Hemophilia B Gene Therapy With AAV8 Vector

NCT01620801 | Terminated Phase 1 DMC

• 1 other identifier: AAV8-hFIX19-101
• Study Type: interventional
• Target: 4
• Locations: 2 countries
• Sites: 3

Brief Summary

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.

Conditions

Hemophilia B

Keywords

AAV; AAV8; Adeno-associated virus; Adeno-associated viral vectors; Hemophilia; Hemophilia B; Severe hemophilia B; Factor IX deficiency; Factor IX; FIX

Outcome Measures

Primary Outcomes (1)

• Number of subjects with adverse events related to investigational product

  Physical exams; clinical labs, including evaluation of FIX inhibitor; and adverse event reporting.

  One year (with 15-year follow-up)

Secondary Outcomes (1)

• Circulating plasma factor IX levels

  One year (with 15-year follow-up)

Study Arms (3)

Low dose

EXPERIMENTAL

AAV8-hFIX19

Biological: AAV8-hFIX19

Middle dose

EXPERIMENTAL

AAV8-hFIX19

Biological: AAV8-hFIX19

High dose

EXPERIMENTAL

AAV8-hFIX19

Biological: AAV8-hFIX19

Interventions

AAV8-hFIX19 BIOLOGICAL

One-time IV vector administration.

High dose; Low dose; Middle dose

Eligibility Criteria

• Age: 18 Years+
• Sex: male
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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)

You may not qualify if:

• 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

Sponsors & Collaborators

• Spark Therapeutics, Inc.: lead
• Children's Hospital of Philadelphia: collaborator
• University of Pittsburgh: collaborator
• Royal Prince Alfred Hospital, Sydney, Australia: collaborator
• St. James's Hospital, Ireland: collaborator

Study Sites (3)

The Children's Hospital of Philadelphia

Philadelphia, Pennsylvania, 19104, United States

Location

University of Pittsburgh

Pittsburgh, Pennsylvania, 15213, United States

Location

Royal Prince Alfred Hospital

Camperdown, New South Wales, Australia

Location

MeSH Terms

Conditions

Hemophilia B; Hemophilia A

Condition Hierarchy (Ancestors)

Blood Coagulation Disorders, Inherited; Blood Coagulation Disorders; Hematologic Diseases; Hemic and Lymphatic Diseases; Coagulation Protein Disorders; Hemorrhagic Disorders; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Genetic Diseases, X-Linked

Study Officials

• Clinical Director

  Spark Therapeutics, Inc.

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 12, 2012
• First Posted: June 15, 2012
• Study Start: October 1, 2012
• Primary Completion: March 1, 2016
• Study Completion: March 1, 2016
• Last Updated: March 12, 2019

Record last verified: 2018-12

Locations

US (2); AU (1)