Trial Outcomes & Findings for An Open-label Safety, Efficacy and Pharmacokinetic Study of a Recombinant FVIII Compared to Recombinant Human Antihemophilic FVIII in Patients With Severe Hemophilia A (NCT NCT01486927)
NCT ID: NCT01486927
Last Updated: 2016-08-09
Results Overview
The investigator rated the efficacy of the treatment based on a 4-point rating scale "excellent, good, moderate or poor/no response". Efficacy ratings of "excellent" or "good" were considered treatment success for this end point; the percentage of bleeding events with a rating of excellent or good and the 95% confidence interval are presented. The denominator includes all treated bleeding events. The 95% confidence interval is based on a model to account for within-subject correlation.
Recruitment status
COMPLETED
Study phase
PHASE2/PHASE3
Target enrollment
175 participants
Primary outcome timeframe
Up to 24 months
Results posted on
2016-08-09
Participant Flow
This multicenter, multinational study enrolled subjects at 54 participating study centers in the United States, Japan, Europe, Australia, Canada, Lebanon, Malaysia, Philippines, Russian Federation, South Africa, and Ukraine.
Screening took place 4 to 28 days prior to first dose of study product (rVIII-SingleChain). A total of 204 subjects were screened, 29 of these did not fulfill all eligibility criteria and were therefore screening failures. A total of 175 subjects were enrolled; 174 subjects were exposed to treatment with rVIII-SingleChain.
Participant milestones
| Measure |
Recombinant Factor VIII (rFVIII)
In Part 1 of the study (a single-sequence crossover pharmacokinetic \[PK\] analysis), 27 subjects received a single injection of octocog alfa followed by a single injection of rVIII-SingleChain. Twenty-six of the 27 subjects from Part 1 then entered Part 2 of the study where they were assigned either to an on-demand or prophylaxis regimen with repeat injections of rVIII-SingleChain until they reached 50 exposure days (EDs). In Part 3 of the study, 148 additional subjects were enrolled and were assigned either to an on-demand or prophylaxis regimen with repeat injections of rVIII-SingleChain until they reached 50 EDs; 64 of these subjects participated in additional PK analyses. Overall, 174 subjects received rVIII-SingleChain as either on-demand or prophylaxis regimens, and 13 subjects participated in the surgical substudy.
|
|---|---|
|
Overall Study
STARTED
|
174
|
|
Overall Study
COMPLETED
|
161
|
|
Overall Study
NOT COMPLETED
|
13
|
Reasons for withdrawal
| Measure |
Recombinant Factor VIII (rFVIII)
In Part 1 of the study (a single-sequence crossover pharmacokinetic \[PK\] analysis), 27 subjects received a single injection of octocog alfa followed by a single injection of rVIII-SingleChain. Twenty-six of the 27 subjects from Part 1 then entered Part 2 of the study where they were assigned either to an on-demand or prophylaxis regimen with repeat injections of rVIII-SingleChain until they reached 50 exposure days (EDs). In Part 3 of the study, 148 additional subjects were enrolled and were assigned either to an on-demand or prophylaxis regimen with repeat injections of rVIII-SingleChain until they reached 50 EDs; 64 of these subjects participated in additional PK analyses. Overall, 174 subjects received rVIII-SingleChain as either on-demand or prophylaxis regimens, and 13 subjects participated in the surgical substudy.
|
|---|---|
|
Overall Study
Knee surgery (prior to surgery substudy)
|
1
|
|
Overall Study
Physician Decision
|
1
|
|
Overall Study
50 Exposure days not reached
|
2
|
|
Overall Study
Withdrawal by Subject
|
8
|
|
Overall Study
Subject did not reach 6 mo of treatment
|
1
|
Baseline Characteristics
An Open-label Safety, Efficacy and Pharmacokinetic Study of a Recombinant FVIII Compared to Recombinant Human Antihemophilic FVIII in Patients With Severe Hemophilia A
Baseline characteristics by cohort
| Measure |
Recombinant Factor VIII (rFVIII)
n=174 Participants
In Part 1 of the study (a single-sequence crossover PK analysis), 27 subjects received a single injection of octocog alfa followed by a single injection of rVIII-SingleChain. Twenty-six of the 27 subjects from Part 1 then entered Part 2 of the study where they were assigned either to an on-demand or prophylaxis regimen with repeat injections of rVIII-SingleChain until they reached 50 EDs. In Part 3 of the study, 148 additional subjects were enrolled and were assigned either to an on-demand or prophylaxis regimen with repeat injections of rVIII-SingleChain until they reached 50 EDs; 64 of these subjects participated in additional PK analyses. Overall, 174 subjects received rVIII-SingleChain as either on-demand or prophylaxis regimens, and 13 subjects participated in the surgical substudy.
|
|---|---|
|
Age, Continuous
|
31.3 years
STANDARD_DEVIATION 11.77 • n=99 Participants
|
|
Age, Customized
Adolescents (12-17 years)
|
14 participants
n=99 Participants
|
|
Age, Customized
Adults (18-65 years)
|
160 participants
n=99 Participants
|
|
Sex: Female, Male
Female
|
0 Participants
n=99 Participants
|
|
Sex: Female, Male
Male
|
174 Participants
n=99 Participants
|
|
Type of FVIII product used before enrollment
Plasma-derived Product
|
83 participants
n=99 Participants
|
|
Type of FVIII product used before enrollment
Recombinant Product
|
91 participants
n=99 Participants
|
|
Treatment modality of FVIII therapy before enrollment
Prophylaxis
|
82 participants
n=99 Participants
|
|
Treatment modality of FVIII therapy before enrollment
On-demand
|
92 participants
n=99 Participants
|
PRIMARY outcome
Timeframe: Up to 24 monthsThe investigator rated the efficacy of the treatment based on a 4-point rating scale "excellent, good, moderate or poor/no response". Efficacy ratings of "excellent" or "good" were considered treatment success for this end point; the percentage of bleeding events with a rating of excellent or good and the 95% confidence interval are presented. The denominator includes all treated bleeding events. The 95% confidence interval is based on a model to account for within-subject correlation.
Outcome measures
| Measure |
rVIII-SingleChain On-demand
n=590 Number of treated bleeding events
The rVIII-SingleChain On-demand group consisted of all subjects in the efficacy population who received at least 1 dose rVIII-SingleChain as part of on-demand treatment during Parts 2 or 3 of the study. There were 27 subjects in the rVIII-SingleChain On-demand group.
|
rVIII-SingleChain Prophylaxis
n=258 Number of treated bleeding events
The rVIII-SingleChain Prophylaxis group consisted of all subjects in the efficacy population who received at least 1 dose rVIII-SingleChain as part of routine prophylaxis treatment during Parts 2 or 3 of the study. There were 146 subjects in the rVIII-SingleChain Prophylaxis group.
|
rVIII-SingleChain
n=848 Number of treated bleeding events
The Efficacy population consisted of all subjects who received at least 1 dose of rVIII-SingleChain as part of either routine prophylaxis treatment or on-demand treatment during Parts 2 or 3 of the study. There were 173 subjects in the Efficacy population.
|
|---|---|---|---|
|
Treatment Success
|
92.4 % bleeding events successfully treated
Interval 87.8 to 95.3
|
92.2 % bleeding events successfully treated
Interval 86.3 to 95.8
|
92.3 % bleeding events successfully treated
Interval 88.9 to 94.8
|
PRIMARY outcome
Timeframe: Up to 24 monthsNumber of subjects who develop inhibitors to FVIII
Outcome measures
| Measure |
rVIII-SingleChain On-demand
n=174 Participants
The rVIII-SingleChain On-demand group consisted of all subjects in the efficacy population who received at least 1 dose rVIII-SingleChain as part of on-demand treatment during Parts 2 or 3 of the study. There were 27 subjects in the rVIII-SingleChain On-demand group.
|
rVIII-SingleChain Prophylaxis
The rVIII-SingleChain Prophylaxis group consisted of all subjects in the efficacy population who received at least 1 dose rVIII-SingleChain as part of routine prophylaxis treatment during Parts 2 or 3 of the study. There were 146 subjects in the rVIII-SingleChain Prophylaxis group.
|
rVIII-SingleChain
The Efficacy population consisted of all subjects who received at least 1 dose of rVIII-SingleChain as part of either routine prophylaxis treatment or on-demand treatment during Parts 2 or 3 of the study. There were 173 subjects in the Efficacy population.
|
|---|---|---|---|
|
Inhibitor Formation to FVIII
|
0 participants
|
—
|
—
|
PRIMARY outcome
Timeframe: Up to 24 monthsThe annualized spontaneous bleeding rate (AsBR) was derived for each subject as follows: 365.25\*(number of spontaneous bleeding episodes requiring treatment) / (observed treatment period of interest).
Outcome measures
| Measure |
rVIII-SingleChain On-demand
n=27 Participants
The rVIII-SingleChain On-demand group consisted of all subjects in the efficacy population who received at least 1 dose rVIII-SingleChain as part of on-demand treatment during Parts 2 or 3 of the study. There were 27 subjects in the rVIII-SingleChain On-demand group.
|
rVIII-SingleChain Prophylaxis
n=146 Participants
The rVIII-SingleChain Prophylaxis group consisted of all subjects in the efficacy population who received at least 1 dose rVIII-SingleChain as part of routine prophylaxis treatment during Parts 2 or 3 of the study. There were 146 subjects in the rVIII-SingleChain Prophylaxis group.
|
rVIII-SingleChain
The Efficacy population consisted of all subjects who received at least 1 dose of rVIII-SingleChain as part of either routine prophylaxis treatment or on-demand treatment during Parts 2 or 3 of the study. There were 173 subjects in the Efficacy population.
|
|---|---|---|---|
|
Annualized Spontaneous Bleeding Rate
|
11.73 Number of spontaneous bleeds per year
Interval 2.8 to 36.5
|
0.00 Number of spontaneous bleeds per year
Interval 0.0 to 2.4
|
—
|
PRIMARY outcome
Timeframe: From the start of surgery through the post-operative recovery (generally up to 14 days after surgery)Subjects received rVIII-SingleChain before and during surgery based on the type of surgery and the clinical status of the subject. The investigator rated the efficacy of the treatment based on a 4-point surgical treatment rating scale of "excellent, good, moderate or poor/no response". Efficacy ratings of "excellent" or "good" were considered treatment success for this end point. The rate of success, defined as the percentage of surgeries with a rating of excellent or good for hemostatic efficacy on the surgical treatment scale is presented for the Surgical Population, based on the total number of surgeries (N=16) as denominator.
Outcome measures
| Measure |
rVIII-SingleChain On-demand
n=13 Participants
The rVIII-SingleChain On-demand group consisted of all subjects in the efficacy population who received at least 1 dose rVIII-SingleChain as part of on-demand treatment during Parts 2 or 3 of the study. There were 27 subjects in the rVIII-SingleChain On-demand group.
|
rVIII-SingleChain Prophylaxis
The rVIII-SingleChain Prophylaxis group consisted of all subjects in the efficacy population who received at least 1 dose rVIII-SingleChain as part of routine prophylaxis treatment during Parts 2 or 3 of the study. There were 146 subjects in the rVIII-SingleChain Prophylaxis group.
|
rVIII-SingleChain
The Efficacy population consisted of all subjects who received at least 1 dose of rVIII-SingleChain as part of either routine prophylaxis treatment or on-demand treatment during Parts 2 or 3 of the study. There were 173 subjects in the Efficacy population.
|
|---|---|---|---|
|
Treatment Success During the Peri-operative Surgical Sub-study
|
100 % of surgeries with successful treatment
|
—
|
—
|
SECONDARY outcome
Timeframe: Before infusion and at up to 10 time points within 72 hours of infusionAUC0-∞ (AUC from 0 extrapolated to infinity) of a single infusion of octocog alfa and rVIII-SingleChain without correction for subject's predose plasma FVIII activity. FVIII activity values for octocog alfa are dose-adjusted for chromogenic potency.
Outcome measures
| Measure |
rVIII-SingleChain On-demand
n=27 Participants
The rVIII-SingleChain On-demand group consisted of all subjects in the efficacy population who received at least 1 dose rVIII-SingleChain as part of on-demand treatment during Parts 2 or 3 of the study. There were 27 subjects in the rVIII-SingleChain On-demand group.
|
rVIII-SingleChain Prophylaxis
The rVIII-SingleChain Prophylaxis group consisted of all subjects in the efficacy population who received at least 1 dose rVIII-SingleChain as part of routine prophylaxis treatment during Parts 2 or 3 of the study. There were 146 subjects in the rVIII-SingleChain Prophylaxis group.
|
rVIII-SingleChain
The Efficacy population consisted of all subjects who received at least 1 dose of rVIII-SingleChain as part of either routine prophylaxis treatment or on-demand treatment during Parts 2 or 3 of the study. There were 173 subjects in the Efficacy population.
|
|---|---|---|---|
|
AUC0-∞ (Part 1)
Octocog alfa
|
1550 IU*h/dL
Standard Deviation 552
|
—
|
—
|
|
AUC0-∞ (Part 1)
rVIII-SingleChain
|
2090 IU*h/dL
Standard Deviation 650
|
—
|
—
|
SECONDARY outcome
Timeframe: Before infusion and at up to 10 time points within 72 hours of infusionCmax of a single infusion of octocog alfa and rVIII-SingleChain with correction for subject's predose plasma FVIII activity. FVIII activity values for octocog alfa are dose-adjusted for chromogenic potency.
Outcome measures
| Measure |
rVIII-SingleChain On-demand
n=27 Participants
The rVIII-SingleChain On-demand group consisted of all subjects in the efficacy population who received at least 1 dose rVIII-SingleChain as part of on-demand treatment during Parts 2 or 3 of the study. There were 27 subjects in the rVIII-SingleChain On-demand group.
|
rVIII-SingleChain Prophylaxis
The rVIII-SingleChain Prophylaxis group consisted of all subjects in the efficacy population who received at least 1 dose rVIII-SingleChain as part of routine prophylaxis treatment during Parts 2 or 3 of the study. There were 146 subjects in the rVIII-SingleChain Prophylaxis group.
|
rVIII-SingleChain
The Efficacy population consisted of all subjects who received at least 1 dose of rVIII-SingleChain as part of either routine prophylaxis treatment or on-demand treatment during Parts 2 or 3 of the study. There were 173 subjects in the Efficacy population.
|
|---|---|---|---|
|
Cmax (Part 1)
Octocog alfa
|
116 IU/dL
Standard Deviation 18.1
|
—
|
—
|
|
Cmax (Part 1)
rVIII-SingleChain
|
113 IU/dL
Standard Deviation 17.4
|
—
|
—
|
SECONDARY outcome
Timeframe: Before infusion and at up to 10 time points within 72 hours of infusionTmax = time of Cmax (with correction for subject's predose plasma FVIII activity) after a single infusion of octocog alfa and rVIII-SingleChain.
Outcome measures
| Measure |
rVIII-SingleChain On-demand
n=27 Participants
The rVIII-SingleChain On-demand group consisted of all subjects in the efficacy population who received at least 1 dose rVIII-SingleChain as part of on-demand treatment during Parts 2 or 3 of the study. There were 27 subjects in the rVIII-SingleChain On-demand group.
|
rVIII-SingleChain Prophylaxis
The rVIII-SingleChain Prophylaxis group consisted of all subjects in the efficacy population who received at least 1 dose rVIII-SingleChain as part of routine prophylaxis treatment during Parts 2 or 3 of the study. There were 146 subjects in the rVIII-SingleChain Prophylaxis group.
|
rVIII-SingleChain
The Efficacy population consisted of all subjects who received at least 1 dose of rVIII-SingleChain as part of either routine prophylaxis treatment or on-demand treatment during Parts 2 or 3 of the study. There were 173 subjects in the Efficacy population.
|
|---|---|---|---|
|
Tmax (Part 1)
Octocog alfa
|
0.583 hours
Interval 0.45 to 0.8
|
—
|
—
|
|
Tmax (Part 1)
rVIII-SingleChain
|
0.683 hours
Interval 0.467 to 1.25
|
—
|
—
|
SECONDARY outcome
Timeframe: Before infusion and at up to 10 time points within 72 hours of infusion.Half-life (t1/2) of a single infusion of octocog alfa and rVIII-SingleChain without correction for subject's predose plasma FVIII activity.
Outcome measures
| Measure |
rVIII-SingleChain On-demand
n=27 Participants
The rVIII-SingleChain On-demand group consisted of all subjects in the efficacy population who received at least 1 dose rVIII-SingleChain as part of on-demand treatment during Parts 2 or 3 of the study. There were 27 subjects in the rVIII-SingleChain On-demand group.
|
rVIII-SingleChain Prophylaxis
The rVIII-SingleChain Prophylaxis group consisted of all subjects in the efficacy population who received at least 1 dose rVIII-SingleChain as part of routine prophylaxis treatment during Parts 2 or 3 of the study. There were 146 subjects in the rVIII-SingleChain Prophylaxis group.
|
rVIII-SingleChain
The Efficacy population consisted of all subjects who received at least 1 dose of rVIII-SingleChain as part of either routine prophylaxis treatment or on-demand treatment during Parts 2 or 3 of the study. There were 173 subjects in the Efficacy population.
|
|---|---|---|---|
|
Half-life (t1/2) (Part 1)
Octocog alfa
|
13.3 hours
Standard Deviation 4.36
|
—
|
—
|
|
Half-life (t1/2) (Part 1)
rVIII-SingleChain
|
14.5 hours
Standard Deviation 3.77
|
—
|
—
|
SECONDARY outcome
Timeframe: Before infusion and at up to 10 time points within 72 hours of infusionMean residence time (MRT) of a single infusion of octocog alfa and rVIII-SingleChain without correction for subject's predose plasma FVIII activity.
Outcome measures
| Measure |
rVIII-SingleChain On-demand
n=27 Participants
The rVIII-SingleChain On-demand group consisted of all subjects in the efficacy population who received at least 1 dose rVIII-SingleChain as part of on-demand treatment during Parts 2 or 3 of the study. There were 27 subjects in the rVIII-SingleChain On-demand group.
|
rVIII-SingleChain Prophylaxis
The rVIII-SingleChain Prophylaxis group consisted of all subjects in the efficacy population who received at least 1 dose rVIII-SingleChain as part of routine prophylaxis treatment during Parts 2 or 3 of the study. There were 146 subjects in the rVIII-SingleChain Prophylaxis group.
|
rVIII-SingleChain
The Efficacy population consisted of all subjects who received at least 1 dose of rVIII-SingleChain as part of either routine prophylaxis treatment or on-demand treatment during Parts 2 or 3 of the study. There were 173 subjects in the Efficacy population.
|
|---|---|---|---|
|
Mean Residence Time (MRT) (Part 1)
Octocog alfa
|
17.1 hours
Standard Deviation 5.57
|
—
|
—
|
|
Mean Residence Time (MRT) (Part 1)
rVIII-SingleChain
|
20.4 hours
Standard Deviation 5.49
|
—
|
—
|
SECONDARY outcome
Timeframe: Before infusion and at up to 10 time points within 72 hours of infusionClearance (Cl) of a single infusion of octocog alfa and rVIII-SingleChain without correction for subject's predose plasma FVIII activity. FVIII activity values for octocog alfa are dose-adjusted for chromogenic potency.
Outcome measures
| Measure |
rVIII-SingleChain On-demand
n=27 Participants
The rVIII-SingleChain On-demand group consisted of all subjects in the efficacy population who received at least 1 dose rVIII-SingleChain as part of on-demand treatment during Parts 2 or 3 of the study. There were 27 subjects in the rVIII-SingleChain On-demand group.
|
rVIII-SingleChain Prophylaxis
The rVIII-SingleChain Prophylaxis group consisted of all subjects in the efficacy population who received at least 1 dose rVIII-SingleChain as part of routine prophylaxis treatment during Parts 2 or 3 of the study. There were 146 subjects in the rVIII-SingleChain Prophylaxis group.
|
rVIII-SingleChain
The Efficacy population consisted of all subjects who received at least 1 dose of rVIII-SingleChain as part of either routine prophylaxis treatment or on-demand treatment during Parts 2 or 3 of the study. There were 173 subjects in the Efficacy population.
|
|---|---|---|---|
|
Clearance (Cl) (Part 1)
Octocog alfa
|
3.68 mL/h/kg
Standard Deviation 1.41
|
—
|
—
|
|
Clearance (Cl) (Part 1)
rVIII-SingleChain
|
2.64 mL/h/kg
Standard Deviation 0.846
|
—
|
—
|
SECONDARY outcome
Timeframe: Before infusion and at up to 10 time points within 72 hours of infusionVolume of distribution at steady-state (Vss) of a single infusion of octocog alfa and rVIII-SingleChain without correction for subject's predose plasma FVIII activity. FVIII activity values for octocog alfa are dose-adjusted for chromogenic potency.
Outcome measures
| Measure |
rVIII-SingleChain On-demand
n=27 Participants
The rVIII-SingleChain On-demand group consisted of all subjects in the efficacy population who received at least 1 dose rVIII-SingleChain as part of on-demand treatment during Parts 2 or 3 of the study. There were 27 subjects in the rVIII-SingleChain On-demand group.
|
rVIII-SingleChain Prophylaxis
The rVIII-SingleChain Prophylaxis group consisted of all subjects in the efficacy population who received at least 1 dose rVIII-SingleChain as part of routine prophylaxis treatment during Parts 2 or 3 of the study. There were 146 subjects in the rVIII-SingleChain Prophylaxis group.
|
rVIII-SingleChain
The Efficacy population consisted of all subjects who received at least 1 dose of rVIII-SingleChain as part of either routine prophylaxis treatment or on-demand treatment during Parts 2 or 3 of the study. There were 173 subjects in the Efficacy population.
|
|---|---|---|---|
|
Volume of Distribution at Steady-state (Vss) (Part 1)
Octocog alfa
|
57.1 mL/kg
Standard Deviation 11.3
|
—
|
—
|
|
Volume of Distribution at Steady-state (Vss) (Part 1)
rVIII-SingleChain
|
50.0 mL/kg
Standard Deviation 7.51
|
—
|
—
|
SECONDARY outcome
Timeframe: At 30 minutes after infusionIncremental recovery of a single infusion of octocog alfa and rVIII-SingleChain with correction for subject's predose plasma FVIII activity. FVIII activity values for octocog alfa are dose-adjusted for chromogenic potency.
Outcome measures
| Measure |
rVIII-SingleChain On-demand
n=27 Participants
The rVIII-SingleChain On-demand group consisted of all subjects in the efficacy population who received at least 1 dose rVIII-SingleChain as part of on-demand treatment during Parts 2 or 3 of the study. There were 27 subjects in the rVIII-SingleChain On-demand group.
|
rVIII-SingleChain Prophylaxis
The rVIII-SingleChain Prophylaxis group consisted of all subjects in the efficacy population who received at least 1 dose rVIII-SingleChain as part of routine prophylaxis treatment during Parts 2 or 3 of the study. There were 146 subjects in the rVIII-SingleChain Prophylaxis group.
|
rVIII-SingleChain
The Efficacy population consisted of all subjects who received at least 1 dose of rVIII-SingleChain as part of either routine prophylaxis treatment or on-demand treatment during Parts 2 or 3 of the study. There were 173 subjects in the Efficacy population.
|
|---|---|---|---|
|
Incremental Recovery (Part 1)
Octocog alfa
|
2.32 [IU/dL]/[IU/kg]
Standard Deviation 0.381
|
—
|
—
|
|
Incremental Recovery (Part 1)
rVIII-SingleChain
|
2.24 [IU/dL]/[IU/kg]
Standard Deviation 0.357
|
—
|
—
|
SECONDARY outcome
Timeframe: Up to 24 monthsThe annualized bleeding rate was derived for each subject as follows: 365.25\*(number of bleeding episodes requiring treatment) / (observed treatment period of interest).
Outcome measures
| Measure |
rVIII-SingleChain On-demand
n=27 Participants
The rVIII-SingleChain On-demand group consisted of all subjects in the efficacy population who received at least 1 dose rVIII-SingleChain as part of on-demand treatment during Parts 2 or 3 of the study. There were 27 subjects in the rVIII-SingleChain On-demand group.
|
rVIII-SingleChain Prophylaxis
n=146 Participants
The rVIII-SingleChain Prophylaxis group consisted of all subjects in the efficacy population who received at least 1 dose rVIII-SingleChain as part of routine prophylaxis treatment during Parts 2 or 3 of the study. There were 146 subjects in the rVIII-SingleChain Prophylaxis group.
|
rVIII-SingleChain
The Efficacy population consisted of all subjects who received at least 1 dose of rVIII-SingleChain as part of either routine prophylaxis treatment or on-demand treatment during Parts 2 or 3 of the study. There were 173 subjects in the Efficacy population.
|
|---|---|---|---|
|
Annualized Bleeding Rate for Total Bleeds and Traumatic Bleeds
Total Bleeds
|
19.64 Number of bleeds per year
Interval 6.2 to 46.5
|
1.14 Number of bleeds per year
Interval 0.0 to 4.2
|
—
|
|
Annualized Bleeding Rate for Total Bleeds and Traumatic Bleeds
Traumatic Bleeds
|
3.12 Number of bleeds per year
Interval 0.0 to 8.4
|
0.00 Number of bleeds per year
Interval 0.0 to 0.9
|
—
|
SECONDARY outcome
Timeframe: During the study (up to 24 months; assessed at Months 1, 2, 3, 4, 5, 6, 9, 12, 15, 18, 21 and 24)Percentage of bleeding episodes requiring 1, 2, 3 or \> 3 infusions of rVIII-SingleChain to achieve hemostasis. The denominator includes all treated bleeding episodes.
Outcome measures
| Measure |
rVIII-SingleChain On-demand
n=590 Treated bleeding episodes
The rVIII-SingleChain On-demand group consisted of all subjects in the efficacy population who received at least 1 dose rVIII-SingleChain as part of on-demand treatment during Parts 2 or 3 of the study. There were 27 subjects in the rVIII-SingleChain On-demand group.
|
rVIII-SingleChain Prophylaxis
n=258 Treated bleeding episodes
The rVIII-SingleChain Prophylaxis group consisted of all subjects in the efficacy population who received at least 1 dose rVIII-SingleChain as part of routine prophylaxis treatment during Parts 2 or 3 of the study. There were 146 subjects in the rVIII-SingleChain Prophylaxis group.
|
rVIII-SingleChain
n=848 Treated bleeding episodes
The Efficacy population consisted of all subjects who received at least 1 dose of rVIII-SingleChain as part of either routine prophylaxis treatment or on-demand treatment during Parts 2 or 3 of the study. There were 173 subjects in the Efficacy population.
|
|---|---|---|---|
|
Proportion of Bleeding Episodes Requiring 1, 2, 3 or > 3 Infusions of rVIII-SingleChain to Achieve Hemostasis
Requiring 1 infusion for hemostasis
|
82.7 Percentage of bleeding episodes
|
76.7 Percentage of bleeding episodes
|
80.9 Percentage of bleeding episodes
|
|
Proportion of Bleeding Episodes Requiring 1, 2, 3 or > 3 Infusions of rVIII-SingleChain to Achieve Hemostasis
Requiring 2 infusions for hemostasis
|
12.0 Percentage of bleeding episodes
|
14.0 Percentage of bleeding episodes
|
12.6 Percentage of bleeding episodes
|
|
Proportion of Bleeding Episodes Requiring 1, 2, 3 or > 3 Infusions of rVIII-SingleChain to Achieve Hemostasis
Requiring 3 infusions for hemostasis
|
3.22 Percentage of bleeding episodes
|
3.88 Percentage of bleeding episodes
|
3.42 Percentage of bleeding episodes
|
|
Proportion of Bleeding Episodes Requiring 1, 2, 3 or > 3 Infusions of rVIII-SingleChain to Achieve Hemostasis
Requiring >3 infusions for hemostasis
|
2.03 Percentage of bleeding episodes
|
5.43 Percentage of bleeding episodes
|
3.07 Percentage of bleeding episodes
|
OTHER_PRE_SPECIFIED outcome
Timeframe: At 30 minutes after infusionIncremental recovery of an initial and repeat infusion of rVIII-SingleChain with correction for subject's predose plasma FVIII activity.
