Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12623000184673
Ethics application status
Approved
Date submitted
17/01/2023
Date registered
21/02/2023
Date last updated
21/02/2023
Date data sharing statement initially provided
21/02/2023
Type of registration
Prospectively registered

Titles & IDs
Public title
Effects of ketone supplementation on recovery from endurance exercise in recreationally active males
Scientific title
Effects of ketone supplementation on rates of muscle protein synthesis following leg cycling in recreational active males
Secondary ID [1] 307811 0
None
Universal Trial Number (UTN)
Trial acronym
KAPER (Ketones and Post-Exercise Recovery)
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Skeletal muscle recovery 327395 0
Condition category
Condition code
Musculoskeletal 324520 324520 0 0
Normal musculoskeletal and cartilage development and function

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
10 well-trained male cyclists/triathletes (A-B grade, training >200km/week, 18-35 years old, BMI 18.5 – 24.9 kg/m^2) will be included in this randomised, double-blind placebo-controlled cross-over study. Prior to the first training session, all participants will complete preliminary testing including a 3-day food record, body composition scan (DXA), fitness testing (VO2peak test) and exercise session familiarisation.

During the experimental visits, a total of 3 muscle biopsies and 10 blood samples (~10 mL / sample) will be obtained from each participant. Participants will complete a total of two experimental exercise sessions with 1-2 weeks of recovery between sessions. The first exercise session of the experimental period will involve random selection for supplementation with either a commercially available ketone ester (KE) or energy-matched placebo (PL), and the second session will involve a single session supplementing with the opposite treatment (i.e., what was not consumed in the first exercise session). Participants will keep a food record and receive dietary instruction from accredited dietitians to meet individual energy targets prior to the two exercise sessions.

On experimental days, participants will report do the lab following an overnight fast. A Teflon catheter will then be inserted into an antecubital (inside of elbow) vein for basal blood collection. A second catheter will be inserted into a pre-heated vein of the opposite hand for blood collection. Following basal blood collection, the plasma phenylalanine pool will be primed with an intravenous dose of L-[ring-(13)C(6)]-phenylalanine and directly thereafter a continuous tracer infusion will commence and participants will be provided with a low-protein, carbohydrate (CHO) rich breakfast (e.g., ~2.0g/kg body mass (BM) CHO, <0.2g/kg BM protein).

Participants will then complete a supervised leg-cycling exercise protocol consisting of 6x30 min continuous blocks of alternating intensities to mimic a cycling road race. Upon completion of the exercise protocol, a first muscle biopsy will be taken from the vastus lateralis muscle to determine the background enrichment and basal muscle protein synthetic rate. Participants will then be fed a recovery beverage containing carbohydrate and protein consistent with current dietary post-exercise recommendations (3g/kg BM CHO, 25 g protein) well as either a ketone ester (573 mg/kg) or taste-matched placebo (bitter tasting solution containing sucrose octaacetate dissolved in water), with a maintenance dose (286 mg/kg ketone or placebo) consumed every hour (i.e., at 1, 2, 3 and 4 h post exercise) to maintain circulating ketone availability.

To determine post-prandial muscle protein synthesis, another 2 biopsies will be taken at 2 h and 5 h post exercise. Participants will then be provided with a self-serve buffet style dinner where they can self-select from a range of healthy, nutritious foods in accordance with their personal preferences. During this time (~45 min), they will be asked to fill out several surveys related to feelings of hunger, fullness, and GI upset/discomfort. Participants will remain in the lab under supervision for the full duration of the experimental visit.
Intervention code [1] 324276 0
Treatment: Other
Intervention code [2] 324277 0
Lifestyle
Comparator / control treatment
Participants will be randomised to treatment (active or placebo), and perform all trials in a cross-over design. The placebo will be a taste matched drink containing a bitter tasting solution (sucrose octaacetate) dissolved in water. Drinks will be provided in identical opaque bottles to prevent visible identification of treatment.
Control group
Placebo

Outcomes
Primary outcome [1] 332357 0
Rates of skeletal muscle protein synthesis (expressed as fractional synthetic rate (FSR in %/h), as measured by incorporation of L-[ring-(13)C(6)]-phenylalanine tracer in muscle biopsy samples as described previously (Smiles et al. 2019, PMID: 30840513).
Timepoint [1] 332357 0
Post exercise skeletal muscle FSR will be determined from muscle biopsies taken immediately post exercise (t=o) and 2 (t=120 min) and 5 h (t=300 min) into the recovery period.
Secondary outcome [1] 413176 0
Composite measures of appetite and satiety (acetylated gherlin, leptin, PYY, PP, Amylin) will be measured in venous blood samples via commercially available ELISA and/or automated blood analyser
Timepoint [1] 413176 0
Appetite and satiety markers will be measured from blood samples collected:
-fasted (prior to consumption of standardised breakfast)
- 1 h and 2 h post prandial prior to start of exercise
- immediately post exercise (t=0)
- t=60min, t=120 min, t=300min post exercise
Secondary outcome [2] 418631 0
Perceived satiety will be measured in individuals using a standardised visual analogue scale (VAS; 100mm)
Timepoint [2] 418631 0
VAS for satiety markers will be collected:
-fasted (prior to consumption of standardised breakfast)
- 2 h post prandial prior to start of exercise
- immediately post exercise (t=0)
- t=120 min, t=300min post exercise
Secondary outcome [3] 418632 0
Measures of gastrointestinal (GI) discomfort will be measured using a 10-point rating modified scale to determine upper and lower gastrointestinal symptoms as well as composite overall gut discomfort.
Timepoint [3] 418632 0
GI discomfort will be measured
-fasted (prior to consumption of standardised breakfast)
- 2 h post prandial prior to start of exercise
- immediately post exercise (t=0)
- t=120 min, t=300min post exercise
Secondary outcome [4] 418649 0
Composite measures of inflammation and iron metabolism (ferritin, hepcidin, IL-6) be measured in venous blood samples via commercially available ELISA and/or automated blood analyser as previously described (McKay et al. 2022, PMID: 34690285)
Timepoint [4] 418649 0
Inflammation and iron metabolism markers will be measured from blood samples collected:
-fasted (prior to consumption of standardised breakfast)
- 2 h post prandial prior to start of exercise
- immediately post exercise (t=0)
- t=60min, t=180, t=300 min post exercise
Secondary outcome [5] 418650 0
Composite measures of bone metabolism (CTX, P1NP, OC) measured in blood serum via an automated blood analyser as previously described (Fensham et al 2022, PMID: 35869933)
Timepoint [5] 418650 0
Bone markers will be measured from blood samples collected:
-fasted (prior to consumption of standardised breakfast)
- 2 h post prandial prior to start of exercise
- immediately post exercise (t=0)
- t=60min , t=120min, t=180 post exercise
Secondary outcome [6] 418653 0
Plasma ketone (beta-hydroxybutyrate) concentrations via commercially available colorimetric kits
Timepoint [6] 418653 0
Ketone concentrations will be assessed
-fasted (prior to consumption of standardised breakfast)
- 2 h post prandial prior to start of exercise
- immediately post exercise (t=0)
- t=60min , t=120min, t=180, t=300 post exercise
Secondary outcome [7] 418655 0
Plasma enrichments of L-[ring-13C6]-phenylalanine via gas chromatography-mass spectrometry (GC-MS)
Timepoint [7] 418655 0
Plasma will be collected
-fasted (prior to consumption of standardised breakfast)
-2 h post prandial prior to the start of exercise
-immediately post exercise (t=0)
-t=30, t=60, t-90, t=120, t=180, t=240, t=300 min post exercise
Secondary outcome [8] 418816 0
Perceived appetite will be measured in individuals using a standardised visual analogue scale (VAS; 100mm)
Timepoint [8] 418816 0
VAS for appetite will be collected:
-fasted (prior to consumption of standardised breakfast)
- 2 h post prandial prior to start of exercise
- immediately post exercise (t=0)
- t=120 min, t=300min post exercise

Eligibility
Key inclusion criteria
Participants will be recruited if they meet the following criteria:
• Male
• Aged 18-35 y
• BMI: 18.5-24.9 kg/m2
• Recreationally active (A-B grade cyclists or triathletes currently cycling ~200km/week) capable of completing the 180 min intermittent intensity exercise protocol
• No cardiopulmonary abnormalities
• No injuries
• Pass the ESSA pre-exercise screening tool and/or obtain GP clearance to exercise
Minimum age
18 Years
Maximum age
35 Years
Sex
Males
Can healthy volunteers participate?
Yes
Key exclusion criteria
Exclusion criteria:
• Known cardiovascular disease or diabetes mellitus
• Known bleeding disorder (i.e. hemophilia A [factor VIII deficiency]
• Hemophilia B [factor IX deficiency]
• von Willebrand disease, or other rare factor deficiencies including I, II, V, VII, X, XI, XII and XIII)
• Major or chronic illness that impairs mobility or eating/digestion
• Taking prescription medications (i.e. beta-blockers, anti-arrhythmic drugs, statins, insulin sensitising drugs, or drugs that increase the risk of bleeding [i.e. anticoagulants, antiplatelets, novel oral anticoagulants [NOAs], nonsteroidal anti-inflammatory drugs [NSAIDs], selective norepinephrine reuptake inhibitors [SNRI], or selective serotonin reuptake inhibitors [SSRIs]
• Unable or unwilling to have a muscle biopsy
• Weight has changed more than 5kg in past 3 months
• Currently on a restrictive diet
• Unable to attend the lab in Fitzroy, Melbourne for the 4 study visits for completion of study protocol

