | Standard Deviation 20.15 |
| Standard Prophylaxis | Maximum Plasma Concentration (C-max) | 74.47 IU/dL | Standard Deviation 11.3 |
Secondary
Mean Difference of Transformed Annualized Bleeding Rate Between On-Demand and Any Prophylaxis Treatment Regimens
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).
Time frame: On-demand 6 months (± 2 weeks); Prophylaxis 12 months (± 2 weeks)
Population: Intent to treat
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| PK-Driven Prophylaxis | 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 |
p-value: <0.0001Paired t-test
Secondary
Mean Difference of Transformed Annualized Bleeding Rate Between On-Demand and PK-Driven Prophylaxis Treatment Regimens
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).
Time frame: On-demand 6 months (± 2 weeks); followed by Prophylaxis 12 months (± 2 weeks)
Population: Intent to treat
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| PK-Driven Prophylaxis | 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 |
p-value: <0.0001Paired t-test
Secondary
Mean Difference of Transformed Annualized Bleeding Rate Between On-Demand and Standard Prophylaxis Treatment Regimens
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).
Time frame: On-demand 6 months (± 2 weeks); followed by Prophylaxis 12 months (± 2 weeks)
Population: Intent to treat
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| PK-Driven Prophylaxis | 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 |
p-value: <0.0001Paired t-Test
Secondary
Mean Residence Time
Computed as total Area Under the Moment Curve (AUMC) divided by the total AUC
Time frame: Pharmacokinetic evaluations: 30 minutes pre-infusion up to 48 hours post-infusion
Population: Intent to Treat Pharmacokinetic Analysis Set
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| PK-Driven Prophylaxis | Mean Residence Time | 17.71 hours | Standard Deviation 7.16 |
| Standard Prophylaxis | Mean Residence Time | 17.88 hours | Standard Deviation 5.67 |
Secondary
Number of Participants Who Reported ≥1 AE Regardless of Relatedness to Investigational Product (IP)
Number of treated participants with 1 or more AE regardless of relatedness to IP
Time frame: Throughout study period (4 years and 5 months)
Population: Safety Analysis Set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| PK-Driven Prophylaxis | Number of Participants Who Reported ≥1 AE Regardless of Relatedness to Investigational Product (IP) | 44 Participants |
Secondary
Number of Participants Who Reported ≥1 AE Regardless of Relatedness to IP by Treatment Regimen
Time frame: Throughout the study period (4 years and 5 months)
Population: Safety Analysis Set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| PK-Driven Prophylaxis | Number of Participants Who Reported ≥1 AE Regardless of Relatedness to IP by Treatment Regimen | 33 participants |
| Standard Prophylaxis | Number of Participants Who Reported ≥1 AE Regardless of Relatedness to IP by Treatment Regimen | 15 participants |
| PK-Driven Prophylaxis | Number of Participants Who Reported ≥1 AE Regardless of Relatedness to IP by Treatment Regimen | 19 participants |
Secondary
Number of Participants With AEs Related to Investigational Product (IP)
Number of treated participants with AEs judged to be possibly or probably related to treatment with IP
Time frame: Throughout study period (4 years and 5 months)
Population: Safety Analysis Set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| PK-Driven Prophylaxis | Number of Participants With AEs Related to Investigational Product (IP) | 4 Participants |
Secondary
Number of Participants With SAEs by Preferred MedDRA Term and Treatment Regimen
