Clinical trial NCT01458106: Study to Evaluate the Safety, Efficacy, and Pharmacokinetics of Recombinant Coagulation Factor VIII Fc Fusion Protein (rFVIIIFc) in Previously Treated Pediatric Subjects With Hemophilia A
Official title: An Open-Label, Multicenter Evaluation of Safety, Pharmacokinetics, and Efficacy of Recombinant Coagulation Factor VIII Fc Fusion Protein, BIIB031, in the Prevention and Treatment of Bleeding Episodes in Pediatric Subjects With Hemophilia A
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Hemophilia A
Lead sponsor: Sanofi
Sponsor class: INDUSTRY
Collaborators: name: Swedish Orphan Biovitrum
First posted: 2011-10-24
Enrollment: 71
Sex: MALE
Maximum age (years): 11
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: The primary objective of the study is to evaluate the safety of Recombinant Coagulation Factor VIII Fc Fusion Protein (rFVIIIFc) in previously treated pediatric subjects with hemophilia A. Secondary objectives of this study in this study population are as follows: to evaluate the efficacy of rFVIIIFc for prevention and treatment of bleeding episodes; to evaluate and assess the pharmacokinetics (PK) of rFVIIIFc; and to evaluate rFVIIIFc consumption for prevention and treatment of bleeding episodes.

Detailed description: Previously treated pediatric participants will be treated with a prophylactic regimen of rFVIIIFc. PK analysis of pre-study factor VIII (FVIII) and rFVIIIFc will be performed in a sub-group of the study participants prior to commencement of prophylactic treatment. After these PK results are available, remaining participants have the option of proceeding directly to prophylactic treatment. After completing the end of study assessments, eligible participants would be able to continue treatment in Study 8HA01EXT.

Eligibility criteria: Key Inclusion Criteria:

* Severe hemophilia A defined as \<1 IU/dL (\<1%) endogenous FVIII
* Male \<12 years of age and weight ≥13 kg
* History of at least 50 documented prior exposure days to FVIII
* No current, or history of, inhibitor development to FVIII

Key Exclusion Criteria:

* Other coagulation disorders in addition to Hemophilia A
* History of anaphylaxis associated with any FVIII or IV immunoglobulin administration

NOTE: Other protocol-defined Inclusion/Exclusion criteria may apply.

