A Gene Transfer Study for Hemophilia A

• ClinicalTrials.gov Identifier: NCT03003533
• Recruitment Status: Active, not recruiting
• First Posted: December 28, 2016
• Last Update Posted: March 30, 2023
• Sponsor: Spark Therapeutics
• Information provided by (Responsible Party): Spark Therapeutics

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Hemophilia A	Genetic: SPK-8011	Phase 1; Phase 2

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 treatment is intravenous (i.v.) injections of factor VIII protein products, either 2-3 times weekly or in response to bleeding.

Recent preliminary clinical data of a hemophilia B gene transfer study (which is also being conducted by Spark Therapeutics) shows all study participants achieving therapeutic factor IX activity levels (average of maintaining factor IX activity levels around 30% of normal with no confirmed bleeds, after receiving Spark gene transfer, with the approach of using the novel bio-engineered recombinant adeno-associated viral (rAAV) vector carrying a high specific activity of a factor IX gene. The approach being tested in this clinical research study uses a further modified novel AAV vector (with a stronger attraction to the human liver) to deliver the human factor VIII (hFVIII) gene into liver cells so that they can produce factor VIII protein.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 50 participants
• Allocation: N/A
• Intervention Model: Sequential Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• 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
• Actual Study Start Date: January 26, 2017
• Estimated Primary Completion Date: December 2023
• Estimated Study Completion Date: December 2023

Arms and Interventions

Arm	Intervention/treatment
Experimental: SPK-8011; All participants who meet the eligibility criteria will receive an outpatient single intravenous (i.v.) administration of SPK-8011.	Genetic: SPK-8011; A novel, bio-engineered, recombinant adeno-associated viral vector carrying human factor VIII gene

Outcome Measures

Primary Outcome Measures :

1. Number of study-related adverse events, including clinically significant abnormal laboratory values [ Time Frame: 52 weeks ]
   adverse events
2. Changes from baseline in FVIII activity levels after a single outpatient administration of SPK-8011 [ Time Frame: 52 weeks ]
   changes in FVIII activity levels

Secondary Outcome Measures :

1. Kinetic assessment of SPK-8011 including shedding of vector DNA in bodily fluids [ Time Frame: 52 weeks ]
   vector shedding
2. Number of participants requiring a course of steroid therapy for the elevations in liver enzymes [ Time Frame: 52 weeks ]
   number of participants requiring steroids

Eligibility Criteria

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

Criteria

Inclusion Criteria:

• Males age18 years or older
• Confirmed diagnosis of hemophilia A as evidenced by their medical history with plasma FVIII activity levels ≤ 2% of normal
• Have received >150 exposure days (EDs) to FVIII concentrates or cryoprecipitate
• Have experienced >10 bleeding events over the previous 12 months only if receiving on-demand therapy and having FVIII baseline level 1-2% of normal
• Have no prior history of allergic reaction to any FVIII product
• Have no measurable inhibitor against Factor VIII as assessed by the central laboratory and have no prior history of inhibitors to FVIII protein
• 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 (* 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

Contacts and Locations

Locations

United States, California

University of California Davis - Hemostasis and Thrombosis Center

Sacramento, California, United States, 94817

United States, Florida

University of Florida Health

Gainesville, Florida, United States, 32610

United States, Massachusetts

Boston Children's Hospital

Boston, Massachusetts, United States, 02115

United States, Mississippi

Mississippi Center for Advanced Medicine

Madison, Mississippi, United States, 39110

United States, New York

Weill Cornell Medicine-Comprehensive Center for Hemophilia and Coagulation Disorders

New York, New York, United States, 10065

United States, Oregon

Oregon Health & Science University

Portland, Oregon, United States, 97239

United States, Pennsylvania

Pennsylvania State University Milton S. Hershey Medical Center

Hershey, Pennsylvania, United States, 10733

Children's Hospital of Philadelphia

Philadelphia, Pennsylvania, United States, 19104

Jefferson University Hospitals

Philadelphia, Pennsylvania, United States, 19107

Hemophilia Center of Western Pennsylvania

Pittsburgh, Pennsylvania, United States, 15213

United States, Virginia

Virginia Commonwealth University School of Medicine

Richmond, Virginia, United States, 23219

Australia, New South Wales

Royal Prince Alfred Hosptial

Camperdown, New South Wales, Australia, 2050

Australia

The Alfred Hospital

Melbourne, Australia, 3004

Canada, Ontario

McMaster University Medical Centre and Juravinski Hospital

Hamilton, Ontario, Canada, L8N 3Z5

Israel

Chaim Sheba Center

Ramat Gan, Tel Hashomer, Israel, 526000

Thailand

Mahidol University - Ramathibody Hospital

Bangkok, Thailand, 10400

Sponsors and Collaborators

Spark Therapeutics

Investigators

• Study Director: Clinical Trial Director; Spark Therapeutics, Inc.

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

• Responsible Party: Spark Therapeutics
• ClinicalTrials.gov Identifier: NCT03003533
• Other Study ID Numbers: SPK-8011-101
• First Posted: December 28, 2016
• Last Update Posted: March 30, 2023
• Last Verified: March 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Undecided

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Spark Therapeutics:

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

Additional relevant MeSH terms:

Hemophilia A; Blood Coagulation Disorders, Inherited; Blood Coagulation Disorders; Hematologic Diseases; Coagulation Protein Disorders; Hemorrhagic Disorders; Genetic Diseases, Inborn