A Gene Transfer Study for Hemophilia A

Gene-transfer, Open-label, Dose-escalation Study of SPK-8011 [Adeno-associated Viral Vector With B-domain Deleted Human Factor VIII Gene] in Individuals With Hemophilia A

This clinical research study is being conducted by Spark Therapeutics, Inc. to determine the safety and efficacy of the factor VIII gene transfer treatment with SPK-8011 in individuals with hemophilia A.

Study Overview

• Status: Completed
• Conditions: Hemophilia A
• Intervention / Treatment: Genetic: SPK-8011

Detailed Description

Hemophilia A is a condition in which blood is unable to clot effectively. It is caused by a mutation or deletion in the gene that is responsible for producing blood-clotting factor VIII protein. Individuals with hemophilia A suffer from repeated bleeding episodes, often into the joints, which can cause chronic joint disease and sometime results in death due to the inability of the blood to clot efficiently. This chronic joint disease can have significant physical, psychosocial, and quality-of-life effects, including financial burden. The current standard of care includes the use of factor-based therapies which are given either as prophylaxis or to treat bleeding, as well as new non-factor prophylaxis therapies.

• Study Type: Interventional
• Enrollment (Actual): 25
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Australia
  • Melbourne, Australia, 3004
    • The Alfred Hospital
  • New South Wales
    • Camperdown, New South Wales, Australia, 2050
      • Royal Prince Alfred Hosptial
• Canada
  • Ontario
    • Hamilton, Ontario, Canada, L8N 3Z5
      • McMaster University Medical Centre and Juravinski Hospital
• Israel
  • Tel Hashomer
    • Ramat Gan, Tel Hashomer, Israel, 526000
      • Chaim Sheba Center
• Thailand
  • Bangkok, Thailand, 10400
    • Mahidol University - Ramathibody Hospital
• United States
  • California
    • Sacramento, California, United States, 94817
      • University of California Davis - Hemostasis and Thrombosis Center
  • Florida
    • Gainesville, Florida, United States, 32610
      • University of Florida Health
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Boston Children's Hospital
  • Mississippi
    • Madison, Mississippi, United States, 39110
      • Mississippi Center for Advanced Medicine
  • New York
    • New York, New York, United States, 10065
      • Weill Cornell Medicine-Comprehensive Center for Hemophilia and Coagulation Disorders
  • Oregon
    • Portland, Oregon, United States, 97239
      • Oregon Health & Science University
  • Pennsylvania
    • Hershey, Pennsylvania, United States, 10733
      • Pennsylvania State University Milton S. Hershey Medical Center
    • Philadelphia, Pennsylvania, United States, 19104
      • Children's Hospital of Philadelphia
    • Philadelphia, Pennsylvania, United States, 19107
      • Jefferson University Hospitals
    • Pittsburgh, Pennsylvania, United States, 15213
      • Hemophilia Center of Western Pennsylvania
  • Virginia
    • Richmond, Virginia, United States, 23219
      • Virginia Commonwealth University School of Medicine

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Males age 18 years or older
• Confirmed diagnosis of hemophilia A as evidenced by their medical history with baseline FVIII activity levels <=2%
• Have received >150 exposure days (EDs) to FVIII concentrates or cryoprecipitate
• Have no prior history of allergic reaction to any FVIII product
• Have no measurable inhibitor against FVIII as assessed by the central laboratory and have no prior history of inhibitors to FVIII protein and no clinical signs or symptoms of decreased response to FVIII administration
• Agree to use reliable barrier contraception

Exclusion Criteria:

• Evidence of active hepatitis B or C
• Currently on antiviral therapy for hepatitis B or C
• Have significant underlying liver disease
• Have serological evidence* of HIV-1 or HIV-2 with CD4 counts ≤200/mm3 and who are on an antiretroviral drug regimen (* participants who are HIV+ and stable with CD4 count >200/mm3 and undetectable viral load are eligible to enroll)
• Have detectable antibodies reactive with AAV-Spark200 capsid
• Participated in a gene transfer trial within the last 52 weeks or in a clinical trial with an investigational product within the last 12 weeks

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: SPK-8011 5x10^11 vg/kg; Participants received a single intravenous (IV) infusion of SPK-8011 5x10^11 vector genomes per kilogram (vg/kg) body weight.	Genetic: SPK-8011; A novel, bio-engineered, recombinant adeno-associated viral vector carrying human factor VIII gene
Experimental: SPK-8011 1x10^12 vg/kg; Participants received a single IV infusion of SPK-8011 1x10^12 vg/kg.	Genetic: SPK-8011; A novel, bio-engineered, recombinant adeno-associated viral vector carrying human factor VIII gene
Experimental: SPK-8011 2x10^12 vg/kg; Participants received a single IV infusion of SPK-8011 2x10^12 vg/kg.	Genetic: SPK-8011; A novel, bio-engineered, recombinant adeno-associated viral vector carrying human factor VIII gene
Experimental: SPK-8011 1.5x10^12 vg/kg; Participants received a single IV infusion of SPK-8011 1.5x10^12 vg/kg.	Genetic: SPK-8011; A novel, bio-engineered, recombinant adeno-associated viral vector carrying human factor VIII gene

