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Safety and Dose Finding Study of DTX101 (AAVrh10FIX) in Adults With Moderate/Severe to Severe Hemophilia B

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ClinicalTrials.gov Identifier: NCT02618915
Recruitment Status : Terminated (Sponsor decision; not due to any safety concerns related to DTX101.)
First Posted : December 2, 2015
Results First Posted : November 14, 2018
Last Update Posted : November 14, 2018
Sponsor:
Information provided by (Responsible Party):
Ultragenyx Pharmaceutical Inc

Tracking Information
First Submitted Date  ICMJE November 23, 2015
First Posted Date  ICMJE December 2, 2015
Results First Submitted Date  ICMJE October 16, 2018
Results First Posted Date  ICMJE November 14, 2018
Last Update Posted Date November 14, 2018
Actual Study Start Date  ICMJE December 16, 2015
Actual Primary Completion Date October 18, 2017   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: October 16, 2018)
  • Number of Participants With Adverse Events (AEs), Treatment-Related Adverse Events (TEAEs), and Serious AEs (SAEs) [ Time Frame: up to 52 weeks after dosing (Cohort 1) or 44 weeks after dosing (Cohort 2) ]
    An AE was defined as any untoward medical occurrence in a participant enrolled into this study (from the time the participant signed the informed consent form until his or her exit from the study), regardless of its causal relationship to study treatment. A TEAE was defined as any event not present before exposure to study product or any event already present that worsened in severity or increased in frequency after exposure to study product.
  • Change From Baseline in FIX Activity at Week 6 [ Time Frame: Baseline, Week 6 ]
    Peak plasma level of FIX after IV administration as determined by the activated partial thromboplastin time (aPTT) clot-based assay. Change from baseline: postbaseline value - baseline value. For the change from baseline, only participants with a value at both baseline visit and the specific postbaseline visit were included.
Original Primary Outcome Measures  ICMJE
 (submitted: November 30, 2015)
  • The incidence of treatment-related adverse events by dosing group [ Time Frame: 52 weeks ]
  • Change from baseline in FIX activity level [ Time Frame: 6 weeks ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: October 16, 2018)
  • Annualized Bleeding Rate [ Time Frame: Week 0 to Week 52 ]
    The number of bleeding episodes per participant was recorded, and the annualized number of bleeding episodes was calculated.
  • Change From Baseline in FIX Activity Over Time [ Time Frame: Baseline, Weeks 2, 4, 6, 8, 12, 16, 24, 32, 40, End of Study (Week 52 for Cohort 1, Week 44 for Cohort 2)/Early Withdrawal ]
    Peak plasma level of FIX after IV administration as determined by the aPTT clot-based assay. Change from baseline: postbaseline value - baseline value. For the change from baseline, only participants with a value at both baseline visit and the specific postbaseline visit were included. Participants were not required to stop prophylactic treatment with recombinant FIX until after Week 4 and may have been restarted on their prophylactic recombinant FIX treatment after Week 14.
  • Annualized FIX Replacement Therapy [ Time Frame: Week 0 to Week 52 ]
    The use of on-demand FIX replacement therapy was recorded by dose (IU/kg) administered, and the annualized use of FIX replacement therapy was calculated. Participants were not required to stop prophylactic treatment with recombinant FIX until after Week 4 and may have been restarted on their prophylactic recombinant FIX treatment after Week 14.
  • Number of Participants With Neutralizing Antibodies to FIX (FIX Inhibitors) [ Time Frame: Day 0 (predose), Weeks 6, 8, 16, 32, 40, End of Study (Week 52 for Cohort 1, Week 44 for Cohort 2)/Early Withdrawal ]
    The development of neutralizing antibodies to FIX (FIX inhibitors), as determined by a Bethesda assay. A value of < 0.3 inhibitor units was considered to be no neutralizing antibodies.
  • Number of Participants With Cell-Mediated Immune Response to FIX [ Time Frame: Day 0 (predose), Weeks 6, 8, 12, 16, 32, 40, 48, End of Study (Week 52 for Cohort 1, Week 44 for Cohort 2)/Early Withdrawal ]
    The development of a cell-mediated immune response to FIX, as determined by enzyme-linked immunospot assay (ELISPOT).
  • Number of Participants Responding to the EuroQoL-5D-5 Level (EQ-5D-5L) Questionnaire [ Time Frame: Baseline (Day 0 predose), Weeks 24, 36, 48, End of Study/Early Withdrawal (up to Week 52) ]
    EQ-5D-5L is a standardized, subject-rated instrument for use as a measure of health outcomes. The EQ 5D-5L includes 2 components: the EQ-5D-5L descriptive system and the EQ visual analogue scale (EQ-VAS). The EQ-5D-5L descriptive system provides a profile of the participant's health state in 5 dimensions (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression). For each dimension, the participant is instructed to indicate whether he or she has "no problems" (1), "some problems" (2), or "severe problems" (3).
  • Number of Participants Responding to the Haemophilia-Specific Quality of Life Questionnaire [ Time Frame: Baseline (Day 0 predose), Weeks 24, 36, 48, End of Study/Early Withdrawal (up to Week 52) ]
    The Haemophilia-Specific Quality of Life questionnaire asks subjects about their perceptions of their health and treatment. The questionnaire is divided into the following 10 dimensions: physical health, feelings, view of themselves, sports & leisure, work & school, dealing with hemophilia, treatment, future, family planning, and partnership & sexuality. Questions are based on a 5-point Likert-scale (1=never, 2=rarely, 3=sometimes, 4=often, 5=all the time). If the question does not apply to the subject, the "not applicable" response is allowed in 3 of the domains (sport & leisure, work & school, family planning). Positively worded items need to be re-coded and domains will be transformed ranging from 0 to 100; higher domain and total scores indicating a higher impairment of health-related quality of life.
  • Average Weekly Use of FIX Replacement Therapy [ Time Frame: Baseline (Screening), Week 0 through Week 52 ]
    The use of on-demand FIX replacement therapy was recorded by dose (IU/kg) administered and the average weekly use of FIX replacement therapy was calculated. Participants were not required to stop prophylactic treatment with recombinant FIX until after Week 4 and may have been restarted on their prophylactic recombinant FIX treatment after Week 14.
Original Secondary Outcome Measures  ICMJE
 (submitted: November 30, 2015)
Number of Bleeding Episodes requiring recombinant FIX infusion [ Time Frame: 52 weeks ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Safety and Dose Finding Study of DTX101 (AAVrh10FIX) in Adults With Moderate/Severe to Severe Hemophilia B
Official Title  ICMJE Phase I/II Open-Label Safety and Dose Finding Study of Adeno-Associated Virus (AAV) rh10-Mediated Gene Transfer of Human Factor IX in Adults With Moderate/Severe to Severe Hemophilia B
Brief Summary A Phase 1/2, open-label, dose-finding safety study of single ascending doses of DTX101 in adult males with moderate/severe to severe hemophilia B.
Detailed Description

Hemophilia B is an X-linked recessive genetic bleeding disorder caused by mutations in the factor IX (FIX) gene. FIX is produced in the liver and is critical for fibrin clot formation. Hemophilia B is characterized by frequent, spontaneous internal bleeding that can lead to chronic arthropathy (joint damage), intracranial hemorrhage, and even death. In patients with moderate/severe to severe hemophilia B, the majority of bleeding episodes occur in the joints and, if not treated, lead to debilitating damage and a decreased quality of life.

This study will evaluate the safety and efficacy of the adeno-associated virus (AAV) to deliver human factor IX (hFIX) gene, the healthy gene necessary to make FIX, to the liver where FIX is normally produced. This study will determine if AAVrh10 can produce clinically meaningful FIX levels in patients with moderately/severe or severe hemophilia B.

This study was previously posted by Dimension Therapeutics, which has been acquired by Ultragenyx in November 2017.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Hemophilia B
Intervention  ICMJE Genetic: DTX101
solution for IV infusion
Other Names:
  • non-replicating recombinant AAVrh10 encoding human FIX (hFIX)
  • AAVrh10FIX
Study Arms  ICMJE
  • Experimental: DTX101, Cohort 1
    a single peripheral intravenous (IV) infusion of 1.6 x 10^12 genome copies (GC)/kg DTX101
    Intervention: Genetic: DTX101
  • Experimental: DTX101, Cohort 2
    a single peripheral IV infusion of 5.0 x 10^12 GC/kg DTX101
    Intervention: Genetic: DTX101
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Terminated
Actual Enrollment  ICMJE
 (submitted: October 16, 2018)
6
Original Estimated Enrollment  ICMJE
 (submitted: November 30, 2015)
12
Actual Study Completion Date  ICMJE October 18, 2017
Actual Primary Completion Date October 18, 2017   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. Male ≥ 18 years of age.
  2. Moderate/severe or severe hemophilia B (baseline FIX activity ≤ 2% of normal or documented history of FIX activity ≤2%).
  3. At least 3 bleeding episodes per year that require on-demand treatment with FIX OR are treated with a prophylactic regimen of FIX.
  4. At least 100 days exposure history to FIX.
  5. No documented history of inhibitors (neutralizing antibodies) to exogenous FIX.
  6. No known allergic reaction to exogenous FIX or any component of DTX101.
  7. Willing to stop prophylactic treatment with recombinant FIX at specified time points during the study.

Exclusion Criteria:

  1. History of significant liver disease (ie, portal hypertension).
  2. Significant hepatic inflammation or cirrhosis.
  3. Evidence of active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection.
  4. History of human immunodeficiency virus (HIV) infection AND any of the following: CD4+ cell count < 350 cells/mm^3, change in antiretroviral therapy regimen within 6 months prior to Day 0, or plasma viral load > 200 copies/mL, on 2 separate occasions, as measured by polymerase chain reaction.
  5. Anti-AAVrh10 neutralizing antibody titer > 1:5.
  6. Participation (current or previous) in another gene therapy study.
  7. Participation in another investigational medicine study within 3 months before screening.

NOTE: Other protocol defined inclusion/exclusion criteria may apply.

Sex/Gender  ICMJE
Sexes Eligible for Study: Male
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Bulgaria,   United Kingdom,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02618915
Other Study ID Numbers  ICMJE 101HEMB01
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Ultragenyx Pharmaceutical Inc
Study Sponsor  ICMJE Ultragenyx Pharmaceutical Inc
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Medical Director Ultragenyx Pharmaceutical Inc
PRS Account Ultragenyx Pharmaceutical Inc
Verification Date October 2018

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP