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A Gene Transfer Study for Hemophilia A

Primary Purpose

Hemophilia A

Status
Active
Phase
Phase 1
Locations
International
Study Type
Interventional
Intervention
SPK-8011
Sponsored by
Spark Therapeutics
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Hemophilia A focused on measuring 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

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)MaleDoes not accept healthy volunteers

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

Sites / Locations

  • University of California Davis - Hemostasis and Thrombosis Center
  • University of Florida Health
  • Boston Children's Hospital
  • Mississippi Center for Advanced Medicine
  • Weill Cornell Medicine-Comprehensive Center for Hemophilia and Coagulation Disorders
  • Oregon Health & Science University
  • Pennsylvania State University Milton S. Hershey Medical Center
  • Children's Hospital of Philadelphia
  • Jefferson University Hospitals
  • Hemophilia Center of Western Pennsylvania
  • Virginia Commonwealth University School of Medicine
  • Royal Prince Alfred Hosptial
  • The Alfred Hospital
  • McMaster University Medical Centre and Juravinski Hospital
  • Chaim Sheba Center
  • Mahidol University - Ramathibody Hospital

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

SPK-8011

Arm Description

All participants who meet the eligibility criteria will receive an outpatient single intravenous (i.v.) administration of SPK-8011.

Outcomes

Primary Outcome Measures

Number of study-related adverse events, including clinically significant abnormal laboratory values
adverse events
Changes from baseline in FVIII activity levels after a single outpatient administration of SPK-8011
changes in FVIII activity levels

Secondary Outcome Measures

Kinetic assessment of SPK-8011 including shedding of vector DNA in bodily fluids
vector shedding
Number of participants requiring a course of steroid therapy for the elevations in liver enzymes
number of participants requiring steroids

Full Information

First Posted
December 16, 2016
Last Updated
July 6, 2023
Sponsor
Spark Therapeutics
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1. Study Identification

Unique Protocol Identification Number
NCT03003533
Brief Title
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

2. Study Status

Record Verification Date
July 2023
Overall Recruitment Status
Active, not recruiting
Study Start Date
January 26, 2017 (Actual)
Primary Completion Date
December 2023 (Anticipated)
Study Completion Date
December 2023 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Spark Therapeutics

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. 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.
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
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

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Sequential Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
50 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
SPK-8011
Arm Type
Experimental
Arm Description
All participants who meet the eligibility criteria will receive an outpatient single intravenous (i.v.) administration of SPK-8011.
Intervention Type
Genetic
Intervention Name(s)
SPK-8011
Intervention Description
A novel, bio-engineered, recombinant adeno-associated viral vector carrying human factor VIII gene
Primary Outcome Measure Information:
Title
Number of study-related adverse events, including clinically significant abnormal laboratory values
Description
adverse events
Time Frame
52 weeks
Title
Changes from baseline in FVIII activity levels after a single outpatient administration of SPK-8011
Description
changes in FVIII activity levels
Time Frame
52 weeks
Secondary Outcome Measure Information:
Title
Kinetic assessment of SPK-8011 including shedding of vector DNA in bodily fluids
Description
vector shedding
Time Frame
52 weeks
Title
Number of participants requiring a course of steroid therapy for the elevations in liver enzymes
Description
number of participants requiring steroids
Time Frame
52 weeks

10. Eligibility

Sex
Male
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility 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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Clinical Trial Director
Organizational Affiliation
Spark Therapeutics, Inc.
Official's Role
Study Director
Facility Information:
Facility Name
University of California Davis - Hemostasis and Thrombosis Center
City
Sacramento
State/Province
California
ZIP/Postal Code
94817
Country
United States
Facility Name
University of Florida Health
City
Gainesville
State/Province
Florida
ZIP/Postal Code
32610
Country
United States
Facility Name
Boston Children's Hospital
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02115
Country
United States
Facility Name
Mississippi Center for Advanced Medicine
City
Madison
State/Province
Mississippi
ZIP/Postal Code
39110
Country
United States
Facility Name
Weill Cornell Medicine-Comprehensive Center for Hemophilia and Coagulation Disorders
City
New York
State/Province
New York
ZIP/Postal Code
10065
Country
United States
Facility Name
Oregon Health & Science University
City
Portland
State/Province
Oregon
ZIP/Postal Code
97239
Country
United States
Facility Name
Pennsylvania State University Milton S. Hershey Medical Center
City
Hershey
State/Province
Pennsylvania
ZIP/Postal Code
10733
Country
United States
Facility Name
Children's Hospital of Philadelphia
City
Philadelphia
State/Province
Pennsylvania
ZIP/Postal Code
19104
Country
United States
Facility Name
Jefferson University Hospitals
City
Philadelphia
State/Province
Pennsylvania
ZIP/Postal Code
19107
Country
United States
Facility Name
Hemophilia Center of Western Pennsylvania
City
Pittsburgh
State/Province
Pennsylvania
ZIP/Postal Code
15213
Country
United States
Facility Name
Virginia Commonwealth University School of Medicine
City
Richmond
State/Province
Virginia
ZIP/Postal Code
23219
Country
United States
Facility Name
Royal Prince Alfred Hosptial
City
Camperdown
State/Province
New South Wales
ZIP/Postal Code
2050
Country
Australia
Facility Name
The Alfred Hospital
City
Melbourne
ZIP/Postal Code
3004
Country
Australia
Facility Name
McMaster University Medical Centre and Juravinski Hospital
City
Hamilton
State/Province
Ontario
ZIP/Postal Code
L8N 3Z5
Country
Canada
Facility Name
Chaim Sheba Center
City
Ramat Gan
State/Province
Tel Hashomer
ZIP/Postal Code
526000
Country
Israel
Facility Name
Mahidol University - Ramathibody Hospital
City
Bangkok
ZIP/Postal Code
10400
Country
Thailand

12. IPD Sharing Statement

Plan to Share IPD
Undecided
Citations:
PubMed Identifier
34788507
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.
Results Reference
derived
PubMed Identifier
32258217
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.
Results Reference
derived

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A Gene Transfer Study for Hemophilia A

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