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

Primary Purpose

Hemophilia B

Status
Active
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
AskBio009
Sponsored by
Baxalta now part of Shire
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Hemophilia B focused on measuring Hemophilia B, factor IX deficiency, gene therapy

Eligibility Criteria

18 Years - 75 Years (Adult, Older Adult)MaleDoes not accept healthy volunteers

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

Sites / Locations

  • Orthopaedic Hemophilia Treatment Center
  • Children's Hospital Los Angeles
  • University of California Davis Medical Center
  • University of California at San Diego Medical Center
  • U of Colorado School of Medicine, Hemophilia & Thrombosis Treatment Center
  • Emory University
  • Rush University Medical Center
  • Children's Hospital of Boston
  • University of Minnesota, Masonic Clinical Research Unit, Clinical and Translational Science Institute
  • Mount Sinai Medical Center
  • The Hemophilia Center, Oregon Health and Science University
  • Medical University of South Carolina
  • Gulf States Hemophilia and Thrombosis Center
  • Bloodworks Northwest
  • BloodCenter of Wisconsin

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

AskBio009 Dose Escalation

Arm Description

Single Dose of a Self-Complementing Optimized Adeno-associated Virus (AAV) Serotype 8 Factor IX Gene Therapy

Outcomes

Primary Outcome Measures

Number of patients experiencing treatment-related adverse events by dose group
Change from baseline in clinical laboratory evaluations

Secondary Outcome Measures

Changes from Baseline in FIX activity levels, FIX protein levels, and Bleeding Episode Severity & Frequency
Immune Response to AskBio009
Detection of AskBio009 genomes in blood, saliva, urine, stool, and semen

Full Information

First Posted
August 27, 2012
Last Updated
September 29, 2022
Sponsor
Baxalta now part of Shire
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1. Study Identification

Unique Protocol Identification Number
NCT01687608
Brief Title
Open-Label Single Ascending Dose of Adeno-associated Virus Serotype 8 Factor IX Gene Therapy in Adults With Hemophilia B
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
Study Type
Interventional

2. Study Status

Record Verification Date
September 2022
Overall Recruitment Status
Active, not recruiting
Study Start Date
February 11, 2013 (Actual)
Primary Completion Date
October 28, 2030 (Anticipated)
Study Completion Date
October 28, 2030 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Baxalta now part of Shire

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
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.
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Hemophilia B
Keywords
Hemophilia B, factor IX deficiency, gene therapy

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
30 (Actual)

8. Arms, Groups, and Interventions

Arm Title
AskBio009 Dose Escalation
Arm Type
Experimental
Arm Description
Single Dose of a Self-Complementing Optimized Adeno-associated Virus (AAV) Serotype 8 Factor IX Gene Therapy
Intervention Type
Biological
Intervention Name(s)
AskBio009
Other Intervention Name(s)
BAX 335
Intervention Description
Single dose IV injection
Primary Outcome Measure Information:
Title
Number of patients experiencing treatment-related adverse events by dose group
Time Frame
Infusion to Week 3 and Infusion to end of study
Title
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 Measure Information:
Title
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
Title
Immune Response to AskBio009
Time Frame
At multiple timepoints from pre-dose through up to 5 years post-dose
Title
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

10. Eligibility

Sex
Male
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
75 Years
Accepts Healthy Volunteers
No
Eligibility 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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Study Director
Organizational Affiliation
Shire
Official's Role
Study Director
Facility Information:
Facility Name
Orthopaedic Hemophilia Treatment Center
City
Los Angeles
State/Province
California
ZIP/Postal Code
90007
Country
United States
Facility Name
Children's Hospital Los Angeles
City
Los Angeles
State/Province
California
ZIP/Postal Code
90027
Country
United States
Facility Name
University of California Davis Medical Center
City
Sacramento
State/Province
California
ZIP/Postal Code
95817
Country
United States
Facility Name
University of California at San Diego Medical Center
City
San Diego
State/Province
California
ZIP/Postal Code
92103-8651
Country
United States
Facility Name
U of Colorado School of Medicine, Hemophilia & Thrombosis Treatment Center
City
Aurora
State/Province
Colorado
ZIP/Postal Code
80045
Country
United States
Facility Name
Emory University
City
Atlanta
State/Province
Georgia
ZIP/Postal Code
30322
Country
United States
Facility Name
Rush University Medical Center
City
Chicago
State/Province
Illinois
ZIP/Postal Code
60612
Country
United States
Facility Name
Children's Hospital of Boston
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
022105
Country
United States
Facility Name
University of Minnesota, Masonic Clinical Research Unit, Clinical and Translational Science Institute
City
Minneapolis
State/Province
Minnesota
ZIP/Postal Code
55455
Country
United States
Facility Name
Mount Sinai Medical Center
City
New York
State/Province
New York
ZIP/Postal Code
10029
Country
United States
Facility Name
The Hemophilia Center, Oregon Health and Science University
City
Portland
State/Province
Oregon
ZIP/Postal Code
97239
Country
United States
Facility Name
Medical University of South Carolina
City
Charleston
State/Province
South Carolina
ZIP/Postal Code
29425
Country
United States
Facility Name
Gulf States Hemophilia and Thrombosis Center
City
Houston
State/Province
Texas
ZIP/Postal Code
77030
Country
United States
Facility Name
Bloodworks Northwest
City
Seattle
State/Province
Washington
ZIP/Postal Code
98104
Country
United States
Facility Name
BloodCenter of Wisconsin
City
Milwaukee
State/Province
Wisconsin
ZIP/Postal Code
53226
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
Yes
IPD Sharing Plan Description
Takeda provides access to the de-identified individual participant data (IPD) for eligible studies to aid qualified researchers in addressing legitimate scientific objectives (Takeda's data sharing commitment is available on https://clinicaltrials.takeda.com/takedas-commitment?commitment=5). These IPDs will be provided in a secure research environment following approval of a data sharing request, and under the terms of a data sharing agreement.
IPD Sharing Access Criteria
IPD from eligible studies will be shared with qualified researchers according to the criteria and process described on https://vivli.org/ourmember/takeda/. For approved requests, the researchers will be provided access to anonymized data (to respect patient privacy in line with applicable laws and regulations) and with information necessary to address the research objectives under the terms of a data sharing agreement.
IPD Sharing URL
https://vivli.org/ourmember/takeda/
Citations:
PubMed Identifier
33067633
Citation
Konkle BA, Walsh CE, Escobar MA, Josephson NC, Young G, von Drygalski A, McPhee SWJ, Samulski RJ, Bilic I, de la Rosa M, Reipert BM, Rottensteiner H, Scheiflinger F, Chapin JC, Ewenstein B, Monahan PE. BAX 335 hemophilia B gene therapy clinical trial results: potential impact of CpG sequences on gene expression. Blood. 2021 Feb 11;137(6):763-774. doi: 10.1182/blood.2019004625.
Results Reference
derived
PubMed Identifier
30003118
Citation
Weber A, Engelmaier A, Voelkel D, Pachlinger R, Scheiflinger F, Monahan PE, Rottensteiner H. Development of Methods for the Selective Measurement of the Single Amino Acid Exchange Variant Coagulation Factor IX Padua. Mol Ther Methods Clin Dev. 2018 Jun 28;10:29-37. doi: 10.1016/j.omtm.2018.05.004. eCollection 2018 Sep 21.
Results Reference
derived

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

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