Pharmacokinetics of rFVIIIFc at Two Vial Strengths

Phase 1CompletedNCT02083965

Bioverativ Therapeutics Inc.19 enrolled

Overview

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.

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.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

Conditions

Severe Hemophilia A

Interventions

rFVIIIFcBIOLOGICAL

Administered as specified in the treatment arm.

Eligibility

Sex: MALEMin age: 12 Years

Medical Language ↔ Plain English

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

Locations (8)

Research Site

Los Angeles, California, United States

Research Site

Salt Lake City, Utah, United States

Research Site

Seattle, Washington, United States

Research Site

Herston, Australia

Outcomes

Primary Outcomes

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 - ∞).

Time frame: 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

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.

Time frame: 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

Maximum Activity (Cmax) as Measured by the aPTT Clotting Assay

Maximum measured concentration of rFVIIIFc.

Time frame: 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

Half-life (t½) as Measured by aPTT Clotting Assay

Time required for the concentration of the drug to reach half of its original value.

Time frame: 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

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.

Time frame: 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

Data from ClinicalTrials.gov

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Research Site

Perth, Australia

Research Site

Basingstoke, United Kingdom

Research Site

Cambridge, United Kingdom

Research Site

London, United Kingdom

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.)

Time frame: 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

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.

Time frame: 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

Time of Cmax (Tmax) as Measured by aPTT Clotting Assay

Time at which maximum activity (Cmax) is observed.

Time frame: 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

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.

Time frame: 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

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) .

Time frame: 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

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.

Time frame: 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

Dose Normalized Area Under the Curve (DNAUC) as Measured by aPTT Clotting Assay

Dose normalized area under the FVIII activity-time curve.

Time frame: 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

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.

Time frame: 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

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 - ∞).

Time frame: 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

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.

Time frame: 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

Cmax as Measured by Two-Stage Chromogenic Clotting Assay

Maximum measured concentration of rFVIIIFc.

Time frame: 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

t½ as Measured by Two-Stage Chromogenic Clotting Assay

Time required for the concentration of the drug to reach half of its original value.

Time frame: 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

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.

Time frame: 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

Vss as Measured by Two-Stage Chromogenic Clotting Assay

Time frame: 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

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.

Time frame: 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

Tmax as Measured by Two-Stage Chromogenic Clotting Assay

Time at which maximum activity (Cmax) is observed.

Time frame: 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

AUClast as Measured by Two-Stage Chromogenic Clotting Assay

Area under the plasma concentration time-curve from zero to the last measured concentration.

Time frame: 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

Lambda Z as Measured by Two-Stage Chromogenic Clotting Assay

First order rate constant associated with the terminal portion of the curve (lambda z).

Time frame: 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

AUCext as Measured by Two-Stage Chromogenic Clotting Assay

Percentage of AUCinf extrapolated from the last data point to infinity.

Time frame: 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

DNAUC as Measured by Two-Stage Chromogenic Clotting Assay

Dose normalized area under the FVIII activity-time curve.

Time frame: 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

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.

Time frame: 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

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.

Time frame: 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)