Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12625000781448
Ethics application status
Approved
Date submitted
3/07/2025
Date registered
24/07/2025
Date last updated
24/07/2025
Date data sharing statement initially provided
24/07/2025
Type of registration
Prospectively registered

Titles & IDs
Public title
The impact of exogenous ketones on exercise capacity in children with inborn errors of muscle energy metabolism
Scientific title
The impact of exogenous ketones on exercise capacity in children with inborn errors of muscle energy metabolism
Secondary ID [1] 314808 0
None
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Long chain fatty acid oxidation disorder 338060 0
HMG-CoA-lyase deficiency 338179 0
Condition category
Condition code
Metabolic and Endocrine 334354 334354 0 0
Metabolic disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
2 study visits only - one intervention, one control

Although participants will all have the 'intervention', they will be randomised to receive either 'intervention' or 'control' at their first visit and then will receive the other at their second visit.

Ketone salt, dosed at 170mg/kg in children with inborn errors of metabolism
Ketone ingested 20mins prior to submaximal treadmill exercise test
Submaximal exercise test will be modified Bruce (no slope), 3min stages until heart rate is at 60-70% of predicted maximum, then cool down for 3 mins.
Blood draws at pre-ketone, 20mins after ketone (pre exercise), and within 5 minutes of ceasing exercise.

Study will be conducted by Senior metabolic dietitian (7 years in metabolics), experienced exercise physiologist, experienced metabolic staff specialists, and experienced sports physician.
Intervention code [1] 331406 0
Treatment: Other
Comparator / control treatment
Same protocol as intervention, however ketones are replaced with isocaloric glucose polymer.
Participants will act as their own control.
Investigator blinded.
Within 2-8 weeks apart (to account for any schedule conflicts, illnesses etc).
Control group
Active

Outcomes
Primary outcome [1] 342045 0
Differences in submaximal exercise capacity as measured by heart rate in children with inborn errors of muscle energy metabolism (IEMEM), between a ketone product, compared to an isocaloric glucose polymer,
Timepoint [1] 342045 0
During cardiopulmonary exercise testing
Primary outcome [2] 342046 0
Differences in submaximal exercise capacity as measured by blood/plasma metabolites in children with inborn errors of muscle energy metabolism (IEMEM), between a ketone product, compared to an isocaloric glucose polymer,
Timepoint [2] 342046 0
20mins before exercise test, immediately before exercise test, immediately after exercise test.
Primary outcome [3] 342160 0
Differences in general quality of life in children with IEMEM - composite primary outcome.
Timepoint [3] 342160 0
Visit 2
Secondary outcome [1] 449412 0
To determine if an exogenous ketone product is safe before exercise in children with IEMEM.
Timepoint [1] 449412 0
During, immediately, or within 48 hours after exercise tests.
Secondary outcome [2] 449781 0
To determine if an exogenous ketone product is acceptable before exercise in children with IEMEM.
Timepoint [2] 449781 0
After each exercise test.
Secondary outcome [3] 449782 0
Differences in submaximal exercise capacity as measured by gaseous exchange in children with inborn errors of muscle energy metabolism (IEMEM), between a ketone product, compared to an isocaloric glucose polymer, - Primary Outcome
Timepoint [3] 449782 0
During exercise tests.

Eligibility
Key inclusion criteria
Age 5 – 18 years old
Diagnosed (by biochemical data or molecular genetic diagnosis) with a long chain fatty acid oxidation disorder (LC-FAOD), or HMG-CoA-lyase deficiency.
Receiving treatment from the Sydney Children’s Hospital Network (SCHN) metabolic service.
Participants or parents/guardians must be able to give fully informed written consent for the investigations being performed.
Participants must be willing and able to attend the exercise testing facility at the Children’s Hospital at Westmead, on two occasions in total.
Minimum age
5 Years
Maximum age
18 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Female participants who are pregnant.
Participants who do not consent to be part of the trial.
Participants at moderate to high risk of adverse events during exercise testing, for example, abdominal aortic aneurysm, pulmonary hypertension, severe aortic stenosis, acute/unstable cardiac status, untreated pulmonary embolism.
Participants younger than 5 years of age – to ensure participants are capable of performing the exercise test.
Participants older than 18 years of age – this falls outside the study population group of interest.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Allocation is not concealed
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Simple randomisation using Microsoft excel random allocation.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Crossover
Other design features
Phase
Not Applicable
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
Sample size will be based on the number of participants currently under care of the SCHN metabolic team who meet the eligibility criteria including age and diagnosis, and agree to participate in the study. Due to the rarity of conditions, the sample size will likely be no more than fifteen.
A study of 15 participants will have 80% power at 5% two-sided alpha to detect within-participant differences (in heart rate, perceived exertion) in a normally-distributed outcome if the true mean difference is large (at least one standard deviation) and within-participant correlation between outcomes for the two nutrients is at least 0.2.
Due to the small and arbitrary sample size and the large number of outcomes to be collected, analysis of outcomes will be mainly descriptive and promising findings will require confirmation in other research. Study outcomes will be interpreted in terms of their clinical importance as well as the strength of statistical evidence.

