Clinical trial NCT02083965: Pharmacokinetics of rFVIIIFc at Two Vial Strengths
Official title: A Randomized, Open-Label, Crossover Study to Evaluate the Pharmacokinetics of 2 Vial Strengths of Recombinant Factor VIII Fc Fusion Protein (rFVIIIFc; BIIB031) in Previously Treated Subjects With Severe Hemophilia A
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Severe Hemophilia A
Lead sponsor: Sanofi
Sponsor class: INDUSTRY
First posted: 2014-03-11
Enrollment: 19
Sex: MALE
Minimum age (years): 12
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

Brief summary: The primary objective of the study is to characterize the pharmacokinetics (PK) of rFVIIIFc administered at vial strengths of 1000 and 3000 IU in subjects with severe hemophilia A. The secondary objective of the study is to evaluate the safety of rFVIIIFc beyond the PK assessment for up to 6 months for a continued treatment period.

Detailed description: This is a randomized, open-label, crossover study during which each participant receives a single injection of rFVIIIFc from 2 different vial concentrations (PK assessment). After the PK assessment, participants are provided with rFVIIIFc for either prophylactic or episodic (on-demand) treatment for up to 6 months.

Eligibility criteria: Key Inclusion Criteria:

* Have severe hemophilia A
* Previously treated subject, defined as having at least 150 documented prior exposure days to any recombinant and/or plasma-derived FVIII and/or cryoprecipitate products (other than any use of rFVIIIFc- study drug or commercial product) at Day 1. Fresh frozen plasma treatment must not be considered in the count for documented exposure days.
* No history of a positive inhibitor test or clinical signs of decreased response to FVIII administrations. Family history of inhibitors will not exclude subjects.
* No measurable inhibitor activity using the Nijmegen-modified Bethesda assay at Screening.
* Platelet count ≥100,000 platelets/μL at screening
* CD4 lymphocytes \>200 mm3 if known as HIV antibody positive at screening.
* Viral load of \<400 copies/mL if known HIV antibody positive at screening.

Key Exclusion Criteria:

* Subject is at high risk of bleeding during the 5-day period between the first and second injections for PK analyses, as per Investigator discretion.
* Previous treatment with rFVIIIFc as study drug or commercial product.
* Other coagulation disorder(s) in addition to hemophilia A.
* History of hypersensitivity or anaphylaxis associated with any FVIII or IV immunoglobulin administration.
* Currently taking (or likely to require during the study) acetylsalicylic acid (ASA), except for low-dose ASA as prophylaxis (other nonsteroidal anti-inflammatory drugs are permitted).
* Concurrent systemic treatment with immunosuppressive drugs within 12 weeks prior to Day 1. Exceptions to this include: ribavirin for treatment of hepatitis C virus (HCV), and/or systemic steroids (a total of 2 courses of pulse treatments lasting no more than 7 days at a dose of ≤1 mg/kg within 12 weeks prior to Day 1) and/or inhaled steroids.

