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Trial registered on ANZCTR


Registration number
ACTRN12623000373673
Ethics application status
Approved
Date submitted
4/02/2023
Date registered
13/04/2023
Date last updated
13/06/2023
Date data sharing statement initially provided
13/04/2023
Type of registration
Prospectively registered

Titles & IDs
Public title
Investigating the effect of a paraprobiotic on sleep quality, stress, and gut health in people with insomnia and elevated stress levels
Scientific title
Effect of heat-inactivated Lactobacillus sp. on sleep, stress and gastrointestinal health in adults with insomnia and elevated stress levels: a randomised, controlled trial
Secondary ID [1] 308737 0
Nil
Universal Trial Number (UTN)
U1111-1281-9126
Trial acronym
PROSLEEP
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Insomnia 328680 0
Stress 328681 0
Gastrointestinal health 328682 0
Condition category
Condition code
Mental Health 325689 325689 0 0
Other mental health disorders
Mental Health 325690 325690 0 0
Anxiety
Oral and Gastrointestinal 325691 325691 0 0
Normal oral and gastrointestinal development and function

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
The intervention consists of tablets containing heat-inactivated Lactobacullus sp. (1 x 10^10 bacterial cells per two tablets). The active tablet will be composed of maltose, dextrin, starch, heat-inactivated lactic acid bacteria powder, and vegetable oil.
The study duration is a nominal total of 12 weeks, with a two-week lead-in phase, eight-week intervention phase, and follow-up two-weeks after the end of the intervention.
The 2-weeks lead-in phase requires participants to complete weekly questionnaires about their sleep patterns, and record their bowel motion, mood, and perception of sleep quality every day on an app designed for this trial.
During the second week of the lead-in period they will complete a non-consecutive 3-day food diary, wear an actigraphy device for seven days to measure sleep and activity levels, and wear an electroencephalogram headband for three nights (at their home) to measure brainwave patterns during sleep.
Participants will collect a faecal and saliva sample one day prior to their baseline visit (end of 2nd week of lead-in phase).
At their baseline visit (beginning of intervention phase) participants will have height and weight measured, complete a set of questionnaires about their mental and physical health, general well-being, and clinical variables.
During the eight-week intervention phase, participants will consume two of their assigned tablets each day (with or without water or food), complete their daily bowel motion and mood/sleep app and complete weekly sleep questionnaires and two-weekly mental health questionnaires. The tablets will be packaged in sachets containing two-weeks supply. Compliance will be monitored by checklist and counting returned tablets.
Participants will attend the study clinic at weeks 2, 4 and 6 to return unused tablets, and pick up their next two weeks of tablets.
At the final clinic visit (end of intervention phase), the aforementioned baseline visit procedures will be repeated. Prior to the final visit, participants will again complete the same set of questionnaires, 7-day actigraph, 3-night EEG, and non-consecutive 3-day food diary, and collect a faecal sample and saliva sample. Participants will receive their reimbursement ($300 grocery vouchers). Attendance of clinic visits and completion of questionnaires will be assessed to measure the adherence of participants.
Two-weeks after the final clinic visit, participants will complete an online survey regarding their mental and physical health, general well-being, and gastrointestinal symptoms; the link to this survey will be sent to the participant by email.
Intervention code [1] 325201 0
Treatment: Other
Comparator / control treatment
The placebo control tablets will be prepared using the same procedures and formula as the active tablets, with dextrin replacing the heat inactivated lactic acid bacteria powder.
Control group
Placebo

