Pharmacokinetic, Efficacy, and Safety Study of Recombinant Factor VIII Single Chain (rVIII-SingleChain) in Children With Severe Hemophilia A

Phase 3CompletedNCT02093897

CSL Behring84 enrolled

Overview

This is an international, multicenter, open-label study to assess the efficacy, safety, and pharmacokinetic (PK) profile of rVIII-SingleChain in pediatric patients with severe hemophilia A. A minimum of 25 previously treated subjects ≥ 6 to \< 12 years of age and at least 25 subjects \< 6 years of age who have undergone \> 50 exposure days (EDs) with a previous Factor VIII (FVIII) product are planned to be enrolled. Subjects will be assigned to either an on-demand or prophylaxis treatment regimen and will receive rVIII-SingleChain at a dose to be determined by the investigator. Hemostatic efficacy will be assessed by the subject/caregiver and the investigator who will assess overall efficacy by a 4-point scale.

Study Type

INTERVENTIONAL

Allocation

Purpose

TREATMENT

Masking

NONE

Enrollment

Conditions

Congenital Hemophilia A

Interventions

Eligibility

Sex: MALEMax age: 11 Years

Medical Language ↔ Plain English

Inclusion Criteria: * Diagnosis of severe hemophilia A defined as \< 1% Factor VIII (FVIII) concentration (FVIII:C) documented in medical records, * Males \< 12 years of age, * Subjects who have received \> 50 EDs with a FVIII product, * Prior PK data (at least incremental recovery and half-life) from previous FVIII exposure for subjects participating in the PK part * Investigator believes that the subject is willing and able to adhere to all protocol requirements. Investigator believes that the subject's parent(s) or legally acceptable representative(s) is / are willing and able to adhere to all protocol requirements. Exclusion Criteria: * Any history of or current FVIII inhibitors * Use of an Investigational Medical Product (IMP) 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, * Known hypersensitivity (allergic reaction or anaphylaxis) to any FVIII product or hamster protein, * 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 before Day 1, * Experienced life-threatening bleeding episode or had major surgery or an orthopedic surgical procedure during the 3 months before rVIII-SingleChain administration.

Locations (37)

Study Site

Aurora, Colorado, United States

Study Site

Chicago, Illinois, United States

Study Site

Melbourne, Victoria, Australia

Study Site

Linz, Austria

Study Site

Vienna, Austria

Study Site

Brest, France

Study Site

Le Kremlin-Bicêtre, France

Study Site

Lille, France

Study Site

Nantes, France

Study Site

Paris, France

...and 27 more locations

Outcomes

Primary Outcomes

Treatment Success

Rate of treatment success where treatment success of a bleeding episode is defined as a rating of "excellent" or "good" based on the investigator's overall clinical assessment of hemostatic efficacy (using a 4-point scale of excellent, good, moderate or poor/no response) on the on-demand and prophylaxis regimens combined. The rate of success was based on the number of treated bleeding events; there were 347 treated bleeding events in the Efficacy Population.

Time frame: Up to 1 year

Secondary Outcomes

Annualized Bleeding Rate

The annualized bleeding rate was defined as the number of bleeding episodes requiring treatment divided by the efficacy evaluation period in days, x 365.25, and is presented separately for the on-demand regimen and the prophylaxis regimens.

Time frame: Up to 1 year

Percentage of Bleeding Episodes Requiring 1, 2, 3, or More Than 3 Infusions of rVIII-SingleChain to Achieve Hemostasis.

Time frame: Up to 1 year

Consumption of rVIII-SingleChain - IU/kg Per Subject Per Month

Time frame: Up to 1 year

Consumption of rVIII-SingleChain - IU/kg Per Subject Per Year

Time frame: Up to 1 year

Consumption of rVIII-SingleChain - IU/kg Per Bleeding Event

Time frame: Up to 1 year

Consumption of rVIII-SingleChain (On-demand Regimen) - Number of Infusions Per Subject Per Month

Time frame: Up to 1 year

Consumption of rVIII-SingleChain (On-demand Regimen) - Number of Infusions Per Subject Per Year

Time frame: Up to 1 year

Incremental Recovery

Incremental recovery expressed as (IU/dL)/(IU/kg) corrected for subject's predose plasma FVIII activity measured using the chromogenic substrate assay.

Time frame: At 1 hour after the start of infusion

Half-life (t1/2) of rVIII-SingleChain

Half-life (t1/2) of rVIII-SingleChain, baseline uncorrected; plasma FVIII activity measured using the chromogenic substrate assay.

Time frame: Immediately before dosing, and at approximately 1, 5, 10, 24, and 48 hours after dosing.

Area Under the Concentration Curve (AUC)

AUC to the last sample with quantifiable drug concentration (AUC0-t), baseline uncorrected; plasma FVIII activity measured using the chromogenic substrate assay.

Time frame: Immediately before dosing, and at approximately 1, 5, 10, 24, and 48 hours after dosing.

Clearance (Cl) of rVIII-SingleChain

Clearance (Cl) of rVIII-SingleChain, baseline uncorrected; plasma FVIII activity measured using the chromogenic substrate assay.

Time frame: Immediately before dosing, and at approximately 1, 5, 10, 24, and 48 hours after dosing.

Number of Subjects With Inhibitor Formation to rVIII-SingleChain

The number of subjects who develop inhibitors to rVIII-SingleChain, defined as a rVIII-SingleChain antibody titer of at least 0.6 Bethesda Units (BU) per mL after receiving study drug.

Time frame: At screening, then after dosing at approximately monthly intervals for 6 months, then every 3 months until reaching 50 EDs, and at the end of study visit (up to approximately 12 months).