Halting Ornithine Transcarbamylase Deficiency With Recombinant AAV in ChildrEn

Brief Title

Halting Ornithine Transcarbamylase Deficiency With Recombinant AAV in ChildrEn

Official Title

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

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).

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 Phase

Phase 1/Phase 2

Study Type


Primary Outcome

Safety - adverse events

Secondary Outcome

 Safety outcomes


Ornithine Transcarbamylase Deficiency



Study Arms / Comparison Groups

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


* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information

Recruitment Status


Estimated Enrollment


Start Date

February 1, 2022

Completion Date

June 30, 2028

Primary Completion Date

June 30, 2024

Eligibility Criteria

        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

          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.




N/A - 16 Years

Accepts Healthy Volunteers



, +44 (0) 20 7907 4669, [email protected]

Administrative Informations



Organization ID


Responsible Party


Study Sponsor

University College, London

Study Sponsor

, , 

Verification Date

October 2021