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

Study Overview
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Brief Summary
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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
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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.

Official Title
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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

Conditions
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Hemophilia B

Intervention / Treatment
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* Genetic: DTX101


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male ≥ 18 years of age. Moderate/severe or severe hemophilia B (baseline FIX activity ≤ 2% of normal or documented history of FIX activity ≤2%). At least 3 bleeding episodes per year that require on-demand treatment with FIX OR are treated with a prophylactic regimen of FIX. At least 100 days exposure history to FIX. No documented history of inhibitors (neutralizing antibodies) to exogenous FIX. No known allergic reaction to exogenous FIX or any component of DTX101. Willing to stop prophylactic treatment with recombinant FIX at specified time points during the study. Exclusion Criteria: History of significant liver disease (ie, portal hypertension). Significant hepatic inflammation or cirrhosis. Evidence of active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection. 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. Anti-AAVrh10 neutralizing antibody titer > 1:5. Participation (current or previous) in another gene therapy study. Participation in another investigational medicine study within 3 months before screening. NOTE: Other protocol defined inclusion/exclusion criteria may apply.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: DTX101, Cohort 1<br>a single peripheral intravenous (IV) infusion of 1.6 x 10^12 genome copies (GC)/kg DTX101 | Genetic: DTX101<br>* solution for IV infusion<br>* Other names: AAVrh10FIX;|
| Experimental: DTX101, Cohort 2<br>a single peripheral IV infusion of 5.0 x 10^12 GC/kg DTX101 | Genetic: DTX101<br>* solution for IV infusion<br>* Other names: AAVrh10FIX;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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. | Baseline, Week 6 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Annualized Bleeding Rate | The number of bleeding episodes per participant was recorded, and the annualized number of bleeding episodes was calculated. | 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. | 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 | 
| 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. | 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. | 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). | 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). | 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. | 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. | Baseline (Screening), Week 0 through Week 52 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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gene therapy, Hemophilia B