Triheptanoin for Long-chain fatty acid oxidation disorders (LC-FAOD)

Inclusion criteria

• {"criterion_text":"- 1. 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\n- 2. Males and females, from 0 (including newborns) to < 18 years of age at time of randomination\n- 3. Have a caregiver(s) willing and able to assist in all applicable study requirements\n- 4. 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\n- 5. 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.\n- 6. 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"}

Exclusion criteria

• {"criterion_text":"- 1. Enrolled in a clinical study involving concurrent use of an investigational drug product within 30 days before Screening\n- 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\n- 3. Treatment with triheptanoin within 60 days of Screening\n- 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\n- 5. Caregiver unwilling or unable to sign informed consent, or release of medical records, or follow study procedures\n- 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.\n- 7. Have a diagnosis of pancreatic insufficiency\n- 8. Pregnant, breastfeeding, or planning to become pregnant (self or partner) at any time during the study.\n\nExclusion Criteria for Liver Sub-study\n- 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\n- 2. Need for anesthesia/sedation to perform liver H-MRS"}

Primary endpoints

• {"endpoint_text":"- Annualized event rate of MCEs","definition_or_measurement_approach":"Annualized event rate of major clinical events (MCEs) measured as frequency per year of MCEs (composite of rhabdomyolysis, cardiomyopathy, and hypoglycemia) as specified in protocol/objectives."}

Secondary endpoints

• {"endpoint_text":"- Annualized duration of MCEs","definition_or_measurement_approach":"Measured as annualized total duration (time) of MCEs per subject"}
• {"endpoint_text":"- Annualized hypoglycemic event-rate captured as MCEs and HCEs","definition_or_measurement_approach":"Annualized frequency of hypoglycemic events captured as MCEs and HCEs"}
• {"endpoint_text":"- CGI-C scale score","definition_or_measurement_approach":"Clinician Global Impression of Change (CGI-C) score as assessed by clinicians"}
• {"endpoint_text":"- Left ventricular ejection fraction, left ventricular systolic volume, and left ventricular wall mass","definition_or_measurement_approach":"Cardiac structure/function measures (echocardiography or imaging) including LVEF, LV systolic volume, LV wall mass"}
• {"endpoint_text":"- Annualized frequency and duration of rhabdomyolysis-MCEs","definition_or_measurement_approach":"Annualized count and duration of rhabdomyolysis-type MCEs"}
• {"endpoint_text":"- Annualized frequency and duration of cardiomyopathy-MCEs","definition_or_measurement_approach":"Annualized count and duration of cardiomyopathy-type MCEs"}
• {"endpoint_text":"- Annualized duration of hypoglycemic-MCEs","definition_or_measurement_approach":"Annualized duration of hypoglycemia-related MCEs"}
• {"endpoint_text":"- Change from baseline in scores for: Caregiver-reported PedsQL 4.0 Generic Core Scale (physical health summary, psychosocial health summary, and total scores) (2 years of age and older) OR PedsQL Infant Scale (physical health summary, psychosocial health summary, and total scores) (ages 1 to < 24 months)","definition_or_measurement_approach":"Change from baseline in caregiver-reported PedsQL (age-appropriate) scores"}
• {"endpoint_text":"- Survival time","definition_or_measurement_approach":"Time-to-event analysis for all-cause survival"}
• {"endpoint_text":"- Annualized hospitalization days","definition_or_measurement_approach":"Annualized number of days spent in hospital per subject"}
• {"endpoint_text":"- Number of missed school or learning opportunity days","definition_or_measurement_approach":"Count of days missed from school or learning opportunities"}
• {"endpoint_text":"- Frequency, severity, and relationship to study drug of TEAEs, serious TEAEs, and AESIs","definition_or_measurement_approach":"Standard safety reporting: incidence, severity and causality assessments of TEAEs, serious TEAEs and AESIs"}
• {"endpoint_text":"- Incidence of TEAEs and serious TEAEs leading to dose modifications, dose reductions, treatment interruptions, discontinuations from study drug, and discontinuations from the study","definition_or_measurement_approach":"Rates of TEAEs/serious TEAEs resulting in treatment changes or discontinuation"}
• {"endpoint_text":"- Plasma concentration levels of heptanoate and betahydroxypentanoate (BHP)","definition_or_measurement_approach":"Pharmacokinetic plasma concentration measurements of heptanoate and BHP"}
• {"endpoint_text":"- Acceptability and Palatability Survey scores of triheptanoin mixed with oral liquids","definition_or_measurement_approach":"Subject/caregiver-reported acceptability and palatability survey scores"}
• {"endpoint_text":"- Change from baseline to 6 months in hepatic PDFF%, assessed by 1HMRS in subjects enrolled in the Liver Substudy","definition_or_measurement_approach":"Change in hepatic proton density fat fraction (%) by 1H-MRS from baseline to 6 months"}

