Hemophilia A
Conditions
Brief summary
This is an open-label, non-randomized, efficacy, safety and pharmacokinetic (PK) study comparing octocog alfa and rVIII-SingleChain. The study consists of three parts, a PK period (Part 1), a continuation of dosing safety and efficacy period (Part 2) and a safety, efficacy, and repeat PK period (Part 3) and also includes a surgical sub-study for subjects enrolled in Parts 2 and 3.
Interventions
BIOLOGICALrVIII-SingleChain
In Part 1 of the study, subjects received a single intravenous infusion of 50 IU/kg recombinant, single-chain coagulation factor VIII (rVIII-SingleChain) preceded by a 4-day washout period. In Parts 2 and 3 of the study, subjects received repeat injections of rVIII-SingleChain either as an on-demand or prophylaxis regimen at a dose and frequency determined by their study doctor. Subjects participating in the Part 3 PK analyses received a single infusion of 50 IU/kg rVIII-SingleChain and a repeat dose of the same strength of rVIII-SingleChain after 3 to 6 months. Subjects from Parts 2 and 3 participating in the surgical substudy received an individualized dose regimen of rVIII-SingleChain, based on the type of surgery and the clinical status of the subject.
BIOLOGICALOctocog alfa
In Part 1 of the study, subjects received a single intravenous infusion of 50 IU/kg of octocog alfa preceded by a 4-day washout period. Octocog alfa is the international nonproprietary name (INN) for recombinant human coagulation factor VIII.
Sponsors
CSL Behring
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
MALE
Age
12 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* Diagnosis of severe hemophilia A defined as \<1% FVIII:C documented in medical records. * Males between 18 and 65 years of age (Parts 1 and 2). * Males between 12 and 65 years of age (Part 3). * Subjects who have received or are currently receiving FVIII products (plasma-derived and/or recombinant FVIII) and have had \>150 exposure days (EDs) with a FVIII product * Written informed consent for study participation obtained before undergoing any study specific procedures.
Exclusion criteria
* Any history of or current FVIII inhibitors * Any first order family history of FVIII inhibitors * Use of an Investigational Medicinal Product within 30 days prior to the first rVIII-SingleChain administration. * Administration of any cryoprecipitate, whole blood or plasma within 30 days prior to administration of rVIII-SingleChain or reference product. * Known hypersensitivity (allergic reaction or anaphylaxis) to any FVIII product or hamster protein. * Any known congenital or acquired coagulation disorder other than congenital FVIII deficiency. * Platelet count \< 100,000/µL at screening. * Human immunodeficiency virus (HIV) positive subjects with a CD4 count \< 200/mm3, in their medical history or at screening if available results are older than one year. (HIV positive subjects may participate in the study and antiviral therapy are permitted, at the discretion of the Investigator). * Subject currently receiving IV immunomodulating agents such as immunoglobulin or chronic systemic corticosteroid treatment. * Subject with serum aspartate aminotransferase (AST) or serum alanine aminotransferase (ALT) values \> 5 times (x) the upper limit of normal (ULN) at Screening. * Subjects with serum creatinine values \> 2 x ULN at Screening. * Evidence of thrombosis, including deep vein thrombosis, stroke, pulmonary embolism, myocardial infarction and arterial embolus within 3 months prior to Day 1. * Experienced life-threatening bleeding episode or had major surgery or an orthopedic surgical procedure during the 3 months prior to Day 1.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Treatment Success | Up to 24 months | 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. |
| Treatment Success During the Peri-operative Surgical Sub-study | 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. |
| Annualized Spontaneous Bleeding Rate | Up to 24 months | The annualized spontaneous bleeding rate (AsBR) was derived for each subject as follows: 365.25\*(number of spontaneous bleeding episodes requiring treatment) / (observed treatment period of interest). |
| Inhibitor Formation to FVIII | Up to 24 months | Number of subjects who develop inhibitors to FVIII |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Half-life (t1/2) (Part 1) | 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. |
