Study to Evaluate the Safety, Pharmacokinetics and Efficacy of Recombinant Factor VIII Fc Fusion Protein (rFVIIIFc) in Previously Treated Subjects With Severe Hemophilia A

NCT01181128 | Completed Phase 3 Results DMC

• 1 other identifier: 997HA301
• Study Type: interventional
• Target: 165
• Locations: 18 countries
• Sites: 63

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.

Conditions

Severe Hemophilia A

Outcome Measures

Primary Outcomes (11)

• Incidence Rate of FVIII Inhibitor Development

  An inhibitor test result ≥0.6 Bethesda units (BU)/mL, identified and confirmed by re-testing of a second sample obtained within 2 to 4 weeks, was considered positive. Both tests were to be performed using the Nijmegen-modified Bethesda Assay by the central laboratory. The incidence rates along with the 95% confidence interval (CI) were summarized for all titers for subjects with 50 or more exposure days (EDs) to rFVIIIFc and a valid inhibitor test after the 50th exposure. In addition, the incidence rates for all subjects regardless of their exposure days to rFVIIIFc were also summarized. The 95% CI was calculated using Clopper-Pearson exact method.

  up to 52 weeks ± 2 weeks

• Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs)

  AE=any untoward medical occurrence that did not necessarily have a causal relationship with treatment, and could be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of study product, whether related or not. TEAE=AE present prior to receiving the first injection of Advate or rFVIIIFc that subsequently worsened in severity or not present prior to receiving the first injection but subsequently appeared before the last visit on study. Serious AE (SAE)=AE resulting in death, immediate risk of death, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability/incapacity, or a congenital anomaly/birth defect, or any other medically important event. AEs emergent between the first Advate injection and first on-study rFVIIIFc injection (Sequential PK Subgroup) or during the surgical/rehabilitation period (Surgery Subgroup) are presented separately.

  up to 52 weeks + 30 days ± 1 week

• Number of Participants With Potentially Clinically Significant Abnormal Laboratory Values From Baseline

  Clinical laboratory evaluations included hematology and blood chemistry. Table does not include laboratory tests evaluated during the surgical/rehabilitation period. ULN=upper limit of normal.

  up to 52 weeks ± 2 weeks

• Number of Participants With Clinically Relevant Abnormalities in Vital Signs or Relevant Changes From Baseline in Vital Signs

  Number of participants with clinically relevant abnormalities or relevant changes from baseline in temperature, pulse (beats per minute \[bpm\]), systolic blood pressure (SBP), and diastolic blood pressure (DBP) are presented. Baseline (BL) is defined as the last non-missing evaluable assessment taken prior and closest to the first rFVIIIFc dose. ↑ signifies increase and ↓ signifies decrease.

  up to 52 weeks ± 2 weeks

• Annualized Bleeding Rate

  Annualized bleeding episodes = (number of bleeding episodes during the efficacy period / number of days during the efficacy period)\*365.25. The efficacy period in Arms 1 and 2 began with the first prophylactic dose of rFVIIIFc and ended with the last dose (regardless of reason for dosing). The efficacy period in Arm 3 began at the time of last PK rFVIIIFc sampling timepoint and ended at the date of the last study visit. Periods of PK evaluations and surgery/rehabilitation are not included in the efficacy period. A bleeding episode started from the first sign of a bleed, and ended 72 hours after the last treatment for the bleeding, within which any symptoms of bleeding at the same location, or injections less than or equal to 72 hours apart, were considered the same bleeding episode.

  up to 52 weeks ± 2 weeks (efficacy period as defined in description)

• Comparison of Annualized Bleeding Rates: Arm 1 Versus Arm 3

  Estimated using the negative binomial model with treatment arm as covariate, based on whole study duration for all participants. Annualized bleeding episodes = (number of bleeding episodes / number of days in the respective period)\*365.25.The efficacy period in Arm 1 began with the first prophylactic dose of rFVIIIFc and ended with the last dose (regardless of reason for dosing). The efficacy period in Arm 3 began at the time of last PK rFVIIIFc sampling timepoint and ended at the date of the last study visit. Periods of PK evaluations and surgery/rehabilitation are not included in the efficacy period. A bleeding episode started from the first sign of a bleed, and ended 72 hours after the last treatment for the bleeding, within which any symptoms of bleeding at the same location, or injections less than or equal to 72 hours apart, were considered part of the same bleeding episode.