Primary outcomes:
measure: Occurrence of FVIII Inhibitor Development
timeFrame: Up to Week 26 +/- 7 days, or up to 50 exposure days (EDs) if reached prior to Week 26
Secondary outcomes:
measure: Annualized Bleeding Rate
timeFrame: Up to Week 26 +/- 7 days (efficacy period as defined in description)
measure: Annualized Joint Bleeding Rate (Spontaneous)
timeFrame: Up to Week 26 +/- 7 days (efficacy period as defined in description)
measure: Participant Assessment of Response to Injections to Treat a Bleeding Episode
timeFrame: Up to Week 26 +/- 7 days
measure: Physician's Global Assessment of the Participant's Response to His rFVIIIFc Regimen
timeFrame: Up to Week 26 +/- 7 days
measure: Annualized rFVIIIFc Consumption Per Participant
timeFrame: Up to Week 26 +/- 7 days (efficacy period as defined in description)
measure: Number of Days From Last Treatment Injection to a Spontaneous Bleeding Episode
timeFrame: Up to Week 26 +/- 7 days (efficacy period as defined in description)
measure: Number of Injections Required for Resolution of a Bleeding Episode
timeFrame: Up to Week 26 +/- 7 days (efficacy period as defined in description)
measure: Total Dose Required for Resolution of a Bleeding Episode
timeFrame: Up to Week 26 +/- 7 days (efficacy period as defined in description)
measure: Maximum Plasma Activity (Cmax; One-stage Activated Partial Thromboplastin Time [aPTT] Clotting Assay)
timeFrame: Baseline (28 ±7 days prior to Day 1) Prestudy FVIII Dosing: predose; 30 ±5 min, 3 hours ±30 min, 24 ±3 hours, 48 ±4 hours post-dose. Day 1 (rFVIIIFc Dosing): predose; 30 ±5 min, 3 hours ±30 min, 24 ±3 hours, 48 ±4 hours, 72 ±7 hours post-dose
measure: Maximum Plasma Activity (Cmax; Two-stage Chromogenic Assay)
timeFrame: Baseline (28 ±7 days prior to Day 1) Prestudy FVIII Dosing: predose; 30 ±5 min, 3 hours ±30 min, 24 ±3 hours, 48 ±4 hours post-dose. Day 1 (rFVIIIFc Dosing): predose; 30 ±5 min, 3 hours ±30 min, 24 ±3 hours, 48 ±4 hours, 72 ±7 hours post-dose
measure: Elimination Half Life (t1/2; One-stage aPTT Clotting Assay)
timeFrame: Baseline (28 ±7 days prior to Day 1) Prestudy FVIII Dosing: predose; 30 ±5 min, 3 hours ±30 min, 24 ±3 hours, 48 ±4 hours post-dose. Day 1 (rFVIIIFc Dosing): predose; 30 ±5 min, 3 hours ±30 min, 24 ±3 hours, 48 ±4 hours, 72 ±7 hours post-dose
measure: Elimination Half Life (t1/2; Two-stage Chromogenic Assay)
timeFrame: Baseline (28 ±7 days prior to Day 1) Prestudy FVIII Dosing: predose; 30 ±5 min, 3 hours ±30 min, 24 ±3 hours, 48 ±4 hours post-dose. Day 1 (rFVIIIFc Dosing): predose; 30 ±5 min, 3 hours ±30 min, 24 ±3 hours, 48 ±4 hours, 72 ±7 hours post-dose
measure: Clearance (CL; One-stage aPTT Clotting Assay)
timeFrame: Baseline (28 ±7 days prior to Day 1) Prestudy FVIII Dosing: predose; 30 ±5 min, 3 hours ±30 min, 24 ±3 hours, 48 ±4 hours post-dose. Day 1 (rFVIIIFc Dosing): predose; 30 ±5 min, 3 hours ±30 min, 24 ±3 hours, 48 ±4 hours, 72 ±7 hours post-dose
measure: Clearance (CL; Two-stage Chromogenic Assay)
timeFrame: Baseline (28 ±7 days prior to Day 1) Prestudy FVIII Dosing: predose; 30 ±5 min, 3 hours ±30 min, 24 ±3 hours, 48 ±4 hours post-dose. Day 1 (rFVIIIFc Dosing): predose; 30 ±5 min, 3 hours ±30 min, 24 ±3 hours, 48 ±4 hours, 72 ±7 hours post-dose
measure: Volume at Steady State (Vss; One-stage aPTT Clotting Assay)
timeFrame: Baseline (28 ±7 days prior to Day 1) Prestudy FVIII Dosing: predose; 30 ±5 min, 3 hours ±30 min, 24 ±3 hours, 48 ±4 hours post-dose. Day 1 (rFVIIIFc Dosing): predose; 30 ±5 min, 3 hours ±30 min, 24 ±3 hours, 48 ±4 hours, 72 ±7 hours post-dose
measure: Volume at Steady State (Vss; Two-stage Chromogenic Assay)
timeFrame: Baseline (28 ±7 days prior to Day 1) Prestudy FVIII Dosing: predose; 30 ±5 min, 3 hours ±30 min, 24 ±3 hours, 48 ±4 hours post-dose. Day 1 (rFVIIIFc Dosing): predose; 30 ±5 min, 3 hours ±30 min, 24 ±3 hours, 48 ±4 hours, 72 ±7 hours post-dose
measure: Dose Normalized Area Under the Curve (DNAUC; One-stage aPTT Clotting Assay)