Participant demographic and clinical characteristics and study outcomes will be presented using standard descriptive statistics: mean, standard deviation and range or median, quartiles and range for continuous variables and frequencies and percentages for categorical variables.

If exercise outcomes are available for both nutrient exercise tests, they will be analysed according to the allocated nutrient regardless of what nutrient (if any) was received. For continuous outcomes (including heart rate, rate of perceived exertion, VO2 and VCO2), carry-over, period and nutrient treatment effects will be explored using t-tests. Exercise outcomes for participants with only a single exercise test will be presented descriptively.

Paired tests and statistical models that account for correlation between repeated observations in the same participant will be used to explore differences between nutrients. Mean within-participant differences in outcomes will be presented with 95% confidence intervals where possible. Safety and acceptability will be presented using standard descriptive statistics.

Different disease severity and types may potentially confound results. Sub-group analysis will be considered, for example on only patients with HMG-CoA-lyase deficiency, and then separately, LC-FAOD. Similarly, sub-group analysis may be conducted on e.g. participants who have an attenuated LC-FAOD phenotype vs a more classical phenotype.

Quality of life data from PedsQL will be compared to normative healthy children population data. Similarly, MetabQoL data will be used to compare to other IEM populations, and provide qualitative insight via on how an IEM diagnosis impacts on QoL. Qualitative feedback and thematic analysis from the semi-structured interviews will be used to guide gaps in the information elicited from the MetabQoL to make future adaptations to the questionnaire so it can be validated in IEMEM.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
1/08/2025
Actual
Date of last participant enrolment
Anticipated
1/10/2025
Actual
Date of last data collection
Anticipated
5/12/2025
Actual
Sample size
Target
15
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW
Recruitment hospital [1] 28165 0
The Children's Hospital at Westmead - Westmead
Recruitment hospital [2] 28166 0
Sydney Children's Hospital - Randwick
Recruitment postcode(s) [1] 44377 0
2145 - Westmead
Recruitment postcode(s) [2] 44378 0
2031 - Randwick

Funding & Sponsors
Funding source category [1] 319365 0
Charities/Societies/Foundations
Name [1] 319365 0
The Sydney Children's Hospital Foundation
Country [1] 319365 0
Australia
Funding source category [2] 319367 0
Other
Name [2] 319367 0
Genetic Metabolic Dietitians International (GMDI)
Country [2] 319367 0
United States of America
Funding source category [3] 319368 0
Other
Name [3] 319368 0
Vitaflo international
Country [3] 319368 0
United Kingdom
Primary sponsor type
Government body
Name
The Sydney Children's Hospitals Network
Address
Country
Australia
Secondary sponsor category [1] 321852 0
None
Name [1] 321852 0
Address [1] 321852 0
Country [1] 321852 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 317941 0
Sydney Children's Hospitals Network Human Research Ethics Committee
Ethics committee address [1] 317941 0
Ethics committee country [1] 317941 0
Australia
Date submitted for ethics approval [1] 317941 0
20/09/2024
Approval date [1] 317941 0
06/12/2024
Ethics approval number [1] 317941 0
2024/ETH01897

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 142630 0
Ms Kiera Batten
Address 142630 0
The Children's Hospital at Westmead, Cnr Hawkesbury Road and Hainsworth Street, Westmead, 2145 NSW Australia
Country 142630 0
Australia
Phone 142630 0
+61 278252225
Fax 142630 0
Email 142630 0
[email protected]
Contact person for public queries
Name 142631 0
Kiera Batten
Address 142631 0
The Children's Hospital at Westmead, Cnr Hawkesbury Road and Hainsworth Street, Westmead, 2145 NSW Australia
Country 142631 0
Australia
Phone 142631 0
+61 278252225
Fax 142631 0
Email 142631 0
[email protected]
Contact person for scientific queries
Name 142632 0
Kiera Batten
Address 142632 0
The Children's Hospital at Westmead,The Children's Hospital at Westmead, Cnr Hawkesbury Road and Hainsworth Street, Westmead, 2145 NSW Australia
Country 142632 0
Australia
Phone 142632 0
+61 278252225
Fax 142632 0
Email 142632 0
[email protected]

Data sharing statement
Will the study consider sharing individual participant data?
No
No IPD sharing reason/comment: Rare disorders, low participant numbers expected and therefore data potentially more easily identifiable.



What supporting documents are/will be available?

No Supporting Document Provided


Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
No additional documents have been identified.