  up to 52 weeks ± 2 weeks (efficacy period as defined in description)

• Area Under the Curve (AUC) Per Dose (One-stage Clotting Assay)

  Dose normalized area under the drug concentration-time curve. Sampling for Advate PK profiling was conducted, following at least 96 hours of washout, at these timepoints: preinjection and at either 30 (±3) minutes or 10 (±3) minutes, 1 hour (±15 minutes), 6 (±1) hours, 24 (±2) hours (Day 1), 48 (±2) hours (Day 2), and 72 (±2) hours (Day 3) from the start of the injection. Sampling for rFVIIIFc PK profiling was conducted at Day 0 (directly following at least 96 hours washout from Advate PK profiling or within 4 weeks of the Advate dose or other rFVIII product) and repeated 12 to 24 weeks later at the following timepoints: preinjection and at 30 (±3) minutes (or 10 (±3) minutes), 1 hour (±15 minutes), 6 (±1) hours, 24 (±2) hours (Day 1), 72 (±2) hours (Day 3), 96 (±2) hours (Day 4), and 120 (±2) hours (Day 5) from the start of the injection.

  See Measure Description for complete time frame.

• Elimination Half Life (t1/2; One-stage Clotting Assay)

  Time required for the activity of the drug to reach half of its original value. Sampling for Advate PK profiling was conducted, following at least 96 hours of washout, at these timepoints: preinjection and at either 30 (±3) minutes or 10 (±3) minutes, 1 hour (±15 minutes), 6 (±1) hours, 24 (±2) hours (Day 1), 48 (±2) hours (Day 2), and 72 (±2) hours (Day 3) from the start of the injection. Sampling for rFVIIIFc PK profiling was conducted at Day 0 (directly following at least 96 hours washout from Advate PK profiling or within 4 weeks of the Advate dose or other rFVIII product) and repeated 12 to 24 weeks later at the following timepoints: preinjection and at 30 (±3) minutes (or 10 (±3) minutes), 1 hour (±15 minutes), 6 (±1) hours, 24 (±2) hours (Day 1), 72 (±2) hours (Day 3), 96 (±2) hours (Day 4), and 120 (±2) hours (Day 5) from the start of the injection.

  See Measure Description for complete time frame.

• Clearance (CL; One-stage Clotting Assay)

  Rate at which the body removes the drug, measured as the volume of the plasma cleared of drug per unit time per unit weight. Sampling for Advate PK profiling was conducted, following at least 96 hours of washout, at these timepoints: preinjection and at either 30 (±3) minutes or 10 (±3) minutes, 1 hour (±15 minutes), 6 (±1) hours, 24 (±2) hours (Day 1), 48 (±2) hours (Day 2), and 72 (±2) hours (Day 3) from the start of the injection. Sampling for rFVIIIFc PK profiling was conducted at Day 0 (directly following at least 96 hours washout from Advate PK profiling or within 4 weeks of the Advate dose or other rFVIII product) and repeated 12 to 24 weeks later at the following timepoints: preinjection and at 30 (±3) minutes (or 10 (±3) minutes), 1 hour (±15 minutes), 6 (±1) hours, 24 (±2) hours (Day 1), 72 (±2) hours (Day 3), 96 (±2) hours (Day 4), and 120 (±2) hours (Day 5) from the start of the injection.

  See Measure Description for complete time frame.

• Mean Residence Time (MRT; One-stage Clotting Assay)

  The average time that a drug molecule is present in the systemic circulation. Sampling for Advate PK profiling was conducted, following at least 96 hours of washout, at these timepoints: preinjection and at either 30 (±3) minutes or 10 (±3) minutes, 1 hour (±15 minutes), 6 (±1) hours, 24 (±2) hours (Day 1), 48 (±2) hours (Day 2), and 72 (±2) hours (Day 3) from the start of the injection. Sampling for rFVIIIFc PK profiling was conducted at Day 0 (directly following at least 96 hours washout from Advate PK profiling or within 4 weeks of the Advate dose or other rFVIII product) and repeated 12 to 24 weeks later at the following timepoints: preinjection and at 30 (±3) minutes (or 10 (±3) minutes), 1 hour (±15 minutes), 6 (±1) hours, 24 (±2) hours (Day 1), 72 (±2) hours (Day 3), 96 (±2) hours (Day 4), and 120 (±2) hours (Day 5) from the start of the injection.

  See Measure Description for complete time frame.

• Incremental Recovery (One-stage Clotting Assay)

  The rise in FVIII activity in IU/dL per unit dose administered in IU/kg. Sampling for Advate PK profiling was conducted, following at least 96 hours of washout, at these timepoints: preinjection and at either 30 (±3) minutes or 10 (±3) minutes, 1 hour (±15 minutes), 6 (±1) hours, 24 (±2) hours (Day 1), 48 (±2) hours (Day 2), and 72 (±2) hours (Day 3) from the start of the injection. Sampling for rFVIIIFc PK profiling was conducted at Day 0 (directly following at least 96 hours washout from Advate PK profiling or within 4 weeks of the Advate dose or other rFVIII product) and repeated 12 to 24 weeks later at the following timepoints: preinjection and at 30 (±3) minutes (or 10 (±3) minutes), 1 hour (±15 minutes), 6 (±1) hours, 24 (±2) hours (Day 1), 72 (±2) hours (Day 3), 96 (±2) hours (Day 4), and 120 (±2) hours (Day 5) from the start of the injection.

  See Measure Description for complete time frame.

Secondary Outcomes (29)

• Comparison of Annualized Bleeding Rates: Arm 2 Versus Arm 3

  up to 52 weeks ± 2 weeks (efficacy period as defined in description)

• Annualized rFVIIIFc Consumption Per Participant

  up to 52 weeks ± 2 weeks (efficacy period as defined in description)

• Participant Assessment of Response to Injections to Treat a Bleeding Episode

  up to 52 weeks ± 2 weeks

• Investigator's Assessment of Participants' Bleeding Response to rFVIIIFc Injection

  up to 52 weeks ± 2 weeks

• Annualized Bleeding Rate by Location of Bleed (Joint, Muscle, Internal, Skin/Mucosa)

  up to 52 weeks ± 2 weeks (efficacy period as defined in description)

Study Arms (3)

Individualized (Tailored) Prophylaxis

EXPERIMENTAL

On rFVIIIFc Day 0, all participants underwent pharmacokinetic (PK) analysis with 50 IU/kg rFVIIIFc to estimate their PK parameters and guide the appropriate dose or interval of dosing. A subset of participants (Sequential PK subgroup) also had PK analyses performed with a single dose of 50 IU/kg Advate (Advate Day 0) within 8 weeks prior to rFVIIIFc Day 0. A \>= 96 hour washout was performed before the PK dose of Advate or rFVIIIFc was administered. Repeat PK profiling with a single dose of 50 IU/kg rFVIIIFc was conducted at Week 14 or after 12 to 24 weeks of prophylaxis with rFVIIIFc. After PK assessments, all participants started twice weekly treatment with 25 IU/kg of rFVIIIFc via intravenous (IV) injection on Day 1 and 50 IU/kg on Day 4, followed by individualized dose and interval modification within the range of 25 to 65 IU/kg every 3 to 5 days, as determined by rFVIIIFc PK analysis, to maintain a trough level of 1% to 3% (or higher, as clinically indicated) FVIII activity.

Drug: Factor VIII (rFVIIIFc); Drug: Advate®

Weekly Prophylaxis

EXPERIMENTAL

65 IU/kg of rFVIIIFc via IV injection every 7 days

Drug: Factor VIII (rFVIIIFc)

Episodic (On-Demand) Dosing

EXPERIMENTAL

10 to 50 IU/kg rFVIIIFc via IV injection, as required to treat a bleeding episode

Drug: Factor VIII (rFVIIIFc)

Interventions

Factor VIII (rFVIIIFc) DRUG

Also known as: Recombinant Factor VIII Fc Fusion Protein

Episodic (On-Demand) Dosing; Individualized (Tailored) Prophylaxis; Weekly Prophylaxis

Advate® DRUG

Also known as: octocog alfa, Antihemophilic Factor [Recombinant] Plasma/Albumin Free Method

Individualized (Tailored) Prophylaxis

Eligibility Criteria

• Age: 12 Years+
• Sex: male
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Bioverativ Therapeutics Inc.: lead
• Swedish Orphan Biovitrum: collaborator

Study Sites (64)

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Little Rock, Arkansas, United States

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Los Angeles, California, United States

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Orange, California, United States

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Sacramento, California, United States

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San Diego, California, United States

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Washington D.C., District of Columbia, United States

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Indianapolis, Indiana, United States

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Iowa City, Iowa, United States

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Louisville, Kentucky, United States

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New Orleans, Louisiana, United States

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Boston, Massachusetts, United States

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East Lansing, Michigan, United States

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Las Vegas, Nevada, United States

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New York, New York, United States

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Chapel Hill, North Carolina, United States

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Philadelphia, Pennsylvania, 19104, United States

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Philadelphia, Pennsylvania, 19107, United States

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Pittsburgh, Pennsylvania, United States

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Houston, Texas, United States

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Salt Lake City, Utah, United States

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Seattle, Washington, United States

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Camperdown, New South Wales, Australia

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Adelaide, South Australia, Australia

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Perth, Western Australia, Australia

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Vienna, 1090, Austria

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Brussels, 1200, Belgium

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Campinas, Brazil

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Calgary, T2N 2T9, Canada

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Toronto, Canada

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Vancouver, V6Z 1Y6, Canada

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Lyon, 69437, France

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Bonn, Northwest, Germany

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Berlin, State of Berlin, Germany

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Hong Kong, Hong Kong

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Bangalore, Karna, India

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Pune, Mahara, India

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New Delhi, National Capital Territory of Delhi, India

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Ludhiana, Punjab, India

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Vellore, Tamil Nadu, India

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Ramat Gan, 52621, Israel

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Florence, FI, Italy

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Milan, MI, Italy

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Vicenza, VI, Italy

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Kashihara-shi, Japan

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Kawasaki-shi, Japan

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Kitakyushu-shi, Japan

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Nagoya, Japan

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Shinjuku-ku, Japan

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Suginami-ku, Japan

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Auckland, 1023, New Zealand

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Christchurch, 8001, New Zealand

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Palmerston North, 4442, New Zealand

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Johannesburg Parktown, Gauteng, South Africa

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Cape Town, W Cape, South Africa

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Barcelona, Spain

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Madrid, Spain

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Gothenburg, 41345, Sweden

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Zurich, Switzerland

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Basingstoke, RG24 9NA, United Kingdom

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Cambridge, CB2 2QQ, United Kingdom

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Glasgow, G4 0SF, United Kingdom

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London, E1 1BB, United Kingdom

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London, NW3 2QG, United Kingdom

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London, SE1 7EH, United Kingdom

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Related Publications (4)

• 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.

  PMID: 24227821 RESULT

• 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.

  PMID: 25196897 RESULT

• Raheja P, Kragh N, Bystricka L, Eriksson D, Aroui K, Mezghani M, Barbier S, Linari S. Long-term efmoroctocog alfa prophylaxis improves perceived pain, mental, and physical health in patients with hemophilia A: post hoc analysis of phase III trials using patient-reported outcomes. Ther Adv Hematol. 2024 Jul 30;15:20406207241257917. doi: 10.1177/20406207241257917. eCollection 2024.

  PMID: 39091324 DERIVED

• 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.

  PMID: 33719084 DERIVED

MeSH Terms

Conditions

Hemophilia A

Interventions

Factor VIII; F8 protein, human

Condition Hierarchy (Ancestors)

Blood Coagulation Disorders, Inherited; Blood Coagulation Disorders; Hematologic Diseases; Hemic and Lymphatic Diseases; Coagulation Protein Disorders; Hemorrhagic Disorders; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities

Intervention Hierarchy (Ancestors)

Blood Coagulation Factors; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Protein Precursors; Biological Factors

Results Point of Contact

• Title: Biogen Study Medical Director
• Organization: Biogen

clinicaltrials@biogen.com

Study Officials

• Medical Director

  Bioverativ Therapeutics Inc.

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 12, 2010
• First Posted: August 13, 2010
• Study Start: November 1, 2010
• Primary Completion: August 1, 2012
• Study Completion: August 1, 2012
• Last Updated: January 8, 2021
• Results First Posted: August 29, 2014

Record last verified: 2017-07

Locations

IN (5); GB (6); ZA (2); IT (3); US (21); BR (1); CA (3); NZ (3); IL (1); ES (2); DE (2); BE (1); SE (1); JP (6); FR (1); AU (3); HK (1); CH (1)