Clinical trial NCT02618915: Safety and Dose Finding Study of DTX101 (AAVrh10FIX) in Adults With Moderate/Severe to Severe Hemophilia B
Official title: 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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
PHASE2
Conditions: Hemophilia B
Keywords: gene therapy
Hemophilia B
Lead sponsor: Ultragenyx Pharmaceutical Inc
Sponsor class: INDUSTRY
First posted: 2015-12-02
Enrollment: 6
Sex: MALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Number of Participants With Adverse Events (AEs), Treatment-Related Adverse Events (TEAEs), and Serious AEs (SAEs)
timeFrame: up to 52 weeks after dosing (Cohort 1) or 44 weeks after dosing (Cohort 2)
measure: Change From Baseline in FIX Activity at Week 6
timeFrame: Baseline, Week 6
Secondary outcomes:
measure: Annualized Bleeding Rate
timeFrame: Week 0 to Week 52
measure: Change From Baseline in FIX Activity Over Time
timeFrame: 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
measure: Annualized FIX Replacement Therapy
timeFrame: Week 0 to Week 52
measure: Number of Participants With Neutralizing Antibodies to FIX (FIX Inhibitors)
timeFrame: Day 0 (predose), Weeks 6, 8, 16, 32, 40, End of Study (Week 52 for Cohort 1, Week 44 for Cohort 2)/Early Withdrawal
measure: Number of Participants With Cell-Mediated Immune Response to FIX
timeFrame: 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
measure: Number of Participants Responding to the EuroQoL-5D-5 Level (EQ-5D-5L) Questionnaire
timeFrame: Baseline (Day 0 predose), Weeks 24, 36, 48, End of Study/Early Withdrawal (up to Week 52)
measure: Number of Participants Responding to the Haemophilia-Specific Quality of Life Questionnaire
timeFrame: Baseline (Day 0 predose), Weeks 24, 36, 48, End of Study/Early Withdrawal (up to Week 52)
measure: Average Weekly Use of FIX Replacement Therapy
timeFrame: Baseline (Screening), Week 0 through Week 52
Other outcomes:
Locations:
city: Little Rock
country: United States
facility: Arkansas Children's Hospital
state: Arkansas
city: Los Angeles
country: United States
facility: Orthopaedic Institute for Children
state: California
city: Gainesville
country: United States
facility: University of Florida
state: Florida
city: Boston
country: United States
facility: Boston Children's Hospital
state: Massachusetts
city: Ann Arbor
country: United States
facility: University of Michigan Hospital and Health Systems, Michigan Clinical Research Unit
state: Michigan
city: Nashville
country: United States
facility: Vanderbilt Hemostasis-Thrombosis Clinic
state: Tennessee
city: Sofia
country: Bulgaria
facility: Specialized Hospital for Active Treatment for Hematological Disease
city: Basingstoke
country: United Kingdom
facility: Basingstoke and North Hampshire Hospital, Haemophilia, Haemostasis and Thrombosis Centre
state: Hampshire
city: Manchester
country: United Kingdom
facility: The Christie NHS Foundation Trust
Study officials:
affiliation: Ultragenyx Pharmaceutical Inc
name: Medical Director
role: STUDY_DIRECTOR
References: