Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12621001685808
Ethics application status
Approved
Date submitted
10/08/2021
Date registered
9/12/2021
Date last updated
9/12/2021
Date data sharing statement initially provided
9/12/2021
Type of registration
Prospectively registered

Titles & IDs
Public title
The acute effects of dried kiwifruit on sleep onset, metabolites and cognition in men
Scientific title
Acute effect of dried kiwifruit on sleep onset, metabolites associated with sleep, mood and morning cognitive performance – a randomised controlled trial in healthy males with poor sleep
Secondary ID [1] 304895 0
None
Universal Trial Number (UTN)
U1111-1268-2664
Trial acronym
Linked study record
This is a new study exploring in depth the results of ACTRN12621000046808.

Health condition
Health condition(s) or problem(s) studied:
Poor sleep 323021 0
Poor cognition 323022 0
Mood state 323023 0
Condition category
Condition code
Diet and Nutrition 320590 320590 0 0
Other diet and nutrition disorders
Mental Health 321011 321011 0 0
Studies of normal psychology, cognitive function and behaviour
Neurological 321012 321012 0 0
Other neurological disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Screening visit
Prospective participants will be provided with the study information sheet and invited to a Human Nutrition Research Unit (HNRU) screening session to sign the consent form and have height and weight measured, complete health questionnaires, and sleep quality questionnaires (PSQI, and ISI). Eligible participants will be enrolled. From this point on, participants will be asked to refrain from eating kiwifruit until the end of the study and maintain a sleep schedule.

A case report form record (CRF) will be generated for all participants who have signed the consent form for the study, regardless of eligibility and/or continuing participation.

Familiarisation
Seven days before the first trial visits, participants will be invited for a familiarisation session. Participants will be asked to arrive at the HNRU between 6-8pm. The HNRU will be dimly lit to collect metabolites of interest. Once arrived, participants will be talked through exactly what would happen on a trial day with the lead researcher. They will be provided with an actigraphy watch to be used until the completion of the study and a survey booklet to be completed before the next trial visit. The survey booklet will contain a three-day food diary and a daily sleep diary. Participants will be told to activate the phase marker on the actigraphy watches when they are about to sleep and upon waking. No biomarker will be collected at his session and it is expected it will take Which will last approximately 1-2 hours.

Once everything is complete, the participant will be escorted to on-site accommodation and asked to return the following morning fasted at an agreed time. Upon arriving in the morning, participants will be provided a standardised breakfast and asked to complete a cognitive test; this is used to ensure practice and learning effects are mitigated for subsequent trial visits. This morning visits will be no more than 2 hours.

Intervention visits
Two days before the scheduled trial visit, participants will be asked to refrain from consuming oranges, pineapples, bananas, mangos, papayas, plums, grapes, cherries, strawberries, tomatoes, capsicum, pistachios, plantains, mushrooms, chocolate, teas and coffee as these are known foods to contain and impact levels of serotonin and melatonin in urine (32-34).

On the day of the trial, participants will attend HNRU between 5-6:30 pm. Participants will be asked to have their last meal five hours before the lab visit and only take water until the visit. On arrival, the participant will be asked whether they have consumed any of the restricted foods two days before or undergone exercise on this day. If the participant has consumed restricted items or exercised, the study visit will be rescheduled. If the participant has not, they will continue with the trial visit and follow the schedule below.

Participants will be asked to complete a set of questionnaires (including abbreviated Profile of Mood States (POMS), International Physical Activity Questionnaire (IPAQ), Weekly Stress Inventory (WSI)) and provide a urine sample. A person trained in cannulation and venepunctures will insert a venous cannula in the arm vein of the participant to collect blood samples across multiple times points. At each blood sample, the participant's level of sleepiness will be rated according to the validated Stanford Sleepiness Scale (SSS). Approximately twenty minutes after the first blood sample, participants will be provided with a standardised evening meal [Man Size Spaghetti and Meatballs (McCain Foods), ~720 kcal], and the intervention to consume. The intervention will be in an opaque white bottle to mask what intervention the participant may be consuming. The dietary interventions will be given in random order. They will include (1) control (Flavour and colour) mixed with 200ml water, (2) control sugar (matched sugar, flavour, and colour) dissolved in 180ml water or (3) freeze-dried whole (flesh and skin) green kiwifruit (32g which is equivalent to two green kiwifruits) dissolved in 170 ml of water. Once the meal is finished, participants will be asked to sit and do light activities such as reading a book. They will also be asked not to use mobile phones or computers during their time in the lab. Six blood samples will be collected (~100mL each) beginning on arrival and 30, 60, 120, 180, 240 min post evening meal.

The last blood sample will be collected at approximately 10-11 pm (differs for each participant) and the cannula will be removed after this. The participant will be asked to complete the POMS survey and provide a urine sample. They will then be provided with a urine sample collection container, saliva collection containers and survey booklet to be completed in their room the following morning. Participants will be escorted to on-site accommodation. Once settled, when the participant is ready for bed, they are asked to activate the phase marker on the actigraphy watch.

Upon waking the following day, participants will be asked to activate the phase marker, collect the whole first-morning urine sample, collect four saliva samples (0, 30, 45, 60 min after waking) and complete the set of surveys. The validated surveys that will be completed in the morning are the SSS, Leeds Sleep Evaluation Questionnaire (LSEQ) and POMS. Participants will be asked to come into HNRU at the allocated time, fasted and with their urine, saliva samples and completed booklet 2-4 hours after waking.

Upon arriving at the HNRU, participants will be provided with a standardised breakfast. The participant will be asked to complete a cognitive test as they did at the familiarisation session. Once they have completed this, the participant will be free to go. Participants will repeat the in-lab visit two more times separated by seven days until each intervention has been consumed.
Intervention code [1] 321288 0
Treatment: Other
Comparator / control treatment
Two controls will be included in this study. A matched sugar control for the kiwifruit powder, and a flavour colour powder will be used as the placebo for this study. The placebo powders contains significantly lower fibre, protein, lipid and micronutrients compared to the kiwifruit powder. All the powders, will be weighed into opaque white bottles to blind both participants and trial investigators to which treatment is being administered. All interventions will be prepared in a food-safe facility by a member of the research team.
Control group
Placebo

Outcomes
Primary outcome [1] 328551 0
Changes in subjective sleep quality will be assessed using the Stanford Sleepiness Scale and the Leeds Sleep Evaluation Questionnaire (composite)
Timepoint [1] 328551 0
During blood sampling at each trial visit, participants will be asked to rate their perceived sleepiness based on the Stanford Sleepiness Scale. Ratings will be asked at baseline upon arrival at the laboratory and 30, 60, 120, 180 and 240 min after complete ingestion of the standardised meal and intervention. The Leeds Sleep Evaluation Questionaire will be completed the morning after each intervention.
Primary outcome [2] 328552 0
Changes in plasma melatonin quantified using commercially available kits.
Timepoint [2] 328552 0
Melatonin will be measured in plasma samples collected at trial visits. At each visit, six blood samples will be collected in a dim light setting (10lx). Samples collected will include baseline upon arrival at the laboratory and 30, 60, 120, 180 and 240 min after complete ingestion of the standardised meal and intervention. Melatonin will be quantified using commercially available kits.
Primary outcome [3] 329683 0
Changes in objective sleep quality measurements (composite of sleep onset latency, wake after sleep onset, total sleep time and sleep efficiency) will be measured using a wrist-worn actigraphy monitor
Timepoint [3] 329683 0
Actigraphy wrist-watch will be worn throughout the entire duration of the study. The sleep period following the evening intervention is what will be used to compare between treatment visits.
Secondary outcome [1] 399404 0
Changes in mood as assessed using the Profile of Mood States (POMS) survey.
Timepoint [1] 399404 0
Three mood surveys will be completed during each trial visit. That is upon arrival, before leaving the research unit, and at home upon waking.
Secondary outcome [2] 399405 0
Changes in cognitive performance as assessed using the Computerised Mental Performance Assessment System (COMPASS, Northumbria University, Newcastle upon Tyne, UK).
Timepoint [2] 399405 0
Cognitive assessment will be completed at each morning trial visit stay.
Secondary outcome [3] 399406 0
Changes in dietary intakes as assessed by 3-day food diaries.
Timepoint [3] 399406 0
The participant will complete three 3-day food diaries before each trial visit.
Secondary outcome [4] 399456 0
Changes in composite inflammatory biomarkers (TNFa, IL-6, IL-1ß, IL-8, IL-12p70) and oxidative stress parameters (reactive oxygen species (ROS)/reactive nitrogen species, superoxide dismutase activity, catalase activity, FRAP and lipid peroxidation concentrations) using a commercial assay kit.
Timepoint [4] 399456 0
These biomarkers will be measured in plasma samples collected at trial visits. At each visit, six blood samples will be collected. Samples collected will include baseline upon arrival at the laboratory and 30, 60, 120, 180 and 240 min after complete ingestion of the standardised meal and intervention. Inflammatory biomarkers will be assayed using a bead-based multiplex panel and measured by flow cytometry. In addition, oxidative stress parameters will be measured using a commercial assay kit.
Secondary outcome [5] 399457 0
Changes in Monoamine Oxidase (MAO) activity using a commercial assay kit.
Timepoint [5] 399457 0
MAO activity will be measured in plasma samples collected at trial visits. At each visit, six blood samples will be collected. Samples collected will include baseline upon arrival at the laboratory and 30, 60, 120, 180 and 240 min after complete ingestion of the standardised meal and intervention.
Secondary outcome [6] 399458 0
Changes in composite targeted metabolomic plasma analyses of 75 metabolites using high-performance liquid chromatography-mass spectrometry.
Timepoint [6] 399458 0
These biomarkers will be measured in plasma samples collected at trial visits. At each visit, six blood samples will be collected. Samples collected will include baseline upon arrival at the laboratory and 30, 60, 120, 180 and 240 min after complete ingestion of the standardised meal and intervention. Metabolites will be quantified using high-performance liquid chromatography-mass spectrometry.

Metabolites and neurotransmitters will be determined in blood using targetted metabolomics. This includes 5-Hydroxyindoleacetic acid, 5-Hydroxytryptophol, N-Acetylserotonin, Tryptophan, Leucine, Lysine, Isoleucine, Alanine, Methionine, Proline, Threonine, Valine, Asparagine, Histidine, Arginine, Tyrosine, Phenylalanine, Cysteic acid, Choline, 3,4-Dihydroxyphenylacetic acid, 3-Methoxytyramine, Homovanillic acid, 3,4-Dihydroxyphenylalanine, Carnosine, Anserine, Kyotorphin, Citrulline, Ornithine, Acetylcholine, 3-Hydroxyanthranilic acid, Homocysteine, 3,4-Dihydroxymandelic acid, Normetanephrine, 3,4-Dihydroxyphenylglycol, 3-Methoxy-4-hydroxyphenylglycol, Vanillylmandelic acid, Cysteine, Glutamine, Glutamate, Aspartate, Glycine, Serine, B-Alanine, Kynurenic acid, 3-Hydroxykynurenine Serotonin, Dopamine, 4-Aminobutyric acid, Histamine, Melatonin, Taurine, Norepinephrine, Epinephrine, Homoserine, Adenosine, Synephrine, Putrescine, Spermidine, Spermine, N-Acetylputrescine, Agmatine, Hypotaurine, Homocysteic acid, Glucose, Tyramine, Phenethylamine, Tryptamine, Octopamine, Glutathione, Kynurenine, 5-Hydroxytryptophan and Ethanolamine.
Secondary outcome [7] 399459 0
Changes in composite Hypothalamic–pituitary–adrenal (HPA) axis hormones (adrenocorticotropic, cortisol, prolactin and growth hormone) in plasma using a commercial assay kit.
Timepoint [7] 399459 0
These hormones will be measured in plasma samples collected at trial visits. At each visit, six blood samples will be collected. Samples collected will include baseline upon arrival at the laboratory and 30, 60, 120, 180 and 240 min after complete ingestion of the standardised meal and intervention. Hormones will be measured using a commercial assay kit.
Secondary outcome [8] 399461 0
Untargeted multi-omic analysis of plasma samples - exploratory outcome
Timepoint [8] 399461 0
Blood plasma samples collected at trial visits will undergo untargeted multi-omic (metabolomics and lipidomics) analysis using validated LC-MS techniques. At each visit, six blood samples will be collected. Samples collected will include baseline upon arrival at the laboratory and 30, 60, 120, 180 and 240 min after complete ingestion of the standardised meal and intervention.
Secondary outcome [9] 399462 0
Changes in composite urinary 6-sulfatoxymelatonin and 5-hydroxyindoleacetic using commercially available kits.
Timepoint [9] 399462 0
Three urine samples will be collected during each trial visit. That is upon arrival, before leaving the research unit, and at home upon waking. 6-sulfatoxymelatonin and 5-hydroxyindoleacetic will be quantified using commercially available kits.
Secondary outcome [10] 399471 0
Changes in waking salivary cortisol response using commercially available kits.
Timepoint [10] 399471 0
Four waking salivary samples will be collected the morning after each trial visit. That is upon waking, and 30, 45, 60 min post wake. Cortisol will be measured using a commercial assay kit.
Secondary outcome [11] 399482 0
Changes in the subjective awakening state as assessed by 100mm visual analogue scale (VAS).
Timepoint [11] 399482 0
The VAS will be completed the morning after each intervention.

