Clinical trial NCT05933200: A Study to Determine the Effect of Triheptanoin Compared With Even-Chain MCT on MCEs in Pediatric Patients With LC-FAOD
Official title: 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)
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Long-chain Fatty Acid Oxidation Disorders (LC-FAOD)
Keywords: 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
Lead sponsor: Ultragenyx Pharmaceutical Inc
Sponsor class: INDUSTRY
First posted: 2023-07-06
Enrollment: 60
Sex: ALL
Maximum age (years): 17
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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: Participants will be randomly assigned 1:1 to receive triheptanoin or MCT oil. The duration of the study is estimated to be 3.5 to 4 years. The study comprises the following: Screening Period, Baseline (Month 0), Double-blind Treatment Period (including Titration and End of Study Visit), Safety Follow-up Phone Visit, and an Open Access Period.

In addition, a substudy will examine the effect of triheptanoin versus MCT on decreasing liver fat fraction 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.

Eligibility criteria: Inclusion Criteria for Main Study:

* Males and females, from 0 (including newborns) to \< 18 years of age at time of randomization
* 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 period following informed consent to 5 days after the last dose of study drug, females of childbearing potential and fertile males must consent to use highly effective contraception. If female, agree not to become pregnant. If male, agree not to 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 or its excipients that, in the judgement of the Investigator, places the subject at increased risk for adverse effects
* Caregiver unwilling or unable to sign informed consent, or release of medical records, or follow study procedures
* Have any comorbid 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 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.
* 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

Primary outcomes:
measure: Annualized Event Rate of Major Clinical Events (MCEs)
timeFrame: Up to Year 4
Secondary outcomes:
measure: Annualized Duration of MCEs
timeFrame: Up to Year 4
measure: Annualized Hypoglycemic Event-rate Captured as MCEs and At-home Clinical Events (HCEs)
timeFrame: Up to Year 4
measure: Clinical Global Impression of Change [CGI-C] Scale Score
timeFrame: Up to Year 4
measure: Change From Baseline in Left Ventricular Ejection Fraction
timeFrame: Baseline, Up to Year 1
measure: Change From Baseline in Left Ventricular Systolic Volume
timeFrame: Baseline, Up to Year 1
measure: Change From Baseline in Left Ventricular Wall Mass
timeFrame: Baseline, Up to Year 1
measure: 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)
timeFrame: Baseline, Month 6
measure: Annualized Frequency of Rhabdomyolysis-MCEs and Cardiomyopathy-MCEs
timeFrame: Up to Year 4
measure: Annualized Duration of Rhabdomyolysis-MCEs, Cardiomyopathy-MCEs, and Hypoglycemic-MCEs
timeFrame: Up to Year 4
measure: Change From Baseline in Caregiver-reported Pediatric Quality of Life Inventory (PedsQL) 4.0 Generic Core Scale Score for Participants 2 Years of Age or Older
timeFrame: Up to Year 4
measure: Change From Baseline in PedsQL Infant Scale Score for Participants Ages 1 to <24 Months
timeFrame: Up to Year 4
measure: Survival Time
timeFrame: Up to Year 4
measure: Annualized Hospitalization Days
timeFrame: Up to Year 4
measure: Number of Missed School or Learning Opportunity Days
timeFrame: Up to Year 4
measure: Number of Participants With Treatment-emergent Adverse Events (TEAEs), Serious TEAEs, and Adverse Events of Special Interest (AESIs)
timeFrame: Up to Year 4
measure: 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
timeFrame: Up to Year 4
measure: Plasma Concentration Levels of Heptanoate
timeFrame: Up to Year 1
measure: Plasma Concentration Levels of Beta Hydroxypentanoate (BHP)
timeFrame: Up to Year 1
measure: Acceptability and Palatability Survey Scores of Triheptanoin Mixed with Oral Liquids
timeFrame: Up to Year 1
Other outcomes:
Locations:
city: Prague
country: Czechia
facility: General University Hospital in Prague-GUH (Všeobecná fakultní nemocnice v Praze- VFN)
city: Freiburg
country: Germany
facility: Universitätsklinikum Freiburg
city: Bunkyo City
country: Japan
facility: Juntendo University Hospital
state: Tokyo
city: Minato City
country: Japan
facility: The Jikei University Hospital
state: Tokyo
city: Warszawa
country: Poland
facility: Instytut Pomnik-Centrum Zdrowia Dziecka
state: Mazowieckie
city: Gdańsk
country: Poland
facility: Gdańksi Uniwersytet Medyczny
state: Pomorskie
city: Riyadh
country: Saudi Arabia
facility: King Faisal Specialist Hospital & Research Centre
city: Barcelona
country: Spain
facility: Sant Joan de Deu Hospital (SJD)
state: Esplugues De Llobregat
city: A Coruña
country: Spain
facility: University Hospital Santiago de Compostela
city: Madrid
country: Spain
facility: University Hospital 12 de Octubre
city: Adana
country: Turkey
facility: Cukurova University
city: Ankara
country: Turkey
facility: Gazi University
city: Bornova-İzmir
country: Turkey
facility: Ege University
city: Istanbul
country: Turkey
facility: Istanbul Universitesi Istanbul Tip Fakultesi Hastanesi
city: Istanbul
country: Turkey
facility: Cerrahpasa Medical Faculty
Study officials:
affiliation: Ultragenyx Pharmaceutical Inc
name: Medical Director
role: STUDY_DIRECTOR
References: