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Trial registered on ANZCTR


Registration number
ACTRN12620000411943
Ethics application status
Approved
Date submitted
13/03/2020
Date registered
27/03/2020
Date last updated
25/10/2021
Date data sharing statement initially provided
27/03/2020
Type of registration
Prospectively registered

Titles & IDs
Public title
SMART Study: Sleep, Microbiota And fRuiT Study
Scientific title
Determining the effect of freeze-dried green kiwifruit powder on sleep quality and underlying mechanisms in healthy males with sub-threshold insomnia: a randomised controlled, double-blind, crossover study
Secondary ID [1] 297698 0
None
Universal Trial Number (UTN)
U1111-1244-3459
Trial acronym
SMART Study
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Poor sleep
 311994 0
Condition category
Condition code
Diet and Nutrition 310559 310559 0 0
Other diet and nutrition disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This is a double-blind, placebo-controlled, parallel cross-over design intervention study that will allow us to evaluate whether long-term supplementation with green kiwifruit powder (which includes the skin) on sleep quality and melatonin concentrations. Additionally, we seek to determine impacts on other metabolites, mood, stress, cognition, host-microbial metabolites and gut microbiota.

Prospective participants who have met the study's inclusion/exclusion criteria will be asked to attend a screening session (approximately 30min) where they will meet with the study’s principal investigator. Enrolled participants will be asked to come into the sleep lab on four separate nights, two weeks apart each time. Two days before each visit, the participant will be asked to abstain from foods rich in melatonin and serotonin. On each in-laboratory visit, subjects will be in the laboratory-based assessments at 17:00 hr and complete surveys and questionnaires. Immediately following the first questionnaire, participants will have a venous cannula inserted and a blood sample taken. Blood samples will be collected every hour until bedtime in a room lit to 10lux. At 18:00 hr, a standardised dinner is served and is to be consumed within 30min. Profile of Mood States (POMS) will be completed on arrival 17:00 hr, before bedtime 22:00 hr and waking 07:00 hr. Upon waking, single blood, urine and faecal sample will be collected. Lastly, the participants will complete a cognitive battery at waking; after this, they will be allowed to leave the laboratory.

Participants will be required to undergo a two-week washout period (no kiwifruit consumption) before starting the first arm of this study, beginning after their screening session. They will then have an in-lab visit after this washout (Baseline). For the first arm of this study, recruited participants will be evenly randomised into two treatment groups: (1) freeze-dried green kiwifruit powder and (2) Placebo group. At the start of the study arm, the trial coordinator will give participants bottles containing pre-weighed amounts of either the freeze-dried green kiwifruit powder (32g) or the placebo (22g). Participants will be instructed to consume the intervention with 200ml of water once daily for two weeks after their evening meal. They will be asked to add 50ml of water to ensure that they consume as much product as possible. The trial coordinator will check-in with each participant weekly and ask participants to return unconsumed items on day 14 of each dietary intervention period to monitor compliance. A text message reminder will be sent daily to remind the participants to consume the intervention.

On day 14 of their supplementation period, participants will be asked to return to the research facility and complete their in-lab sleep quality as previously described. The difference is that after their standardised dinner is served, they will also be given the intervention they are currently allocated to.

Like the first prior arm, participants will be required to under two weeks of washout. They will undergo the same dietary restrictions. This can start as early as the day after the first trial arm. Following the washout period, participants will return for the third time (baseline 2) to have similar measures measured as above. They will then be asked to consume the dietary intervention (placebo or kiwifruit powder) they did not receive during the first arm. Furthermore, participants will undergo the same sleep quality measures and biochemical measures as the first trial arm on day 14 of their supplementation period.
Intervention code [1] 313929 0
Treatment: Other
Comparator / control treatment
A matched sugar control for the kiwifruit powder will be used as the placebo for this study. The placebo powder contains significantly lower fibre, protein, lipid and micronutrients compared to the kiwifruit powder. Both the kiwifruit and placebo 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] 319417 0
Changes in subjective and objective sleep quality
Timepoint [1] 319417 0
Subjective sleep quality will be assessed using the Stanford Sleepiness Scale, Pittsburgh Sleep Quality Index and Insomnia Severity Index. Subjective measures will be measured at each overnight sleep session. The two questionnaires Pittsburgh Sleep Quality Index and Insomnia Severity index will be completed upon arrival at the facility. During each blood sample, the participant will be asked to rate their perceived sleepiness based on the Stanford Sleepiness Scale.

Objective sleep quality measurements (sleep onset latency, wake after sleep onset, total sleep time and sleep efficiency) will be measured using wrist-worn actigraphy monitor. The actigraphy watches will be used on the non-dominant arm for the entire duration of the study (approx. 10 weeks).
Primary outcome [2] 323218 0
Changes in Dim Light Melatonin Onset in plasma
Timepoint [2] 323218 0
Hourly blood samples will be collected in a dim light setting (10lx) upon arrival until participants sleep. Melatonin in the plasma will be quantified using a radioimmunoassay method. Blood collections are at baseline, 14 days after intervention consumption and 14 days after a washout on each intervention.
Primary outcome [3] 323278 0
Changes in 6-sulfatoxymelatonin in urine
Timepoint [3] 323278 0
Frist morning void urine samples will be used to quantify 6-sulfatoxymelatonin using ELISA kit. Urine collections are at baseline, 14 days after intervention consumption and 14 days after a washout on each intervention.
Secondary outcome [1] 368079 0
Changes in mood
Timepoint [1] 368079 0
The mood will be assessed using the Profile of Mood States (POMS) survey. Mood assessment will be conducted at baseline, 14 days after intervention consumption and 14 days after washout.
Secondary outcome [2] 369548 0
Changed in targeted metabolomic plasma analyses of 72 metabolites will be undertaken with high-performance liquid chromatography mass spectrometry.
Timepoint [2] 369548 0
At each of the overnight sleeps in the laboratory, eight blood samples hourly and a single will be collected. 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. Blood collections are at baseline, 14 days after intervention consumption and 14 days after a washout on each intervention.
Secondary outcome [3] 369549 0
Changes in gut microbiota
Timepoint [3] 369549 0
At each of the overnight sleeps in the laboratory, a single faecal sample will be collected. DNA and RNA is extracted from the faecal sample, and the relative abundance of gut microbiota is determined by next-generation sequencing analysis. Faecal sample collections are at baseline, 14 days after intervention consumption and 14 days after a washout on each intervention.
Secondary outcome [4] 381412 0
Changes in stress
Timepoint [4] 381412 0
The Kessler Psychological Distress Scale (K10) will be used to measure stress. Stress assessment will be conducted at baseline, 14 days after intervention consumption and 14 days after washout.
Secondary outcome [5] 381413 0
Changes in cognitive performance
Timepoint [5] 381413 0
The cognitive testing will use the Cambridge Neuropsychological Test Automated Battery (CANTAB) software. Cognitive assessment will be conducted at baseline, 14 days after intervention consumption and 14 days after washout.
Secondary outcome [6] 394138 0
Changes in plasma inflammatory biomarkers and oxidative stress parameters undertaken with ELISA kits
Timepoint [6] 394138 0
At each of the overnight sleeps in the laboratory, eight blood samples hourly and a single morning sample will be collected. Inflammatory biomarkers undertaken with ELISA kits, This includes measures of Tumor necrosis factor alpha (TNFa), Interleukin 6 (IL-6) and Interleukin 1 beta (IL-1ß). Oxidative stress parameters include reactive oxygen species (ROS)/reactive nitrogen species, Superoxide Dismutase (SOD) Activity, Catalase activity and lipid peroxidation concentrations.
Secondary outcome [7] 394139 0
Changes in Monoamine Oxidase (MAO) activity undertaken ELISA kits
Timepoint [7] 394139 0
At each of the overnight sleeps in the laboratory, eight blood samples hourly and a single morning sample will be collected. Monoamine Oxidase (MAO) activity with ELISA kits, This includes measures of MAO A and MAO B.
Secondary outcome [8] 394140 0
Changes in Hypothalamic–pituitary–adrenal (HPA) axis hormones in blood will be undertaken with ELISA kits.
Timepoint [8] 394140 0
At each of the overnight sleeps in the laboratory, eight blood samples hourly and a single morning sample will be collected. Adrenocorticotropic Hormone, Cortisol, Prolactin and Growth Hormone (GH) are four key HPA hormones which have shown to change due to sleep. This will be quantified using ELISA kits.
Secondary outcome [9] 394141 0
Changes to subjective ratings of Gastrointestinal Symptoms
Timepoint [9] 394141 0
The Gastrointestinal Symptom Rating Scale (GSRS) will be used to measure this. Gastrointestinal Symptoms assessment will be conducted at baseline, 14 days after intervention consumption and 14 days after washout.
Secondary outcome [10] 394142 0
Changes in dietary intakes
Timepoint [10] 394142 0
The participant will complete four 3-day food diaries before each in-lab sleep visit. This will be conducted before each baseline and in the last seven days, participants are on each 14-day 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)
Glycated haemoglobin (HbA1c) test, value <41mmol/mol (greater than this is considered prediabetes) (Braatvedt et al., 2012)
Minimum age
18 Years
Maximum age
45 Years
Sex
Males
Can healthy volunteers participate?
No
Key exclusion criteria
Use of specific prescribed medication as listed below or recreational drugs use:
Diuretics, Oral or inhaled steroids, Cholinergic antispasmodics, Lactulose, Metamucil, Antibiotics, Sedative/hypnotic medication, Laxatives, Antacids, Cholesterol-lowering medications, Proton pump inhibitors (acid reflux treatments), Vitamin/mineral supplements, Heparin, Antidepressants
Excessive alcohol intake defined as >20g of pure alcohol (2 drinks)/d on average. (>21 standard drinks a week)
Smoke cigarettes
History of gastrointestinal surgery or gastrointestinal disorders including inflammatory bowel disease (IBD), ulcerative colitis, coeliac disease, Crohn’s disease
Medical conditions (e.g., cardiorespiratory, diabetes mellitus, bleeding disorders)
Psychiatric conditions (e.g., Major depressive disorder, Schizophrenia)
Antibiotic consumption (1 month before the study and during the study)
Significant weight loss during the past six months
Being on a controlled diet or dietary weight loss regimen within four weeks before and during the study
Vegetarian/vegan
Aversion to blood sampling
Allergies to dairy products or eggs or fruits
Participants will be asked to abstain from alcohol before attending a sleep session at the laboratory and to abstain from caffeinated beverages and vigorous exercise eight hours before their averaged bedtimes
Diagnosed with or symptoms of COVID-19