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)
Sealed opaque envelopes.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Simple randomisation using computer-generated, randomised sequence. An independent third party will prepare the computer-generated randomisation lists and sealed envelopes for randomisation.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s

Intervention assignment
Crossover
Other design features
Phase
Not Applicable
Type of endpoint/s
Efficacy
Statistical methods / analysis
Statistical analysis: Data obtained will be analysed using Generalised Linear Mixed Models. Statistics will analyse factor (time: baseline, 2 h and/or 5 h post-exercise) and treatment (ketone vs. placebo). Statistical significance will be set at P<0.05. A power calculation was performed with differences in postprandial MPS as the primary outcome measure. Based on published data (Koopman R et al. Nutr. 2009 PMID: 19625697), we estimate the standard deviation for MPS to be ~0.0065 %/h. We estimate that to determine an ~20% difference between treatments at an a level of 0.05 and power (1 - ß) of 0.8, we will need to recruit 7 subjects. This is considered clinically relevant difference between interventions. Therefore, to account for possible dropouts, we will recruit a total of 10 subjects to participate in the study.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
28/02/2023
Actual
Date of last participant enrolment
Anticipated
4/09/2023
Actual
Date of last data collection
Anticipated
2/10/2023
Actual
Sample size
Target
10
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
VIC

Funding & Sponsors
Funding source category [1] 312079 0
University
Name [1] 312079 0
Australian Catholic University
Country [1] 312079 0
Australia
Primary sponsor type
Individual
Name
Dr Jamie Whitfield
Address
Exercise and Nutrition Research Program
Mary MacKillop Institute for Health Resarch
Level 5, 215 Spring Street
Melbourne, VIC 3000
Country
Australia
Secondary sponsor category [1] 313598 0
Individual
Name [1] 313598 0
Dr. Alannah McKay
Address [1] 313598 0
Exercise and Nutrition Research Program
Mary MacKillop Institute for Health Research
Level 5, 215 Spring Street
Melbourne, VIC 3000
Country [1] 313598 0
Australia
Secondary sponsor category [2] 313599 0
Individual
Name [2] 313599 0
Professor Louise Burke
Address [2] 313599 0
Exercise and Nutrition Research Program
Mary MacKillop Institute for Health Research
Level 5, 215 Spring Street
Melbourne, VIC 3000
Country [2] 313599 0
Australia
Secondary sponsor category [3] 313600 0
Individual
Name [3] 313600 0
Professor John Hawley
Address [3] 313600 0
Exercise and Nutrition Research Program
Mary MacKillop Institute for Health Research
Level 5, 215 Spring Street
Melbourne, VIC 3000
Country [3] 313600 0
Australia
Secondary sponsor category [4] 314948 0
Individual
Name [4] 314948 0
Professor Luc van Loon
Address [4] 314948 0
Department of Human Biology NUTRIM School of Nutrition and Translational Research in Metabolism,
Maastricht University Medical Centre,
P.O. Box 616, 6200 MD,
Maastricht
Country [4] 314948 0
Netherlands

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 311487 0
Australian Catholic University Human Research Ethics Committee (ACU HREC)
Ethics committee address [1] 311487 0
Ethics committee country [1] 311487 0
Australia
Date submitted for ethics approval [1] 311487 0
15/03/2022
Approval date [1] 311487 0
29/06/2022
Ethics approval number [1] 311487 0
2022-2580H

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

Contacts
Principal investigator
Name 121274 0
Dr Jamie Whitfield
Address 121274 0
Exercise and Nutrition Research Program
Mary MacKillop Institute for Health Resarch
Level 5, 215 Spring Street
Melbourne, VIC 3000
Country 121274 0
Australia
Phone 121274 0
+61 3 9230 8252
Fax 121274 0
Email 121274 0
[email protected]
Contact person for public queries
Name 121275 0
Jamie Whitfield
Address 121275 0
Exercise and Nutrition Research Program
Mary MacKillop Institute for Health Resarch
Level 5, 215 Spring Street
Melbourne, VIC 3000
Country 121275 0
Australia
Phone 121275 0
+61 3 9230 8252
Fax 121275 0
Email 121275 0
[email protected]
Contact person for scientific queries
Name 121276 0
Jamie Whitfield
Address 121276 0
Exercise and Nutrition Research Program
Mary MacKillop Institute for Health Resarch
Level 5, 215 Spring Street
Melbourne, VIC 3000
Country 121276 0
Australia
Phone 121276 0
+61 3 9230 8252
Fax 121276 0
Email 121276 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
Potentially identifiable data


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.