NOTE: Other protocol-defined inclusion/exclusion Criteria May Apply

Primary outcomes:
measure: Area Under the Concentration-time Curve From Time Zero to Infinity (AUCinf) as Measured by Activated Partial Thromboplastin Time (aPTT) Clotting Assay
timeFrame: Predose, 0.5 hour (+-5 minutes); 1 hour and 6 hours (+-10 minutes); and 24, 48, 72, and 96 hours (+-60 minutes) after each injection
measure: Incremental Recovery (IR, K Value) as Estimated From the FVIII Activity Data Measured by aPTT Clotting Assay
timeFrame: Predose, 0.5 hour (+-5 minutes); 1 hour and 6 hours (+-10 minutes); and 24, 48, 72, and 96 hours (+-60 minutes) after each injection
Secondary outcomes:
measure: Maximum Activity (Cmax) as Measured by the aPTT Clotting Assay
timeFrame: Predose, 0.5 hour (+-5 minutes); 1 hour and 6 hours (+-10 minutes); and 24, 48, 72, and 96 hours (+-60 minutes) after each injection
measure: Half-life (t½) as Measured by aPTT Clotting Assay
timeFrame: Predose, 0.5 hour (+-5 minutes); 1 hour and 6 hours (+-10 minutes); and 24, 48, 72, and 96 hours (+-60 minutes) after each injection
measure: Clearance (CL) as Measured by the aPTT Clotting Assay
timeFrame: Predose, 0.5 hour (+-5 minutes); 1 hour and 6 hours (+-10 minutes); and 24, 48, 72, and 96 hours (+-60 minutes) after each injection
measure: Volume of Distribution at Steady State (Vss) as Measured by the aPTT Clotting Assay
timeFrame: Predose, 0.5 hour (+-5 minutes); 1 hour and 6 hours (+-10 minutes); and 24, 48, 72, and 96 hours (+-60 minutes) after each injection
measure: Mean Residence Time (MRT) as Measured by the aPTT Clotting Assay
timeFrame: Predose, 0.5 hour (+-5 minutes); 1 hour and 6 hours (+-10 minutes); and 24, 48, 72, and 96 hours (+-60 minutes) after each injection
measure: Time of Cmax (Tmax) as Measured by aPTT Clotting Assay
timeFrame: Predose, 0.5 hour (+-5 minutes); 1 hour and 6 hours (+-10 minutes); and 24, 48, 72, and 96 hours (+-60 minutes) after each injection
measure: Area Under the Curve to the Last Measurable Time Point (AUClast) as Measured by aPTT Clotting Assay
timeFrame: Predose, 0.5 hour (+-5 minutes); 1 hour and 6 hours (+-10 minutes); and 24, 48, 72, and 96 hours (+-60 minutes) after each injection
measure: Terminal Exponential Rate Constant (Lambda Z) as Measured by aPTT Clotting Assay
timeFrame: Predose, 0.5 hour (+-5 minutes); 1 hour and 6 hours (+-10 minutes); and 24, 48, 72, and 96 hours (+-60 minutes) after each injection
measure: Percentage of AUCinf From the Last Data Point to Infinity (AUCext) as Measured by aPTT Clotting Assay
timeFrame: Predose, 0.5 hour (+-5 minutes); 1 hour and 6 hours (+-10 minutes); and 24, 48, 72, and 96 hours (+-60 minutes) after each injection
measure: Dose Normalized Area Under the Curve (DNAUC) as Measured by aPTT Clotting Assay
timeFrame: Predose, 0.5 hour (+-5 minutes); 1 hour and 6 hours (+-10 minutes); and 24, 48, 72, and 96 hours (+-60 minutes) after each injection
measure: Terminal Exponential Volume of Distribution (Vz) as Measured by aPTT
timeFrame: Predose, 0.5 hour (+-5 minutes); 1 hour and 6 hours (+-10 minutes); and 24, 48, 72, and 96 hours (+-60 minutes) after each injection
measure: AUCinf as Estimated From the FVIII Activity Data as Measured by Two-Stage Chromogenic Clotting Assay
timeFrame: Predose, 0.5 hour (+-5 minutes); 1 hour and 6 hours (+-10 minutes); and 24, 48, 72, and 96 hours (+-60 minutes) after each injection
measure: IR, K Value as Measured by Two-Stage Chromogenic Clotting Assay
timeFrame: Predose, 0.5 hour (+-5 minutes); 1 hour and 6 hours (+-10 minutes); and 24, 48, 72, and 96 hours (+-60 minutes) after each injection
measure: Cmax as Measured by Two-Stage Chromogenic Clotting Assay
timeFrame: Predose, 0.5 hour (+-5 minutes); 1 hour and 6 hours (+-10 minutes); and 24, 48, 72, and 96 hours (+-60 minutes) after each injection
measure: t½ as Measured by Two-Stage Chromogenic Clotting Assay
timeFrame: Predose, 0.5 hour (+-5 minutes); 1 hour and 6 hours (+-10 minutes); and 24, 48, 72, and 96 hours (+-60 minutes) after each injection
measure: CL as Measured by Two-Stage Chromogenic Clotting Assay
timeFrame: Predose, 0.5 hour (+-5 minutes); 1 hour and 6 hours (+-10 minutes); and 24, 48, 72, and 96 hours (+-60 minutes) after each injection
measure: Vss as Measured by Two-Stage Chromogenic Clotting Assay
timeFrame: Predose, 0.5 hour (+-5 minutes); 1 hour and 6 hours (+-10 minutes); and 24, 48, 72, and 96 hours (+-60 minutes) after each injection
measure: MRT as Measured by Two-Stage Chromogenic Clotting Assay
timeFrame: Predose, 0.5 hour (+-5 minutes); 1 hour and 6 hours (+-10 minutes); and 24, 48, 72, and 96 hours (+-60 minutes) after each injection
measure: Tmax as Measured by Two-Stage Chromogenic Clotting Assay
timeFrame: Predose, 0.5 hour (+-5 minutes); 1 hour and 6 hours (+-10 minutes); and 24, 48, 72, and 96 hours (+-60 minutes) after each injection
measure: AUClast as Measured by Two-Stage Chromogenic Clotting Assay
timeFrame: Predose, 0.5 hour (+-5 minutes); 1 hour and 6 hours (+-10 minutes); and 24, 48, 72, and 96 hours (+-60 minutes) after each injection
measure: Lambda Z as Measured by Two-Stage Chromogenic Clotting Assay
timeFrame: Predose, 0.5 hour (+-5 minutes); 1 hour and 6 hours (+-10 minutes); and 24, 48, 72, and 96 hours (+-60 minutes) after each injection
measure: AUCext as Measured by Two-Stage Chromogenic Clotting Assay
timeFrame: Predose, 0.5 hour (+-5 minutes); 1 hour and 6 hours (+-10 minutes); and 24, 48, 72, and 96 hours (+-60 minutes) after each injection
measure: DNAUC as Measured by Two-Stage Chromogenic Clotting Assay
timeFrame: Predose, 0.5 hour (+-5 minutes); 1 hour and 6 hours (+-10 minutes); and 24, 48, 72, and 96 hours (+-60 minutes) after each injection
measure: Vz as Measured by Two-Stage Chromogenic Clotting Assay
timeFrame: Predose, 0.5 hour (+-5 minutes); 1 hour and 6 hours (+-10 minutes); and 24, 48, 72, and 96 hours (+-60 minutes) after each injection
measure: Development of Inhibitor as Measured by the Nijmegen-Modified Bethesda Assay
timeFrame: Predose, Month 3, Month 6/early withdrawal. Additionally: If inhibitor suspected; at 10-15 EDs; 2-4 weeks prior to scheduled surgery; preoperatively on day of surgery; 1-2 weeks post-surgery; at last postoperative visit (last 2 for major surgery only)
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: Research Site
state: California
city: Salt Lake City
country: United States
facility: Research Site
state: Utah
city: Seattle
country: United States
facility: Research Site
state: Washington
city: Herston
country: Australia
facility: Research Site
city: Perth
country: Australia
facility: Research Site
city: Basingstoke
country: United Kingdom
facility: Research Site
city: Cambridge
country: United Kingdom
facility: Research Site
city: London
country: United Kingdom
facility: Research Site
Study officials:
affiliation: Bioverativ Therapeutics Inc.
name: Medical Director
role: STUDY_DIRECTOR
References: