A Phase 3 Randomized, Double-Blind, Placebo-Controlled Study of Adeno-Associated Virus Serotype 8 (AAV8)-Mediated Gene Transfer of Human Ornithine Transcarbamylase (OTC) in Patients with Late-Onset OTC Deficiency

Phase 3

Recruiting

Conditions: Late-onset Ornithine transcarbamylase (OTC) deficiency
10014699

Registration Number: NL-OMON54260

Lead Sponsor: ltragenyx Pharmaceutical Inc.

Brief Summary: Not available

Detailed Description: Not available

Recruitment & Eligibility

Status: Recruiting

Sex: Not specified

Target Recruitment: 4

Inclusion Criteria

Eligible individuals must meet all of the following criteria:
1. Male or female patient 12 years of age or older at the time of signed
informed consent.
2. Provide informed consent after the nature of the study has been explained,
and prior to any research-related procedures. If a minor, willing and able (if
possible) to provide assent and have a legally authorized representative
provide informed consent after the nature of the study has been explained, and
prior to any research-related procedures.
3. 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).
4. Documented history of >= 1 symptomatic hyperammonemia episode with ammonia
level >= 100 µmol/L for confirmation of clinical disease.
5. Subject is free from symptomatic hyperammonemia and has not required
emergent active intervention for hyperammonemia within 4 weeks before
screening/baseline.
6. Plasma spot ammonia level on Day 1 (predose) is <= 200 µmol/L. If the Day 1
(predose) ammonia level is inconsistent with the patient*s clinical status, the
ammonia level may be repeated to ensure accurate results.
7. Plasma 24-hour ammonia (AUC0-24) is <= 4800 µmol*h/L at screening. If the
ammonia AUC0-24 is inconsistent with the patient*s clinical status, the
assessment may be repeated to ensure accurate results.
8. If on ongoing daily ammonia scavenger therapy, must be at stable daily
dose(s) for >= 4 weeks prior to screening.
9. If on a protein-restricted diet, must be on a stable protein-restricted diet
as evidenced by a stable amount of total protein intake (ie, daily protein
intake in grams per day does not vary more than 20%) for >= 4 weeks prior to
screening.
10. Willing and able to comply with study procedures and requirements,
including periodic inpatient hospitalizations, frequent blood and urine
collections, blood collections over a 24-hour period, questionnaires, cognitive
assessments, and subject/caregiver reported outcomes. If a minor, must have a
caregiver(s) willing and able to assist in all applicable study requirements.
11. From the time written informed consent is provided through Week 128,
females of childbearing potential and fertile males must consent to use highly
effective contraception as defined by the United States Food and Drug
Administration (FDA) and Clinical Trial Facilitation Coordination Group (CTFG)
Recommendations Related to Contraception and Pregnancy in Clinical Trials. If
female, agree not to become pregnant. If male, agree not father a child or
donate sperm.

Exclusion Criteria

Individuals who meet any of Exclusion Criteria 1 to 17 will not be eligible to
participate in the study. Individuals who meet Exclusion Criteria 18:
1. At the Baseline Visit (Day 0), plasma ammonia level > 200 µmol/L OR signs
and symptoms of hyperammonemia needing emergent active intervention. If the
ammonia level is inconsistent with the patient*s clinical status, the ammonia
level may be repeated to ensure accurate results.
2. Liver transplant, including hepatocyte cell therapy/transplant.
3. History of liver disease as evidenced by any of the following: portal
hypertension, ascites, splenomegaly, esophageal varices, hepatic
encephalopathy, or a liver biopsy with evidence of stage 3 fibrosis.
4. Significant hepatic inflammation or cirrhosis as evidenced by imaging or any
of the following laboratory abnormalities: alanine aminotransferase (ALT) or
aspartate aminotransferase (AST) > 1.5 × ULN, total bilirubin > 1.5 × ULN,
alkaline phosphatase > 2.5 × ULN. NOTE: Any of the LFTs may be retested.
5. 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.
6. 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. NOTE: Patients with
a history of HCV infection must have documentation of 2 negative viral assays
by PCR, collected at least 6 months apart, to be considered negative for HCV.
Patients with a history of HCV infection who test positive for HCV RNA at
screening can be rescreened once, after they have been treated and have
documentation of at least 2 negative samples collected at least 6 months apart.
7. History of human immunodeficiency virus (HIV) infection AND any of the
following: CD4+ cell count < 350 cells/mm3, change in antiretroviral therapy
regimen within 6 months prior to Baseline (Day 0), or plasma viral load > 200
copies/mL, documented on 2 separate occasions, as measured by PCR.
8. Active infection (viral or bacterial).
9. Detectable pre-existing antibodies to the AAV8 capsid.
10. History of a malignancy for which the patient has received treatment in the
past 2 years except for prostate cancer treated with watchful waiting or
surgically removed nonmelanoma skin cancer.
11. Any of the following that, in the judgment of the Investigator, places the
subject at increased risk for adverse effects:
• Known hypersensitivity to DTX301, its excipients, or its placebo
• Known hypersensitivity to prednisolone, its excipients, or its placebo
12. Chronic use of inhibitors of urea synthesis (eg, valproic acid) or drugs
that significantly affect renal clearance (eg, probenecid).
13. 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, including but not limited to:
• Underlying conditions that may require systemic corticosteroids if the
condition worsens (eg, autoimmune disorders)
• Subjects in a catabolic state (eg, due to current infection), or in whom a
catabolic state may be reasonably foreseeable (eg, d

Study & Design

Study Type: Interventional

Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
<p>• Percentage of subjects at Week 64 who have achieved complete response (ITT,<br /><br>DTX301 vs Placebo, test for superiority)<br /><br>• Plasma ammonia as measured by 24-hour ammonia (AUC0 24) at Week 64 for all<br /><br>subjects as assessed by the geometric mean ratio (ITT, DTX301 vs Placebo, test<br /><br>for non-inferiority)</p><br>

Secondary Outcome Measures