Clinical trial NCT01181128: Study to Evaluate the Safety, Pharmacokinetics and Efficacy of Recombinant Factor VIII Fc Fusion Protein (rFVIIIFc) in Previously Treated Subjects With Severe Hemophilia A
Official title: A-LONG: An Open-Label, Multicenter Evaluation of the Safety, Pharmacokinetics, and Efficacy of Recombinant Factor VIII Fc Fusion Protein (rFVIIIFc) in the Prevention and Treatment of Bleeding in Previously Treated Subjects With Severe Hemophilia A
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Severe Hemophilia A
Lead sponsor: Sanofi
Sponsor class: INDUSTRY
Collaborators: name: Swedish Orphan Biovitrum
First posted: 2010-08-13
Enrollment: 165
Sex: MALE
Minimum age (years): 12
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The primary objectives of this study are: to evaluate the safety and tolerability of rFVIIIFc administered as a prophylaxis (Arm 1), weekly (Arm 2), on-demand (Arm 3), and surgical treatment regimen; to evaluate the efficacy of the rFVIIIFc tailored prophylaxis regimen (Arm 1); to evaluate the efficacy of rFVIIIFc administered as an on-demand (Arm 3) and surgical treatment regimen. The secondary objectives of this study are: to characterize the PK profile of rFVIIIFc and compare the PK of rFVIIIFc with the currently marketed product, Advate®; to characterize the range of dose and schedules required to adequately prevent bleeding in a prophylaxis regimen, maintain hemostasis in a surgical setting, or to treat bleeding episodes in an on-demand, weekly treatment, or prophylaxis setting.

Detailed description: Participants are assigned to one of three treatment regimens: 1) a tailored prophylaxis regimen, 2) a weekly dosing regimen, or 3) an on-demand regimen. Treatment continued for 28 (±2) to 52 (±2) weeks. PK assessments for all participants are conducted on varying schedules, according to participants' group assignments. Additionally, two subgroups are defined. One subgroup of participants undergo PK profiling with a single dose of the comparator Advate®. A second subgroup consists of participants from any of the treatment arms that required surgery during the study. Depending upon country location, participants might have the option of continuing treatment within study 8HA01EXT (NCT01454739).

Eligibility criteria: Inclusion Criteria:

* Male, ≥12 years of age with weight at least 40 kg
* Diagnosed with severe hemophilia A, defined as \<1 IU/dL (\<1%) endogenous Factor VIII)
* History of at least 150 documented prior exposure days to any Factor VIII product
* Platelet count ≥100,000 cells/μL

Exclusion Criteria:

* History of Factor VIII inhibitors
* Kidney and liver dysfunction
* Diagnosed with other coagulation disorder(s) in addition to hemophilia A
* Prior history of hypersensitivity or anaphylaxis associated with any FVIII or IV immunoglobulin administration

Primary outcomes:
measure: Incidence Rate of FVIII Inhibitor Development
timeFrame: up to 52 weeks ± 2 weeks
measure: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs)
timeFrame: up to 52 weeks + 30 days ± 1 week
measure: Number of Participants With Potentially Clinically Significant Abnormal Laboratory Values From Baseline
timeFrame: up to 52 weeks ± 2 weeks
measure: Number of Participants With Clinically Relevant Abnormalities in Vital Signs or Relevant Changes From Baseline in Vital Signs
timeFrame: up to 52 weeks ± 2 weeks
measure: Annualized Bleeding Rate
timeFrame: up to 52 weeks ± 2 weeks (efficacy period as defined in description)
measure: Comparison of Annualized Bleeding Rates: Arm 1 Versus Arm 3
timeFrame: up to 52 weeks ± 2 weeks (efficacy period as defined in description)
measure: Area Under the Curve (AUC) Per Dose (One-stage Clotting Assay)
timeFrame: See Measure Description for complete time frame.
measure: Elimination Half Life (t1/2; One-stage Clotting Assay)
timeFrame: See Measure Description for complete time frame.
measure: Clearance (CL; One-stage Clotting Assay)
timeFrame: See Measure Description for complete time frame.
measure: Mean Residence Time (MRT; One-stage Clotting Assay)
timeFrame: See Measure Description for complete time frame.
measure: Incremental Recovery (One-stage Clotting Assay)
timeFrame: See Measure Description for complete time frame.
Secondary outcomes:
measure: Comparison of Annualized Bleeding Rates: Arm 2 Versus Arm 3
timeFrame: up to 52 weeks ± 2 weeks (efficacy period as defined in description)
measure: Annualized rFVIIIFc Consumption Per Participant
timeFrame: up to 52 weeks ± 2 weeks (efficacy period as defined in description)
measure: Participant Assessment of Response to Injections to Treat a Bleeding Episode
timeFrame: up to 52 weeks ± 2 weeks
measure: Investigator's Assessment of Participants' Bleeding Response to rFVIIIFc Injection
timeFrame: up to 52 weeks ± 2 weeks
measure: Annualized Bleeding Rate by Location of Bleed (Joint, Muscle, Internal, Skin/Mucosa)
timeFrame: up to 52 weeks ± 2 weeks (efficacy period as defined in description)
measure: Annualized Joint Bleeding Rate (Spontaneous and Traumatic)
timeFrame: up to 52 weeks ± 2 weeks (efficacy period as defined in description)
measure: Number of Days From Last Treatment Injection to a New Bleeding Episode
timeFrame: up to 52 weeks ± 2 weeks (efficacy period as defined in description)
measure: Number of Injections Required for Resolution of a Bleeding Episode
timeFrame: up to 52 weeks ± 2 weeks (efficacy period as defined in description)
measure: Number of Injections Required for Resolution of a Bleeding Episode by Location of Bleed
timeFrame: up to 52 weeks ± 2 weeks (efficacy period as defined in description)
measure: Total Dose Per Injection Required for Resolution of a Bleeding Episode by Location of Bleed
timeFrame: up to 52 weeks ± 2 weeks (efficacy period as defined in description)
measure: Volume at Steady State (Vss; One-stage Clotting Assay)
timeFrame: See Measure Description for complete time frame.
measure: Volume at Steady State (Vss; Two-stage Chromogenic Assay)
timeFrame: See Measure Description for complete time frame.
measure: Time to 1% and 3% FVIII Activity (One-stage Clotting Assay)
timeFrame: See Measure Description for complete time frame.
measure: Time to 1% and 3% FVIII Activity (Two-stage Chromogenic Assay)
timeFrame: See Measure Description for complete time frame.
measure: Time at Maximum Activity (Tmax; One-stage Clotting Assay)
timeFrame: See Measure Description for complete time frame.
measure: Time at Maximum Activity (Tmax; Two-stage Chromogenic Assay)
timeFrame: See Measure Description for complete time frame.
measure: Area Under the Curve (AUC) Per Dose (Two-stage Chromogenic Assay)
timeFrame: See Measure Description for complete time frame.
measure: Elimination Half Life (t1/2; Two-stage Chromogenic Assay)
timeFrame: See Measure Description for complete time frame.
measure: Clearance (CL; Two-stage Chromogenic Assay)
timeFrame: See Measure Description for complete time frame.
measure: Mean Residence Time (MRT; Two-stage Chromogenic Assay)
timeFrame: See Measure Description for complete time frame.
measure: Incremental Recovery (Two-stage Chromogenic Assay)
timeFrame: See Measure Description for complete time frame.
measure: Hemophilia-Specific Quality of Life Index for Adults (Haem-A-QoL) Questionnaire: Change From Baseline to Week 14
timeFrame: Baseline, Week 14
measure: Hemophilia-Specific Quality of Life Index for Adults (Haem-A-QoL) Questionnaire: Change From Baseline to Week 28
timeFrame: Baseline, Week 28
measure: Hemophilia-Specific Quality of Life Index for Children (Haemo-QoL) Questionnaire: Change From Baseline to Week 14 and Week 28 in Haemo-QoL III Total Score
timeFrame: Baseline, Week 14, Week 28
measure: Investigators'/Surgeons' Assessment of Participants' Response to rFVIIIFc for Major Surgery
timeFrame: up to 52 weeks
measure: Number of Injections Required to Maintain Hemostasis During Major Surgery
timeFrame: up to 52 weeks
measure: Dose Per Injection and Total Dose Required to Maintain Hemostasis During Major Surgery
timeFrame: up to 52 weeks ± 2 weeks
measure: Estimated Total Blood Loss During Major Surgery
timeFrame: up to 52 weeks ± 2 weeks
measure: Number of Transfusions Required Per Surgery
timeFrame: up to 52 weeks ± 2 weeks
Other outcomes:
Locations:
city: Little Rock
country: United States
facility: Research Site
state: Arkansas
city: Los Angeles
country: United States
facility: Research Site
state: California
city: Orange
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: Washington
country: United States
facility: Research Site
state: District of Columbia
city: Indianapolis
country: United States
facility: Research Site
state: Indiana
city: Iowa City
country: United States
facility: Research Site
state: Iowa
city: Louisville
country: United States
facility: Research Site
state: Kentucky
city: New Orleans
country: United States
facility: Research Site
state: Louisiana
city: Boston
country: United States
facility: Research Site
state: Massachusetts
city: East Lansing
country: United States
facility: Research Site
state: Michigan
city: Las Vegas
country: United States
facility: Research Site
state: Nevada
city: New York
country: United States
facility: Research Site
state: New York
city: Chapel Hill
country: United States
facility: Research Site
state: North Carolina
city: Philadelphia
country: United States
facility: Research Site
state: Pennsylvania
city: Philadelphia
country: United States
facility: Research Site
state: Pennsylvania
city: Pittsburgh
country: United States
facility: Research Site
state: Pennsylvania
city: Houston
country: United States
facility: Research Site
state: Texas
city: Salt Lake City
country: United States
facility: Research Site
state: Utah
city: Seattle
country: United States
facility: Research Site
state: Washington
city: Camperdown
country: Australia
facility: Research Site
state: New South Wales
city: Adelaide
country: Australia
facility: Research Site
state: South Australia
city: Perth
country: Australia
facility: Research Site
state: Western Australia
city: Wien
country: Austria
facility: Research Site
city: Bruxelles
country: Belgium
facility: Research Site
city: Campinas
country: Brazil
facility: Research Site
city: Calgary
country: Canada
facility: Research Site
city: Toronto
country: Canada
facility: Research Site
city: Vancouver
country: Canada
facility: Research Site
city: Lyon Cedex 3
country: France
facility: Research Site
city: Berlin
country: Germany
facility: Research Site
state: BE
city: Bonn
country: Germany
facility: Research Site
state: Northwest
city: Hong Kong
country: Hong Kong
facility: Research Site
city: New Delhi
country: India
facility: Research Site
state: Delhi
city: Bangalore
country: India
facility: Research Site
state: Karna
city: Pune
country: India
facility: Research Site
state: Mahara
city: Ludhiana
country: India
facility: Research Site
state: Punjab
city: Vellore
country: India
facility: Research Site
state: Tamilnadu
city: Ramat Gan
country: Israel
facility: Research Site
city: Firenze
country: Italy
facility: Research Site
state: FI
city: Milano
country: Italy
facility: Research Site
state: MI
city: Vicenza
country: Italy
facility: Research Site
state: VI
city: Kashihara-shi
country: Japan
facility: Research Site
city: Kawasaki-shi
country: Japan
facility: Research Site
city: Kitakyushu-shi
country: Japan
facility: Research Site
city: Nagoya-shi
country: Japan
facility: Research Site
city: Shinjuku-ku
country: Japan
facility: Research Site
city: Suginami-ku
country: Japan
facility: Research Site
city: Auckland
country: New Zealand
facility: Research Site
city: Christchurch
country: New Zealand
facility: Research Site
city: Palmerston North
country: New Zealand
facility: Research Site
city: Johannesburg Parktown
country: South Africa
facility: Research Site
state: Gauteng
city: Cape Town
country: South Africa
facility: Research Site
state: W Cape
city: Barcelona
country: Spain
facility: Research Site
city: Madrid
country: Spain
facility: Research Site
city: Göteborg
country: Sweden
facility: Research Site
city: Zurich
country: Switzerland
facility: Research Site
city: Basingstoke
country: United Kingdom
facility: Research Site
city: Cambridge
country: United Kingdom
facility: Research Site
city: Glasgow
country: United Kingdom
facility: Research Site
city: London
country: United Kingdom
facility: Research Site
city: London
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: Mahlangu J, Powell JS, Ragni MV, Chowdary P, Josephson NC, Pabinger I, Hanabusa H, Gupta N, Kulkarni R, Fogarty P, Perry D, Shapiro A, Pasi KJ, Apte S, Nestorov I, Jiang H, Li S, Neelakantan S, Cristiano LM, Goyal J, Sommer JM, Dumont JA, Dodd N, Nugent K, Vigliani G, Luk A, Brennan A, Pierce GF; A-LONG Investigators. Phase 3 study of recombinant factor VIII Fc fusion protein in severe hemophilia A. Blood. 2014 Jan 16;123(3):317-25. doi: 10.1182/blood-2013-10-529974. Epub 2013 Nov 13.
citation: Shapiro AD, Ragni MV, Kulkarni R, Oldenberg J, Srivastava A, Quon DV, Pasi KJ, Hanabusa H, Pabinger I, Mahlangu J, Fogarty P, Lillicrap D, Kulke S, Potts J, Neelakantan S, Nestorov I, Li S, Dumont JA, Jiang H, Brennan A, Pierce GF. Recombinant factor VIII Fc fusion protein: extended-interval dosing maintains low bleeding rates and correlates with von Willebrand factor levels. J Thromb Haemost. 2014 Nov;12(11):1788-800. doi: 10.1111/jth.12723. Epub 2014 Oct 10.
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.