Time frame: Throughout the study period (4 years and 5 months)
Population: Safety Analysis Set
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| PK-Driven Prophylaxis | Number of Participants With SAEs by Preferred MedDRA Term and Treatment Regimen | ABDOMINAL PAIN | 1 participants |
| PK-Driven Prophylaxis | Number of Participants With SAEs by Preferred MedDRA Term and Treatment Regimen | NAUSEA | 1 participants |
| PK-Driven Prophylaxis | Number of Participants With SAEs by Preferred MedDRA Term and Treatment Regimen | TOOTH ABSCESS | 1 participants |
| PK-Driven Prophylaxis | Number of Participants With SAEs by Preferred MedDRA Term and Treatment Regimen | JOINT DISLOCATION | 1 participants |
| PK-Driven Prophylaxis | Number of Participants With SAEs by Preferred MedDRA Term and Treatment Regimen | HAEMOPHILIC ARTHROPATHY | 1 participants |
| PK-Driven Prophylaxis | Number of Participants With SAEs by Preferred MedDRA Term and Treatment Regimen | SYNOVITIS | 1 participants |
| PK-Driven Prophylaxis | Number of Participants With SAEs by Preferred MedDRA Term and Treatment Regimen | CALCULUS URINARY | 1 participants |
| PK-Driven Prophylaxis | Number of Participants With SAEs by Preferred MedDRA Term and Treatment Regimen | HOSPITALIZATION | 1 participants |
| PK-Driven Prophylaxis | Number of Participants With SAEs by Preferred MedDRA Term and Treatment Regimen | PULPITIS DENTAL | 0 participants |
| PK-Driven Prophylaxis | Number of Participants With SAEs by Preferred MedDRA Term and Treatment Regimen | SOMNAMBULISM | 0 participants |
| PK-Driven Prophylaxis | Number of Participants With SAEs by Preferred MedDRA Term and Treatment Regimen | FACTOR VIII INHIBITION (UNCONFIRMED) | 0 participants |
| PK-Driven Prophylaxis | Number of Participants With SAEs by Preferred MedDRA Term and Treatment Regimen | APPENDICITIS | 0 participants |
| PK-Driven Prophylaxis | Number of Participants With SAEs by Preferred MedDRA Term and Treatment Regimen | PAIN IN EXTREMITY | 0 participants |
| Standard Prophylaxis | Number of Participants With SAEs by Preferred MedDRA Term and Treatment Regimen | JOINT DISLOCATION | 0 participants |
| Standard Prophylaxis | Number of Participants With SAEs by Preferred MedDRA Term and Treatment Regimen | PAIN IN EXTREMITY | 0 participants |
| Standard Prophylaxis | Number of Participants With SAEs by Preferred MedDRA Term and Treatment Regimen | FACTOR VIII INHIBITION (UNCONFIRMED) | 0 participants |
| Standard Prophylaxis | Number of Participants With SAEs by Preferred MedDRA Term and Treatment Regimen | HOSPITALIZATION | 0 participants |
| Standard Prophylaxis | Number of Participants With SAEs by Preferred MedDRA Term and Treatment Regimen | TOOTH ABSCESS | 0 participants |
| Standard Prophylaxis | Number of Participants With SAEs by Preferred MedDRA Term and Treatment Regimen | ABDOMINAL PAIN | 0 participants |
| Standard Prophylaxis | Number of Participants With SAEs by Preferred MedDRA Term and Treatment Regimen | SOMNAMBULISM | 1 participants |
| Standard Prophylaxis | Number of Participants With SAEs by Preferred MedDRA Term and Treatment Regimen | PULPITIS DENTAL | 1 participants |
| Standard Prophylaxis | Number of Participants With SAEs by Preferred MedDRA Term and Treatment Regimen | SYNOVITIS | 0 participants |
| Standard Prophylaxis | Number of Participants With SAEs by Preferred MedDRA Term and Treatment Regimen | HAEMOPHILIC ARTHROPATHY | 0 participants |
| Standard Prophylaxis | Number of Participants With SAEs by Preferred MedDRA Term and Treatment Regimen | NAUSEA | 0 participants |
| Standard Prophylaxis | Number of Participants With SAEs by Preferred MedDRA Term and Treatment Regimen | APPENDICITIS | 0 participants |
| Standard Prophylaxis | Number of Participants With SAEs by Preferred MedDRA Term and Treatment Regimen | CALCULUS URINARY | 0 participants |
| PK-Driven Prophylaxis | Number of Participants With SAEs by Preferred MedDRA Term and Treatment Regimen | FACTOR VIII INHIBITION (UNCONFIRMED) | 1 participants |
| PK-Driven Prophylaxis | Number of Participants With SAEs by Preferred MedDRA Term and Treatment Regimen | JOINT DISLOCATION | 0 participants |
| PK-Driven Prophylaxis | Number of Participants With SAEs by Preferred MedDRA Term and Treatment Regimen | HAEMOPHILIC ARTHROPATHY | 1 participants |
| PK-Driven Prophylaxis | Number of Participants With SAEs by Preferred MedDRA Term and Treatment Regimen | PAIN IN EXTREMITY | 0 participants |
| PK-Driven Prophylaxis | Number of Participants With SAEs by Preferred MedDRA Term and Treatment Regimen | SYNOVITIS | 0 participants |
| PK-Driven Prophylaxis | Number of Participants With SAEs by Preferred MedDRA Term and Treatment Regimen | CALCULUS URINARY | 0 participants |
| PK-Driven Prophylaxis | Number of Participants With SAEs by Preferred MedDRA Term and Treatment Regimen | APPENDICITIS | 1 participants |
| PK-Driven Prophylaxis | Number of Participants With SAEs by Preferred MedDRA Term and Treatment Regimen | HOSPITALIZATION | 0 participants |
| PK-Driven Prophylaxis | Number of Participants With SAEs by Preferred MedDRA Term and Treatment Regimen | PULPITIS DENTAL | 0 participants |
| PK-Driven Prophylaxis | Number of Participants With SAEs by Preferred MedDRA Term and Treatment Regimen | SOMNAMBULISM | 0 participants |
| PK-Driven Prophylaxis | Number of Participants With SAEs by Preferred MedDRA Term and Treatment Regimen | ABDOMINAL PAIN | 0 participants |
| PK-Driven Prophylaxis | Number of Participants With SAEs by Preferred MedDRA Term and Treatment Regimen | NAUSEA | 0 participants |
| PK-Driven Prophylaxis | Number of Participants With SAEs by Preferred MedDRA Term and Treatment Regimen | TOOTH ABSCESS | 0 participants |
| SAEs Outside of the 3 Treatment Arms | Number of Participants With SAEs by Preferred MedDRA Term and Treatment Regimen | SOMNAMBULISM | 0 participants |
| SAEs Outside of the 3 Treatment Arms | Number of Participants With SAEs by Preferred MedDRA Term and Treatment Regimen | HOSPITALIZATION | 0 participants |
| SAEs Outside of the 3 Treatment Arms | Number of Participants With SAEs by Preferred MedDRA Term and Treatment Regimen | JOINT DISLOCATION | 0 participants |
| SAEs Outside of the 3 Treatment Arms | Number of Participants With SAEs by Preferred MedDRA Term and Treatment Regimen | ABDOMINAL PAIN | 0 participants |
| SAEs Outside of the 3 Treatment Arms | Number of Participants With SAEs by Preferred MedDRA Term and Treatment Regimen | CALCULUS URINARY | 0 participants |
| SAEs Outside of the 3 Treatment Arms | Number of Participants With SAEs by Preferred MedDRA Term and Treatment Regimen | SYNOVITIS | 0 participants |
| SAEs Outside of the 3 Treatment Arms | Number of Participants With SAEs by Preferred MedDRA Term and Treatment Regimen | TOOTH ABSCESS | 0 participants |
| SAEs Outside of the 3 Treatment Arms | Number of Participants With SAEs by Preferred MedDRA Term and Treatment Regimen | NAUSEA | 0 participants |
| SAEs Outside of the 3 Treatment Arms | Number of Participants With SAEs by Preferred MedDRA Term and Treatment Regimen | HAEMOPHILIC ARTHROPATHY | 0 participants |
| SAEs Outside of the 3 Treatment Arms | Number of Participants With SAEs by Preferred MedDRA Term and Treatment Regimen | PULPITIS DENTAL | 0 participants |
| SAEs Outside of the 3 Treatment Arms | Number of Participants With SAEs by Preferred MedDRA Term and Treatment Regimen | PAIN IN EXTREMITY | 1 participants |
| SAEs Outside of the 3 Treatment Arms | Number of Participants With SAEs by Preferred MedDRA Term and Treatment Regimen | APPENDICITIS | 0 participants |
| SAEs Outside of the 3 Treatment Arms | Number of Participants With SAEs by Preferred MedDRA Term and Treatment Regimen | FACTOR VIII INHIBITION (UNCONFIRMED) | 0 participants |
Secondary
Number of Participants With Severe SAEs and Severe Non-SAEs by Preferred MedDRA Term and Treatment Regimen
This outcome is focused only on SEVERE SAEs and SEVERE non-SAEs
Time frame: Throughout the study period (4 years and 5 months)
Population: Safety Analysis Set
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| PK-Driven Prophylaxis | Number of Participants With Severe SAEs and Severe Non-SAEs by Preferred MedDRA Term and Treatment Regimen | ABDOMINAL PAIN (non-SAE) | 1 participants |
| PK-Driven Prophylaxis | Number of Participants With Severe SAEs and Severe Non-SAEs by Preferred MedDRA Term and Treatment Regimen | HAEMOPHILIC ARTHROPATHY (non-SAE) | 1 participants |
| PK-Driven Prophylaxis | Number of Participants With Severe SAEs and Severe Non-SAEs by Preferred MedDRA Term and Treatment Regimen | TOOTH ABSCESS (SAE) | 1 participants |
| PK-Driven Prophylaxis | Number of Participants With Severe SAEs and Severe Non-SAEs by Preferred MedDRA Term and Treatment Regimen | HAEMOPHILIC ARTHROPATHY (SAE) | 0 participants |
| PK-Driven Prophylaxis | Number of Participants With Severe SAEs and Severe Non-SAEs by Preferred MedDRA Term and Treatment Regimen | ARTHRALGIA (non-SAE) | 1 participants |
| Standard Prophylaxis | Number of Participants With Severe SAEs and Severe Non-SAEs by Preferred MedDRA Term and Treatment Regimen | HAEMOPHILIC ARTHROPATHY (non-SAE) | 0 participants |
| Standard Prophylaxis | Number of Participants With Severe SAEs and Severe Non-SAEs by Preferred MedDRA Term and Treatment Regimen | TOOTH ABSCESS (SAE) | 0 participants |
| Standard Prophylaxis | Number of Participants With Severe SAEs and Severe Non-SAEs by Preferred MedDRA Term and Treatment Regimen | HAEMOPHILIC ARTHROPATHY (SAE) | 0 participants |
| Standard Prophylaxis | Number of Participants With Severe SAEs and Severe Non-SAEs by Preferred MedDRA Term and Treatment Regimen | ABDOMINAL PAIN (non-SAE) | 0 participants |
| Standard Prophylaxis | Number of Participants With Severe SAEs and Severe Non-SAEs by Preferred MedDRA Term and Treatment Regimen | ARTHRALGIA (non-SAE) | 0 participants |
| PK-Driven Prophylaxis | Number of Participants With Severe SAEs and Severe Non-SAEs by Preferred MedDRA Term and Treatment Regimen | ARTHRALGIA (non-SAE) | 0 participants |
| PK-Driven Prophylaxis | Number of Participants With Severe SAEs and Severe Non-SAEs by Preferred MedDRA Term and Treatment Regimen | ABDOMINAL PAIN (non-SAE) | 0 participants |
| PK-Driven Prophylaxis | Number of Participants With Severe SAEs and Severe Non-SAEs by Preferred MedDRA Term and Treatment Regimen | TOOTH ABSCESS (SAE) | 0 participants |
| PK-Driven Prophylaxis | Number of Participants With Severe SAEs and Severe Non-SAEs by Preferred MedDRA Term and Treatment Regimen | HAEMOPHILIC ARTHROPATHY (non-SAE) | 1 participants |
| PK-Driven Prophylaxis | Number of Participants With Severe SAEs and Severe Non-SAEs by Preferred MedDRA Term and Treatment Regimen | HAEMOPHILIC ARTHROPATHY (SAE) | 1 participants |
Secondary
Physical Component Scores (PCS) HRQoL Scores Change From On-Demand Period Through Prophylaxis Period
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.
