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.
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
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
6
solution for IV infusion
Arkansas Children's Hospital
Little Rock, Arkansas, United States
Orthopaedic Institute for Children
Los Angeles, California, United States
University of Florida
Gainesville, Florida, United States
Number of Participants With Adverse Events (AEs), Treatment-Related Adverse Events (TEAEs), and Serious AEs (SAEs)
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.
Time frame: up to 52 weeks after dosing (Cohort 1) or 44 weeks after dosing (Cohort 2)
Change From Baseline in FIX Activity at 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.
Time frame: Baseline, Week 6
Annualized Bleeding Rate
The number of bleeding episodes per participant was recorded, and the annualized number of bleeding episodes was calculated.
Time frame: Week 0 to Week 52
Change From Baseline in FIX Activity Over Time
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.
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
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Boston Children's Hospital
Boston, Massachusetts, United States
University of Michigan Hospital and Health Systems, Michigan Clinical Research Unit
Ann Arbor, Michigan, United States
Vanderbilt Hemostasis-Thrombosis Clinic
Nashville, Tennessee, United States
Specialized Hospital for Active Treatment for Hematological Disease
Sofia, Bulgaria
Basingstoke and North Hampshire Hospital, Haemophilia, Haemostasis and Thrombosis Centre
Basingstoke, Hampshire, United Kingdom
The Christie NHS Foundation Trust
Manchester, United Kingdom
Annualized FIX Replacement Therapy
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.
Time frame: Week 0 to Week 52
Number of Participants With Neutralizing Antibodies to FIX (FIX Inhibitors)
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.
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
Number of Participants With Cell-Mediated Immune Response to FIX
The development of a cell-mediated immune response to FIX, as determined by enzyme-linked immunospot assay (ELISPOT).
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
Number of Participants Responding to the EuroQoL-5D-5 Level (EQ-5D-5L) Questionnaire
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).
Time frame: Baseline (Day 0 predose), Weeks 24, 36, 48, End of Study/Early Withdrawal (up to Week 52)
Number of Participants Responding to the Haemophilia-Specific Quality of Life Questionnaire
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.
Time frame: Baseline (Day 0 predose), Weeks 24, 36, 48, End of Study/Early Withdrawal (up to Week 52)
Average Weekly Use of FIX Replacement Therapy
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.
Time frame: Baseline (Screening), Week 0 through Week 52