Halting Ornithine Transcarbamylase Deficiency With Recombinant AAV in ChildrEn

NCT05092685 | Recruiting Phase 1 DMC

• 1 other identifier: 18/0123
• Study Type: interventional
• Target: 12
• Locations: 1 country
• Sites: 1

Brief Summary

Ornithine transcarbamylase deficiency (OTCD) is an inherited metabolic liver disease which means that the body cannot maintain normal levels of ammonia. Ammonia levels can rise (called hyperammonaemic decompensations) which can be life-threatening and may result in impaired neurological development in children. OTCD is a rare genetic disorder characterised by complete or partial lack of the enzyme ornithine transcarbamylase (OTC).

Conditions

Ornithine Transcarbamylase Deficiency

Outcome Measures

Primary Outcomes (1)

• Safety - adverse events

  Incidence of adverse events (AEs), treatment-related adverse events and serious adverse events (SAEs) for each dosing group assessed by severity and relationship to study product.

  12 months post-infusion

Secondary Outcomes (11)

• Safety outcomes

  Over 12 months post-infusion

• Safety outcomes

  Over 12 months post-infusion

• Safety outcomes

  Over 12 months post-infusion

• Safety outcomes

  Over 12 months post-infusion

• Efficacy outcomes

  Over 12 months post-infusion

Other Outcomes (9)

• Exploratory outcomes

  Over 12 months post-infusion

• Exploratory outcomes

  Over 12 months post-infusion

• Exploratory outcomes

  Over 12 months post-infusion

Study Arms (1)

AAVLK03hOTC (also known as ssAAV-LK03.hAAT.hcoOTC)

EXPERIMENTAL

Dose escalation in three groups from 6x10\^11vg/kg (low dose), 2x10\^12vg/kg (intermediate dose) to 6x10\^12vg/kg (high dose). Dose expansion in a fourth group with the best acceptable safety:efficacy ratio

Genetic: AAVLK03hOTC

Interventions

AAVLK03hOTC GENETIC

Peripheral intravenous infusion of AAVLK03hOTC.

Also known as: Also known as ssAAV-LK03.hAAT.hcoOTC

AAVLK03hOTC (also known as ssAAV-LK03.hAAT.hcoOTC)

Eligibility Criteria

• Age: 0 Days - 16 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• Patient (male or female) aged ≤16 years at time of written informed consent. For the dose escalation phase patients must be aged 6-16, for the dose expansion phase patients must be aged 0-16 (at the time of written informed consent).
• OTC deficiency confirmed via enzymatic or molecular analysis. This may include identification of pathogenic mutations or liver OTC activity that is \<20% of normal activity.
• Patient has severe disease defined by reduced protein allowance and prescribed at least one ammonia scavenger drug.
• Patient (if capable of signing) and parents or legal representative have signed a written informed consent form.
• Females of childbearing potential must have a negative pregnancy test in serum or urine at the screening and Day 0 infusion visits, and use an adequate contraception method from the screening visit until 4 weeks after the first negative plasma sample monitoring vector genomes copies or the week 52 visit, whatever comes first.
• 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, whatever comes first.
• Patient's ammonia level at baseline visit (pre-gene therapy infusion) is \<100µmol/L and is within the range of historical ammonia levels obtained when the patient was clinically stable.
• Patient has been on a stable dose of ammonia scavenger and stable protein allowance for the last 4 weeks at the baseline visit.
• Patient is willing to commit to an additional 4 years of long-term safety follow-up.

You may not qualify if:

• Titres of the neutralising antibodies against AAV-LK03 \>1:5 serum dilution.
• 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.
• Evidence of severe unexplained liver disease including but not limited to liver malignancy, liver cirrhosis, or acute liver failure.
• Evidence of active hepatitis B or C virus (HBV and HCV respectively) documented by hepatitis B surface antigen (HBsAg) or HCV RNA positivity.
• Positive PCR for human immunodeficiency virus (HIV).
• Liver transplant including hepatocytes/cells infusion.
• Current participation in another clinical trial of an investigational medicinal product or medical device, or participation within previous 12 months.
• Patient has contraindication to immunosuppression.
• Active infection (bacterial or viral).
• Pregnant or breastfeeding females.
• Patients with any other significant condition or disability that, in the investigator opinion, may interfere with the patient's optimal participation in the study.

Sponsors & Collaborators

• University College, London: lead

Study Sites (1)

Great Ormond Street Hospital

London, WC1N 3JH, United Kingdom

RECRUITING

MeSH Terms

Conditions

Ornithine Carbamoyltransferase Deficiency Disease

Condition Hierarchy (Ancestors)

Urea Cycle Disorders, Inborn; Brain Diseases, Metabolic, Inborn; Brain Diseases, Metabolic; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Genetic Diseases, X-Linked; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Amino Acid Metabolism, Inborn Errors; Metabolism, Inborn Errors; Metabolic Diseases; Nutritional and Metabolic Diseases

Study Officials

• Federicco Mingozzi

  Genethon

  STUDY CHAIR

Central Study Contacts

Trial Manager

CONTACT

+44 (0) 20 7907 4669; cctu.horace@ucl.ac.uk

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 28, 2021
• First Posted: October 25, 2021
• Study Start: November 1, 2023
• Primary Completion (Estimated): June 30, 2026
• Study Completion (Estimated): June 30, 2027
• Last Updated: November 7, 2023

Record last verified: 2023-10

Locations

GB (1)