timeFrame: Baseline (28 ±7 days prior to Day 1) Prestudy FVIII Dosing: predose; 30 ±5 min, 3 hours ±30 min, 24 ±3 hours, 48 ±4 hours post-dose. Day 1 (rFVIIIFc Dosing): predose; 30 ±5 min, 3 hours ±30 min, 24 ±3 hours, 48 ±4 hours, 72 ±7 hours post-dose
measure: Dose Normalized Area Under the Curve (DNAUC; Two-stage Chromogenic Assay)
timeFrame: Baseline (28 ±7 days prior to Day 1) Prestudy FVIII Dosing: predose; 30 ±5 min, 3 hours ±30 min, 24 ±3 hours, 48 ±4 hours post-dose. Day 1 (rFVIIIFc Dosing): predose; 30 ±5 min, 3 hours ±30 min, 24 ±3 hours, 48 ±4 hours, 72 ±7 hours post-dose
measure: Mean Residence Time (MRT; One-stage aPTT Clotting Assay)
timeFrame: Baseline (28 ±7 days prior to Day 1) Prestudy FVIII Dosing: predose; 30 ±5 min, 3 hours ±30 min, 24 ±3 hours, 48 ±4 hours post-dose. Day 1 (rFVIIIFc Dosing): predose; 30 ±5 min, 3 hours ±30 min, 24 ±3 hours, 48 ±4 hours, 72 ±7 hours post-dose
measure: Mean Residence Time (MRT; Two-stage Chromogenic Assay)
timeFrame: Baseline (28 ±7 days prior to Day 1) Prestudy FVIII Dosing: predose; 30 ±5 min, 3 hours ±30 min, 24 ±3 hours, 48 ±4 hours post-dose. Day 1 (rFVIIIFc Dosing): predose; 30 ±5 min, 3 hours ±30 min, 24 ±3 hours, 48 ±4 hours, 72 ±7 hours post-dose
measure: Incremental Recovery (IR; One-stage aPTT Clotting Assay)
timeFrame: Baseline (28 ±7 days prior to Day 1) Prestudy FVIII Dosing: predose; 30 ±5 min, 3 hours ±30 min, 24 ±3 hours, 48 ±4 hours post-dose. Day 1 (rFVIIIFc Dosing): predose; 30 ±5 min, 3 hours ±30 min, 24 ±3 hours, 48 ±4 hours, 72 ±7 hours post-dose
measure: Incremental Recovery (IR; Two-stage Chromogenic Assay)
timeFrame: Baseline (28 ±7 days prior to Day 1) Prestudy FVIII Dosing: predose; 30 ±5 min, 3 hours ±30 min, 24 ±3 hours, 48 ±4 hours post-dose. Day 1 (rFVIIIFc Dosing): predose; 30 ±5 min, 3 hours ±30 min, 24 ±3 hours, 48 ±4 hours, 72 ±7 hours post-dose
measure: Time at Maximum Activity (Tmax; One-stage aPTT Clotting Assay)
timeFrame: Baseline (28 ±7 days prior to Day 1) Prestudy FVIII Dosing: predose; 30 ±5 min, 3 hours ±30 min, 24 ±3 hours, 48 ±4 hours post-dose. Day 1 (rFVIIIFc Dosing): predose; 30 ±5 min, 3 hours ±30 min, 24 ±3 hours, 48 ±4 hours, 72 ±7 hours post-dose
measure: Time at Maximum Activity (Tmax; Two-stage Chromogenic Assay)
timeFrame: Baseline (28 ±7 days prior to Day 1) Prestudy FVIII Dosing: predose; 30 ±5 min, 3 hours ±30 min, 24 ±3 hours, 48 ±4 hours post-dose. Day 1 (rFVIIIFc Dosing): predose; 30 ±5 min, 3 hours ±30 min, 24 ±3 hours, 48 ±4 hours, 72 ±7 hours post-dose
measure: Lambda Z (One-stage aPTT Clotting Assay)
timeFrame: Baseline (28 ±7 days prior to Day 1) Prestudy FVIII Dosing: predose; 30 ±5 min, 3 hours ±30 min, 24 ±3 hours, 48 ±4 hours post-dose. Day 1 (rFVIIIFc Dosing): predose; 30 ±5 min, 3 hours ±30 min, 24 ±3 hours, 48 ±4 hours, 72 ±7 hours post-dose
measure: Lambda Z (Two-stage Chromogenic Assay)
timeFrame: Baseline (28 ±7 days prior to Day 1) Prestudy FVIII Dosing: predose; 30 ±5 min, 3 hours ±30 min, 24 ±3 hours, 48 ±4 hours post-dose. Day 1 (rFVIIIFc Dosing): predose; 30 ±5 min, 3 hours ±30 min, 24 ±3 hours, 48 ±4 hours, 72 ±7 hours post-dose
measure: Volume at Terminal Phase (Vz; One-stage aPTT Clotting Assay)
timeFrame: Baseline (28 ±7 days prior to Day 1) Prestudy FVIII Dosing: predose; 30 ±5 min, 3 hours ±30 min, 24 ±3 hours, 48 ±4 hours post-dose. Day 1 (rFVIIIFc Dosing): predose; 30 ±5 min, 3 hours ±30 min, 24 ±3 hours, 48 ±4 hours, 72 ±7 hours post-dose
measure: Volume at Terminal Phase (Vz; Two-stage Chromogenic Assay)
timeFrame: Baseline (28 ±7 days prior to Day 1) Prestudy FVIII Dosing: predose; 30 ±5 min, 3 hours ±30 min, 24 ±3 hours, 48 ±4 hours post-dose. Day 1 (rFVIIIFc Dosing): predose; 30 ±5 min, 3 hours ±30 min, 24 ±3 hours, 48 ±4 hours, 72 ±7 hours post-dose
measure: Area Under the Curve to the Last Measurable Timepoint (AUClast; One-stage aPTT Clotting Assay)
timeFrame: Baseline (28 ±7 days prior to Day 1) Prestudy FVIII Dosing: predose; 30 ±5 min, 3 hours ±30 min, 24 ±3 hours, 48 ±4 hours post-dose. Day 1 (rFVIIIFc Dosing): predose; 30 ±5 min, 3 hours ±30 min, 24 ±3 hours, 48 ±4 hours, 72 ±7 hours post-dose
