Late-onset Ornithine transcarbamylase (OTC) deficiency MedDRA version: 20.0 Level: LLT Classification code 10071107 Term: Ornithine transcarbamylase deficiency System Organ Class: 100000004850
Conditions
Interventions
Product Name: DTX301
Pharmaceutical Form: Concentrate for solution for infusion
INN or Proposed INN: avalotcagene ontaparvovec
CAS Number: 2227000-30-6
Current Sponsor code: DTX301
Concentration unit:
Sponsors
Ultragenyx Pharmaceutical Inc.
Eligibility
Sex/Gender
All
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 documentation via enzymatic, biochemical, or molecular testing. 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. Are the trial subjects under 18? yes Number of subjects for this age range: 12 F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 38 F.1.3 Elderly (>=65 years) no F.1.3.1 Number of subjects for this age range
Exclusion criteria
Exclusion criteria: Individuals who meet any of the following exclusion criteria will not be eligible to participate: 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. Serum creatinine > 2.0 mg/dL at screening. 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 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, due to planned procedures) • Subject is considered vulnerable by local regulations (eg, imprisoned or institutionalized) • Subject is unable to fast safely for 12 hours 14. Marked neurological deficit or compromise that, in the Investigator’s opinion, would interfere with the subject’s safety or ability to participate in the study. 15. Pregnant or breastfeeding or planning to become pregnant within 64 weeks after receiving DTX30
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: To evaluate the efficacy of DTX301 on the improvement of OTC function by maintaining safe plasma ammonia levels;Secondary Objective: - To evaluate the effect of DTX301 on ureagenesis - To evaluate the effect of DTX301 on the Hyperammonemia Indicator Questionnaire (HI-Q) - To evaluate the effect of DTX301 on executive and verbal function (Cogstate Cognitive Assessment) - To evaluate the effect of DTX301 on occurrence of HACs - To evaluate the effect of DTX301 on plasma ammonia over time - To evaluate the safety of DTX301 - To describe the immune response to OTC protein (anti-OTC antibodies) ;Primary end point(s): • Percentage of subjects at Week 64 who have achieved complete response, response, or no response (ITT, DTX301 vs Placebo, test for superiority) • Plasma ammonia as measured by 24-hour ammonia (AUC0-24) at Week 64 (ITT, DTX301 vs Placebo, test for non-inferiority);Timepoint(s) of evaluation of this end point: Week 64 | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): • Change in ureagenesis: the comparison of mean change in ureagenesis (AUC0-4) from baseline to Week 64 between DTX301 and Placebo treatment arms to assess the capacity to restore efficient function of the urea cycle (DTX301 vs Placebo, test for superiority). • Change from baseline to Week 64 in the HI-Q (DTX301 vs Placebo, test for superiority) • Change from baseline to Week 64 in Cogstate Cognitive Assessment (DTX301 vs Placebo) • Rate of HACs from baseline to Week 64 compared to the 15-month pre-enrollment period (DTX301 vs Placebo) • Maintenance or reduction of plasma ammonia (AUC0-24) after reduction or discontinuation of baseline disease management (Baseline vs post reduction/discontinuation for subjects who reduce or discontinue baseline disease management after DTX301) • Change in plasma ammonia (AUC0-24) from baseline to Week 64 for all subjects (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;Timepoint(s) of evaluation of this end point: Week 64 | — |
Countries
Argentina, Australia, Brazil, Canada, Croatia, France, Germany, Italy, Japan, Netherlands, Portugal, Spain, United Kingdom, United States
Contacts
Public ContactGene Therapy Regulatory Affairs
Ultragenyx Pharmaceutical, Inc.
Outcome results
None listed