| Cmax (Part 1) | Before infusion and at up to 10 time points within 72 hours of infusion | Cmax of a single infusion of octocog alfa and rVIII-SingleChain with correction for subject's predose plasma FVIII activity. FVIII activity values for octocog alfa are dose-adjusted for chromogenic potency. |
| Tmax (Part 1) | Before infusion and at up to 10 time points within 72 hours of infusion | Tmax = time of Cmax (with correction for subject's predose plasma FVIII activity) after a single infusion of octocog alfa and rVIII-SingleChain. |
| Mean Residence Time (MRT) (Part 1) | Before infusion and at up to 10 time points within 72 hours of infusion | Mean residence time (MRT) of a single infusion of octocog alfa and rVIII-SingleChain without correction for subject's predose plasma FVIII activity. |
| Clearance (Cl) (Part 1) | Before infusion and at up to 10 time points within 72 hours of infusion | Clearance (Cl) of a single infusion of octocog alfa and rVIII-SingleChain without correction for subject's predose plasma FVIII activity. FVIII activity values for octocog alfa are dose-adjusted for chromogenic potency. |
| Volume of Distribution at Steady-state (Vss) (Part 1) | Before infusion and at up to 10 time points within 72 hours of infusion | Volume of distribution at steady-state (Vss) of a single infusion of octocog alfa and rVIII-SingleChain without correction for subject's predose plasma FVIII activity. FVIII activity values for octocog alfa are dose-adjusted for chromogenic potency. |
| Incremental Recovery (Part 1) | At 30 minutes after infusion | Incremental recovery of a single infusion of octocog alfa and rVIII-SingleChain with correction for subject's predose plasma FVIII activity. FVIII activity values for octocog alfa are dose-adjusted for chromogenic potency. |
| Annualized Bleeding Rate for Total Bleeds and Traumatic Bleeds | Up to 24 months | The annualized bleeding rate was derived for each subject as follows: 365.25\*(number of bleeding episodes requiring treatment) / (observed treatment period of interest). |
| Proportion of Bleeding Episodes Requiring 1, 2, 3 or > 3 Infusions of rVIII-SingleChain to Achieve Hemostasis | 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. |
| AUC0-∞ (Part 1) | Before infusion and at up to 10 time points within 72 hours of infusion | AUC0-∞ (AUC from 0 extrapolated to infinity) of a single infusion of octocog alfa and rVIII-SingleChain without correction for subject's predose plasma FVIII activity. FVIII activity values for octocog alfa are dose-adjusted for chromogenic potency. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Tmax (Part 3) | 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. |
| Cmax (Part 3) | Before infusion and at up to 12 time points within 96 hours of infusion | Cmax of an initial and repeat infusion of rVIII-SingleChain with correction for subject's predose plasma FVIII activity. |
| AUC0-∞ (Part 3) | Before infusion and at up to 12 time points within 96 hours of infusion | AUC0-∞ (AUC from 0 extrapolated to infinity) of an initial and repeat infusion of rVIII-SingleChain without correction for subject's predose plasma FVIII activity. |
| Volume of Distribution at Steady-state (Vss) (Part 3) | 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. |
| Half-life (t1/2) (Part 3) | 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. |
| Mean Residence Time (MRT) (Part 3) | 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. |
| Incremental Recovery (Part 3) | At 30 minutes after infusion | Incremental recovery of an initial and repeat infusion of rVIII-SingleChain with correction for subject's predose plasma FVIII activity. |
| Clearance (Cl) (Part 3) | 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. |
Countries
Australia, Austria, Canada, Czechia, Germany, Hungary, Italy, Japan, Lebanon, Malaysia, Netherlands, Philippines, Poland, Romania, Russia, South Africa, Spain, Ukraine, United Kingdom, United States
Participant flow
Recruitment details
This multicenter, multinational study enrolled subjects at 54 participating study centers in the United States, Japan, Europe, Australia, Canada, Lebanon, Malaysia, Philippines, Russian Federation, South Africa, and Ukraine.
Pre-assignment details
Screening took place 4 to 28 days prior to first dose of study product (rVIII-SingleChain). A total of 204 subjects were screened, 29 of these did not fulfill all eligibility criteria and were therefore screening failures. A total of 175 subjects were enrolled; 174 subjects were exposed to treatment with rVIII-SingleChain.
