Open-Label Single Ascending Dose of Adeno-associated Virus Serotype 8 Factor IX Gene Therapy in Adults With Hemophilia B

Study Description

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Brief Summary:

The purpose of this study is to evaluate the safety of single ascending IV doses of a Factor IX (FIX) Gene Therapy in up to 16 Adults with Hemophilia B.

Condition or disease	Intervention/treatment	Phase
Hemophilia B	Biological: AskBio009	Phase 1; Phase 2

Detailed Description:

Hemophilia B is a genetic X-linked bleeding disorder caused by a deficiency in blood-clotting Factor IX (FIX) activity. FIX is synthesized in the liver and circulates in the blood as a proenzyme. Current treatment for hemophilia B is based on replacement of the deficient FIX with IV injections of recombinant FIX protein prophylactically or as needed to treat bleeding episodes. This clinical program will test a gene transfer approach involving the use of a gene delivery vector carrying a FIX gene. This first-in-humans study is intended to evaluate the safety, kinetics, and if possible, the dose of AskBio009 required to achieve stable plasma FIX activity between 10% and 40% of normal activity.

Study Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	30 participants
Intervention Model:	Single Group Assignment
Masking:	None (Open Label)
Primary Purpose:	Treatment
Official Title:	A Phase 1/2 Open-Label, Single Ascending Dose Trial of a Self-Complementing Optimized Adeno-associated Virus Serotype 8 Factor IX Gene Therapy (AskBio009) in Adults With Hemophilia B
Actual Study Start Date :	January 28, 2013
Estimated Primary Completion Date :	October 28, 2030
Estimated Study Completion Date :	October 28, 2030

Arms and Interventions

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Arm	Intervention/treatment
Experimental: AskBio009 Dose Escalation; Single Dose of a Self-Complementing Optimized Adeno-associated Virus (AAV) Serotype 8 Factor IX Gene Therapy	Biological: AskBio009; Single dose IV injection; Other Name: BAX 335

Outcome Measures

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Primary Outcome Measures :

1. Number of patients experiencing treatment-related adverse events by dose group [ Time Frame: Infusion to Week 3 and Infusion to end of study ]
2. Change from baseline in clinical laboratory evaluations [ Time Frame: Change from baseline at week 3 and change from baseline at the end of study ]

Secondary Outcome Measures :

1. Changes from Baseline in FIX activity levels, FIX protein levels, and Bleeding Episode Severity & Frequency [ Time Frame: At multiple timepoints from pre-dose through up to 5 years post-dose ]
2. Immune Response to AskBio009 [ Time Frame: At multiple timepoints from pre-dose through up to 5 years post-dose ]
3. Detection of AskBio009 genomes in blood, saliva, urine, stool, and semen [ Time Frame: At multiple timepoints from pre-dose through up to 1 years post-dose ]

Eligibility Criteria

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Ages Eligible for Study:	18 Years to 75 Years (Adult, Senior)
Sexes Eligible for Study:	Male
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

• Males age 18-75 years, inclusive
• Established hemophilia B with ≥3 hemorrhages per year requiring treatment with exogenous FIX OR use of FIX prophylaxis because of history of frequent bleeding episodes
• Plasma FIX activity ≤2% (<1% for first cohort; then per protocol)
• Negative for active Hepatitis C virus (HCV), defined as Hepatitis C virus antibody negative and negative (undetectable) PCR test for plasma Hepatitis C virus ribonucleic acid (RNA) OR if Hepatitis C virus antibody positive must have ≥2 consecutive negative (undetectable) PCR tests for plasma HCV RNA at least 3 months apart, and negative at screening

Exclusion Criteria:

• Family history of inhibitor to FIX protein or personal laboratory evidence of having developed inhibitors to FIX protein at any time (>0.6 Bethesda Units on any single test)
• Documented prior allergic reaction to any FIX product
• Detectable AAV8 neutralizing antibodies

• Markers of hepatic inflammation or overt or occult cirrhosis as evidenced by one or more of the following:

  • Platelet count <175,000/μL
  • Albumin ≤3.5 g/dL
  • Total bilirubin >1.5 x ULN and direct bilirubin ≥0.5 mg/dL
  • Alkaline phosphatase >2.0 x ULN
  • ALT or AST >2.0 x ULN (except for subjects who are HIV infected)
  • Liver biopsy in the past indicating moderate or severe fibrosis (Metavir staging of 2 or greater)
  • History of ascites, varices, variceal hemorrhage or hepatic encephalopathy

Contacts and Locations

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Locations

United States, California
Orthopaedic Hemophilia Treatment Center
Los Angeles, California, United States, 90007
Children's Hospital Los Angeles
Los Angeles, California, United States, 90027
University of California Davis Medical Center
Sacramento, California, United States, 95817
University of California at San Diego Medical Center
San Diego, California, United States, 92103-8651
United States, Colorado
U of Colorado School of Medicine, Hemophilia & Thrombosis Treatment Center
Aurora, Colorado, United States, 80045
United States, Georgia
Emory University
Atlanta, Georgia, United States, 30322
United States, Illinois
Rush University Medical Center
Chicago, Illinois, United States, 60612
United States, Massachusetts
Children's Hospital of Boston
Boston, Massachusetts, United States, 022105
United States, Minnesota
University of Minnesota, Masonic Clinical Research Unit, Clinical and Translational Science Institute
Minneapolis, Minnesota, United States, 55455
United States, New York
Mount Sinai Medical Center
New York, New York, United States, 10029
United States, Oregon
The Hemophilia Center, Oregon Health and Science University
Portland, Oregon, United States, 97239
United States, South Carolina
Medical University of South Carolina
Charleston, South Carolina, United States, 29425
United States, Texas
Gulf States Hemophilia and Thrombosis Center
Houston, Texas, United States, 77030
United States, Washington
Bloodworks Northwest
Seattle, Washington, United States, 98104
United States, Wisconsin
BloodCenter of Wisconsin
Milwaukee, Wisconsin, United States, 53226

Sponsors and Collaborators

Baxalta now part of Shire

Investigators

Study Director:	John Chapin, MD	Baxalta now part of Shire

More Information

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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Responsible Party:	Baxalta now part of Shire
ClinicalTrials.gov Identifier:	NCT01687608 History of Changes
Other Study ID Numbers:	AskBio009-101
First Posted:	September 19, 2012
Last Update Posted:	November 8, 2017
Last Verified:	November 2017

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

Keywords provided by Shire ( Baxalta now part of Shire ):

Hemophilia B; factor IX deficiency; gene therapy

Additional relevant MeSH terms:

Hemophilia A; Hemophilia B; Blood Coagulation Disorders, Inherited; Blood Coagulation Disorders; Hematologic Diseases	Coagulation Protein Disorders; Hemorrhagic Disorders; Genetic Diseases, Inborn; Genetic Diseases, X-Linked