Evaluating the Effects of Prebiotics on Sleep, the Gut Microbiome, Cognition, Immune Function and Stress

Study Overview
=================
Brief Summary
-----------------
The aim of the proposed randomised, double-blind, controlled, parallel groups trial is to assess the sleep, gut microbiome, cognitive, immune and stress effects of 56 days administration of three formulations of a prebiotic-based intervention, in comparison to a placebo control, in a cohort of healthy adults reporting poor sleep quality.

Official Title
-----------------
Evaluating the Effects of Prebiotic-based Interventions on Sleep, the Gut Microbiome, Cognition, Immune Function and Stress Following 56 Days Consumption in Healthy Volunteers

Conditions
-----------------
Sleep

Intervention / Treatment
-----------------
* Dietary Supplement: Prebiotic
* Other: Control


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Participants must self-assess themselves as being in good health. Have a stable sleep/wake schedule (bedtime between 9pm and 1am and wake time between 6am and 10am at least 5 nights per week) Aged 25 to 60 years at the time of randomisation Fluent in English Identify as a 'poor sleeper' as defined subjectively (i.e. poor sleep quality, unrefreshing sleep) and a total score of >5 on the Pittsburgh Sleep Quality Index (PSQI). Exclusion Criteria: Member of own household currently participating in this trial Evidence of current or recent sleep disorders (e.g. sleep apnoea, insomnia, circadian rhythm disorders), taking any medication which exerts sedative effects, affects the CNS and/or sleep, or be currently unwell with any illness that affects sleep (i.e. disorders of the CNS). An initial screening for sleep disorders will be conducted using the Sleep Disorders Symptom Checklist-25 (SDS-CL; Klingman et al., 2017). If a participant reports positively to any of the 25 questions in terms of being affected for three nights per week, or more, this will be followed up using a clinical interview according to the International Classification of Sleep Disorders (ICSD-3) to exclude on the basis of a sleep disorder History of seizures or epilepsy Shift working or have a history of shift work within the previous six months Currently, or within the previous 8 weeks, consuming any prebiotic or probiotic products/supplements (including specifically oligosaccharides) Participation in any other intervention research trials Sleeping at a location other than their usual residence more than two nights per week during participation Travel across multiple time zones within the last three months or have planned travel across multiple time zones during the study Current or recent mood disturbances or Axis I disorders Current misuse of alcohol and/or drugs Current smoker Recent (within the last 12 weeks) infection and/or use of antibiotic medication Pregnant, seeking to become pregnant or lactating Those using (including within the last 2 weeks) proton-pump inhibitors Milk allergy

Ages Eligible for Study
-----------------
Minimum Age: 25 Years
Maximum Age: 60 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Other
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Investigational Supplement 1 (INV-1)<br>The total daily supplement to be consumed by participants is 33.0 g. This will be administered as 2 separate doses mixed with water, a 16.5 g dose (two 8.25 g sachets) to be consumed in the morning (AM dose) and a 16.5 g dose (two 8.25 g sachets) to be consumed in the evening (PM dose). Supplementation will last 56 days. | Dietary Supplement: Prebiotic<br>* The bioactive ingredients used in this study include bovine milk fat globule membrane (MFGM), bovine lactoferrin and a prebiotic blend of polydextrose and galactooligosaccharides (PDX/GOS).<br>|
| Active Comparator: Investigational Supplement 1 (INV-2)<br>The total daily supplement to be consumed by participants is 33.0 g. This will be administered as 2 separate doses mixed with water, a 16.5 g dose (two 8.25 g sachets) to be consumed in the morning (AM dose) and a 16.5 g dose (two 8.25 g sachets) to be consumed in the evening (PM dose). Supplementation will last 56 days. | Dietary Supplement: Prebiotic<br>* The bioactive ingredients used in this study include bovine milk fat globule membrane (MFGM), bovine lactoferrin and a prebiotic blend of polydextrose and galactooligosaccharides (PDX/GOS).<br>|
| Active Comparator: Investigational Supplement 1 (INV-3)<br>The total daily supplement to be consumed by participants is 33.0 g. This will be administered as 2 separate doses mixed with water, a 16.5 g dose (two 8.25 g sachets) to be consumed in the morning (AM dose) and a 16.5 g dose (two 8.25 g sachets) to be consumed in the evening (PM dose). Supplementation will last 56 days. | Dietary Supplement: Prebiotic<br>* The bioactive ingredients used in this study include bovine milk fat globule membrane (MFGM), bovine lactoferrin and a prebiotic blend of polydextrose and galactooligosaccharides (PDX/GOS).<br>|
