Evaluation of Triheptanoin Versus Even-Chain Medium-Chain Triglycerides on Major Clinical Events in Pediatric Long-Chain Fatty Acid Oxidation Disorders

Trial ID: 2023-509809-76-00
Protocol: UX007-CL302
Sponsor: Ultragenyx Pharmaceutical Inc.

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Diseases & Conditions

Fatty acid oxidation disorder

Objectives

The primary objective of this study is to evaluate the effect of **triheptanoin** compared to medium-chain triglycerides (MCT) on the frequency of major clinical events (MCEs) in pediatric patients with long-chain fatty acid oxidation disorders (LC-FAOD). This is clinically relevant as MCEs, which include rhabdomyolysis, cardiomyopathy, and hypoglycemia, significantly impact the health and quality of life of patients with LC-FAOD. Reducing the frequency of these events could lead to improved patient outcomes and reduced healthcare burden.

Secondary objectives include:

Evaluating the effect of triheptanoin versus MCT on reducing the duration of MCEs.
Assessing the reduction in the frequency of hypoglycemic events captured as MCEs and/or hypoglycemic clinical events (HCEs).
Evaluating clinician-reported changes in overall health status and functioning.
Assessing the effect on liver fat fraction and cardiac structure and function.
Determining the contribution of each component MCE to the composite MCE primary endpoint.
Evaluating the effect on physical health, psychosocial health, and total health-related quality of life (HRQoL).
Assessing the effect on all-cause mortality.

Participants

The clinical trial involves a total of **30 participants** diagnosed with **Long-chain Fatty Acid Oxidation Disorders (LC-FAOD)**. The study population includes both **males and females** ranging from **newborns to under 18 years of age**. Participants were selected based on a confirmed diagnosis of LC-FAOD, which includes conditions such as carnitine palmitoyl transferase (CPT) I deficiency, CPT II deficiency, carnitine/acylcarnitine translocase (CACT) deficiency, very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency, long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency, or mitochondrial trifunctional protein (TFP) deficiency. The trial population is considered vulnerable, and participants must have a caregiver willing to assist with study requirements. Lifestyle considerations such as diet and physical activity are not specified, but participants must comply with study instructions and requirements. The trial does not specify any particular health status beyond the inclusion of individuals with significant clinical manifestations of LC-FAOD.

Plans and Procedures

The clinical trial is designed as a **randomized, double-blind, controlled** study to evaluate the effect of **triheptanoin** compared to even-chain, medium-chain triglycerides (MCT) on major clinical events (MCEs) in pediatric patients diagnosed with **Long-chain Fatty Acid Oxidation Disorders (LC-FAOD)**. The trial will span an estimated duration from February 2023 to June 2027. Participants will be randomly assigned to receive either triheptanoin or MCT, both administered as oral liquids. The primary endpoint is the annualized event rate of MCEs, with secondary endpoints including the duration of MCEs, hypoglycemic event rates, and various clinical and quality of life measures.

The study involves several key visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, confirmed diagnosis of LC-FAOD, and significant clinical manifestations of the disorder. Following randomization, participants will attend regular follow-up visits to monitor safety, efficacy, and adherence to the study protocol. The end-of-study visit will conclude the participant's involvement, assessing final outcomes and any adverse events. The expected length of participant involvement is up to 24 months, with conditions for early termination including significant adverse events or non-compliance with study procedures.

Inclusion criteria require participants to have a confirmed diagnosis of LC-FAOD, be under 18 years of age, and have a caregiver and legally authorized representative to provide consent. Exclusion criteria are not explicitly detailed in the provided data. The trial aims to provide comprehensive data on the efficacy and safety of triheptanoin in managing LC-FAOD, contributing to the understanding of treatment options for this rare metabolic disorder.

Treatment

The clinical trial involves the administration of **Triheptanoin**, an experimental medication, to evaluate its effect on major clinical events in pediatric patients with long-chain fatty acid oxidation disorders. **Triheptanoin** is provided in an **oral liquid** pharmaceutical form and is administered via the **oral route**. The maximum daily dose is set at 35% percent, with a total maximum dose of 35% percent over a treatment period of 24 months. The medication is of chemical origin and is not a pediatric formulation. The product is identified by the sponsor product code **UX007** and is manufactured by Ultragenyx Pharmaceutical Inc. Compliance with the dosing schedule will be monitored throughout the study.

The comparator treatment in this study is a formulation of **Even-chain, Medium-chain Triglycerides** (MCT), which is also administered in an **oral form**. This treatment consists of a combination of active substances: **Glycerol**, **Doconexent**, **Icosapent**, and **DL-alpha-tocopherol**, all of which are of chemical origin. The pharmaceutical form is designated as **PHF00061MIG**, and the administration route is oral. The maximum daily and total dose for this treatment is also 35% percent, with a treatment duration of 24 months. The product will be newly packed and labeled specifically for the clinical trial. This comparator is classified as a dietary supplement and is not a pediatric formulation. Monitoring of participant compliance with the dosing regimen will be conducted to ensure adherence to the study protocol.