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Treatment-emergent Adverse Events (TEAEs)	An adverse event (AE) was defined as any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. Serious adverse events (SAEs) were defined as adverse events that result in death, are life-threatening, require inpatient hospitalization or prolongation of existing hospitalization, result in persistent or significant disability or incapacity, are a congenital anomaly or birth defect, or are an important medical event that jeopardized participant and required medical intervention to prevent 1 of the outcomes listed in this definition. A TEAE is defined as an AE with an onset date on or following SPK-8011 administration. A summary of other non-serious AEs and all serious AEs, regardless of causality is located in Reported AE section.	From date of first dose to Week 52/End of Study (EOS) Visit
Number of Participants Who Received Corticosteroids for Presumed Immune Response		Up to Week 52/EOS Visit
Peak Factor VIII (FVIII) Activity Levels Assessed by One-Stage Coagulation Assay (OSA)	Median peak FVIII activity up to Week 52	Up to Week 52/EOS visit
Nominal FVIII Level by OSA at Week 52/EOS	Steady-state FVIII activity measured by median FVIII levels at week 52 by OSA.	Up to Week 52/EOS Visit
Spontaneous Bleeds Annualized Bleeding Rate		Week 5 up to Week 52/EOS Visit
Total Annualized FVIII Infusion Rate		Week 5 up to Week 52/EOS Visit

Secondary Outcome Measures

Outcome Measure	Time Frame
Time to Achieve Peak FVIII Activity Level	Up to Week 52/EOS Visit
Number of Participants With Vector-shedding Confirmed Below Quantifiable Limits (BQL) of SPK-8011-101 in Bodily Fluids	Up to Week 52/EOS Visit
Incidence of Immune Response to the BDD-hFVIII Transgene	Up to Week 52/EOS Visit

Collaborators and Investigators

• Sponsor: Spark Therapeutics, Inc.
• Investigators: Study Director: Clinical Trial Director, Spark Therapeutics, Inc.

Publications and helpful links

General Publications

• George LA, Monahan PE, Eyster ME, Sullivan SK, Ragni MV, Croteau SE, Rasko JEJ, Recht M, Samelson-Jones BJ, MacDougall A, Jaworski K, Noble R, Curran M, Kuranda K, Mingozzi F, Chang T, Reape KZ, Anguela XM, High KA. Multiyear Factor VIII Expression after AAV Gene Transfer for Hemophilia A. N Engl J Med. 2021 Nov 18;385(21):1961-1973. doi: 10.1056/NEJMoa2104205.
• Ran G, Chen X, Xie Y, Zheng Q, Xie J, Yu C, Pittman N, Qi S, Yu FX, Agbandje-McKenna M, Srivastava A, Ling C. Site-Directed Mutagenesis Improves the Transduction Efficiency of Capsid Library-Derived Recombinant AAV Vectors. Mol Ther Methods Clin Dev. 2020 Mar 13;17:545-555. doi: 10.1016/j.omtm.2020.03.007. eCollection 2020 Jun 12.

Study record dates

Study Major Dates

• Study Start (Actual): January 26, 2017
• Primary Completion (Actual): December 5, 2023
• Study Completion (Actual): December 5, 2023

Study Registration Dates

• First Submitted: December 16, 2016
• First Submitted That Met QC Criteria: December 21, 2016
• First Posted (Estimated): December 28, 2016

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: December 5, 2024
• Last Verified: December 1, 2024

More Information

Terms related to this study

• Keywords: Gene Therapy; Hematologic Diseases; Genetic Diseases, Inborn; Blood Coagulation Disorders; Hemorrhagic Disorders; Gene Transfer; Recombinant; Genetic Diseases, X-Linked; Adeno-Associated Virus (AAV); Coagulation Protein Disorders; Blood Coagulation Disorders, Inherited; Factor VIII (FVIII); Factor VIII (FVIII) Deficiency; Factor VIII (FVIII) Gene; Factor VIII (FVIII) Protein; Vector
• Additional Relevant MeSH Terms: Genetic Diseases, Inborn; Hematologic Diseases; Blood Coagulation Disorders; Hemorrhagic Disorders; Blood Coagulation Disorders, Inherited; Coagulation Protein Disorders; Hemophilia A
• Other Study ID Numbers: SPK-8011-101

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No