Clinical trial NCT03003533: A Gene Transfer Study for Hemophilia A
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Hemophilia A
Keywords: Adeno-Associated Virus (AAV)
Blood Coagulation Disorders
Blood Coagulation Disorders, Inherited
Coagulation Protein Disorders
Factor VIII (FVIII)
Factor VIII (FVIII) Deficiency
Factor VIII (FVIII) Gene
Factor VIII (FVIII) Protein
Genetic Diseases, Inborn
Genetic Diseases, X-Linked
Gene Therapy
Gene Transfer
Hematologic Diseases
Hemorrhagic Disorders
Recombinant
Vector
Lead sponsor: Spark Therapeutics, Inc.
Sponsor class: INDUSTRY
First posted: 2016-12-28
Enrollment: 25
Sex: MALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

Brief summary: 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.

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.

Eligibility criteria: 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

Primary outcomes:
measure: Number of Participants With Treatment-emergent Adverse Events (TEAEs)
timeFrame: From date of first dose to Week 52/End of Study (EOS) Visit
measure: Number of Participants Who Received Corticosteroids for Presumed Immune Response
timeFrame: Up to Week 52/EOS Visit
measure: Peak Factor VIII (FVIII) Activity Levels Assessed by One-Stage Coagulation Assay (OSA)
timeFrame: Up to Week 52/EOS visit
measure: Nominal FVIII Level by OSA at Week 52/EOS
timeFrame: Up to Week 52/EOS Visit
measure: Spontaneous Bleeds Annualized Bleeding Rate
timeFrame: Week 5 up to Week 52/EOS Visit
measure: Total Annualized FVIII Infusion Rate
timeFrame: Week 5 up to Week 52/EOS Visit
Secondary outcomes:
measure: Time to Achieve Peak FVIII Activity Level
timeFrame: Up to Week 52/EOS Visit
measure: Number of Participants With Vector-shedding Confirmed Below Quantifiable Limits (BQL) of SPK-8011-101 in Bodily Fluids
timeFrame: Up to Week 52/EOS Visit
measure: Incidence of Immune Response to the BDD-hFVIII Transgene
timeFrame: Up to Week 52/EOS Visit
Other outcomes:
Locations:
city: Sacramento
country: United States
facility: University of California Davis - Hemostasis and Thrombosis Center
state: California
city: Gainesville
country: United States
facility: University of Florida Health
state: Florida
city: Boston
country: United States
facility: Boston Children's Hospital
state: Massachusetts
city: Madison
country: United States
facility: Mississippi Center for Advanced Medicine
state: Mississippi
city: New York
country: United States
facility: Weill Cornell Medicine-Comprehensive Center for Hemophilia and Coagulation Disorders
state: New York
city: Portland
country: United States
facility: Oregon Health & Science University
state: Oregon
city: Hershey
country: United States
facility: Pennsylvania State University Milton S. Hershey Medical Center
state: Pennsylvania
city: Philadelphia
country: United States
facility: Children's Hospital of Philadelphia
state: Pennsylvania
city: Philadelphia
country: United States
facility: Jefferson University Hospitals
state: Pennsylvania
city: Pittsburgh
country: United States
facility: Hemophilia Center of Western Pennsylvania
state: Pennsylvania
city: Richmond
country: United States
facility: Virginia Commonwealth University School of Medicine
state: Virginia
city: Camperdown
country: Australia
facility: Royal Prince Alfred Hosptial
state: New South Wales
city: Melbourne
country: Australia
facility: The Alfred Hospital
city: Hamilton
country: Canada
facility: McMaster University Medical Centre and Juravinski Hospital
state: Ontario
city: Ramat Gan
country: Israel
facility: Chaim Sheba Center
state: Tel Hashomer
city: Bangkok
country: Thailand
facility: Mahidol University - Ramathibody Hospital
Study officials:
affiliation: Spark Therapeutics, Inc.
name: Clinical Trial Director
role: STUDY_DIRECTOR
References:
citation: 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.
citation: 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.