Efficacy

Efficacy in this clinical trial will be assessed by evaluating the effect of **triheptanoin** compared to even-chain, medium-chain triglycerides (MCT) on the frequency of major clinical events (MCEs) in pediatric patients with long-chain fatty acid oxidation disorders (LC-FAOD). The primary endpoint for efficacy evaluation is the annualized event rate of MCEs. Secondary endpoints include the annualized duration of MCEs, annualized hypoglycemic event-rate captured as MCEs and hypoglycemic clinical events (HCEs), and changes in scores on the Caregiver-reported PedsQL 4.0 Generic Core Scale or PedsQL Infant Scale, depending on the age of the participants. Additional secondary endpoints involve cardiac function parameters such as left ventricular ejection fraction, left ventricular systolic volume, and left ventricular wall mass, as well as the annualized frequency and duration of rhabdomyolysis-MCEs and cardiomyopathy-MCEs.

Measurements will be collected at various timepoints throughout the study, including baseline and subsequent intervals, to assess changes over time. The trial will utilize validated scales and laboratory tests to gather data on these endpoints. For instance, the PedsQL scales will be used to evaluate quality of life, while cardiac function will be assessed through imaging techniques. Plasma concentration levels of heptanoate and betahydroxypentanoate (BHP) will also be measured to provide additional insights into the pharmacokinetics of the treatment. The study is designed to ensure comprehensive data collection and analysis to determine the efficacy of triheptanoin in reducing the frequency and severity of MCEs in the target population.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Confirmed diagnosis of LC-FAOD: carnitine palmitoyl transferase (CPT) I deficiency, CPT II deficiency, carnitine/acylcarnitine translocase (CACT) deficiency, very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency, long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency, or mitochondrial trifunctional protein (TFP) deficiency. Diagnosis must be confirmed by results of acylcarnitine profiles, fatty acid oxidation probe studies in cultured fibroblasts, or mutation analysis obtained from medical records
Males and females, from 0 (including newborns) to < 18 years of age at time of randomination
Have a caregiver(s) willing and able to assist in all applicable study requirements
Have a legally authorized representative willing and able to provide written informed consent after the nature of the study has been explained and prior to any research-related procedures, and the study subject to be able to provide age-appropriate written assent
Have ANY ONE of the following significant clinical manifestations of LC-FAOD: - At least 2 in the prior year, or 3 in the prior 2 years, of severe major episodes of metabolic decompensation (eg, hypoglycemia, rhabdomyolysis, or exacerbation of cardiomyopathy, requiring ER/urgent care unit visits or hospitalizations) - Recurrent symptomatic hypoglycemia (clinical symptoms of hypoglycemia) requiring intervention - Susceptibility to hypoglycemia after short periods of fasting (less than 4 to 12 hours, depending on age) - Evidence of functional cardiomyopathy requiring ongoing medical management or clinical manifestation of heart failure - Sibling(s) with the same pathogenic variant who presented with MCEs - Subject with pathogenic variants that are known or suspected to be associated with absent or severely reduced enzyme activity or with severe disease manifestations.
From the time of informed consent to 5 days after the last dose of study drug in this study, females of childbearing potential and fertile males must consent to use highly effective methods of contraception as described in Appendix 2. If female, agree not to become pregnant. If male, agree not to father a child or donate sperm. Inclusion Criteria for Liver Sub-study: 1. Enrollment in the Main Study of Study UX007-CL302 2. Age > 2 years 3. Liver fat content ≥ 2% and < 20% PDFF as assessed by 1H-MRS 4. Body mass index < 95th percentile 5. Able to comply with instructions (remaining still during scan) and requirements (eg, constraints on recent meals, no metallic items or implanted devices in the body, no recent contrast agents) for liver HMRS scan

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Exclusion Criteria

Enrolled in a clinical study involving concurrent use of an investigational drug product within 30 days before Screening 2. Use of a prohibited medication (eg, valproate products or pancreatic lipase inhibitors) within 30 days before Screening, or unwilling to avoid a prohibited medication or other substance that may confound study objectives 3. Treatment with triheptanoin within 60 days of Screening 4. History of known hypersensitivity to triheptanoin or MCT or its excipients that, in the judgment of the Investigator, places the subject at increased risk for adverse effects 5. Caregiver unwilling or unable to sign informed consent, or release of medical records, or follow study procedures 6. Have any comorbid conditions, including unstable major organsystem disease(s) that in the opinion of the Investigator places the subject at increased risk of complications, interferes with study participation or compliance, or confounds study objectives or interpretation of results. History of metabolic decompensation(s) with metabolic acidosis, hyperammonemia, and/or liver enzyme elevations does not constitute an exclusion criterion unless in the opinion of the Investigator places the subject at increased risk of complications, interferes with study participation or compliance, or confounds study objectives or interpretation of results. 7. Have a diagnosis of pancreatic insufficiency 8. Pregnant, breastfeeding, or planning to become pregnant (self or partner) at any time during the study. Exclusion Criteria for Liver Sub-study 1. Acute or chronic liver disease other than LC-FAOD that presents with increased risk of liver fat (eg, hepatic cirrhosis, viral toxic or drug hepatitis, diabetes mellitus) and/or metabolic syndrome 2. Need for anesthesia/sedation to perform liver H-MRS