Clinical Study of DTX301 AAV- Mediated Gene Transfer for Ornithine Transcarbamylase(OTC) Deficiency

Study Overview
=================
Brief Summary
-----------------
The primary objective is to evaluate the efficacy of DTX301 on the improvement of ornithine transcarbamylase (OTC) function by maintaining safe plasma ammonia levels with removal of dietary protein restriction and alternative pathway medication.

Detailed Description
-----------------
This study is a Phase 3, randomized, double-blind, placebo-controlled study of DTX301 in patients with late-onset OTC deficiency 12 years of age and older. Participants will be randomized 1:1 to DTX301 or placebo group and followed closely for 64 weeks. At week 64 eligible patients will crossover and receive DTX301 if they had previously received placebo or placebo if they had previously received DTX301. The planned study duration is up to 324 weeks. Upon completion of this study or early withdrawal, all participants who received DTX301 are invited to enroll in the Disease Monitoring Program (DMP) for follow-up for up to an additional 5 years.

Official Title
-----------------
A Phase 3, Randomized, Double-blind, Placebo-controlled Study of Adeno-associated Virus (AAV) Serotype 8 (AAV8)-Mediated Gene Transfer of Human Ornithine Transcarbamylase (OTC) in Patients With Late-onset OTC Deficiency

Conditions
-----------------
OTC Deficiency

Intervention / Treatment
-----------------
* Genetic: DTX301
* Other: Placebo
* Drug: Oral Corticosteroids
* Drug: Placebo for oral corticosteroids
* Drug: Sodium Acetate


Participation Criteria
=================
Eligibility Criteria
-----------------
Key Inclusion Criteria: Confirmed clinical diagnosis of late-onset OTC deficiency with historical documentation via enzymatic (ie, liver biopsy), biochemical (ie, hyperammonemia in the presence of elevated plasma glutamine, low citrulline, and elevated spot urine orotic acid), or molecular testing (ie, OTC analysis) Free from symptomatic hyperammonemia and has not required emergent active intervention for hyperammonemia within 4 weeks before screening/baseline Plasma spot ammonia level on Day 1 (predose) is ≤ 200 µmol/L If on ongoing daily ammonia scavenger therapy, must be at stable daily dose(s) for ≥ 4 weeks prior to screening If on a protein-restricted diet, must be on a stable total daily protein intake that does not vary more than 20% for ≥ 4 weeks prior to screening From the time written informed consent through Week 128, females of childbearing potential and fertile males must consent to use highly effective contraception. If female, agree not to become pregnant. If male, agree not father a child or donate sperm Key Exclusion Criteria: Significant hepatic inflammation or cirrhosis Estimated glomerular filtration rate < 60 mL/min/1.73 m2 at screening by the CKD EPI creatinine-based formula (Levey et al., 2009) for subjects ≥ 18 years of age or the Schwartz bedside formula (Schwartz and Work, 2009) for subjects < 18 years of age Evidence of active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection, documented by current use of antiviral therapy for HBV or HCV or by hepatitis B surface antigen (HBsAg) or HCV RNA positivity Active infection (viral or bacterial) Detectable pre-existing antibodies to the AAV8 capsid Presence or history of any condition that, in the view of the Investigator, would interfere with participation, pose undue risk, or would confound interpretation of results Participation (current or previous) in another gene transfer study Note: Additional inclusion/exclusion criteria may apply, per protocol

Ages Eligible for Study
-----------------
Minimum Age: 12 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: DTX301, Then Placebo<br>Participants receive single peripheral intravenous (IV) infusion of DTX301 in solution. At week 64, participants receive single peripheral IV infusion of placebo. | Genetic: DTX301<br>* non-replicating, self-complementary recombinant adeno-associated virus serotype 8 (AAV8) vector<br>* Other names: avalotcagene ontaparvovec;Other: Placebo<br>* normal saline infusion<br>Drug: Oral Corticosteroids<br>* Participants who receive DTX301 solution will receive oral corticosteroids.<br>* Other names: Prednisolone;Drug: Placebo for oral corticosteroids<br>* Participants who receive Placebo will receive placebo corticosteroids to maintain the study blind<br>Drug: Sodium Acetate<br>* A tracer for the Ureagenesis Rate Test (URT)<br>|
| Experimental: Placebo, Then DTX301<br>Participants receive single peripheral IV infusion of placebo. At week 64, participants receive single peripheral IV infusion of DTX301 in solution. | Genetic: DTX301<br>* non-replicating, self-complementary recombinant adeno-associated virus serotype 8 (AAV8) vector<br>* Other names: avalotcagene ontaparvovec;Other: Placebo<br>* normal saline infusion<br>Drug: Oral Corticosteroids<br>* Participants who receive DTX301 solution will receive oral corticosteroids.<br>* Other names: Prednisolone;Drug: Placebo for oral corticosteroids<br>* Participants who receive Placebo will receive placebo corticosteroids to maintain the study blind<br>Drug: Sodium Acetate<br>* A tracer for the Ureagenesis Rate Test (URT)<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Who Have Achieved Complete Response (DTX301 vs Placebo) |  | Week 64 | 
| Plasma Ammonia as Measured by 24-hour Ammonia (AUC0-24) at Week 64 |  | Week 64 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Who Have Achieved Complete Response, Response, or No Response |  | Week 64 | 
| Change from Baseline to Week 64 in the Hyperammonemia Questionnaire |  | Baseline, Week 64 | 
| Change from Baseline to Week 64 in Cogstate Cognitive Assessment |  | Baseline, Week 64 | 
| Rate of Hyperammonemic Crises (HACs) from Baseline to Week 64 Compared to Pre-enrollment |  | Pre-enrollment, Baseline, Week 64 | 
| Change from Baseline in Plasma Ammonia (AUC0-24) After Reduction or Discontinuation of Baseline Disease Management For DTX301 Participants |  | Baseline, up to Week 64 | 
| Change in Plasma Ammonia (AUC0-24) From Baseline to Week 64 For All Participants |  | Baseline, Week 64 | 
| Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, Related TEAEs, Related Serious TEAEs and Adverse Events of Special Interest (AESIs) |  | Up to Week 324 | 
| Number of Participants With Clinically Significant Changes From Baseline in Laboratory Values, Physical Examination Results, and Vital Sign Measurements |  | Baseline, up to Week 324 | 
| Number of Participants With Anti-OTC Antibodies |  | Up to Week 324 |