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Trial registered on ANZCTR


Registration number
ACTRN12621000105842
Ethics application status
Approved
Date submitted
7/12/2020
Date registered
2/02/2021
Date last updated
15/09/2021
Date data sharing statement initially provided
2/02/2021
Type of registration
Retrospectively registered

Titles & IDs
Public title
The effect of a short-term ketogenic diet on cognitive function, sleep, fatigue, heart rate variability and mood.
Scientific title
The effect of a short-term ketogenic diet on cognitive function, sleep, fatigue, heart rate variability and mood in healthy, male adults.
Secondary ID [1] 302266 0
Nil known.
Universal Trial Number (UTN)
U1111-1259-8175
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Cognitive function 318988 0
Sleep 318989 0
Fatigue 318990 0
Mood 318992 0
Condition category
Condition code
Neurological 316960 316960 0 0
Studies of the normal brain and nervous system
Mental Health 318400 318400 0 0
Studies of normal psychology, cognitive function and behaviour

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
STUDY DESIGN
This study is a randomised, controlled, counterbalanced, cross-over trial. Participants will undertake a 7-day baseline testing period, followed by two intervention periods with a washout period of 12 days. Each intervention period will comprise a 14-day dietary adaptation period and then a 36-h period of extended wakefulness. The study will be conducted at the Aviation Medicine Unit, Royal New Zealand Air Force Base in Whenuapai, Auckland, New Zealand. All participants will be informed of the study’s risks and will be required to provide written consent prior to their participation.

FAMILIARISATION, BASELINE TESTING AND DIETARY ADAPTATION
Prior to commencing the study, participants will perform the cognitive test battery and questionnaires on 5 separate occasions to familiarise themselves with the protocols and to remove learning effects. Participants will continue ingesting their habitual diet during the 7 days of the baseline testing and then will be required to complete, in a randomised order, a carbohydrate diet or a very-low-carbohydrate, high-fat, ketogenic diet for 14 days during the dietary adaptation period. Participants will be requested to: 1) abstain from over-the-counter medications (e.g. anti-histamines), dietary supplements, alcohol and napping; 2) avoid caffeine, or reduce daily caffeine intake to a maximum of 100 mg ingested prior to 1200 h (i.e. no caffeine can be ingested after 1200); and 3) maintain their normal sleep/wake cycle and physical activity levels. Because the intervention will be applied under free-living conditions, all other lifestyle choices will be allowed to vary naturally; however, participants will be requested to maintain normal lifestyle choices. Participants will be requested to avoid exercising in the 2 hours prior to bed. Daily sleep, daytime subjective sleepiness, mood, hunger, waking heart rate variability and capillary blood glucose and D-b-hydroxybutyrate measurements will be ascertained. Sleepiness, mood and hunger will be measured at 1600 to minimise the influence of time of day on perception. On the morning of day 7 of baseline testing and days 7 and 14 of dietary adaptation, cognitive performance (psychomotor vigilance task, running memory continuous performance test, 2-choice reaction time) will be measured prior to breakfast and exercising. Daily and weekly testing for daytime subjective sleepiness, mood, hunger and cognitive performance will occur within ±0.5 h of the first measure.

EXTENDED WAKEFULNESS
On the night of day 14 during dietary adaptation, participants will be reminded to continue their habitual sleeping patterns and aim for an 8 h sleep in preparation for the period of extended wakefulness. Sleep duration will be confirmed by actigraphy and a sleep diary. On the morning of day 15, participants will be woken by phone call at 0630 and will not be allowed to fall back to sleep or consume caffeine after waking. Participants will present to the Aviation Medicine Unit at approximately 0700 h to commence a 36-h period of continuous wakefulness from approximately 0730. This period will comprise of 6 x 6-h blocks commencing with a meal. Cognitive performance (psychomotor vigilance task, running memory continuous performance test, 2-choice reaction time), subjective sleepiness, mood, hunger, capillary blood glucose and D-b-hydroxybutyrate will be measured 1, 3 and 5 h following each meal (i.e. 2-h between tests). Participants will remain awake in the laboratory and be continuously monitored; a New Zealand Defence Force Medic will be on call during this time. The environment will be strictly controlled in terms of scheduled activities and environmental conditions. Participants will have free time to read, watch movies, play board games, and interact with other participants and research staff; however, no vigorous physical activity, interaction with people external to the study or use of phones will be allowed. Light exposure will be kept at a constant lux. Ambient temperature will be kept at 20-22 °C. Participants will not be informed of the time. Following completion, participants will be provided with transport home and requested to refrain from duty for a 24-h period to allow for sufficient recovery.

