Gene therapy for a rare disorder caused by an enzyme deficiency
- Conditions
- Ornithine transcarbamylase deficiencyNutritional, Metabolic, Endocrine
- Registration Number
- ISRCTN47106904
- Lead Sponsor
- niversity of London
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- Ongoing
- Sex
- All
- Target Recruitment
- 12
1. Patient (male or female) aged =16 years old at the time of written informed consent. For the dose escalation phase patients must be aged 6-16 years, for the dose expansion phase patients must be aged 0-16 years (at the time of written informed consent).
2. OTC deficiency confirmed via enzymatic or molecular analysis. This may include the identification of pathogenic mutations or liver OTC activity that is <20% of normal activity.
3. Patient has severe disease defined by reduced protein allowance and is prescribed at least one ammonia scavenger drug
4. Patient (if capable of signing) and parent or legal representative have signed a written informed consent form
5. Females of childbearing potential must have a negative pregnancy test in serum or urine at the screening and day 0 infusion visits, and use a highly effective contraception method from the screening visit until 4 weeks after the first negative plasma sample monitoring vector genomes copies or the week 52 visit, whichever comes first
6. Sexually active boys must use an adequate contraception method (abstinence or use of condom with spermicide) from at least 14 days prior to the infusion and until 4 weeks after the first negative plasma sample monitoring vector genomes copies or the week 52 visit, whichever comes first
7. Patient’s ammonia level at the baseline visit (pre-gene therapy infusion) is <100 ?mol/L and is within the range of historical ammonia levels obtained when the patient was clinically stable
8. Patient has been on a stable dose of ammonia scavenger and stable protein allowance for the last 4 weeks at the baseline visit
9. Patient is willing to commit to an additional 4 years of long-term safety follow-up on a separate trial following the first 52 weeks of the HORACE trial
1. Titres of the neutralising antibodies against AAV-LK03 >1:40 serum dilution
2. Significant hepatic inflammation as evidenced by the following laboratory abnormalities: alanine aminotransferase or aspartate aminotransferase or bilirubin >2 x upper limit of normal (ULN), alkaline phosphatase >3 x ULN
3. Evidence of severe unexplained liver disease (unexplained by OTC deficiency) including but not limited to liver malignancy, liver cirrhosis, or acute liver failure
4. Evidence of active hepatitis B or C virus (HBV and HCV respectively) documented by hepatitis B surface antigen (HBsAg) or HCV RNA positivity
5. Positive PCR for human immunodeficiency virus (HIV)
6. Liver transplant including hepatocytes/cells infusion
7. Current participation in another clinical trial of an investigational medicinal product or medical device, or participation within the previous 12 months
8. Patient has contraindications to sodium (1,2-13C2) acetate or immunosuppression including prednisolone
9. Active infection (bacterial or viral)
10. Pregnant or breastfeeding females
11. Patients with other serious underlying medical conditions including malignancy and severe (= grade 3) functional organ impairment (liver, kidney, respiratory) according to CTCAE v5.0. For neurological symptoms considered as sequelae of previous hyperammonaemic decompensation and which are considered stable (i.e. not evolving), a grade 3 will be acceptable. Grades 4 and 5 will preclude inclusion
12. Patients with any other significant condition or disability that, in the investigator's opinion, may interfere with the patient’s optimal participation in the study
Study & Design
- Study Type
- Interventional
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method
- Secondary Outcome Measures
Name Time Method