Participants by arm
| Arm | Count |
|---|---|
| Recombinant Factor VIII (rFVIII) 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. | 174 |
| Total | 174 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | 50 Exposure days not reached | 2 |
| Overall Study | Knee surgery (prior to surgery substudy) | 1 |
| Overall Study | Physician Decision | 1 |
| Overall Study | Subject did not reach 6 mo of treatment | 1 |
| Overall Study | Withdrawal by Subject | 8 |
Baseline characteristics
| Characteristic | Recombinant Factor VIII (rFVIII) |
|---|---|
| Age, Continuous | 31.3 years STANDARD_DEVIATION 11.77 |
| Age, Customized Adolescents (12-17 years) | 14 participants |
| Age, Customized Adults (18-65 years) | 160 participants |
| Sex: Female, Male Female | 0 Participants |
| Sex: Female, Male Male | 174 Participants |
| Treatment modality of FVIII therapy before enrollment On-demand | 92 participants |
| Treatment modality of FVIII therapy before enrollment Prophylaxis | 82 participants |
| Type of FVIII product used before enrollment Plasma-derived Product | 83 participants |
| Type of FVIII product used before enrollment Recombinant Product | 91 participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 45 / 174 |
| serious Total, serious adverse events | 8 / 174 |
Outcome results
Primary
Annualized Spontaneous Bleeding Rate
The annualized spontaneous bleeding rate (AsBR) was derived for each subject as follows: 365.25\*(number of spontaneous bleeding episodes requiring treatment) / (observed treatment period of interest).
Time frame: Up to 24 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| rVIII-SingleChain On-demand | Annualized Spontaneous Bleeding Rate | 11.73 Number of spontaneous bleeds per year |
| rVIII-SingleChain Prophylaxis | Annualized Spontaneous Bleeding Rate | 0.00 Number of spontaneous bleeds per year |
Comparison: A test of the null hypothesis of no difference on AsBR between the 2 comparison groups was based on the Poisson Regression method. The corresponding prophylaxis/on-demand ratio with 95% confidence interval (CI) was calculated.p-value: <0.000195% CI: [0.07, 0.1]Poisson, regression
Primary
Inhibitor Formation to FVIII
Number of subjects who develop inhibitors to FVIII
Time frame: Up to 24 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| rVIII-SingleChain On-demand | Inhibitor Formation to FVIII | 0 participants |
Primary
Treatment Success
The investigator rated the efficacy of the treatment based on a 4-point rating scale excellent, good, moderate or poor/no response. Efficacy ratings of excellent or good were considered treatment success for this end point; the percentage of bleeding events with a rating of excellent or good and the 95% confidence interval are presented. The denominator includes all treated bleeding events. The 95% confidence interval is based on a model to account for within-subject correlation.
Time frame: Up to 24 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| rVIII-SingleChain On-demand | Treatment Success | 92.4 % bleeding events successfully treated |
| rVIII-SingleChain Prophylaxis | Treatment Success | 92.2 % bleeding events successfully treated |
| rVIII-SingleChain | Treatment Success | 92.3 % bleeding events successfully treated |
Primary
Treatment Success During the Peri-operative Surgical Sub-study
Subjects received rVIII-SingleChain before and during surgery based on the type of surgery and the clinical status of the subject. The investigator rated the efficacy of the treatment based on a 4-point surgical treatment rating scale of excellent, good, moderate or poor/no response. Efficacy ratings of excellent or good were considered treatment success for this end point. The rate of success, defined as the percentage of surgeries with a rating of excellent or good for hemostatic efficacy on the surgical treatment scale is presented for the Surgical Population, based on the total number of surgeries (N=16) as denominator.
Time frame: From the start of surgery through the post-operative recovery (generally up to 14 days after surgery)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| rVIII-SingleChain On-demand | Treatment Success During the Peri-operative Surgical Sub-study | 100 % of surgeries with successful treatment |
Secondary
Annualized Bleeding Rate for Total Bleeds and Traumatic Bleeds
The annualized bleeding rate was derived for each subject as follows: 365.25\*(number of bleeding episodes requiring treatment) / (observed treatment period of interest).
Time frame: Up to 24 months
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| rVIII-SingleChain On-demand | Annualized Bleeding Rate for Total Bleeds and Traumatic Bleeds | Total Bleeds | 19.64 Number of bleeds per year |
| rVIII-SingleChain On-demand | Annualized Bleeding Rate for Total Bleeds and Traumatic Bleeds | Traumatic Bleeds | 3.12 Number of bleeds per year |
| rVIII-SingleChain Prophylaxis | Annualized Bleeding Rate for Total Bleeds and Traumatic Bleeds | Total Bleeds | 1.14 Number of bleeds per year |
| rVIII-SingleChain Prophylaxis | Annualized Bleeding Rate for Total Bleeds and Traumatic Bleeds | Traumatic Bleeds | 0.00 Number of bleeds per year |
Secondary
AUC0-∞ (Part 1)
AUC0-∞ (AUC from 0 extrapolated to infinity) of a single infusion of octocog alfa and rVIII-SingleChain without correction for subject's predose plasma FVIII activity. FVIII activity values for octocog alfa are dose-adjusted for chromogenic potency.
