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

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Ultragenyx Pharmaceutical Inc.

Participant type

Pediatric, Patients

Age range

0-17 years

Gender

Male and Female

Therapeutic area

Diseases [C] - Nutritional and Metabolic Diseases [C18]

Trial duration

28 Feb 2023 → ongoing

Decision date (initial)

2024-05-29

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

Ultragenyx Pharmaceutical Inc.

External identifiers

EU CT number

2023-509809-76-00

EudraCT number

2022-001539-10

ClinicalTrials.gov

NCT05933200

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy, Efficacy, Pharmacokinetic

Evaluate the effect of triheptanoin versus Medium-chain Triglycerides (MCT) on frequency of major clinical events (MCE)

Secondary objectives 1

1. 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 liver fat fraction (Liver Substudy–Primary) Evaluate the effect of triheptanoin versus MCT on cardiac structure and function 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 are in the protocol

Conditions and MedDRA coding

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

Study design 3 periods

Regulatory references

Scientific advice from competent authorities

Federal Institute For Drugs And Medical Devices, Federal Agency For Medicines And Health Products, Swedish Medical Products Agency, Icelandic Medicines Agency, European Medicines Agency

EMA paediatric investigation plan (PIP)

EMEA-001920-PIP04-19

Plan to share IPD

No

IPD plan description

There is no individual participant data to be shared

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 6

1. 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
2. 2. Males and females, from 0 (including newborns) to < 18 years of age at time of randomination
3. 3. Have a caregiver(s) willing and able to assist in all applicable study requirements
4. 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. 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. 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 1

1. 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 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

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Annualized event rate of MCEs

Secondary endpoints 16

1. Annualized duration of MCEs
2. Annualized hypoglycemic event-rate captured as MCEs and HCEs
3. CGI-C scale score
4. Left ventricular ejection fraction, left ventricular systolic volume, and left ventricular wall mass
5. Annualized frequency and duration of rhabdomyolysis-MCEs
6. Annualized frequency and duration of cardiomyopathy-MCEs
7. Annualized duration of hypoglycemic-MCEs
8. 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)
9. Survival time
10. Annualized hospitalization days
11. Number of missed school or learning opportunity days
12. Frequency, severity, and relationship to study drug of TEAEs, serious TEAEs, and AESIs
13. Incidence of TEAEs and serious TEAEs leading to dose modifications, dose reductions, treatment interruptions, discontinuations from study drug, and discontinuations from the study
14. Plasma concentration levels of heptanoate and betahydroxypentanoate (BHP)
15. Acceptability and Palatability Survey scores of triheptanoin mixed with oral liquids
16. Change from baseline to 6 months in hepatic PDFF%, assessed by 1HMRS in subjects enrolled in the Liver Substudy

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Comparator 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Ultragenyx Pharmaceutical Inc.

Sponsor organisation

Ultragenyx Pharmaceutical Inc.

Address

60 Leveroni Court Suite 200

City

Novato

Postcode

94949-5746

Country

United States

Scientific contact point

Organisation

Ultragenyx Pharmaceutical Inc.

Contact name

Medical Information

Public contact point

Organisation

Ultragenyx Pharmaceutical Inc.

Contact name

Ultragenyx trial information group

Third parties 9

Locations

4 EU/EEA countries · 7 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 109 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

7 submissions — initial application plus substantial / non-substantial modifications