Hemophilia B Gene Therapy - Spark

This study is currently recruiting participants. (see Contacts and Locations)
Verified December 2013 by Spark Therapeutics, LLC
Sponsor:
Collaborators:
Children's Hospital of Philadelphia
University of Pittsburgh
Royal Prince Alfred Hospital, Sydney, Australia
St. James's Hospital, Ireland
Information provided by (Responsible Party):
Spark Therapeutics, LLC
ClinicalTrials.gov Identifier:
NCT01620801
First received: June 12, 2012
Last updated: December 20, 2013
Last verified: December 2013
  Purpose

Hemophilia B is a bleeding disease in males due to very low levels of coagulation factor IX (FIX) in the blood. The current treatment is intravenous injection of FIX clotting factor concentrates, in response to bleeding. This study will focus on the severe, most common type of hemophilia B. This study plans to use a virus called adeno-associated virus (AAV), which in nature causes no disease, and can be engineered to deliver the human FIX gene (AAV8-hFIX19 vector) to liver cells, where FIX is normally made. This study will use the AAV8-hFIX19 vector.


Condition Intervention Phase
Hemophilia B
Biological: AAV8-hFIX19
Phase 1
Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase 1 Safety Study in Subjects With Severe Hemophilia B (Factor IX Deficiency) Using a Single-Stranded, Adeno-Associated Pseudotype 8 Viral Vector to Deliver the Gene for Human Factor IX

Resource links provided by NLM:


Further study details as provided by Spark Therapeutics, LLC:

Primary Outcome Measures:
  • Number of subjects with adverse events related to investigational product [ Time Frame: One year (with 15-year follow-up) ] [ Designated as safety issue: Yes ]
    Physical exams; clinical labs, including evaluation of FIX inhibitor; and adverse event reporting.


Secondary Outcome Measures:
  • Circulating plasma factor IX levels [ Time Frame: One year (with 15-year follow-up) ] [ Designated as safety issue: Yes ]
    Factor IX activity and antigen; PT; and aPTT.


Estimated Enrollment: 15
Study Start Date: October 2012
Estimated Study Completion Date: October 2029
Estimated Primary Completion Date: October 2019 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Low dose
AAV8-hFIX19
Biological: AAV8-hFIX19
One-time IV vector administration.
Experimental: Middle dose
AAV8-hFIX19
Biological: AAV8-hFIX19
One-time IV vector administration.
Experimental: High dose
AAV8-hFIX19
Biological: AAV8-hFIX19
One-time IV vector administration.

Detailed Description:

Hemophilia B is a bleeding disease in males due to very low levels of coagulation factor IX (FIX) in the blood. The major effect on health is joint disease caused by repeated bleeds into joints like the knee, hip, ankles and elbows. Rarely, the disease causes death due to bleeding into the brain or other important organs. The current treatment is intravenous injection of FIX clotting factor concentrates, in response to bleeding. This study will focus on the severe, most common type of hemophilia B.

This study plans to use a virus called adeno-associated virus (AAV), which in nature causes no disease, and can be engineered to deliver the human FIX gene (AAV8-hFIX19 vector) to liver cells, where FIX is normally made. Medical researchers in the United States and England have recently used an AAV vector similar to the one planned for this study, and found that after a single intravenous injection of the vector, blood levels of FIX reached levels greater than 1%, high enough to change the course of disease from severe to moderate. This means that the need to take FIX clotting factor concentrates has decreased, or even stopped. While these are important results, it needs to be noted that two of the six subjects who received the vector at higher doses developed inflammation of the liver. These subjects were treated with a steroid medication called Prednisolone, which is commonly used for serious types of inflammation. Prednisolone seemed to decrease the liver inflammation, as measured by a decrease in blood levels of elevated liver enzymes, and stability of FIX levels at greater than 1% of normal.

