Late-onset Ornithine transcarbamylase (OTC) deficiency
Conditions
Interventions
We will treat the patient once with the study drug. It will be given as a
one-time infusion through the vein. The infusion will take approximately 30
minutes. The infusion cannot be reversed or undo
Sponsors
Ultragenyx Pharmaceutical Inc.
Eligibility
Age
12 Years to 64 Years
Inclusion criteria
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 by 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. Patient is currently receiving ammonia scavenger therapy and/or protein-restricted diet, is free from symptomatic hyperammonemia and has not required emergent active intervention for hyperammonemia within 4 weeks before screening/baseline. 6. Plasma 24-hour ammonia (AUC0-24) is = 4 weeks prior to screening. 8. 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. 9. 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 patient/caregiver reported outcome assessments. If a minor, must have a caregiver(s) willing and able to assist in all applicable study requirements. 10. 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 to not father a child or donate sperm.
Exclusion criteria
Exclusion criteria: Individuals who meet any of Exclusion Criteria 1 to 16 will not be eligible to participate in the study. Individuals who meet Exclusion Criteria 17 will not be eligible to undergo the URT: 1. Liver transplant, including hepatocyte cell therapy/transplant. 2. 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. 3. 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 (except if patient has a diagnosis of Gilbert's syndrome), alkaline phosphatase > 2.5 × ULN. NOTE: Any of the LFTs may be retested. 4. Estimated glomerular filtration rate = 18 years of age or the Schwartz bedside formula (Schwartz and Work, 2009) for patients 200 copies/mL, documented on 2 separate occasions, as measured by PCR. 7. Active infection (viral or bacterial). 8. Detectable pre-existing antibodies to the AAV8 capsid. 9. 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. 10. Any of the following that, in the judgment of the Investigator, places the patient at increased risk for adverse effects: • Known hypersensitivity to DTX301, its excipients, or its placebo • Known hypersensitivity to prednisolone, its excipients, or its placebo 11. Chronic use of inhibitors of urea synthesis (eg, valproic acid) or drugs that significantly affect renal clearance (eg, probenecid). 12. Presence or history of any condition that, in the view of the Investigator, would interfere with participation, pose undue risk, or confound interpretation of results, including but not limited to: • Underlying conditions that may require systemic corticosteroids if the condition worsens (eg, autoimmune disorders) • Patient in a catabolic state (eg, due to current infection), or in whom a catabolic state may be reasonably foreseeable (eg, due to planned procedures) • Patient is considered vulnerable by local regulations (eg, imprisoned or institutionalized) 13. Marked neurological deficit or compromise t
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| • Plasma ammonia as measured by 24-hour ammonia (AUC0 24) at Week 64 for all patients as assessed by the geometric mean ratio (Modified Intention-to-Treat [mITT], DTX301 vs Placebo, test for noninferiority) • Percentage of patients at Week 64 who have achieved complete response (mITT, DTX301 vs Placebo, test for superiority)a | — |
Secondary
| Measure | Time frame |
|---|---|
| • Percentage of patients at Week 64 who have achieved complete response, response, or no response (mITT, DTX301 vs Placebo, test for superiority)a • PGIC-Overall Change score (DTX301 vs Placebo) at Week 64 • Rate of HACs from baseline to Week 64 compared to the 15-month pre-enrollment period (DTX301 vs Placebo) • Change in plasma ammonia (AUC0 24) after 64 weeks of DTX301 exposure (comparison between those who had a reduction of baseline disease management vs not) • Change in plasma ammonia (AUC0-24) from baseline to Week 64 for all patients (DTX301 vs Placebo) • Incidence of TEAEs, TESAEs, treatment-related TEAEs, treatment-related TESAEs, and AESIs • Clinically significant changes in laboratory values, physical examination results, and vital sign measurements • Development of anti-OTC antibodies | — |
Countries
Netherlands
Outcome results
None listed