Time frame: Before infusion and at up to 10 time points within 72 hours of infusion
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| rVIII-SingleChain On-demand | AUC0-∞ (Part 1) | Octocog alfa | 1550 IU*h/dL | Standard Deviation 552 |
| rVIII-SingleChain On-demand | AUC0-∞ (Part 1) | rVIII-SingleChain | 2090 IU*h/dL | Standard Deviation 650 |
Secondary
Clearance (Cl) (Part 1)
Clearance (Cl) of a single infusion of octocog alfa and rVIII-SingleChain without correction for subject's predose plasma FVIII activity. FVIII activity values for octocog alfa are dose-adjusted for chromogenic potency.
Time frame: Before infusion and at up to 10 time points within 72 hours of infusion
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| rVIII-SingleChain On-demand | Clearance (Cl) (Part 1) | Octocog alfa | 3.68 mL/h/kg | Standard Deviation 1.41 |
| rVIII-SingleChain On-demand | Clearance (Cl) (Part 1) | rVIII-SingleChain | 2.64 mL/h/kg | Standard Deviation 0.846 |
Secondary
Cmax (Part 1)
Cmax of a single infusion of octocog alfa and rVIII-SingleChain with correction for subject's predose plasma FVIII activity. FVIII activity values for octocog alfa are dose-adjusted for chromogenic potency.
Time frame: Before infusion and at up to 10 time points within 72 hours of infusion
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| rVIII-SingleChain On-demand | Cmax (Part 1) | Octocog alfa | 116 IU/dL | Standard Deviation 18.1 |
| rVIII-SingleChain On-demand | Cmax (Part 1) | rVIII-SingleChain | 113 IU/dL | Standard Deviation 17.4 |
Secondary
Half-life (t1/2) (Part 1)
Half-life (t1/2) of a single infusion of octocog alfa and rVIII-SingleChain without correction for subject's predose plasma FVIII activity.
Time frame: Before infusion and at up to 10 time points within 72 hours of infusion.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| rVIII-SingleChain On-demand | Half-life (t1/2) (Part 1) | Octocog alfa | 13.3 hours | Standard Deviation 4.36 |
| rVIII-SingleChain On-demand | Half-life (t1/2) (Part 1) | rVIII-SingleChain | 14.5 hours | Standard Deviation 3.77 |
Secondary
Incremental Recovery (Part 1)
Incremental recovery of a single infusion of octocog alfa and rVIII-SingleChain with correction for subject's predose plasma FVIII activity. FVIII activity values for octocog alfa are dose-adjusted for chromogenic potency.
Time frame: At 30 minutes after infusion
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| rVIII-SingleChain On-demand | Incremental Recovery (Part 1) | Octocog alfa | 2.32 [IU/dL]/[IU/kg] | Standard Deviation 0.381 |
| rVIII-SingleChain On-demand | Incremental Recovery (Part 1) | rVIII-SingleChain | 2.24 [IU/dL]/[IU/kg] | Standard Deviation 0.357 |
Secondary
Mean Residence Time (MRT) (Part 1)
Mean residence time (MRT) of a single infusion of octocog alfa and rVIII-SingleChain without correction for subject's predose plasma FVIII activity.
Time frame: Before infusion and at up to 10 time points within 72 hours of infusion
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| rVIII-SingleChain On-demand | Mean Residence Time (MRT) (Part 1) | Octocog alfa | 17.1 hours | Standard Deviation 5.57 |
| rVIII-SingleChain On-demand | Mean Residence Time (MRT) (Part 1) | rVIII-SingleChain | 20.4 hours | Standard Deviation 5.49 |
Secondary
Proportion of Bleeding Episodes Requiring 1, 2, 3 or > 3 Infusions of rVIII-SingleChain to Achieve Hemostasis
Percentage of bleeding episodes requiring 1, 2, 3 or \> 3 infusions of rVIII-SingleChain to achieve hemostasis. The denominator includes all treated bleeding episodes.
Time frame: During the study (up to 24 months; assessed at Months 1, 2, 3, 4, 5, 6, 9, 12, 15, 18, 21 and 24)
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| rVIII-SingleChain On-demand | 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 |
| rVIII-SingleChain On-demand | 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 |
| rVIII-SingleChain On-demand | 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 |
| rVIII-SingleChain On-demand | 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 |
| rVIII-SingleChain Prophylaxis | Proportion of Bleeding Episodes Requiring 1, 2, 3 or > 3 Infusions of rVIII-SingleChain to Achieve Hemostasis | Requiring >3 infusions for hemostasis | 5.43 Percentage of bleeding episodes |
| rVIII-SingleChain Prophylaxis | Proportion of Bleeding Episodes Requiring 1, 2, 3 or > 3 Infusions of rVIII-SingleChain to Achieve Hemostasis | Requiring 1 infusion for hemostasis | 76.7 Percentage of bleeding episodes |
| rVIII-SingleChain Prophylaxis | Proportion of Bleeding Episodes Requiring 1, 2, 3 or > 3 Infusions of rVIII-SingleChain to Achieve Hemostasis | Requiring 3 infusions for hemostasis | 3.88 Percentage of bleeding episodes |
| rVIII-SingleChain Prophylaxis | Proportion of Bleeding Episodes Requiring 1, 2, 3 or > 3 Infusions of rVIII-SingleChain to Achieve Hemostasis | Requiring 2 infusions for hemostasis | 14.0 Percentage of bleeding episodes |
| rVIII-SingleChain | Proportion of Bleeding Episodes Requiring 1, 2, 3 or > 3 Infusions of rVIII-SingleChain to Achieve Hemostasis | Requiring >3 infusions for hemostasis | 3.07 Percentage of bleeding episodes |
| rVIII-SingleChain | Proportion of Bleeding Episodes Requiring 1, 2, 3 or > 3 Infusions of rVIII-SingleChain to Achieve Hemostasis | Requiring 2 infusions for hemostasis | 12.6 Percentage of bleeding episodes |
| rVIII-SingleChain | Proportion of Bleeding Episodes Requiring 1, 2, 3 or > 3 Infusions of rVIII-SingleChain to Achieve Hemostasis | Requiring 3 infusions for hemostasis | 3.42 Percentage of bleeding episodes |
| rVIII-SingleChain | Proportion of Bleeding Episodes Requiring 1, 2, 3 or > 3 Infusions of rVIII-SingleChain to Achieve Hemostasis | Requiring 1 infusion for hemostasis | 80.9 Percentage of bleeding episodes |
Secondary
Tmax (Part 1)
Tmax = time of Cmax (with correction for subject's predose plasma FVIII activity) after a single infusion of octocog alfa and rVIII-SingleChain.
Time frame: Before infusion and at up to 10 time points within 72 hours of infusion
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| rVIII-SingleChain On-demand | Tmax (Part 1) | Octocog alfa | 0.583 hours |
| rVIII-SingleChain On-demand | Tmax (Part 1) | rVIII-SingleChain | 0.683 hours |
Secondary
Volume of Distribution at Steady-state (Vss) (Part 1)
Volume of distribution at steady-state (Vss) of a single infusion of octocog alfa and rVIII-SingleChain without correction for subject's predose plasma FVIII activity. FVIII activity values for octocog alfa are dose-adjusted for chromogenic potency.
Time frame: Before infusion and at up to 10 time points within 72 hours of infusion
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| rVIII-SingleChain On-demand | Volume of Distribution at Steady-state (Vss) (Part 1) | Octocog alfa | 57.1 mL/kg | Standard Deviation 11.3 |
| rVIII-SingleChain On-demand | Volume of Distribution at Steady-state (Vss) (Part 1) | rVIII-SingleChain | 50.0 mL/kg | Standard Deviation 7.51 |
Other Pre-specified
AUC0-∞ (Part 3)
AUC0-∞ (AUC from 0 extrapolated to infinity) of an initial and repeat infusion of rVIII-SingleChain without correction for subject's predose plasma FVIII activity.
Time frame: Before infusion and at up to 12 time points within 96 hours of infusion
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| rVIII-SingleChain On-demand | AUC0-∞ (Part 3) | Initial, n = 64 | 1830 IU*h/dL | Standard Deviation 640 |
| rVIII-SingleChain On-demand | AUC0-∞ (Part 3) | Repeat, n = 30 | 1880 IU*h/dL | Standard Deviation 649 |
Other Pre-specified
Clearance (Cl) (Part 3)
Clearance (Cl) of an initial and repeat infusion of rVIII-SingleChain without correction for subject's predose plasma FVIII activity.
Time frame: Before infusion and at up to 12 time points within 96 hours of infusion.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| rVIII-SingleChain On-demand | Clearance (Cl) (Part 3) | Initial, n = 64 | 3.15 mL/h/kg | Standard Deviation 1.21 |
| rVIII-SingleChain On-demand | Clearance (Cl) (Part 3) | Repeat, n = 30 | 3.05 mL/h/kg | Standard Deviation 1.1 |
Other Pre-specified
Cmax (Part 3)
Cmax of an initial and repeat infusion of rVIII-SingleChain with correction for subject's predose plasma FVIII activity.
Time frame: Before infusion and at up to 12 time points within 96 hours of infusion
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| rVIII-SingleChain On-demand | Cmax (Part 3) | Repeat, n = 29 | 108 IU/dL | Standard Deviation 18.5 |
| rVIII-SingleChain On-demand | Cmax (Part 3) | Initial, n = 63 | 99.9 IU/dL | Standard Deviation 19.9 |
Other Pre-specified
Half-life (t1/2) (Part 3)
Half-life (t1/2) of an initial and repeat infusion of rVIII-SingleChain without correction for subject's predose plasma FVIII activity.
Time frame: Before infusion and at up to 12 time points within 96 hours of infusion.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| rVIII-SingleChain On-demand | Half-life (t1/2) (Part 3) | Initial, n = 64 | 14.1 hours | Standard Deviation 3.82 |
| rVIII-SingleChain On-demand | Half-life (t1/2) (Part 3) | Repeat, n = 30 | 12.9 hours | Standard Deviation 3.7 |
Other Pre-specified
Incremental Recovery (Part 3)
Incremental recovery of an initial and repeat infusion of rVIII-SingleChain with correction for subject's predose plasma FVIII activity.
Time frame: At 30 minutes after infusion
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| rVIII-SingleChain On-demand | Incremental Recovery (Part 3) | Initial, n = 63 | 1.85 [IU/dL]/[IU/kg] | Standard Deviation 0.404 |
| rVIII-SingleChain On-demand | Incremental Recovery (Part 3) | Repeat, n = 29 | 1.99 [IU/dL]/[IU/kg] | Standard Deviation 0.352 |
Other Pre-specified
Mean Residence Time (MRT) (Part 3)
Mean residence time (MRT) of an initial and repeat infusion of rVIII-SingleChain without correction for subject's predose plasma FVIII activity.
Time frame: Before infusion and at up to 12 time points within 96 hours of infusion.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| rVIII-SingleChain On-demand | Mean Residence Time (MRT) (Part 3) | Initial, n = 64 | 20.3 hours | Standard Deviation 5.36 |
| rVIII-SingleChain On-demand | Mean Residence Time (MRT) (Part 3) | Repeat, n = 30 | 18.9 hours | Standard Deviation 5.39 |
Other Pre-specified
Tmax (Part 3)
Tmax = time of Cmax (with correction for subject's predose plasma FVIII activity) after an initial and repeat infusion of rVIII-SingleChain.
Time frame: Before infusion and at up to 12 time points within 96 hours of infusion.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| rVIII-SingleChain On-demand | Tmax (Part 3) | Initial, n = 63 | 0.333 hours |
| rVIII-SingleChain On-demand | Tmax (Part 3) | Repeat, n = 29 | 0.317 hours |
Other Pre-specified
Volume of Distribution at Steady-state (Vss) (Part 3)
Volume of distribution at steady-state (Vss) of an initial and repeat infusion of rVIII-SingleChain without correction for subject's predose plasma FVIII activity.
Time frame: Before infusion and at up to 12 time points within 96 hours of infusion.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| rVIII-SingleChain On-demand | Volume of Distribution at Steady-state (Vss) (Part 3) | Initial, n = 64 | 59.5 mL/kg | Standard Deviation 14.2 |
| rVIII-SingleChain On-demand | Volume of Distribution at Steady-state (Vss) (Part 3) | Repeat, n = 30 | 53.1 mL/kg | Standard Deviation 8.74 |