Outcomes
Primary outcome [1] 333743 0
Change in self-reported sleep quality, measured by Pittsburgh Sleep Quality Index global score
Timepoint [1] 333743 0
Baseline (beginning of intervention phase) and end of intervention (week 8)
Secondary outcome [1] 418119 0
Change in self-reported stress, measured with the Perceived Stress Questionnaire- Recent Stress
Timepoint [1] 418119 0
Baseline (beginning of intervention phase), week 2, week 4, week 6, end of intervention (week 8), and 2-week post-intervention follow-up
Secondary outcome [2] 418120 0
Change in sleep quality, measured as a composite of sleep onset latency (time taken to fall asleep) and sleep stages (Rapid Eye Movement and Non-Rapid Eye Movement sleep), measured with an EEG headband
Timepoint [2] 418120 0
Baseline (beginning of intervention phase) and end of intervention (week 8)
Secondary outcome [3] 418121 0
Change in complete spontaneous bowel movements using a bowel habit diary app designed for this study
Timepoint [3] 418121 0
Daily, starting from 2-weeks prior to start of intervention and finishing 2-weeks post-intervention
Secondary outcome [4] 418122 0
Change in self-reported anxiety, as measured with the State-Trait Anxiety Inventory - Trait version, as an exploratory analysis
Timepoint [4] 418122 0
Baseline (beginning of intervention phase), week 2, week 4, week 6, end of intervention (week 8), and 2-week post-intervention follow-up
Secondary outcome [5] 418123 0
Change in self-reported anxiety, as measured with the Hospital Anxiety and Depression Scale anxiety subscale, as an exploratory outcome
Timepoint [5] 418123 0
Baseline (beginning of intervention phase), week 2, week 4, week 6, end of intervention (week 8), and 2-week post-intervention follow-up
Secondary outcome [6] 418124 0
Change in self-reported depression, as measured with the Hospital Anxiety and Depression Scale depression subscale
Timepoint [6] 418124 0
Baseline (beginning of intervention phase), week 2, week 4, week 6, end of intervention (week 8), and 2-week post-intervention follow-up
Secondary outcome [7] 418125 0
Change in subjective sleep quality, measured by the Pittsburgh Sleep Quality Index, as an exploratory analysis
Timepoint [7] 418125 0
Baseline (beginning of intervention phase) and end of intervention (week 8)
Secondary outcome [8] 418126 0
Change in salivary cortisol levels, as an exploratory analysis
Timepoint [8] 418126 0
Baseline (beginning of intervention phase) and end of intervention (week 8)
Secondary outcome [9] 418127 0
Change in physical activity levels, as measured with actigraphy wristwatch for 7-days, as an exploratory analysis
Timepoint [9] 418127 0
Baseline (beginning of intervention phase) and end of intervention (week 8)
Secondary outcome [10] 418128 0
Change in physical activity levels, as measured with a daily diary administered during the 7-days wearing the actigraphy wristwatch
Timepoint [10] 418128 0
Baseline (beginning of intervention phase) and end of intervention (week 8)
Secondary outcome [11] 418129 0
Change in self-reported sleep disturbance, as measured with the Patient Reported Outcomes Measurement Information System (PROMIS): Sleep Disturbance and Sleep Impairment subscales, as an exploratory analysis
Timepoint [11] 418129 0
Weekly, starting from 2-weeks prior to the start of the intervention and finishing 2-weeks post-intervention
Secondary outcome [12] 418130 0
Change in the stool microbiota composition and functional potential as assessed as a composite outcome, from shotgun metagenomic sequencing, as an exploratory analysis
Timepoint [12] 418130 0
Baseline (beginning of intervention phase) and end of intervention (week 8)
Secondary outcome [13] 420657 0
Change in sleep onset latency (time taken to fall asleep), measured with an EEG headband
Timepoint [13] 420657 0
Baseline (beginning of intervention phase) and end of intervention (week 8)
Secondary outcome [14] 420658 0
Change in time spent in Rapid Eye Movement sleep stage, measured with an EEG headband
Timepoint [14] 420658 0
Baseline (beginning of intervention phase) and end of intervention (week 8)
Secondary outcome [15] 420659 0
Change in time spent in Non-Rapid Eye Movement sleep stages (total time in N1, N2 and N3 stages, combined), measured with an EEG headband
Timepoint [15] 420659 0
Baseline (beginning of intervention phase) and end of intervention (week 8)
Secondary outcome [16] 420660 0
Change in habitual sleep onset latency (time taken to fall asleep), measured with an actigraphy wristwatch for 7-days
Timepoint [16] 420660 0
Baseline (beginning of intervention phase) and end of intervention (week 8)
Secondary outcome [17] 420661 0
Change in habitual sleep timing (sleep onset and sleep offset), measured with an actigraphy wristwatch for 7-days
Timepoint [17] 420661 0
Baseline (beginning of intervention phase) and end of intervention (week 8)
Secondary outcome [18] 420662 0
Change in habitual sleep quantity (sleep period time and total sleep time), measured with an actigraphy wristwatch for 7-days
Timepoint [18] 420662 0
Baseline (beginning of intervention phase) and end of intervention (week 8)
Secondary outcome [19] 420663 0
Change in habitual sleep quality (sleep efficiency and waking after sleep onset and number of sleep awakenings) measured with an actigraphy wristwatch for 7-days
Timepoint [19] 420663 0
Baseline (beginning of intervention phase) and end of intervention (week 8)
Secondary outcome [20] 420664 0
Change in subjective sleep latency, measured by the Pittsburgh Sleep Quality Index, as an exploratory analysis
Timepoint [20] 420664 0
Baseline (beginning of intervention phase) and end of intervention (week 8)
Secondary outcome [21] 420665 0
Change in subjective sleep duration, measured by the Pittsburgh Sleep Quality Index, as an exploratory analysis
Timepoint [21] 420665 0
Baseline (beginning of intervention phase) and end of intervention (week 8)
Secondary outcome [22] 420666 0
Change in subjective habitual sleep efficiency, measured by the Pittsburgh Sleep Quality Index, as an exploratory analysis
Timepoint [22] 420666 0
Baseline (beginning of intervention phase) and end of intervention (week 8)
Secondary outcome [23] 420667 0
Change in subjective sleep disturbances, measured by the Pittsburgh Sleep Quality Index, as an exploratory analysis
Timepoint [23] 420667 0
Baseline (beginning of intervention phase) and end of intervention (week 8)
Secondary outcome [24] 420668 0
Change in use of sleeping medications, measured by the Pittsburgh Sleep Quality Index, as an exploratory analysis
Timepoint [24] 420668 0
Baseline (beginning of intervention phase) and end of intervention (week 8)
Secondary outcome [25] 420669 0
Change in subjective daytime dysfunction, measured by the Pittsburgh Sleep Quality Index, as an exploratory analysis
Timepoint [25] 420669 0
Baseline (beginning of intervention phase) and end of intervention (week 8)
Secondary outcome [26] 420670 0
Change in the stool microbiota composition as assessed from shotgun metagenomic sequencing, as an exploratory analysis
Timepoint [26] 420670 0
Baseline (beginning of intervention phase) and end of intervention (week 8)
Secondary outcome [27] 420671 0
Change in the stool microbiota functional potential as assessed from shotgun metagenomic sequencing, as an exploratory analysis
Timepoint [27] 420671 0
Baseline (beginning of intervention phase) and end of intervention (week 8)
Secondary outcome [28] 420672 0
Change in self-reported daily impairment, as measured with the Patient Reported Outcomes Measurement Information System (PROMIS): Sleep Disturbance and Sleep Impairment subscales, as an exploratory analysis
Timepoint [28] 420672 0
Weekly, starting from 2-weeks prior to the start of the intervention and finishing 2-weeks post-intervention

Eligibility
Key inclusion criteria
To be eligible to participate, people must meet both 1 and 2 of the following inclusion criteria:
1) Experiencing sleep disturbances (difficulty getting to sleep, and/or staying asleep and/or waking too early over the last three months).
2) Experiencing elevated stress
Minimum age
18 Years
Maximum age
45 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
- having a current clinical diagnosis of a sleep disorder (such as sleep apnea, sleep movement disorder or narcolepsy) or have had a recent major depressive episode or clincal diagnosis of schizophrenia, manic-depression or bipolar disorder
- taking prescribed medications for a sleep disorder or psychiatric disorder
- taken antibiotics wihtin the month before starting the trial
- medical history of severe gastrointestinal disorder (such as inflammatory bowel disease, coeliac disease) or clinically significant medical condition
- taking prescribed medications such as opioid pain killers, non-steroidal anti-inflammatory drugs
- are pregnant or lactating
- are current smokers
- have excessive alcohol intake (>21 standard drinks a week)
- unwilling to avoid probiotic or prebiotic supplements, or foods/beverages containing high levels of live lactic acid bacteria

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)
The intervention products are packaged in sachets labelled ‘A’ and ‘B’. The study Sponsor will hold the allocation code until end of analyses.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
A randomisation list will be prepared using a statistical software package by an independent Biostatistician.
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
Parallel
Other design features
Phase
Not Applicable
Type of endpoint/s
Efficacy
Statistical methods / analysis
Sample size calculations are based on reported effect sizes for Pittsburgh Sleep Quality Index (PSQI) global scores from previous studies. A sample size of 40 per group will detect a difference in global PSQI change scores, of approximately 1.7, between treatment and placebo groups as statistically significant (two-tailed a=0.05) with 80% power (ß=0.20). This equates to a moderate effect size of approximately 0.6. The sample size is set at 45 participants per group to account for attrition.

The analyses will be undertaken using both the intention-to-treat population (ITT) and the per-protocol population (PP). The Intention to treat population will include those who are randomised after all pre-intervention procedures and take at least 1 dose of study medication. The ITT population will be used for the primary analyses. The PP population will include those in the ITT who have no major protocol violations and have all the study assessments required for the analysis of any outcome and consume at least 80% of the randomised treatment. There will be no imputation of missing data.
Presenting demographic and clinical features and all outcomes will be summarised using standard descriptive statistics including means, medians, standard deviations and ranges and frequencies and percentages depending on the variable types. These will be summarised by randomised group.
Continuous outcomes including the primary outcome (Global PSQI) will be compared as levels or changes between randomised groups using general linear mixed models. These models will include participant as a random effect and time and randomised group as fixed factors. A-priori planned comparisons of the changes from baseline to end of treatment will be undertaken for all measures with multiple assessments during the 8-week intervention study. If any of the continuous outcome measures are not adequately normally distributed and this cannot be remedied by transformation, then these will be compared using non-parametric methods.
All analyses will be undertaken using SPSS v28 and a two-tailed p-value <0.05 will be taken to indicate statistical significance.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
1/05/2023
Actual
10/05/2023
Date of last participant enrolment
Anticipated
30/09/2023
Actual
Date of last data collection
Anticipated
3/11/2023
Actual
Sample size
Target
90
Accrual to date
13
Final
Recruitment outside Australia
Country [1] 25246 0
New Zealand
State/province [1] 25246 0
Dunedin

Funding & Sponsors
Funding source category [1] 312960 0
Commercial sector/Industry
Name [1] 312960 0
Asahi Quality and Innovations Ltd
Country [1] 312960 0
Japan
Primary sponsor type
University
Name
University of Otago
Address
Department of Human Nutrition
University of Otago
PO Box 56
Dunedin 9054
Country
New Zealand
Secondary sponsor category [1] 315428 0
None
Name [1] 315428 0
Address [1] 315428 0
Country [1] 315428 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 312232 0
Southern Health and Disability Ethics Committees
Ethics committee address [1] 312232 0
Ethics committee country [1] 312232 0
New Zealand
Date submitted for ethics approval [1] 312232 0
29/11/2022
Approval date [1] 312232 0
13/02/2023
Ethics approval number [1] 312232 0
2023 FULL 13860

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

Contacts
Principal investigator
Name 123926 0
Dr Jody Miller
Address 123926 0
Department of Human Nutrition
University of Otago
PO Box 56
Dunedin 9054
Country 123926 0
New Zealand
Phone 123926 0
+64 4 479 7559
Fax 123926 0
Email 123926 0
[email protected]
Contact person for public queries
Name 123927 0
Jody Miller
Address 123927 0
Department of Human Nutrition
University of Otago
PO Box 56
Dunedin 9054
Country 123927 0
New Zealand
Phone 123927 0
+64 4 479 7559
Fax 123927 0
Email 123927 0
[email protected]
Contact person for scientific queries
Name 123928 0
Jody Miller
Address 123928 0
Department of Human Nutrition
University of Otago
PO Box 56
Dunedin 9054
Country 123928 0
New Zealand
Phone 123928 0
+64 4 479 7559
Fax 123928 0
Email 123928 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
Individual data is not available to the public. it would be a breach of data security.


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.