This study will use the AAV8-hFIX19 vector. The vector will be injected once into a peripheral vein of each subject, while the subject is in the hospital. If everything is fine, the subject will be discharged from the hospital the next day. Three doses of vector (low, middle, and high) will be tested in up to 15 different subjects, depending on safety outcome (as determined by blood and urine tests) and results of FIX levels. If some subjects develop liver inflammation, a short, tapering course of corticosteroids will be used.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Male
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Willingness to adhere to the clinical protocol and 15-year long-term follow-up as evidenced by written informed consent
  • Adult males at least 18 years of age
  • A. Severe FIX deficiency (<1% normal circulating FIX) or B. Moderately severe FIX deficiency (1-2% normal circulating FIX, inclusive) and a severe bleeding phenotype as defined by at least one of the following: i. On prophylaxis for a history of bleeding or ii. On demand therapy with a current or past history of frequent bleeding [4 or more bleeding episodes in the last 12 months or chronic hemophilic arthropathy (pain, joint destruction, and loss of range of motion) in one or more joints]
  • No history of inhibitor against FIX
  • No history of an allergic reaction or anaphylaxis to FIX products
  • Greater than 20 exposure days of treatment with FIX protein
  • Anti-AAV8 neutralizing titer measured at < 1:5
  • Acceptable laboratory values: hemoglobin ≥ 11% gm; WBC ≥ 3,500/μL; platelets ≥ 100,000/μL; AST, ALT, alkaline phosphatase ≤ 2x ULN; bilirubin ≤ 1.2 gm/dL; and creatinine ≤ 1.5 gm/dL
  • Subject agrees to use barrier contraception until at least two consecutive semen samples after vector administration are negative for vector sequences (may be for up to several months)

Exclusion Criteria:

  • Subjects with active hepatitis B or C, and HBsAg or HCV RNA viral load positivity, respectively. Negative viral assays in two samples, collected at least six months apart, will be required to be considered negative. Both natural clearers and those who have cleared HCV on antiviral therapy are eligible.
  • Subjects currently on antiviral therapy for hepatitis B or C
  • Subjects with significant underlying liver disease, as defined by presence of portal hypertension, splenomegaly, varices, ascites, edema, gastrointestinal bleeding, encephalopathy, reduction below normal limits of serum albumin, or prior liver biopsy demonstrating significant fibrosis, specifically ≥ Metavir 3 fibrosis
  • Subjects with serological evidence of HIV who have CD4 counts ≤ 200/mm3. Subjects who are HIV-positive and stable, with an adequate CD4 count (> 200/mm3) and undetectable viral load (< 50 gc/mL) measured twice in the six months prior to enrollment, on an antiretroviral drug regimen are eligible to enroll.
  • History of inhibitor against FIX
  • Anti-AAV8 antibody titers ≥ 1:5
  • History of chronic infection or other chronic diseases which the investigators consider to constitute an unacceptable risk
  • Subjects who have participated in a previous gene therapy research trial within one year of enrollment
  • Subjects who have participated in a clinical study with an investigational drug within six months of enrollment
  • Any other condition that would not allow the potential subject to complete follow-up examinations during the course of the study or, in the opinion of the investigator, makes the potential subject unsuitable for the study
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01620801

Contacts
Contact: Amy Lange, RN (267) 425-0133 langea@email.chop.edu

Locations
United States, Pennsylvania
The Children's Hospital of Philadelphia Recruiting
Philadelphia, Pennsylvania, United States, 19104
Contact: Amy Lange    267-425-0133    langea@email.chop.edu   
Principal Investigator: Leslie J Raffini, MD         
University of Pittsburgh Recruiting
Pittsburgh, Pennsylvania, United States, 15213
Contact: Judith Kadosh, RN, BSN    412-209-7263    JKadosh@itxm.org   
Principal Investigator: Margaret V Ragni, MD         
Australia, New South Wales
Royal Prince Alfred Hospital Not yet recruiting
Camperdown, New South Wales, Australia
Principal Investigator: John Rasko, MD         
Sponsors and Collaborators
Spark Therapeutics, LLC
Children's Hospital of Philadelphia
University of Pittsburgh
Royal Prince Alfred Hospital, Sydney, Australia
St. James's Hospital, Ireland
Investigators
Principal Investigator: Margaret V Ragni, MD University of Pittsburgh
  More Information

No publications provided

Responsible Party: Spark Therapeutics, LLC
ClinicalTrials.gov Identifier: NCT01620801     History of Changes
Other Study ID Numbers: AAV8-hFIX19-101
Study First Received: June 12, 2012
Last Updated: December 20, 2013
Health Authority: United States: Food and Drug Administration
United States: NIH Office of Biotechnology Activities
Australia: Therapeutic Goods Administration

Keywords provided by Spark Therapeutics, LLC:
AAV
AAV8
Adeno-associated virus
Adeno-associated viral vectors
Hemophilia
Hemophilia B
Severe hemophilia B
Factor IX deficiency
Factor IX
FIX

Additional relevant MeSH terms:
Hemophilia B
Hemophilia A
Blood Coagulation Disorders, Inherited
Blood Coagulation Disorders
Hematologic Diseases
Coagulation Protein Disorders
Hemorrhagic Disorders
Genetic Diseases, Inborn
Genetic Diseases, X-Linked

ClinicalTrials.gov processed this record on July 26, 2014