Eligibility
Key inclusion criteria
Healthy males
Aged between 18-45 years of age
Body mass index (BMI) (18.5-30kg/m2)
Physically active but no more than 2 hours per day
Poor sleepers, defined as having an ISI (Insomnia Severity Index) score of >8 (Ree, Pollitt, & Harvey, 2006) and the Pittsburgh Sleep Quality Index (PSQI) score >5 (Buysse, Reynolds III, Monk, Berman, & Kupfer, 1988)
Minimum age
18 Years
Maximum age
45 Years
Sex
Males
Can healthy volunteers participate?
No
Key exclusion criteria
The intended participants will be healthy males who are poor sleepers as defined by a screening survey (PSQI and ISI), aged between 18-45years old, and have a body mass index between 18.5-30kg/m2. Exclusion criteria will include use of certain medications that affect digestion and sleep, excessive alcohol intake, smoking, history of gastrointestinal disorders, medical conditions related to digestive function and chronic sleep disorders, psychiatric conditions, antibiotic consumption (1 month prior), blood donation (3 months prior), on a strict weight loss diet, vegan/vegetarian, diagnosed with COVID-19, aversion to blood sampling or difficult veins, and allergies to dairy, eggs, cereals, soy and kiwifruit.

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)
Eligible volunteers are assigned a subject number and randomised onto a treatment visit schedule based on a Latin square design balanced for the order of presentation and carry-over effect. Treatments will be assigned a code. The treatment code will be held by two scientists who are not responsible for treatment dispensing or data collection. The unblinded scientists are responsible for allocating a random treatment position to the volunteers and preparing the study interventions.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Randomisation will be conducted using a 6 × 3 Williams design balanced for the order of presentation and carryover effects. Randomisation will be performed using the method of randomly permuted blocks (https://www.randomizer.org/).
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
Efficacy
Statistical methods / analysis
A power analysis was performed to estimate variance components using data from our study where dried kiwifruits were given and sleep was measured. Calculations were done on the primary endpoint of sleep onset latency (0.25) and subjective measures of getting to sleep (0.23). The model based upon an estimated error variance was taken from a recently completed study and calculated. Using the power of 80% suggests that the number of subjects required is estimated to fall between 30-36 participants. Given the potential for participants to withdraw from the study and ensure the design is balanced for order and carryover effects, recruiting 42 people will allow 80% power even after potential withdraws.

Demographic and anthropometric characteristics will be summarised using descriptive statistics. All outcome variables will be analysed using a mixed-effects linear model to account for the repeated measurements that yield period, sequence, and carryover effects and to model the various intra-patient and inter-patient variability sources. Where the repeated measures linear mixed model ANOVA is significant, Bonferroni post hoc analysis will be used for comparisons between conditions. Relations of measures and metabolites were tested using Pearson's Correlation Coefficient. Statistical significance will be accepted at P < 0.05. All data are presented as means ± SEs. Heat maps will be generated to enable better data visualisation. Where appropriate, the original data will be transformed to achieve normality and constant variance in the residuals. Statistical significance for all parameters will be set at P < 0.05 with a confidence level of 95%.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
28/02/2022
Actual
Date of last participant enrolment
Anticipated
30/06/2022
Actual
Date of last data collection
Anticipated
30/11/2022
Actual
Sample size
Target
42
Accrual to date
Final
Recruitment outside Australia
Country [1] 24009 0
New Zealand
State/province [1] 24009 0
Palmerston North

Funding & Sponsors
Funding source category [1] 309265 0
Other
Name [1] 309265 0
Riddet Institute
Country [1] 309265 0
New Zealand
Primary sponsor type
University
Name
Massey University
Address
Massey University Manawatu (Turitea)
Tennent Drive
Palmerston North 4474
New Zealand
Country
New Zealand
Secondary sponsor category [1] 310356 0
None
Name [1] 310356 0
Address [1] 310356 0
Country [1] 310356 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 309107 0
Central Health and Disability Ethics Committees
Ethics committee address [1] 309107 0
Ethics committee country [1] 309107 0
New Zealand
Date submitted for ethics approval [1] 309107 0
27/10/2021
Approval date [1] 309107 0
24/11/2021
Ethics approval number [1] 309107 0
11089

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

Contacts
Principal investigator
Name 112998 0
Mr Alex Kanon
Address 112998 0
Riddet Institute
Massey University
Private Bag 11222
Palmerston North 4442
Country 112998 0
New Zealand
Phone 112998 0
+64 6 951 7292
Fax 112998 0
Email 112998 0
[email protected]
Contact person for public queries
Name 112999 0
Sharon Henare
Address 112999 0
School of Health Sciences
College of Health
Massey University
Private Bag 11222
Palmerston North 4442
Country 112999 0
New Zealand
Phone 112999 0
+64 6 951 7289
Fax 112999 0
Email 112999 0
[email protected]
Contact person for scientific queries
Name 113000 0
Warren McNabb
Address 113000 0
Riddet Institute
Massey University
Private Bag 11222
Palmerston North 4442
Country 113000 0
New Zealand
Phone 113000 0
+64 6 951 7742
Fax 113000 0
Email 113000 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


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.