measure: Area Under the Curve to the Last Measurable Timepoint (AUClast; Two-stage Chromogenic Assay)
timeFrame: Baseline (28 ±7 days prior to Day 1) Prestudy FVIII Dosing: predose; 30 ±5 min, 3 hours ±30 min, 24 ±3 hours, 48 ±4 hours post-dose. Day 1 (rFVIIIFc Dosing): predose; 30 ±5 min, 3 hours ±30 min, 24 ±3 hours, 48 ±4 hours, 72 ±7 hours post-dose
measure: Area Under the Curve to Infinity (AUCinf; One-stage aPTT Clotting Assay)
timeFrame: Baseline (28 ±7 days prior to Day 1) Prestudy FVIII Dosing: predose; 30 ±5 min, 3 hours ±30 min, 24 ±3 hours, 48 ±4 hours post-dose. Day 1 (rFVIIIFc Dosing): predose; 30 ±5 min, 3 hours ±30 min, 24 ±3 hours, 48 ±4 hours, 72 ±7 hours post-dose
measure: Area Under the Curve to Infinity (AUCinf; Two-stage Chromogenic Assay)
timeFrame: Baseline (28 ±7 days prior to Day 1) Prestudy FVIII Dosing: predose; 30 ±5 min, 3 hours ±30 min, 24 ±3 hours, 48 ±4 hours post-dose. Day 1 (rFVIIIFc Dosing): predose; 30 ±5 min, 3 hours ±30 min, 24 ±3 hours, 48 ±4 hours, 72 ±7 hours post-dose
measure: Percentage of AUCinf Extrapolated From the Last Data Point to Infinity (%AUCext; One-stage aPTT Clotting Assay)
timeFrame: Baseline (28 ±7 days prior to Day 1) Prestudy FVIII Dosing: predose; 30 ±5 min, 3 hours ±30 min, 24 ±3 hours, 48 ±4 hours post-dose. Day 1 (rFVIIIFc Dosing): predose; 30 ±5 min, 3 hours ±30 min, 24 ±3 hours, 48 ±4 hours, 72 ±7 hours post-dose
measure: Percentage of AUCinf Extrapolated From the Last Data Point to Infinity (%AUCext; Two-stage Chromogenic Assay)
timeFrame: Baseline (28 ±7 days prior to Day 1) Prestudy FVIII Dosing: predose; 30 ±5 min, 3 hours ±30 min, 24 ±3 hours, 48 ±4 hours post-dose. Day 1 (rFVIIIFc Dosing): predose; 30 ±5 min, 3 hours ±30 min, 24 ±3 hours, 48 ±4 hours, 72 ±7 hours post-dose
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: Research Site
state: California
city: Sacramento
country: United States
facility: Research Site
state: California
city: San Diego
country: United States
facility: Research Site
state: California
city: Aurora
country: United States
facility: Research Site
state: Colorado
city: Chicago
country: United States
facility: Research Site
state: Illinois
city: Indianapolis
country: United States
facility: Research Site
state: Indiana
city: Saint Louis
country: United States
facility: Research Site
state: Missouri
city: Las Vegas
country: United States
facility: Research Site
state: Nevada
city: Cincinnati
country: United States
facility: Research Site
state: Ohio
city: Columbus
country: United States
facility: Research Site
state: Ohio
city: Portland
country: United States
facility: Research Site
state: Oregon
city: Pittsburgh
country: United States
facility: Research Site
state: Pennsylvania
city: Brisbane
country: Australia
facility: Research Site
state: Queensland
city: Melbourne
country: Australia
facility: Research Site
state: Victoria
city: Hong Kong
country: Hong Kong
facility: Research Site
city: Dublin
country: Ireland
facility: Research Site
city: Groningen
country: Netherlands
facility: Research Site
city: Lublin
country: Poland
facility: Research Site
city: Johannesburg
country: South Africa
facility: Research Site
city: Cambridge
country: United Kingdom
facility: Research Site
state: Cambridgshire
city: Basingstoke
country: United Kingdom
facility: Research Site
state: Hampshire
city: Glasgow
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:
citation: Katragadda S, Neelakantan S, Diao L, Wong N. Population Pharmacokinetic Analysis of Recombinant Factor VIII Fc Fusion Protein in Subjects With Severe Hemophilia A: Expanded to Include Pediatric Subjects. J Clin Pharmacol. 2021 Jul;61(7):889-900. doi: 10.1002/jcph.1854. Epub 2021 Apr 14.
citation: Young G, Mahlangu J, Kulkarni R, Nolan B, Liesner R, Pasi J, Barnes C, Neelakantan S, Gambino G, Cristiano LM, Pierce GF, Allen G. Recombinant factor VIII Fc fusion protein for the prevention and treatment of bleeding in children with severe hemophilia A. J Thromb Haemost. 2015 Jun;13(6):967-77. doi: 10.1111/jth.12911. Epub 2015 Apr 23.