DIETARY INTERVENTION
For each dietary condition, participants will be provided with comprehensive education from a registered dietitian, including an individualised meal plan specific to the individual’s estimated energy requirements. The ketogenic diet will aim to comprise <40 g/day of carbohydrate, 15-20% energy intake from protein and >75% energy intake from fat. To mitigate reductions in serum electrolytes during the ketogenic diet, participants will ingest an electrolyte capsule (Pure Electrolyte Replacement Capsule; Pure Sports Nutrition, New Zealand) containing 440 mg sodium chloride, 150 mg potassium citrate, 100 mg magnesium citrate and 50 mg calcium citrate, twice daily (i.e. morning and afternoon) and be prescribed high-sodium fluids. Participants will be required to purchase and prepare their own food and fluid. The carbohydrate diet will aim to comprise >45% energy intake from carbohydrate, 15-20% energy intake from protein and <40% energy intake from fat. A registered dietitian will be available at all times, either via phone, email or in person, to provide guidance and support. Water consumption will be encouraged throughout the study.

During the 36-h period of extended wakefulness, participants will be provided meals by the research team in accordance with their dietary allocation. Meals will be provided at approximately 0730 h (breakfast), 1330 h (lunch), 1930 h (dinner) and 0130 h (night), with each comprising 25% of the participant’s daily energy requirements (based on habitual energy intake minus 10% for sedentariness). Participants will be instructed not to talk about food and the researchers will avoid discussions about food throughout the period of extended wakefulness. Participants will continue ingesting their prescribed dietary allocation (i.e. carbohydrate or ketogenic diet). Participants on the ketogenic diet will ingest an electrolyte capsule three times daily (i.e. approximately 0800, 1600 and 0000). All meals will be formulated by a registered dietitian. For each group, no caffeine or alcohol will be allowed and only non-caffeinated beverages will be made available, which can be consumed as required.

DIETARY MONITORING
To monitor dietary compliance, participants will be trained in dietary reporting and requested to provide an image-assisted (alongside a fiducial marker), weighed dietary record in real-time to a registered dietitian via a mobile phone application (WhatsApp; Facebook, San Francisco, CA). Diet records will be required on: 1) 3 non-consecutive days during baseline testing; 2) days 1, 3, 6, 8, 10 and 12 during the dietary adaptation period; 3) and 3 non-consecutive days during the washout period (to confirm participants have returned to their habitual diet). Where under- or mis-reporting is suspected, participants will be required to provide a 24-h dietary recall or repeat the dietary report the subsequent day. If incompliance is suspected, participants will receive dietetic intervention. Each dietary record will be coded (FoodWorks Professional Edition, Version 8; Xyris Software, Australia), with images validating the reported intakes. To help maintain energy balance, participants will report their daily morning body mass and will be advised to prevent a >2% fluctuation. Verification of compliance to the ketogenic diet will be via morning capillary blood D-b-hydroxybutyrate concentrations.

During the 36-h period of continuous wakefulness, participants will only be able to consume food provided by the research team and will be under the continuous monitoring of research staff. Participants will measure capillary blood D-b-hydroxybutyrate concentrations every two hours to verify dietary compliance.
Intervention code [1] 318553 0
Lifestyle
Comparator / control treatment
The carbohydrate diet will aim to comprise >45% energy intake from CHO, 15-20% energy intake from protein and <40% energy intake from fat.
Control group
Active

Outcomes
Primary outcome [1] 325062 0
Cognitive function using a computerised test battery.
Timepoint [1] 325062 0
Day 7 and 14 during the dietary adaptation period and at 2 hourly intervals during the extended wakefulness period.
Primary outcome [2] 325063 0
Sleep using actigraphy and written diary.
Timepoint [2] 325063 0
Daily during the dietary adaptation period.
Primary outcome [3] 325068 0
Heart rate variability using photoplethysmography via mobile phone application.
Timepoint [3] 325068 0
Daily during the dietary adaptation phase.
Secondary outcome [1] 386723 0
Mood using a validated subjective questionnaire from the Automated Neuropsychological Assessment Metrics test battery.
Timepoint [1] 386723 0
Daily during the dietary adaptation phase and at 2 hourly intervals during the extended wakefulness phase.
Secondary outcome [2] 386724 0
Sleepiness using a subjective questionnaire (i.e. Stanford Sleepiness Scale).
Timepoint [2] 386724 0
Daily during the dietary adaptation phase and at 2 hourly intervals during the extended wakefulness phase.
Secondary outcome [3] 386726 0
Capillary blood glucose concentration using point-of-care device.
Timepoint [3] 386726 0
Daily during the dietary adaptation phase and at 2 hourly intervals during the extended wakefulness phase.
Secondary outcome [4] 389598 0
Hunger using a study-specific subjective questionnaire.
Timepoint [4] 389598 0
Daily during the dietary adaptation phase and at 2 hourly intervals during the extended wakefulness phase.
Secondary outcome [5] 390319 0
Capillary D-beta-hydroxybutyrate concentration using point-of-care device.
Timepoint [5] 390319 0
Daily during the dietary adaptation phase and at 2 hourly intervals during the extended wakefulness phase.

