A Study to Determine the Effect of Triheptanoin Compared With Even-chain, MCT on MCEs in Pediatric Patients With LC-FAOD

Study Overview
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Brief Summary
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The main goal of this study is to evaluate the effects of triheptanoin versus Medium-chain Triglycerides (MCT) on frequency of Major Clinical Events (MCEs).

Detailed Description
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Participants will be randomly assigned 1:1 to receive triheptanoin or MCT oil. The duration of the study, which is estimated to be 3.5 to 4 years and comprises of the following: Screening Period, Baseline (Month 0), Double-blind Treatment Period (including Titration and End of Study Visit), and Safety Follow-up Phone Visit. In addition, a substudy will examine the effect of triheptanoin versus MCT on decreasing hepatic lipid content to avoid or improve steatosis in subjects with LC-FAOD. Participants older than 2 years of age at selected sites will be invited to screen for the Liver Substudy.

Official Title
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A Randomized, Double-blind, Multicenter Study to Determine the Effect of Triheptanoin Compared With Even-chain, Medium-chain Triglycerides (MCT) on Major Clinical Events (MCEs) in Pediatric Patients With Long-chain Fatty Acid Oxidation Disorders (LC-FAOD)

Conditions
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Long-chain Fatty Acid Oxidation Disorders (LC-FAOD)

Intervention / Treatment
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* Drug: Triheptanoin
* Dietary Supplement: MCT Oil


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria for Main Study: Males and females, from 0 (including newborns) to < 18 years of age Confirmed diagnosis of LC-FAOD 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 participant 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 Participant 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. If female, agree not to become pregnant. If male, agree not father a child or donate sperm Inclusion Criteria for Liver Substudy: Enrollment in the Main Study of Study UX007-CL302 Age > 2 years Liver fat content ≥ 2% and < 20% PDFF as assessed by 1 H-MRS Body mass index < 95th percentile 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 1 H-MRS scan Exclusion Criteria for Main Study: Enrolled in a clinical study involving concurrent use of an investigational drug product within 30 days before Screening 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 Treatment with triheptanoin within 60 days of Screening History of known hypersensitivity to triheptanoin or MCT Caregiver unwilling or unable to sign informed consent, or release of medical records, or follow study procedures Have any co-morbid conditions, including unstable major organ-system 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. 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 Have a diagnosis of pancreatic insufficiency Pregnant, breastfeeding, or planning to become pregnant (self or partner) at any time during the study Exclusion Criteria for Liver Substudy: 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 Need for anesthesia/sedation to perform liver 1 H-MRS

Ages Eligible for Study
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Maximum Age: 17 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Triheptanoin<br>Participants will be given prescriptions for Triheptanoin in mL/day, which will be divided into approximately 4 administrations per day, with precise instructions for administration. Triheptanoin will be titrated up to the first 6 weeks of the study. After titration, the dose is to remain stable for the remainder of the Double-blind Treatment Period. | Drug: Triheptanoin<br>* Liquid for oral (PO) or enteral feeding tube administration<br>* Other names: Dojolvi;|
| Active Comparator: MCT<br>Participants will be given prescriptions for MCT in mL/day, which will be divided into approximately 4 administrations per day, with precise instructions for administration. MCT will be titrated up to the first 6 weeks of the study. After titration, the dose is to remain stable for the remainder of the Double-blind Treatment Period. | Dietary Supplement: MCT Oil<br>* Liquid for oral (PO) or enteral feeding tube administration<br>* Other names: Medium-chain Triglyceride;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Annualized Event Rate of Major Clinical Events (MCEs) During the Double-blind Treatment Period |  | Up to Year 4 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Annualized Duration of MCEs During the Double-blind Treatment Period |  | Up to Year 4 | 
| Annualized Hypoglycemic Event-rate Captured as MCEs and/or At-home Clinical Events (HCEs) During the Double-blind Treatment Period |  | Up to Year 4 | 
| Clinician-reported Change in Global Impression of Disease Severity (Clinical Global Impression of Change [CGI-C] Scale) Score at End of Study (EOS) |  | Up to Year 4 | 
| Change From Baseline in Left Ventricular Ejection Fraction |  | Baseline, Up to Year 1 | 
| Change From Baseline in Left Ventricular Systolic Volume |  | Baseline, Up to Year 1 | 
| Change From Baseline in Left Ventricular Wall Mass |  | Baseline, Up to Year 1 | 
| Liver Substudy (Single Study Site Only): Change from Baseline to 6 Months in Hepatic Proton Density Fat Fraction (PDFF%), Assessed by 1H-Magnetic Resonance Spectroscopy (1H-MRS) |  | Baseline, Month 6 | 
| Liver Substudy (Single Study Site Only): Change From Baseline to 6 Months in Creatine Kinase/Alanine Aminotransferase (CK/ALT) |  | Baseline, Month 6 | 
| Liver Substudy (Single Study Site Only): Change From Baseline to 6 Months in Alanine Aminotransferase (ALT) |  | Baseline, Month 6 | 
| Liver Substudy (Single Study Site Only): Change From Baseline to 6 Months in Aspartate Aminotransferase (AST) |  | Baseline, Month 6 | 
| Annualized Frequency of Rhabdomyolysis and Cardiomyopathy-MCEs During the Double-blind Treatment Period |  | Up to Year 4 | 
| Annualized Duration of Rhabdomyolysis, Cardiomyopathy, and Hypoglycemic-MCEs During the Double-blind Treatment Period |  | Up to Year 4 | 
| Change From Baseline to EOS in Caregiver-reported Pediatric Quality of Life Inventory (PedsQL) 4.0 Generic Core Scale Score for Participants 2 Years of Age or Older |  | Up to Year 4 | 
| Change From Baseline to EOS in PedsQL Infant Scale Score for Participants Ages 1 to <24 Months |  | Up to Year 4 | 
| Survival Time During the Double-blind Treatment Period |  | Up to Year 4 | 
| Annualized Hospitalization Days During the Double-blind Treatment Period |  | Up to Year 4 | 
| Number of Missed School or Learning Opportunity Days During the Double-blind Treatment Period |  | Up to Year 4 | 
| Number of Participants With Treatment-emergent Adverse Events (TEAEs), Serious TEAEs, and Adverse Events of Special Interest (AESIs) |  | Up to Year 4 | 
| Number of Participants With TEAEs and Serious TEAEs Leading to Dose Modifications, Dose Reductions, Treatment Interruptions, Discontinuations From Study Drug, and Discontinuations From the Study |  | Up to Year 4 | 
| Plasma Concentration Levels of Heptanoate |  | Up to Year 1 | 
| Plasma Concentration Levels of Beta Hydroxypentanoate (BHP) |  | Up to Year 1 | 
| Acceptability and Palatability Survey Scores of Triheptanoin Mixed with Oral Liquids |  | Up to Year 1 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Carnitine Palmitoyl Transferase (CPT) I Deficiency, Carnitine Palmitoyl Transferase (CPT) II Deficiency, Carnitine/acylcarnitine Translocase (CACT) Deficiency, Very Long Chain Acyl-coenzyme A Dehydrogenase (VLCAD) Deficiency, Long-chain 3-hydroxyacyl-coenzyme A Dehydrogenase (LCHAD) Deficiency, Mitochondrial Trifunctional Protein (TFP) Deficiency