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

Study Overview
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Brief Summary
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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.

Official Title
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A Phase I/III Open-label, Multicenter, Crossover Safety, Efficacy and Pharmacokinetic Study of Recombinant Coagulation Factor VIII (rFVIII) Compared to Recombinant Human Antihaemophilic Factor VIII (rFVIII; INN: Octocog Alfa) in Subjects With Hemophilia A, and a Repeat PK, Safety and Efficacy Study

Conditions
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Hemophilia A

Intervention / Treatment
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* Biological: rVIII-SingleChain
* Biological: Octocog alfa


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 12 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Recombinant Factor VIII (rFVIII)<br> | Biological: rVIII-SingleChain<br>* 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.<br>* Other names: CSL627;Biological: Octocog alfa<br>* 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.<br>* Other names: Human coagulation factor VIII (rDNA);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Up to 24 months | 
| Inhibitor Formation to FVIII | Number of subjects who develop inhibitors to FVIII | Up to 24 months | 
| 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). | Up to 24 months | 
| 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. | From the start of surgery through the post-operative recovery (generally up to 14 days after surgery) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Before infusion and at up to 10 time points within 72 hours of infusion | 
| 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. | Before infusion and at up to 10 time points within 72 hours of infusion | 
| 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. | Before infusion and at up to 10 time points within 72 hours of infusion | 
| 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. | Before infusion and at up to 10 time points within 72 hours of infusion. | 
| 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. | Before infusion and at up to 10 time points within 72 hours of infusion | 
| 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. | Before infusion and at up to 10 time points within 72 hours of infusion | 
| 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. | Before infusion and at up to 10 time points within 72 hours of infusion | 
| 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. | At 30 minutes after infusion | 
| 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). | Up to 24 months | 
| 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. | During the study (up to 24 months; assessed at Months 1, 2, 3, 4, 5, 6, 9, 12, 15, 18, 21 and 24) |