| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated | Long-chain Fatty Acid Oxidation Disorders (LC-FAOD)
| |
| E.1.1.1 | Medical condition in easily understood language | Long-chain Fatty Acid Oxidation Disorders (LC-FAOD)
| |
| E.1.1.2 | Therapeutic area | Diseases [C] - Nutritional and Metabolic Diseases [C18] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 | | E.1.2 | Level | PT | | E.1.2 | Classification code | 10077951 | | E.1.2 | Term | Fatty acid oxidation disorder | | E.1.2 | System Organ Class | 10010331 - Congenital, familial and genetic disorders | |
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial | | Evaluate the effect of triheptanoin versus MCT on frequency of MCEs | |
| E.2.2 | Secondary objectives of the trial | - Evaluate the effect of triheptanoin versus MCT on reducing the duration of MCEs
- Evaluate the effect of triheptanoin versus MCT on reducing the frequency of hypoglycemic events captured as MCEs and/or HCEs
- Evaluate the effect of triheptanoin versus MCT on clinician-reported change in overall health status and functioning
- Evaluate the effect of triheptanoin versus MCT on reducing the frequency of cardiomyopathy MCEs
- Evaluate the effect of triheptanoin versus MCT on hepatic lipids (Liver Substudy – Primary)
- Assess the contribution of each component MCE (rhabdomyolysis, cardiomyopathy, and hypoglycemia) to the composite MCE primary endpoint (which includes all 3 types of MCEs)
- Assess the effect of triheptanoin versus MCT on physical health, psychosocial health, and total HRQoL
- Evaluate the effect of triheptanoin versus MCT on all-cause mortality
(...) Additional Secondary objectives can be found in the protocol (section 6) | |
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives | A Liver sub-study will be conducted at selected sites with appropriate expertise, facilities, and equipment.
(...) details about this sub-study can be found in the protocol (section 7.1.2) | |
| E.3 | Principal inclusion criteria | 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, and 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
2. Males and females, from newborn to < 17 years of age
3. Have a caregiver(s) willing and able to assist in all applicable study requirements
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
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.
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 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 H-MRS scan | |
| E.4 | Principal exclusion criteria | 1. 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
5. Caregiver unwilling or unable to sign informed consent, or release of medical records, or follow study procedures
6. 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.
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 | |
| E.5 End points |
| E.5.1 | Primary end point(s) | | Annualized event rate of MCEs during the Double-blind Treatment Period | |
| E.5.1.1 | Timepoint(s) of evaluation of this end point | |
| E.5.2 | Secondary end point(s) | - Annualized duration of MCEs during the Double-blind
Treatment Period
- Annualized hypoglycemic event-rate captured as MCEs and/or HCEs during the Double-blind Treatment Period
- Clinician-reported change in global impression of
disease severity (Clinical Global Impression of Change [CGI-C] scale) score at EOS
- Annualized frequency of cardiomyopathy-MCEs during the Double-blind Treatment Period
- Change from baseline to 6 months in hepatic PDFF%,
assessed by 1H-MRS in subjects enrolled in the Liver Substudy
- Annualized frequency and duration of rhabdomyolysis-MCEs during the Double-blind Treatment Period
- Annualized frequency and duration of cardiomyopathy-MCEs during the Double-blind Treatment Period
- Annualized duration of hypoglycemic-MCEs during the Double-blind Treatment Period
- Change from baseline to EOS 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)
- Survival time during the Double-blind Treatment Period
- Change from baseline to 6 months in CK/ALT, ALT, AST in subjects enrolled in the Liver Substudy
- Annualized hospitalization days during the Double-blind Treatment Period
- Number of missed school or learning opportunity days during the Double-blind Treatment Period
- Frequency, severity, and relationship to study drug of TEAEs, serious TEAEs, and AESIs
- Incidence of TEAEs and serious TEAEs leading to dose modifications, dose reductions, treatment interruptions, discontinuations from study drug, and discontinuations from the study | |
| E.5.2.1 | Timepoint(s) of evaluation of this end point | |
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 | The trial involves single site in the Member State concerned | No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 6 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned | | Saudi Arabia | | Poland | | Spain | | Turkey | | United Kingdom | |
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 | Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial | | The end of the study is defined as when the last subject enrolled has completed 2 years of treatment. | |
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
