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

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

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.

Study Overview

• Status: Completed
• Conditions: Hemophilia A
• Intervention / Treatment: Biological: rVIII-SingleChain; Biological: Octocog alfa

• Study Type: Interventional
• Enrollment (Actual): 175
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• Australia
  • Nedlands, Australia, WA 6009
    • Study Site
  • Perth, Australia, WA 6000
    • Study Site
• Austria
  • Graz, Austria, 8036
    • Study Site
  • Vienna, Austria, 1090
    • Study Site
• Canada
  • New Brunswick, Canada, E2L 4L2
    • Study Site
• Czech Republic
  • Hradec Králové, Czech Republic, 500 05
    • Study Site
• Germany
  • Berlin, Germany, 10249
    • Study Site
  • Berlin, Germany, 13353
    • Study Site
  • Bonn, Germany, 53127
    • Study Site
  • Gießen, Germany, 35392
    • Study Site
  • Hamburg, Germany, 20095
    • Study Site
  • Hannover, Germany, 30159
    • Study Site
  • Heidelberg, Germany, 69123
    • Study Site
• Hungary
  • Debrecen, Hungary, H-4032
    • Study Site
• Italy
  • Florence, Italy, 50134
    • Study Site
  • Milan, Italy, 20122
    • Study Site
  • Padova, Italy, 35123
    • Study Site
  • Padova, Italy, 35128
    • Study Site
  • Torino, Italy, 10126
    • Study Site
• Japan
  • Kashihara, Nara, Japan
    • Study Site
  • Kitakyushu, Fukuoka, Japan
    • Study Site
  • Nagoya, Japan, 466-85660
    • Study Site
  • Nishinomiya, Hyogo, Japan
    • Study Site
  • Okayama, Japan, 710-8602
    • Study Site
  • Saitama, Japan
    • Study Site
  • Suginami-ku, Tokyo, Japan
    • Study Site
  • Tokyo, Japan, 160-0023
    • Study Site
• Lebanon
  • Beirut, Lebanon
    • Study Site
• Malaysia
  • Kuala Lumpur, Malaysia, 50400
    • Study Site
• Netherlands
  • Utrecht, Netherlands, 3584 CX
    • Study Site
• Philippines
  • Cebu City, Philippines, 6000
    • Study Site
  • Davao City, Philippines, 8000
    • Study Site
• Poland
  • Gdansk, Poland, 80-952
    • Study Site
  • Krakow, Poland, 31-501
    • Study Site
  • Silesia
    • Wroclaw, Silesia, Poland, 50-367
      • Study Site
• Romania
  • Bucharest, Romania, 011026
    • Study Site
• Russian Federation
  • Barnaul, Russian Federation, 656038
    • Study Site
  • Kemerovo, Russian Federation, 650066
    • Study Site
• South Africa
  • Cape Town, South Africa, 7295
    • Study Site
  • Johannesburg, South Africa, 2193
    • Study Site
• Spain
  • Barcelona, Spain
    • Study Site
  • La Coruna, Spain
    • Study Site
  • Valencia, Spain, 46026
    • Study Site
• Ukraine
  • Dnipropetrovsk, Ukraine, 49102
    • Study Site
  • Donetsk, Ukraine, 830045
    • Study Site
  • Lviv, Ukraine, 79044
    • Study Site
• United Kingdom
  • London, United Kingdom, NW3 2QG
    • Study Site
• United States
  • California
    • Sacramento, California, United States, 95817
      • Study Site
    • San Diego, California, United States, 92103
      • Study Site
  • Colorado
    • Aurora, Colorado, United States, 80045
      • Study Site
  • Connecticut
    • Hartford, Connecticut, United States, 06106
      • Study Site
  • Florida
    • Miami, Florida, United States, 33136
      • Study Site
  • Illinois
    • Chicago, Illinois, United States, 60612-3833
      • Study Site
  • Louisiana
    • New Orleans, Louisiana, United States, 70112
      • Study Site
  • Texas
    • Houston, Texas, United States, 77030
      • Study Site
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53226
      • Study Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 12 years to 65 years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Male

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Recombinant Factor VIII (rFVIII)

Biological: rVIII-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.; Other Names: Recombinant Factor VIII (rFVIII); CSL627; Biological: Octocog 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.; Other Names: Human coagulation factor VIII (rDNA)

What is the study measuring?

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)

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incremental Recovery (Part 3)	Incremental recovery of an initial and repeat infusion of rVIII-SingleChain with correction for subject's predose plasma FVIII activity.	At 30 minutes after infusion
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.	Before infusion and at up to 12 time points within 96 hours of infusion.
Clearance (Cl) (Part 3)	Clearance (Cl) of an initial and repeat infusion of rVIII-SingleChain without correction for subject's predose plasma FVIII activity.	Before infusion and at up to 12 time points within 96 hours of infusion.
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.	Before infusion and at up to 12 time points within 96 hours of infusion.
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.	Before infusion and at up to 12 time points within 96 hours of infusion.
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.	Before infusion and at up to 12 time points within 96 hours of infusion.
Cmax (Part 3)	Cmax of an initial and repeat infusion of rVIII-SingleChain with correction for subject's predose plasma FVIII activity.	Before infusion and at up to 12 time points within 96 hours of infusion
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.	Before infusion and at up to 12 time points within 96 hours of infusion

Collaborators and Investigators

• Sponsor: CSL Behring

Publications and helpful links

General Publications

• Mahlangu J, Kuliczkowski K, Karim FA, Stasyshyn O, Kosinova MV, Lepatan LM, Skotnicki A, Boggio LN, Klamroth R, Oldenburg J, Hellmann A, Santagostino E, Baker RI, Fischer K, Gill JC, P'Ng S, Chowdary P, Escobar MA, Khayat CD, Rusen L, Bensen-Kennedy D, Blackman N, Limsakun T, Veldman A, St Ledger K, Pabinger I; AFFINITY Investigators. Efficacy and safety of rVIII-SingleChain: results of a phase 1/3 multicenter clinical trial in severe hemophilia A. Blood. 2016 Aug 4;128(5):630-7. doi: 10.1182/blood-2016-01-687434. Epub 2016 Jun 21.

Study record dates

Study Major Dates

• Study Start: February 1, 2012
• Primary Completion (Actual): December 1, 2014
• Study Completion (Actual): December 1, 2014

Study Registration Dates

• First Submitted: November 19, 2011
• First Submitted That Met QC Criteria: December 5, 2011
• First Posted (Estimate): December 7, 2011

Study Record Updates

• Last Update Posted (Estimate): August 9, 2016
• Last Update Submitted That Met QC Criteria: June 24, 2016
• Last Verified: June 1, 2016

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Hematologic Diseases; Blood Coagulation Disorders, Inherited; Coagulation Protein Disorders; Hemorrhagic Disorders; Genetic Diseases, Inborn; Blood Coagulation Disorders; Hemophilia A; Coagulants; Factor VIII
• Other Study ID Numbers: CSL627_1001; 2011-002393-23 (EudraCT Number)