Time frame: 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
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| PK-Driven Prophylaxis | Physical Component Scores (PCS) HRQoL Scores Change From On-Demand Period Through Prophylaxis Period | -2.76 Scores on a scale |
p-value: 0.0002Wilcoxon signed-rank test
Secondary
Terminal Half-life
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%.
Time frame: Pharmacokinetic evaluations: 30 minutes pre-infusion up to 48 hours post-infusion
Population: Intent to Treat Pharmacokinetic Analysis Set
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| PK-Driven Prophylaxis | Terminal Half-life | 13.91 hours | Standard Deviation 5.07 |
| Standard Prophylaxis | Terminal Half-life | 14.66 hours | Standard Deviation 5.21 |
Secondary
Total Area Under the Curve (AUC)
Total AUC estimated by AUC 0-48h plus an area extrapolated from the log-linear regression model
Time frame: Pharmacokinetic evaluations: 30 minutes pre-infusion up to 48 hours post-infusion
Population: Intent to Treat Pharmacokinetic Analysis Set
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| PK-Driven Prophylaxis | Total Area Under the Curve (AUC) | 1334.45 IU*h/dL | Standard Deviation 454.33 |
| Standard Prophylaxis | Total Area Under the Curve (AUC) | 1061.26 IU*h/dL | Standard Deviation 452.87 |
Secondary
Total Weight-Adjusted Dose of rAHF-PFM Used Per Year for Each Prophylaxis Arm
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.
Time frame: 12 months ±2 weeks
Population: Intent to treat
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| PK-Driven Prophylaxis | Total Weight-Adjusted Dose of rAHF-PFM Used Per Year for Each Prophylaxis Arm | 5197.8 IU/kg |
| Standard Prophylaxis | Total Weight-Adjusted Dose of rAHF-PFM Used Per Year for Each Prophylaxis Arm | 5768.2 IU/kg |
p-value: 0.4924Wilcoxon-Rank Sum (Mann-Whitney)
Secondary
Volume of Distribution at Steady State
Computed as weight-adjusted clearance \* mean residence time
Time frame: Pharmacokinetic evaluations: 30 minutes pre-infusion up to 48 hours post-infusion
Population: Intent to Treat Pharmacokinetic Analysis Set
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| PK-Driven Prophylaxis | Volume of Distribution at Steady State | 0.65 dL/kg | Standard Deviation 0.19 |
| Standard Prophylaxis | Volume of Distribution at Steady State | 0.84 dL/kg | Standard Deviation 0.19 |
Secondary
Weight-Adjusted Clearance
Computed as the weight-adjusted dose divided by total AUC
Time frame: Pharmacokinetic evaluations: 30 minutes pre-infusion up to 48 hours post-infusion
Population: Intent to Treat Pharmacokinetic Analysis Set
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| PK-Driven Prophylaxis | Weight-Adjusted Clearance | 3.89 mL/(kg*h) | Standard Deviation 1.21 |
| Standard Prophylaxis | Weight-Adjusted Clearance | 5.17 mL/(kg*h) | Standard Deviation 1.94 |
Post Hoc
Median (IQR) Annualized Bleed Rates
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.
Time frame: On-demand 6 months (± 2 weeks); Prophylaxis 12 months (± 2 weeks)
Population: Per-Protocol Efficacy Analysis Set
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| PK-Driven Prophylaxis | Median (IQR) Annualized Bleed Rates | 43.98 Bleeding episodes |
| Standard Prophylaxis | Median (IQR) Annualized Bleed Rates | 0.99 Bleeding episodes |
| PK-Driven Prophylaxis | Median (IQR) Annualized Bleed Rates | 1.00 Bleeding episodes |
| SAEs Outside of the 3 Treatment Arms | Median (IQR) Annualized Bleed Rates | 1.00 Bleeding episodes |
p-value: <0.0001Wilcoxon Signed-Rank Test