Outcome measures
| Measure |
rVIII-SingleChain On-demand
n=63 Participants
The rVIII-SingleChain On-demand group consisted of all subjects in the efficacy population who received at least 1 dose rVIII-SingleChain as part of on-demand treatment during Parts 2 or 3 of the study. There were 27 subjects in the rVIII-SingleChain On-demand group.
|
rVIII-SingleChain Prophylaxis
The rVIII-SingleChain Prophylaxis group consisted of all subjects in the efficacy population who received at least 1 dose rVIII-SingleChain as part of routine prophylaxis treatment during Parts 2 or 3 of the study. There were 146 subjects in the rVIII-SingleChain Prophylaxis group.
|
rVIII-SingleChain
The Efficacy population consisted of all subjects who received at least 1 dose of rVIII-SingleChain as part of either routine prophylaxis treatment or on-demand treatment during Parts 2 or 3 of the study. There were 173 subjects in the Efficacy population.
|
|---|---|---|---|
|
Incremental Recovery (Part 3)
Initial, n = 63
|
1.85 [IU/dL]/[IU/kg]
Standard Deviation 0.404
|
—
|
—
|
|
Incremental Recovery (Part 3)
Repeat, n = 29
|
1.99 [IU/dL]/[IU/kg]
Standard Deviation 0.352
|
—
|
—
|
OTHER_PRE_SPECIFIED outcome
Timeframe: Before infusion and at up to 12 time points within 96 hours of infusion.Volume of distribution at steady-state (Vss) of an initial and repeat infusion of rVIII-SingleChain without correction for subject's predose plasma FVIII activity.
Outcome measures
| Measure |
rVIII-SingleChain On-demand
n=64 Participants
The rVIII-SingleChain On-demand group consisted of all subjects in the efficacy population who received at least 1 dose rVIII-SingleChain as part of on-demand treatment during Parts 2 or 3 of the study. There were 27 subjects in the rVIII-SingleChain On-demand group.
|
rVIII-SingleChain Prophylaxis
The rVIII-SingleChain Prophylaxis group consisted of all subjects in the efficacy population who received at least 1 dose rVIII-SingleChain as part of routine prophylaxis treatment during Parts 2 or 3 of the study. There were 146 subjects in the rVIII-SingleChain Prophylaxis group.
|
rVIII-SingleChain
The Efficacy population consisted of all subjects who received at least 1 dose of rVIII-SingleChain as part of either routine prophylaxis treatment or on-demand treatment during Parts 2 or 3 of the study. There were 173 subjects in the Efficacy population.
|
|---|---|---|---|
|
Volume of Distribution at Steady-state (Vss) (Part 3)
Initial, n = 64
|
59.5 mL/kg
Standard Deviation 14.2
|
—
|
—
|
|
Volume of Distribution at Steady-state (Vss) (Part 3)
Repeat, n = 30
|
53.1 mL/kg
Standard Deviation 8.74
|
—
|
—
|
OTHER_PRE_SPECIFIED outcome
Timeframe: Before infusion and at up to 12 time points within 96 hours of infusion.Clearance (Cl) of an initial and repeat infusion of rVIII-SingleChain without correction for subject's predose plasma FVIII activity.
Outcome measures
| Measure |
rVIII-SingleChain On-demand
n=64 Participants
The rVIII-SingleChain On-demand group consisted of all subjects in the efficacy population who received at least 1 dose rVIII-SingleChain as part of on-demand treatment during Parts 2 or 3 of the study. There were 27 subjects in the rVIII-SingleChain On-demand group.
|
rVIII-SingleChain Prophylaxis
The rVIII-SingleChain Prophylaxis group consisted of all subjects in the efficacy population who received at least 1 dose rVIII-SingleChain as part of routine prophylaxis treatment during Parts 2 or 3 of the study. There were 146 subjects in the rVIII-SingleChain Prophylaxis group.
|
rVIII-SingleChain
The Efficacy population consisted of all subjects who received at least 1 dose of rVIII-SingleChain as part of either routine prophylaxis treatment or on-demand treatment during Parts 2 or 3 of the study. There were 173 subjects in the Efficacy population.
|
|---|---|---|---|
|
Clearance (Cl) (Part 3)
Initial, n = 64
|
3.15 mL/h/kg
Standard Deviation 1.21
|
—
|
—
|
|
Clearance (Cl) (Part 3)
Repeat, n = 30
|
3.05 mL/h/kg
Standard Deviation 1.1
|
—
|
—
|
OTHER_PRE_SPECIFIED outcome
Timeframe: Before infusion and at up to 12 time points within 96 hours of infusion.Mean residence time (MRT) of an initial and repeat infusion of rVIII-SingleChain without correction for subject's predose plasma FVIII activity.
Outcome measures
| Measure |
rVIII-SingleChain On-demand
n=64 Participants
The rVIII-SingleChain On-demand group consisted of all subjects in the efficacy population who received at least 1 dose rVIII-SingleChain as part of on-demand treatment during Parts 2 or 3 of the study. There were 27 subjects in the rVIII-SingleChain On-demand group.
|
rVIII-SingleChain Prophylaxis
The rVIII-SingleChain Prophylaxis group consisted of all subjects in the efficacy population who received at least 1 dose rVIII-SingleChain as part of routine prophylaxis treatment during Parts 2 or 3 of the study. There were 146 subjects in the rVIII-SingleChain Prophylaxis group.
|
rVIII-SingleChain
The Efficacy population consisted of all subjects who received at least 1 dose of rVIII-SingleChain as part of either routine prophylaxis treatment or on-demand treatment during Parts 2 or 3 of the study. There were 173 subjects in the Efficacy population.
|
|---|---|---|---|
|
Mean Residence Time (MRT) (Part 3)
Initial, n = 64
|
20.3 hours
Standard Deviation 5.36
|
—
|
—
|
|
Mean Residence Time (MRT) (Part 3)
Repeat, n = 30
|
18.9 hours
Standard Deviation 5.39
|
—
|
—
|
OTHER_PRE_SPECIFIED outcome
Timeframe: Before infusion and at up to 12 time points within 96 hours of infusion.Half-life (t1/2) of an initial and repeat infusion of rVIII-SingleChain without correction for subject's predose plasma FVIII activity.
Outcome measures
| Measure |
rVIII-SingleChain On-demand
n=64 Participants
The rVIII-SingleChain On-demand group consisted of all subjects in the efficacy population who received at least 1 dose rVIII-SingleChain as part of on-demand treatment during Parts 2 or 3 of the study. There were 27 subjects in the rVIII-SingleChain On-demand group.
|
rVIII-SingleChain Prophylaxis
The rVIII-SingleChain Prophylaxis group consisted of all subjects in the efficacy population who received at least 1 dose rVIII-SingleChain as part of routine prophylaxis treatment during Parts 2 or 3 of the study. There were 146 subjects in the rVIII-SingleChain Prophylaxis group.
|
rVIII-SingleChain
The Efficacy population consisted of all subjects who received at least 1 dose of rVIII-SingleChain as part of either routine prophylaxis treatment or on-demand treatment during Parts 2 or 3 of the study. There were 173 subjects in the Efficacy population.
|
|---|---|---|---|
|
Half-life (t1/2) (Part 3)
Initial, n = 64
|
14.1 hours
Standard Deviation 3.82
|
—
|
—
|
|
Half-life (t1/2) (Part 3)
Repeat, n = 30
|
12.9 hours
Standard Deviation 3.7
|
—
|
—
|
OTHER_PRE_SPECIFIED outcome
Timeframe: Before infusion and at up to 12 time points within 96 hours of infusion.Tmax = time of Cmax (with correction for subject's predose plasma FVIII activity) after an initial and repeat infusion of rVIII-SingleChain.
Outcome measures
| Measure |
rVIII-SingleChain On-demand
n=63 Participants
The rVIII-SingleChain On-demand group consisted of all subjects in the efficacy population who received at least 1 dose rVIII-SingleChain as part of on-demand treatment during Parts 2 or 3 of the study. There were 27 subjects in the rVIII-SingleChain On-demand group.
|
rVIII-SingleChain Prophylaxis
The rVIII-SingleChain Prophylaxis group consisted of all subjects in the efficacy population who received at least 1 dose rVIII-SingleChain as part of routine prophylaxis treatment during Parts 2 or 3 of the study. There were 146 subjects in the rVIII-SingleChain Prophylaxis group.
|
rVIII-SingleChain
The Efficacy population consisted of all subjects who received at least 1 dose of rVIII-SingleChain as part of either routine prophylaxis treatment or on-demand treatment during Parts 2 or 3 of the study. There were 173 subjects in the Efficacy population.
|
|---|---|---|---|
|
Tmax (Part 3)
Initial, n = 63
|
0.333 hours
Interval 0.117 to 1.22
|
—
|
—
|
|
Tmax (Part 3)
Repeat, n = 29
|
0.317 hours
Interval 0.117 to 0.667
|
—
|
—
|
OTHER_PRE_SPECIFIED outcome
Timeframe: Before infusion and at up to 12 time points within 96 hours of infusionCmax of an initial and repeat infusion of rVIII-SingleChain with correction for subject's predose plasma FVIII activity.
Outcome measures
| Measure |
rVIII-SingleChain On-demand
n=63 Participants
The rVIII-SingleChain On-demand group consisted of all subjects in the efficacy population who received at least 1 dose rVIII-SingleChain as part of on-demand treatment during Parts 2 or 3 of the study. There were 27 subjects in the rVIII-SingleChain On-demand group.
|
rVIII-SingleChain Prophylaxis
The rVIII-SingleChain Prophylaxis group consisted of all subjects in the efficacy population who received at least 1 dose rVIII-SingleChain as part of routine prophylaxis treatment during Parts 2 or 3 of the study. There were 146 subjects in the rVIII-SingleChain Prophylaxis group.
|
rVIII-SingleChain
The Efficacy population consisted of all subjects who received at least 1 dose of rVIII-SingleChain as part of either routine prophylaxis treatment or on-demand treatment during Parts 2 or 3 of the study. There were 173 subjects in the Efficacy population.
|
|---|---|---|---|
|
Cmax (Part 3)
Initial, n = 63
|
99.9 IU/dL
Standard Deviation 19.9
|
—
|
—
|
|
Cmax (Part 3)
Repeat, n = 29
|
108 IU/dL
Standard Deviation 18.5
|
—
|
—
|
OTHER_PRE_SPECIFIED outcome
Timeframe: Before infusion and at up to 12 time points within 96 hours of infusionAUC0-∞ (AUC from 0 extrapolated to infinity) of an initial and repeat infusion of rVIII-SingleChain without correction for subject's predose plasma FVIII activity.
Outcome measures
| Measure |
rVIII-SingleChain On-demand
n=64 Participants
The rVIII-SingleChain On-demand group consisted of all subjects in the efficacy population who received at least 1 dose rVIII-SingleChain as part of on-demand treatment during Parts 2 or 3 of the study. There were 27 subjects in the rVIII-SingleChain On-demand group.
|
rVIII-SingleChain Prophylaxis
The rVIII-SingleChain Prophylaxis group consisted of all subjects in the efficacy population who received at least 1 dose rVIII-SingleChain as part of routine prophylaxis treatment during Parts 2 or 3 of the study. There were 146 subjects in the rVIII-SingleChain Prophylaxis group.
|
rVIII-SingleChain
The Efficacy population consisted of all subjects who received at least 1 dose of rVIII-SingleChain as part of either routine prophylaxis treatment or on-demand treatment during Parts 2 or 3 of the study. There were 173 subjects in the Efficacy population.
|
|---|---|---|---|
|
AUC0-∞ (Part 3)
Initial, n = 64
|
1830 IU*h/dL
Standard Deviation 640
|
—
|
—
|
|
AUC0-∞ (Part 3)
Repeat, n = 30
|
1880 IU*h/dL
Standard Deviation 649
|
—
|
—
|
Adverse Events
Safety Population
Serious events: 8 serious events
Other events: 45 other events
Deaths: 0 deaths
Serious adverse events
| Measure |
Safety Population
n=174 participants at risk
The Safety Population comprised all subjects treated with rVIII-SingleChain.
|
|---|---|
|
Injury, poisoning and procedural complications
Ankle fracture
|
0.57%
1/174 • Number of events 1 • For the duration of the study, approximately 2 years, 10 months.
The Safety Population comprised all subjects treated with rVIII-SingleChain. A total of 14592 rVIII-SingleChain infusions were administered to 174 subjects during the study.
|
|
Investigations
Blood uric acid increased
|
0.57%
1/174 • Number of events 1 • For the duration of the study, approximately 2 years, 10 months.
The Safety Population comprised all subjects treated with rVIII-SingleChain. A total of 14592 rVIII-SingleChain infusions were administered to 174 subjects during the study.
|
|
Respiratory, thoracic and mediastinal disorders
Tonsillar haemorrhage
|
0.57%
1/174 • Number of events 1 • For the duration of the study, approximately 2 years, 10 months.
The Safety Population comprised all subjects treated with rVIII-SingleChain. A total of 14592 rVIII-SingleChain infusions were administered to 174 subjects during the study.
|
|
Immune system disorders
Hypersensitivity
|
0.57%
1/174 • Number of events 1 • For the duration of the study, approximately 2 years, 10 months.
The Safety Population comprised all subjects treated with rVIII-SingleChain. A total of 14592 rVIII-SingleChain infusions were administered to 174 subjects during the study.
|
|
Blood and lymphatic system disorders
Anaemia
|
0.57%
1/174 • Number of events 1 • For the duration of the study, approximately 2 years, 10 months.
The Safety Population comprised all subjects treated with rVIII-SingleChain. A total of 14592 rVIII-SingleChain infusions were administered to 174 subjects during the study.
|
|
Blood and lymphatic system disorders
Thrombocytopenia
|
0.57%
1/174 • Number of events 1 • For the duration of the study, approximately 2 years, 10 months.
The Safety Population comprised all subjects treated with rVIII-SingleChain. A total of 14592 rVIII-SingleChain infusions were administered to 174 subjects during the study.
|
|
Psychiatric disorders
Suicidal ideation
|
0.57%
1/174 • Number of events 1 • For the duration of the study, approximately 2 years, 10 months.
The Safety Population comprised all subjects treated with rVIII-SingleChain. A total of 14592 rVIII-SingleChain infusions were administered to 174 subjects during the study.
|
|
Gastrointestinal disorders
Varices oesophageal
|
0.57%
1/174 • Number of events 1 • For the duration of the study, approximately 2 years, 10 months.
The Safety Population comprised all subjects treated with rVIII-SingleChain. A total of 14592 rVIII-SingleChain infusions were administered to 174 subjects during the study.
|
|
Infections and infestations
Postoperative wound infection
|
0.57%
1/174 • Number of events 1 • For the duration of the study, approximately 2 years, 10 months.
The Safety Population comprised all subjects treated with rVIII-SingleChain. A total of 14592 rVIII-SingleChain infusions were administered to 174 subjects during the study.
|
|
Infections and infestations
Viral infection
|
0.57%
1/174 • Number of events 1 • For the duration of the study, approximately 2 years, 10 months.
The Safety Population comprised all subjects treated with rVIII-SingleChain. A total of 14592 rVIII-SingleChain infusions were administered to 174 subjects during the study.
|
Other adverse events
| Measure |
Safety Population
n=174 participants at risk
The Safety Population comprised all subjects treated with rVIII-SingleChain.
|
|---|---|
|
Nervous system disorders
Headache
|
7.5%
13/174 • Number of events 14 • For the duration of the study, approximately 2 years, 10 months.
The Safety Population comprised all subjects treated with rVIII-SingleChain. A total of 14592 rVIII-SingleChain infusions were administered to 174 subjects during the study.
|
|
Musculoskeletal and connective tissue disorders
Arthralgia
|
11.5%
20/174 • Number of events 22 • For the duration of the study, approximately 2 years, 10 months.
The Safety Population comprised all subjects treated with rVIII-SingleChain. A total of 14592 rVIII-SingleChain infusions were administered to 174 subjects during the study.
|
|
Infections and infestations
Nasopharyngitis
|
10.3%
18/174 • Number of events 22 • For the duration of the study, approximately 2 years, 10 months.
The Safety Population comprised all subjects treated with rVIII-SingleChain. A total of 14592 rVIII-SingleChain infusions were administered to 174 subjects during the study.
|
Additional Information
Results disclosure agreements
- Principal investigator is a sponsor employee CSL agreements and restrictions on publishing may vary with individual investigators; however, CSL will not prohibit any investigator from publishing. CSL supports the publication of results from all centers of a multi-center trial and generally requires that reports based on single-site data not precede the primary publication of the entire clinical trial.
- Publication restrictions are in place
Restriction type: OTHER