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)
The randomisation plan for assigning volunteers onto the Latin square design is generated using a randomization plan generator available at 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
Demographic and anthropometric characteristics will be summarized using descriptive statistics. All outcome variables will be analysed using a mixed-effects linear model ANOVA to account for the repeated measurements that yield period, sequence, and carryover effects and to model the various sources of intra-patient and inter-patient variability. Where the repeated measures linear mixed model ANOVA is significant, Tukey’s post hoc analysis will be used for comparisons between conditions.

A power analysis was performed to provide estimates of variance components using data from Lin et al. 2011, where two green kiwifruits were given, and sleep was measured. Calculations were done on the primary endpoint of sleep onset latency, total sleep time and sleep efficiency. The model-based upon an estimated error variance was taken from Lin et al. 2011 and calculated, using the power of 0.8 suggests that the number of subjects required is estimated to fall between 12-14 participants. Given the potential for participants to withdraw from the study, recruiting 16 people will allow for 80% power even after potential withdraws.

Recruitment
Recruitment status
Withdrawn
Reason for early stopping/withdrawal
Other reasons/comments
Other reasons
New ethics approval was sought so a new record has been submitted.
Date of first participant enrolment
Anticipated
3/05/2021
Actual
Date of last participant enrolment
Anticipated
30/11/2021
Actual
Date of last data collection
Anticipated
31/01/2022
Actual
Sample size
Target
16
Accrual to date
Final
Recruitment outside Australia
Country [1] 21981 0
New Zealand
State/province [1] 21981 0
Auckland

Funding & Sponsors
Funding source category [1] 302222 0
Other
Name [1] 302222 0
Riddet Institute
Country [1] 302222 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] 302834 0
None
Name [1] 302834 0
Address [1] 302834 0
Country [1] 302834 0
Other collaborator category [1] 281016 0
Other Collaborative groups
Name [1] 281016 0
NZ Respiratory & Sleep Institute
Address [1] 281016 0
Ascot Office Park
93-95 Ascot Ave
Greenlane East
Auckland 1051
Country [1] 281016 0
New Zealand

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 302902 0
Massey University Human Ethics
Ethics committee address [1] 302902 0
Ethics committee country [1] 302902 0
New Zealand
Date submitted for ethics approval [1] 302902 0
18/11/2019
Approval date [1] 302902 0
19/03/2020
Ethics approval number [1] 302902 0
SOA 19/78

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

Contacts
Principal investigator
Name 91786 0
Mr Alex Kanon
Address 91786 0
Riddet Institute
Massey University
Private Bag 11222
Palmerston North 4442
Country 91786 0
New Zealand
Phone 91786 0
+64 6 951 7742
Fax 91786 0
Email 91786 0
[email protected]
Contact person for public queries
Name 91787 0
Sharon Henare
Address 91787 0
School of Health Sciences
College of Health
Massey University
Private Bag 11222
Palmerston North 4442
Country 91787 0
New Zealand
Phone 91787 0
+64 6 3569099 84289
Fax 91787 0
Email 91787 0
[email protected]
Contact person for scientific queries
Name 91788 0
Warren McNabb
Address 91788 0
Riddet Institute
Massey University
Private Bag 11222
Palmerston North 4442
Country 91788 0
New Zealand
Phone 91788 0
+64 6 951 7742
Fax 91788 0
Email 91788 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.