| Placebo Comparator: Control<br>The total daily supplement to be consumed by participants is 33.0 g. This will be administered as 2 separate doses mixed with water, a 16.5 g dose (two 8.25 g sachets) to be consumed in the morning (AM dose) and a 16.5 g dose (two 8.25 g sachets) to be consumed in the evening (PM dose). Supplementation will last 56 days. | Other: Control<br>* Maltodextrin<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Lab-recorded polysomnography- Sleep Quality | percentage of time in staged sleep from total sleep recorded time | Change from protocol days 2 and 3 (baseline) and 59 and 60 following 56 days of supplement consumption | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Lab-recorded polysomnography- Sleep onset latency | minutes taken from intention to sleep to first epoch of any stage of sleep | Change from protocol days 2 and 3 (baseline) and 59 and 60 following 56 days of supplement consumption | 
| Lab-recorded polysomnography- Total sleep time | minutes of staged sleep over entire sleep duration period | Change from protocol days 2 and 3 (baseline) and 59 and 60 following 56 days of supplement consumption | 
| Lab-recorded polysomnography- Number of awakenings | number of <15 second bouts of Wake surrounded, at both ends, by any sleep stage | Change from protocol days 2 and 3 (baseline) and 59 and 60 following 56 days of supplement consumption | 
| Lab-recorded polysomnography- Wake after sleep onset | cumulative minutes of scored Wake during entire sleep duration following sleep initiation | Change from protocol days 2 and 3 (baseline) and 59 and 60 following 56 days of supplement consumption | 
| Lab-recorded polysomnography- Time spent in stages of rapid eye movement (REM) and non-REM sleep | percentage of time spent in REM, N1, N2, N3 | Change from protocol days 2 and 3 (baseline) and 59 and 60 following 56 days of supplement consumption | 
| Lab-recorded polysomnography- REM Rebound | length, frequency and depth of REM sleep | Change from protocol days 2 and 3 (baseline) and 59 and 60 following 56 days of supplement consumption | 
| Lab-recorded polysomnography- Sleep microstructure | including k-complexes - >.0.5 secs. negative then positive wave and fast/slow sleep spindles - >.0.5 secs. sinusoidal waves 11-16Hz | Change from protocol days 2 and 3 (baseline) and 59 and 60 following 56 days of supplement consumption | 
| Actigraphy - Sleep onset latency | recorded minutes taken from intention to sleep to sleep initiation | Change from baseline following 56 days of supplement consumption | 
| Actigraphy - Total sleep time | recorded minutes asleep over entire sleep period | Change from baseline following 56 days of supplement consumption | 
| Actigraphy - Number of awakenings | recorded number of awakenings during entire sleep period | Change from baseline following 56 days of supplement consumption | 
| Actigraphy - Wake after sleep onset (WASO) | recorded minutes awake during the entire sleep period following sleep onset | Change from baseline following 56 days of supplement consumption | 
| Actigraphy - Sleep efficiency | ratio of the total time spent asleep (total sleep time) in a night compared to the total amount of time spent in bed (percentage) | Change from baseline following 56 days of supplement consumption | 
| Blood Pressure and Heart Rate (BP/HR) | Measured using a fully automatic oscillometric device | Change from baseline following 56 days of supplement consumption | 
| Body Mass Index (BMI) | calculated using standard formula: weight (kg) / [height (m)]2 | Change from baseline following 56 days of supplement consumption | 
| Waist-to-Hip Ratio (WHR) | WHR will be calculated by dividing waist circumference by hip circumference. | Change from baseline following 56 days of supplement consumption | 
| Pittsburgh Sleep Quality Index (PSQI) | Pittsburgh Sleep Quality Index (PSQI): Total Score. The PSQI is a validated self-rating instrument assessing aspects of sleep quality.Minimum score 0 (better); maximum score 21 (worse) < or = 5 associated with good sleep quality; > 5 associated with poor sleep quality. | Change from baseline following 56 days of supplement consumption | 
| Profile of Mood States (POMS) | Profile of Mood States (POMS): Mood scores. The Profile of Mood States (POMS) is a psychological rating scale used to assess transient, distinct mood states. 65 adjectives rated on 5-point scale 0= not at all; 1=a little; 2=moderately; 3=quite a bit; 4=extremely. Factor analysis: 6 subscales tension-anxiety (9 items, score range: 0-36) depression (15 items, range 0-60) anger-hostility (12 items, range 0-48) vigor-activity (8 items, range 0-32) fatigue (7 items, range 0-28) confusion-bewilderment (7 items, range 0-28) Total mood disturbance (TMD): (range 0-200) | Change from baseline following 56 days of supplement consumption | 
| Depression, Anxiety and Stress Scale - 21 Items (DASS-21) | A 21-item measure of mood over the previous week (each item is rated on scale from 0-3). Scoring creates 3 component scores: depression, anxiety and stress (each on a scale of 0-21) with higher scores indicating higher symptomology. Cut-off scores, according to each set of symptoms, are available (normal, mild, moderate, severe and extremely severe) or total scores can be derived by multiplying the sum of all three component scores by 2. | Change from baseline following 56 days of supplement consumption | 
| State-Trait Anxiety Inventory (STAI) | A 40-item measure of current and general anxiety levels. Each item is rated on a scale from 1-4. Scoring creates two components: state anxiety (20 items) and trait anxiety (20 items), with a range for each between 20-80. Following transformation through reversed coding, higher scores indicate higher levels of anxiety. | Change from baseline following 56 days of supplement consumption | 
| Work Productivity and Activity Impairment questionnaire (WPAI) | A 6-item measure of the impact of an individual's health on their work over the previous week. There are 4 component scores: presenteeism, activity impairment, absenteeism and overall work productivity. All items have varying response formats and higher scores indicate more impairment in each domain. Overall scores can also be summed and multiplied by 100 for an overall impairment index. | Change from baseline following 56 days of supplement consumption | 
| 12-Item Short Form Survey (SF-12) | A 12-item measure of current perceptions of health status. All items have varying response formats and result in 8 component scores: 1) Limitations in physical activities because of health problems, 2) Limitations in social activities because of physical or emotional problems, 3) Limitations in usual role activities because of physical health problems, 4) Bodily pain, 5) General mental health (psychological distress and well-being), 6) Limitations in usual role activities because of emotional problems, 7) Vitality (energy and fatigue) and 8) General health perceptions. | Change from baseline following 56 days of supplement consumption | 
| Perceived Stress Scale (PSS | Perceived Stress Scale (PSS): Total Score. The PSS is comprised of 14 items intended to measure how unpredictable, uncontrollable, and overloaded individuals find their life circumstances.Participants rate items on a 5-point Likert scale, ranging from 0 - Never to 4 - Very often. Scores range from 0-56 higher scores indicate greater perceived stress | Change from baseline following 56 days of supplement consumption | 
| Gastrointestinal symptoms questionnaire | This in-house developed questionnaire is to be completed at the start and end of the trial, during the baseline and chronic lab visits respectively. When completing the assessment, participants will answer in relation to their experiences in the previous 7 days. The questionnaire asks 11 questions, plus a 12th open-ended question, about gastrointestinal experiences, with 5 possible ratings; 'not at all' (score of 0), 'A little' (score of 1), 'a moderate amount' (score of 2), 'quite a lot' (score of 3) and 'a severe amount' (score of 4). Scores can range between 0-44 with a higher score indicating a more negative experience of symptoms | Change from baseline following 56 days of supplement consumption | 
| Sleep Diary -Total Sleep Time | how long, in minutes, the individual reports being asleep during the night between initiation and termination of sleep, accounting for nocturnal wake periods | Change from baseline following 56 days of supplement consumption | 
| Sleep Diary -Time in bed | how long, in minutes, the individual reports being in bed intending to sleep | Change from baseline following 56 days of supplement consumption | 
| Sleep Diary -Sleep Latency | how long, in minutes, the individual felt it took them to fall asleep after intending to sleep | Change from baseline following 56 days of supplement consumption | 
| Sleep Diary -Number of Awakenings | number of perceived awakenings over the sleep period | Change from baseline following 56 days of supplement consumption | 
| Sleep Diary - Wake After Sleep Onset (WASO) | how long, in minutes, the individual reports being awake during the night after sleep initiation | Change from baseline following 56 days of supplement consumption | 
| Sleep Diary - Sleep Efficiency | Total Sleep Time divided by Time in Bed x 100, expressed as a percentage | Change from baseline following 56 days of supplement consumption | 
| Sleep Diary - Sleep Quality | 4 items (each scored on a 0-4 scale) covering nocturnal physical and psychological tension, sleep enjoyment and feelings of restedness. Items can be summed (range 0-16) with higher scores indicating poorer sleep quality. | Change from baseline following 56 days of supplement consumption | 
| Dietary assessment- Intake24 | The Intake 24 measure (https://intake24.co.uk/) will assess participants dietary recall over the previous 24 hour period. The generated results provide an indication of overall calorie intake as well as fibre, sugar, calcium, total fat, saturated fat, vitamin C, iron, folate, fruit and vegetable and red meat intake. | Change from baseline following 56 days of supplement consumption | 
| Perceived sleep quality (VAS) | Assessed weekly via numerical rating scales. This will generate individual scores of 0-4 (0= 'Extremely poor' to 4= 'Extremely good') | Change from baseline following 56 days of supplement consumption | 
| Subjective Stress (VAS) | Assessed weekly via numerical rating scales. This will generate individual scores of 0-4 (0= 'Extremely poor' to 4= 'Extremely good') | Change from baseline following 56 days of supplement consumption | 
| Subjective mood (VAS) | Assessed weekly via numerical rating scales. This will generate individual scores of 0-4 (0= 'Extremely poor' to 4= 'Extremely good') | Change from baseline following 56 days of supplement consumption | 
| Subjective productivity (VAS) | Assessed weekly via numerical rating scales. This will generate individual scores of 0-4 (0= 'Extremely poor' to 4= 'Extremely good') | Change from baseline following 56 days of supplement consumption | 
| COMPASS global performance measures | Speed of performance, and accuracy of performance measured by Computerised Mental Performance Assessment System (COMPASS, Northumbria University) | Change from baseline following 56 days of supplement consumption | 
| Cognitive domain factor score | Speed of attention, accuracy of attention, speed of memory, accuracy of working memory, and accuracy of episodic memory measured by Computerised Mental Performance Assessment System (COMPASS, Northumbria University) | Change from baseline following 56 days of supplement consumption | 
| Cognitive Function under stressful conditions | Cognitive performance (multi tasking using Serial Subtractions (3s, 7s, 17s) and tracking simultaneously) during acute stress as a consequence of theOBSERVED MULTITASKING STRESSOR (OMS) | Change from baseline following 56 days of supplement consumption | 
| Changes in subjective stress; as assessed by the 'state, trait anxiety inventory' (STAI) | Subjective stress will be measured via the state, trait anxiety inventory before and after each completion of the observed multitasking stressor (OMS) | Change from baseline following 56 days of supplement consumption | 
| Changes in objective stress; as assessed by salivary cortisol levels | Saliva samples will be taken from participants before and after each completion of the observed multitasking stressor (OMS) and the change in salivary cortisol levels between pre- and post-OMS | Change from baseline following 56 days of supplement consumption | 
| Changes in objective stress; as assessed by salivary alpha-amylase levels | Saliva samples will be taken from participants before and after each completion of the observed multitasking stressor (OMS) and the change in salivary cortisol levels between pre- and post-OMS | Change from baseline following 56 days of supplement consumption | 
| Changes in objective stress; as assessed by galvanic skin response (GSR) | Galvanic skin response (GSR) will be recorded throughout the observed multitasking stressor (OMS) | Change from baseline following 56 days of supplement consumption | 
| Changes in objective stress; as assessed by heart rate (HR) | Heart rate (HR) will be recorded throughout the observed multitasking stressor (OMS) | Change from baseline following 56 days of supplement consumption | 
| Gut microbiome assessments (gut bacterial profile) | Assessed via analysis of self collected stool samples at baseline, during active supplementation and after 56 days of supplementation. | Change from baseline following 56 days of supplement consumption | 
| Immunological marker Assessment -Blood | Immune function (identification of blood biomarkers of immune function in samples collected at baseline and chronic lab visits) | Change from baseline following 56 days of supplement consumption | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Immune Function, Gut Microbiome, Stress, Cognition