Ornithine Transcarbamylase DeficiencyPhase 1/2HORACENCT05092685
Halting Ornithine Transcarbamylase Deficiency With Recombinant AAV in ChildrEn
A Phase 1/2 study testing AAVLK03hOTC in people with Ornithine Transcarbamylase Deficiency, run by University College, London at 1 site in United Kingdom.
Trial 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. Read more about this study
- Who is it for?
- Ages 0 days to 16 years
- Conditions the study is for
- Ornithine Transcarbamylase Deficiency
- What is being tested?
- AAVLK03hOTC
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 12 participants
- Where
- 1 siteUnited Kingdom
- Study dates
- 1 Nov 2023to 30 Jun 2027
- Phase
- Phase 1/2
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 0 days to 16 years
- All sexes
- No healthy volunteers
- Child
Who may be able to join
- 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.
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- 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.
Who cannot join
- 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.
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- 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 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.
- Patients with any other significant condition or disability that, in the investigator opinion, may interfere with the patient's optimal participation in the study.
Trial locations and contacts
1 site in 1 country. Contact the study team or a site near you to ask about taking part.
United Kingdom1 site, 1 recruiting
- Recruiting
Great Ormond Street Hospital
London, WC1N 3JH
Anupam Chakrapani, Dr, Anupam.Chakrapani@gosh.nhs.uk
About this study
Official title: 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).
Read the 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.
- Conditions
- Ornithine Transcarbamylase Deficiency
- Being tested
- AAVLK03hOTC
- Medical subject headings
- Ornithine Carbamoyltransferase Deficiency Disease
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
AAVLK03hOTCGenetic
Also called Also known as ssAAV-LK03.hAAT.hcoOTC
Peripheral intravenous infusion of AAVLK03hOTC.
| Study group | Role | What they receive |
|---|---|---|
| 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 Receives: Genetic: AAVLK03hOTC |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 12 months post-infusion
Secondary outcomes (11)
Safety outcomes
- Change from baseline level of transaminases (AST and ALT).
Measured: Over 12 months post-infusion
Safety outcomes
Change from baseline level of humoral and cellular immune responses the AAV-LK03 capsid.
Measured: Over 12 months post-infusion
Safety outcomes
- Change from baseline level of cellular immune against hOTC.
Measured: Over 12 months post-infusion
Safety outcomes
- Viral shedding: plasma/saliva/urine/stool samples.
Measured: Over 12 months post-infusion
Efficacy outcomes
Clinical parameters
- Monitoring of number and frequency of hyperammonaemic episodes and hospitalisations
Measured: Over 12 months post-infusion
Efficacy outcomes
Clinical parameters
- Monitoring of daily protein allowance using the Nutritics food diary app
Measured: Over 12 months post-infusion
Efficacy outcomes
Clinical parameters
- Monitoring number of ammonia scavenger drugs.
Measured: Over 12 months post-infusion
Efficacy outcomes
Biological parameters
- Change from baseline levels of glutamine and glutamate.
Measured: Over 12 months post-infusion
Efficacy outcomes
Biological parameters
- Change from baseline levels of ammonaemia.
Measured: Over 12 months post-infusion
Efficacy outcomes
Biological parameters
- Change from baseline levels of urine orotic acid.
Measured: Over 12 months post-infusion
Efficacy outcomes
Functional parameters:
- Change from baseline rate of ureagenesis rate.
Measured: Over 12 months post-infusion
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted25 Oct 2021
- Study start1 Nov 2023
- Primary completion30 Jun 2026 (estimated)
- Study completion30 Jun 2027 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Ornithine Transcarbamylase DeficiencyStudies of the same condition, open and under way.
- More trials run by University College, LondonThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1/2
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 12 participants (estimated)
Sponsor and investigators
- Lead sponsor
- University College, London
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Federicco Mingozzi, Study chair, Genethon
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT05092685
- Sponsor's protocol ID
- 18/0123
- Acronym
- HORACE
- Status last verified
- Oct 2023
- First submitted
- 28 Sep 2021
- Last updated
- 7 Nov 2023
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Undecided: Written requests will be considered by the HORACE Trial Management Group.
Study at a glance
From the registry record, last updated by the sponsor on 7 Nov 2023. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Phase I/II Open Label, Multicentre Clinical Trial to Assess Safety and Efficacy of AAVLK03hOTC for Paediatric Patients With Ornithine Transcarbamylase Deficiency.
- ClinicalTrials.gov ID
- NCT05092685
- Acronym / sponsor ID
- HORACE / 18/0123
- Conditions
- Ornithine Transcarbamylase Deficiency
- Phase
- Phase 1/2
- Study type
- Interventional
- Recruitment status
- Recruiting
- Enrolment
- 12 participants (estimated)
- Lead sponsor
- University College, LondonUniversity, hospital or other
- Study start
- 1 Nov 2023 (actual)
- Primary completion
- 30 Jun 2026 (estimated)
- Study completion
- 30 Jun 2027 (estimated)
- First posted
- 25 Oct 2021 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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).
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 design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| AAVLK03hOTC (also known as ssAAV-LK03.hAAT.hcoOTC) | Experimental | Genetic: AAVLK03hOTCDose 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 |
Who may qualify
- Ages
- 0 days to 16 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child
Key inclusion criteria (9 listed)
- 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.
Key exclusion criteria (12 listed)
- 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).
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| AAVLK03hOTCAlso: Also known as ssAAV-LK03.hAAT.hcoOTCPeripheral intravenous infusion of AAVLK03hOTC. | Genetic | AAVLK03hOTC (also known as ssAAV-LK03.hAAT.hcoOTC) |
Primary outcome
Safety - adverse events
Time frame: 12 months post-infusion
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.
11 secondary outcomes
Safety outcomes
Time frame: Over 12 months post-infusion
Safety outcomes
Time frame: Over 12 months post-infusion
Safety outcomes
Time frame: Over 12 months post-infusion
Safety outcomes
Time frame: Over 12 months post-infusion
Efficacy outcomes
Time frame: Over 12 months post-infusion
Efficacy outcomes
Time frame: Over 12 months post-infusion
Efficacy outcomes
Time frame: Over 12 months post-infusion
Efficacy outcomes
Time frame: Over 12 months post-infusion
Efficacy outcomes
Time frame: Over 12 months post-infusion
Efficacy outcomes
Time frame: Over 12 months post-infusion
Efficacy outcomes
Time frame: Over 12 months post-infusion
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 7 Nov 2023.
- Individual participant dataSharing planned: Undecided. Written requests will be considered by the HORACE Trial Management Group.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part.
Federicco Mingozzi study chair
Genethon
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1/2 study testing AAVLK03hOTC in people with Ornithine Transcarbamylase Deficiency, run by University College, London at 1 site in United Kingdom.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 9 inclusion and 12 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: looking for participants now, as of the sponsor's last update on 7 Nov 2023. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United Kingdom. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this combined phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
Contact Trial Manager (+44 (0) 20 7907 4669, cctu.horace@ucl.ac.uk), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Safety - adverse events (time frame: 12 months post-infusion). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 7 Nov 2023.