Eligibility
Key inclusion criteria
1) aged 18-50 years; 2) non-obese (i.e. body mass index < 30); 3) healthy; 4) consuming a mixed-diet; 5) habitually going to sleep between 2100-0000 h and waking between 0600-0900 h.
Minimum age
18 Years
Maximum age
50 Years
Sex
Males
Can healthy volunteers participate?
Yes
Key exclusion criteria
1) habitually consuming a ketogenic diet or exogenous ketones within the previous 2 years; 2) smoker; 3) average caffeinated beverage consumption more than 3 cups per day; 4) have a medical, psychiatric or sleep disorder; 5) habitually sleep less than 7 h or more than 9 h; 6) regularly consume medications or medications acting on the central nervous system; 7) history of drug or alcohol abuse; 8) food allergies or engaging in restrictive dietary patterns; 9) trans-meridian travel or shift-work in the 28 days prior to the study.

Participants will also be required to have an Epworth Sleepiness score less than 10; a global Pittsburgh Sleep Quality Index score equal to or less than 5; normal scores on the 21-item Depression Anxiety Stress scale; and scoring as moderately evening or intermediate chronotype on the Horne-Ostberg Morningness/Eveningness questionnaire.

Study design
Purpose of the study
Prevention
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Participants will be randomised to either dietary condition after confirming their eligibility using central randomisation by computer (www.randomizer.org).
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Participants will be randomised to either dietary condition using www.randomizer.org.
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Crossover
Other design features
Counter-balanced.
Phase
Not Applicable
Type of endpoint/s
Efficacy
Statistical methods / analysis
A sample size of 12 is recommended based on similar publications; however, a sample size of 15 will be recruited due to factoring in a dropout rate of 20%.

Variables will be analysed using linear mixed models and correlations will be determined. Significance will be accepted at p < 0.05.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
Actual
14/01/2021
Date of last participant enrolment
Anticipated
26/02/2021
Actual
26/02/2021
Date of last data collection
Anticipated
31/05/2021
Actual
31/05/2021
Sample size
Target
12
Accrual to date
Final
8
Recruitment outside Australia
Country [1] 22959 0
New Zealand
State/province [1] 22959 0
Auckland

Funding & Sponsors
Funding source category [1] 306686 0
Government body
Name [1] 306686 0
Aviation Medicine Unit, Royal New Zealand Air Force
Country [1] 306686 0
New Zealand
Funding source category [2] 306690 0
University
Name [2] 306690 0
Massey University
Country [2] 306690 0
New Zealand
Primary sponsor type
Government body
Name
New Zealand Defence Force
Address
Defence House 34 Bowen Street
Pipitea
Wellington 6011
New Zealand
Country
New Zealand
Secondary sponsor category [1] 307238 0
University
Name [1] 307238 0
Massey University
Address [1] 307238 0
Dairy Flat Highway
Albany
Auckland, 0632
New Zealand
Country [1] 307238 0
New Zealand

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 306863 0
New Zealand Defence Force
Ethics committee address [1] 306863 0
Ethics committee country [1] 306863 0
New Zealand
Date submitted for ethics approval [1] 306863 0
07/08/2020
Approval date [1] 306863 0
20/08/2020
Ethics approval number [1] 306863 0
Ethics committee name [2] 306868 0
Massey University Ethics Committee
Ethics committee address [2] 306868 0
Ethics committee country [2] 306868 0
New Zealand
Date submitted for ethics approval [2] 306868 0
17/08/2020
Approval date [2] 306868 0
07/12/2020
Ethics approval number [2] 306868 0

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

Contacts
Principal investigator
Name 105274 0
Dr David Shaw
Address 105274 0
Aviation Medicine Unit
RNZAF Base Auckland
Whenuapai
Auckland, 0618
Country 105274 0
New Zealand
Phone 105274 0
+64 21 0827 6137
Fax 105274 0
Email 105274 0
david.shaw2@nzdf.mil.nz
Contact person for public queries
Name 105275 0
David Shaw
Address 105275 0
Aviation Medicine Unit
RNZAF Base Auckland
Whenuapai
Auckland, 0618
Country 105275 0
New Zealand
Phone 105275 0
+64 21 0827 6137
Fax 105275 0
Email 105275 0
david.shaw2@nzdf.mil.nz
Contact person for scientific queries
Name 105276 0
David Shaw
Address 105276 0
Aviation Medicine Unit
RNZAF Base Auckland
Whenuapai
Auckland, 0618
Country 105276 0
New Zealand
Phone 105276 0
+64 21 0827 6137
Fax 105276 0
Email 105276 0
david.shaw2@nzdf.mil.nz

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
Embargoed by the New Zealand Defence Force.


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.