Halting Ornithine Transcarbamylase Deficiency With Recombinant AAV in ChildrEn (HORACE)

Phase I/II Open Label, Multicentre Clinical Trial to Assess Safety and Efficacy of AAVLK03hOTC for Paediatric Patients With Ornithine Transcarbamylase Deficiency.

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).

Study Overview

• Status: Recruiting
• Conditions: Ornithine Transcarbamylase Deficiency
• Intervention / Treatment: Genetic: AAVLK03hOTC

Detailed Description

OTC is a key element of the urea cycle, which is how the liver breaks down and removes extra nitrogen from the body. For people with OTCD the extra nitrogen builds up in the form of excess ammonia (hyperammonemia) in the blood.

Ammonia is toxic and people with OTCD suffer 'hyperammonaemic decompensations' when ammonia levels in the blood rise too high. The symptoms of these hyperammonaemic decompensations include vomiting, impaired movement, and progressive lethargy. If left untreated these hyperammonaemic decompensations may result in life-threatening complications or coma. OTCD is managed with drugs that reduce the amount of ammonia in the blood (ammonia-scavenging drugs) and a low protein diet. However, sometimes hyperammonaemic decompensations still occur.

Liver transplants for people with OTCD can be life-saving but there may be a long wait for a suitable liver and neurological damage may occur before a liver transplant is possible.

The HORACE study is testing a new gene therapy (AAVLK03hOTC) which specifically targets the liver so that it can start making OTC. The investigators hope that a single injection of gene therapy for children with OTCD could help the liver work normally and reduce hyperammonaemic decompensations and their associated risks.

This gene-therapy treatment could serve as a 'bridge-to-transplant' where children could grow up in a metabolically stable condition until a liver transplant is possible. This could minimise longer-term neurological damage caused by hyperammonaemic decompensations.

• Study Type: Interventional
• Enrollment (Estimated): 12
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Trial Manager; Phone Number: +44 (0) 20 7907 4669; Email: cctu.horace@ucl.ac.uk

Study Locations

• United Kingdom
  • London, United Kingdom, WC1N 3JH
    • Recruiting
    • Great Ormond Street Hospital
    • Contact: Anupam Chakrapani, Dr; Email: Anupam.Chakrapani@gosh.nhs.uk

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 year to 14 years (Child)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. 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).
2. 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.
3. Patient has severe disease defined by reduced protein allowance and prescribed at least one ammonia scavenger drug.
4. Patient (if capable of signing) and parents 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 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.
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, whatever comes first.
7. 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.
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.

Exclusion criteria:

1. Titres of the neutralising antibodies against AAV-LK03 >1:5 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 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 previous 12 months.
8. Patient has contraindication to immunosuppression.
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 as stable (i.e. not evolving), a grade 3 will be acceptable. Grade 4 and 5 will preclude inclusion.
12. Patients with any other significant condition or disability that, in the investigator opinion, may interfere with the patient's optimal participation in the study.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: AAVLK03hOTC (also known as ssAAV-LK03.hAAT.hcoOTC); 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; Peripheral intravenous infusion of AAVLK03hOTC.; Other Names: Also known as ssAAV-LK03.hAAT.hcoOTC

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety outcomes	• Change from baseline level of transaminases (AST and ALT).	Over 12 months post-infusion
Safety outcomes	Change from baseline level of humoral and cellular immune responses the AAV-LK03 capsid.	Over 12 months post-infusion
Safety outcomes	• Change from baseline level of cellular immune against hOTC.	Over 12 months post-infusion
Safety outcomes	• Viral shedding: plasma/saliva/urine/stool samples.	Over 12 months post-infusion
Efficacy outcomes	Clinical parameters • Monitoring of number and frequency of hyperammonaemic episodes and hospitalisations	Over 12 months post-infusion
Efficacy outcomes	Clinical parameters • Monitoring number of ammonia scavenger drugs.	Over 12 months post-infusion
Efficacy outcomes	Biological parameters • Change from baseline levels of glutamine and glutamate.	Over 12 months post-infusion
Efficacy outcomes	Biological parameters • Change from baseline levels of ammonaemia.	Over 12 months post-infusion
Efficacy outcomes	Functional parameters: • Change from baseline rate of ureagenesis rate.	Over 12 months post-infusion
Efficacy outcomes	Clinical parameters • Monitoring of daily protein allowance using the Nutritics food diary app	Over 12 months post-infusion
Efficacy outcomes	Biological parameters • Change from baseline levels of urine orotic acid.	Over 12 months post-infusion

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Exploratory outcomes	• Change from baseline neurocognitive assessment, as measured by the Bayley - III for participants aged 6months to 3 years	Over 12 months post-infusion
Exploratory outcomes	• Change from baseline neurocognitive assessment as measured WPPSI-IV for participants aged 2 years 6 months to 7 years 7 months	Over 12 months post-infusion
Exploratory outcomes	• Change from baseline neurocognitive assessment as measured by the WISC-V for participants aged 6 years to 16 years and 11months	Over 12 months post-infusion
Exploratory outcomes	• Change from baseline behavioural assessment as measured by the Child Behaviour Checklist	Over 12 months post-infusion
Exploratory outcomes	• Change from baseline in adaptive functioning, as measured by the Vineland	Over 12 months post-infusion
Exploratory outcomes	Change in quality of life, as measured by the Paediatric Quality of Life inventory	Over 12 months post-infusion
Exploratory outcomes	Quantification of viral vector integration in hepatocytes, from liver samples	At 12 months post-infusion
Exploratory outcomes	• Assessment of OTC enzymatic activity	Over 12 months post-infusion
Exploratory outcomes	Assessment of vector genome copy numbers in liver samples	Over 12 months post-infusion

Collaborators and Investigators

• Sponsor: University College, London
• Investigators: Study Chair: Federicco Mingozzi, Genethon

Study record dates

Study Major Dates

• Study Start (Actual): November 1, 2023
• Primary Completion (Estimated): June 30, 2026
• Study Completion (Estimated): June 30, 2027

Study Registration Dates

• First Submitted: September 28, 2021
• First Submitted That Met QC Criteria: October 21, 2021
• First Posted (Actual): October 25, 2021

Study Record Updates

• Last Update Posted (Actual): November 7, 2023
• Last Update Submitted That Met QC Criteria: November 3, 2023
• Last Verified: October 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Metabolic Diseases; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Genetic Diseases, Inborn; Genetic Diseases, X-Linked; Metabolism, Inborn Errors; Brain Diseases, Metabolic; Brain Diseases, Metabolic, Inborn; Amino Acid Metabolism, Inborn Errors; Urea Cycle Disorders, Inborn; Ornithine Carbamoyltransferase Deficiency Disease
• Other Study ID Numbers: 18/0123

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED
• IPD Plan Description: Written requests will be considered by the HORACE Trial Management Group.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No