Methods

• Country-specific recruitment arrangements documents available (recruitment arrangements files listed for Poland, Germany, Spain, Czechia) – likely site-based recruitment through metabolic/congenital disease units (documents present but content not extracted)
• Direct-to-patient access of study drug (Marken LLP) – described in third-party duties as 'Direct to patient access of study drug'
• Patient travel support (Gray Consulting Inc.) – support for travel to study visits as described in third-party duties
• Central medical/scientific contact and trial recruitment email (Ultragenyx trial information group: trialrecruitment@ultragenyx.com)
• Local site recruitment via specialist clinics (sites listed include metabolic disease units and pediatric clinics) as implied by site lists

Spain

Latest Decision Or Authorization Date

28-05-2024

Number Of Sites

3

Number Of Participants

15

Germany

Latest Decision Or Authorization Date

13-06-2024

Number Of Sites

1

Number Of Participants

8

Czechia

Latest Decision Or Authorization Date

29-05-2024

Number Of Sites

1

Number Of Participants

7

Poland

Latest Decision Or Authorization Date

03-06-2024

Number Of Sites

2

Number Of Participants

10

Primary sponsor

Full Name

Ultragenyx Pharmaceutical Inc.

Organisation Type

Pharmaceutical company

Country Of Registered Address

United States

Contract research organisations

Name

PPD Development L.P.

Name

Almac Clinical Services Limited

Name

Bioclinica Inc.

Responsibilities

Medical image analysis, Central reader for the ECHO images; For liver sub study collecting and anonymizing the images

Name

Marken LLP

Responsibilities

Direct to patient access of study drug

Name

Labcorp Central Laboratory Services SARL

Responsibilities

PK sample storage and shipment

Third parties

• {"country":"United States","full_name":"Metabolon Inc.","duties_or_roles":"Pharmacokinetics (PK) Sample Analysis","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Bioclinica Inc.","duties_or_roles":"Medical image analysis, Central reader for the ECHO images; For liver sub study collecting and anonymizing the images","organisation_type":"Laboratory/Research/Testing facility"}
• {"country":"United States","full_name":"Oracle America Inc.","duties_or_roles":"","organisation_type":"Pharmaceutical company"}
• {"country":"United Kingdom (Northern Ireland)","full_name":"Almac Clinical Services Limited","duties_or_roles":"","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"PPD Development L.P.","duties_or_roles":"","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Marken LLP","duties_or_roles":"Direct to patient access of study drug","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Gray Consulting Inc.","duties_or_roles":"Patient Travel Support","organisation_type":"Pharmaceutical company"}
• {"country":"United Kingdom","full_name":"Primevigilance Limited","duties_or_roles":"","organisation_type":"Pharmaceutical company"}
• {"country":"Switzerland","full_name":"Labcorp Central Laboratory Services SARL","duties_or_roles":"Pharmacokinetics (PK) Sample storage and shipment","organisation_type":"Pharmaceutical company"}