Pharmacokinetics of rFVIIIFc at Two Vial Strengths

Severe Hemophilia A Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02083965
• Other study ID #: 997HA307
• Secondary ID: 2013-003013-18
• Status: Completed
• Phase: Phase 1
• Start date: March 2014
• Est. completion date: May 2015

Study information

• Verified date: May 2017
• Source: Sanofi
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 19
• Est. completion date: May 2015
• Est. primary completion date: October 2014
• Accepts healthy volunteers: No
• Gender: Male
• Age group: 12 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Hemophilia A
• Severe Hemophilia A

Intervention

Biological:
• rFVIIIFc
Administered as specified in the treatment arm.

Locations

Country	Name	City	State
Australia	Research Site	Herston
Australia	Research Site	Perth
United Kingdom	Research Site	Basingstoke
United Kingdom	Research Site	Cambridge
United Kingdom	Research Site	London
United States	Research Site	Los Angeles	California
United States	Research Site	Salt Lake City	Utah
United States	Research Site	Seattle	Washington

Sponsors (1)

Lead Sponsor	Collaborator
Bioverativ Therapeutics Inc.

Countries where clinical trial is conducted

United States,  Australia,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Area Under the Concentration-time Curve From Time Zero to Infinity (AUCinf) as Measured by Activated Partial Thromboplastin Time (aPTT) Clotting Assay	Area under the plasma concentration versus time curve (AUC) from time zero (pre-dose) to extrapolated infinite time (0 - 8).	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
Primary	Incremental Recovery (IR, K Value) as Estimated From the FVIII Activity Data Measured by aPTT Clotting Assay	The rise in FVIII activity in IU/dL per unit dose administered in IU/kg (IR, K value), as estimated from the FVIII activity data.	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	Maximum Activity (Cmax) as Measured by the aPTT Clotting Assay	Maximum measured concentration of rFVIIIFc.	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	Half-life (t½) as Measured by aPTT Clotting Assay	Time required for the concentration of the drug to reach half of its original value.	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	Clearance (CL) as Measured by the aPTT Clotting Assay	The measure of the efficiency of the body to remove the drug and the unit is the volume of the plasma or blood cleared of drug per unit time.	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	Volume of Distribution at Steady State (Vss) as Measured by the aPTT Clotting Assay	The apparent volume of distribution at steady state. (Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired blood concentration of a drug.)	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	Mean Residence Time (MRT) as Measured by the aPTT Clotting Assay	The average time at which the number of absorbed molecules reside in the body, after single-dose administration.	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	Time of Cmax (Tmax) as Measured by aPTT Clotting Assay	Time at which maximum activity (Cmax) is observed.	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	Area Under the Curve to the Last Measurable Time Point (AUClast) as Measured by aPTT Clotting Assay	Area under the plasma concentration time-curve from zero to the last measured concentration.	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	Terminal Exponential Rate Constant (Lambda Z) as Measured by aPTT Clotting Assay	First order rate constant associated with the terminal portion of the curve (lambda z) .	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	Percentage of AUCinf From the Last Data Point to Infinity (AUCext) as Measured by aPTT Clotting Assay	Percentage of AUCinf extrapolated from the last data point to infinity.	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	Dose Normalized Area Under the Curve (DNAUC) as Measured by aPTT Clotting Assay	Dose normalized area under the FVIII activity-time curve.	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	Terminal Exponential Volume of Distribution (Vz) as Measured by aPTT	The theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug.	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	AUCinf as Estimated From the FVIII Activity Data as Measured by Two-Stage Chromogenic Clotting Assay	Area under the plasma concentration versus time curve (AUC) from time zero (pre-dose) to extrapolated infinite time (0 - 8).	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	IR, K Value as Measured by Two-Stage Chromogenic Clotting Assay	The rise in FVIII activity in IU/dL per unit dose administered in IU/kg (IR, K value), as estimated from the FVIII activity data.	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	Cmax as Measured by Two-Stage Chromogenic Clotting Assay	Maximum measured concentration of rFVIIIFc.	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	t½ as Measured by Two-Stage Chromogenic Clotting Assay	Time required for the concentration of the drug to reach half of its original value.	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	CL as Measured by Two-Stage Chromogenic Clotting Assay	The measure of the efficiency of the body to remove the drug and the unit is the volume of the plasma or blood cleared of drug per unit time.	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	Vss as Measured by Two-Stage Chromogenic Clotting Assay	The apparent volume of distribution at steady state. (Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired blood concentration of a drug.)	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	MRT as Measured by Two-Stage Chromogenic Clotting Assay	The average time at which the number of absorbed molecules reside in the body, after single-dose administration.	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	Tmax as Measured by Two-Stage Chromogenic Clotting Assay	Time at which maximum activity (Cmax) is observed.	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	AUClast as Measured by Two-Stage Chromogenic Clotting Assay	Area under the plasma concentration time-curve from zero to the last measured concentration.	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	Lambda Z as Measured by Two-Stage Chromogenic Clotting Assay	First order rate constant associated with the terminal portion of the curve (lambda z).	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	AUCext as Measured by Two-Stage Chromogenic Clotting Assay	Percentage of AUCinf extrapolated from the last data point to infinity.	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	DNAUC as Measured by Two-Stage Chromogenic Clotting Assay	Dose normalized area under the FVIII activity-time curve.	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	Vz as Measured by Two-Stage Chromogenic Clotting Assay	The theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug.	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	Development of Inhibitor as Measured by the Nijmegen-Modified Bethesda Assay	An inhibitor test result =0.6 Bethesda units (BU)/mL, confirmed on 2 separate samples drawn 2 to 4 weeks apart, was considered positive. Both tests were to be performed by the central laboratory using the Nijmegen-modified Bethesda Assay. An exact 95% confidence interval (CI) for the proportion of subjects with a confirmed inhibitor was calculated using the Clopper-Pearson method for a binomial proportion. Percentage of participants with confirmed inhibitor development was summarized overall.	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)