Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12622000631707
Ethics application status
Approved
Date submitted
15/04/2022
Date registered
28/04/2022
Date last updated
19/04/2023
Date data sharing statement initially provided
28/04/2022
Type of registration
Prospectively registered

Titles & IDs
Public title
Effects of a probiotic intervention on cognitive symptoms and gut-brain biomarkers in multiple sclerosis (MS); a pilot study.
Scientific title
Effects of a 12-week multi-strain probiotic intervention on cognitive symptoms, kynurenine biomarkers and the gut microbiota in multiple sclerosis (MS); a pilot quasi-randomised, double-blind, placebo-controlled trial.
Secondary ID [1] 306950 0
Nil known.
Universal Trial Number (UTN)
U1111-1277-2120
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Relapsing Remitting Multiple Sclerosis 326060 0
Condition category
Condition code
Neurological 323372 323372 0 0
Multiple sclerosis

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
A combination of phase 1 and RCT's have recently demonstrated positive effects of probiotic interventions on brain lesion volume, clinical disability scores, inflammatory cytokine response, mood, and the gut microbiota in MS. This pilot study aims to determine if these effects extend to the kynurenine pathway of tryptophan metabolism and to cognitive symptoms in people living with relapsing remitting MS. The intervention in this study will be an orally administered multi-strain probiotic blend, containing live, freeze-dried bacteria, sold under the trade name ‘Vivomixx’ in Australia. It will be given as a 2 x sachet dose (totaling 900 billion CFU) once daily, for a period of 12 weeks. This will be self-administered by participants at home. A fact sheet containing the instructions for preparation and consumption will be provided to participants at the time the intervention is dispensed. This will contain the details from the manufacturers product information card, as well as the study contact, and will be reviewed by both the project team physician (neurologist) and clinical neuropsychologist. All investigators responsible for product dispensing will be appropriately trained in the research protocol including the storage, preparation and consumption instructions of the intervention. Planned assessment of intervention adherence includes a compliance schedule sheet for participants to tick off daily dose (to be returned at their end-of-intervention assessment), brief automated compliance text message at the end of each week asking whether all doses were taken during the week (Y/N) and if no, how many were missed, and return of unused sachets at the end of the 12-week period to be counted and recorded by the study coordinator.
Intervention code [1] 323395 0
Treatment: Other
Intervention code [2] 323396 0
Rehabilitation
Comparator / control treatment
The control treatment will be a similar looking and tasting placebo sachet containing maltose only.
Control group
Placebo

Outcomes
Primary outcome [1] 331107 0
10/36 SPATIAL RECOGNITION TEST - Total correct on the 3 learning trials, and total correct after the delay. (Part of Rao’s Brief Repeatable Neuropsychological battery specifically developed to assess cognitive functioning in MS)
Timepoint [1] 331107 0
Baseline and follow-up (within 7 days of completion of the 12-week intervention).
Primary outcome [2] 331108 0
SELECTIVE REMINDING TEST - Total number of words recalled in the 5 learning trials and total words recalled following the delay. (Part of Rao’s Brief Repeatable Neuropsychological battery specifically developed to assess cognitive functioning in MS).
Timepoint [2] 331108 0
Baseline and follow-up (within 7 days of completion of the 12-week intervention).
Primary outcome [3] 331109 0
PACED SERIAL ADDITION TEST - total number of correct responses produced over the two trials. (Part of Rao’s Brief Repeatable Neuropsychological battery specifically developed to assess cognitive functioning in MS).
Timepoint [3] 331109 0
Baseline and follow-up (within 7 days of completion of the 12-week intervention)..
Secondary outcome [1] 408757 0
Primary Outcome: SYMBOL DIGITS MODALITY TEST (oral version) - The total number of correct numbers produced. (Part of Rao’s Brief Repeatable Neuropsychological battery specifically developed to assess cognitive functioning in MS).
Timepoint [1] 408757 0
Baseline and follow-up (within 7 days of completion of the 12-week intervention).
Secondary outcome [2] 408758 0
Primary Outcome: VERBAL FLUENCY TASK - total number of words produced correctly. (Part of Rao’s Brief Repeatable Neuropsychological battery specifically developed to assess cognitive functioning in MS).
Timepoint [2] 408758 0
Baseline and follow-up (within 7 days of completion of the 12-week intervention).
Secondary outcome [3] 408759 0
Primary Outcome: CONNER’S CONTINUOUS PERFORMANCE TEST - omission and commission errors (sustained attention) and change in response speed at various intervals (vigilance).
Timepoint [3] 408759 0
Baseline and follow-up (within 7 days of completion of the 12-week intervention).
Secondary outcome [4] 408760 0
THE EMOTION RECOGNITION TASK - number correct out of 120.
Timepoint [4] 408760 0
Baseline and follow-up (within 7 days of completion of the 12-week intervention).
Secondary outcome [5] 408761 0
THE AWARENESS OF SOCIAL INFERENCE TEST (SHORT VERSION) PART 1 - Emotion Evaluation Test - number correct out of 10.
Timepoint [5] 408761 0
Baseline and follow-up (within 7 days of completion of the 12-week intervention).
Secondary outcome [6] 408762 0
THE AWARENESS OF SOCIAL INFERENCE TEST (SHORT VERSION) PART 2 - Social Inference (minimal) - number correct out of 36.
Timepoint [6] 408762 0
Baseline and follow-up (within 7 days of completion of the 12-week intervention).
Secondary outcome [7] 408763 0
PERCEIVED DEFICITS QUESTIONNAIRE 20 ITEM - total score out of 80.
Timepoint [7] 408763 0
Baseline and follow-up (within 7 days of completion of the 12-week intervention).
Secondary outcome [8] 408764 0
SOCIAL AND EMOTIONAL QUESTIONNAIRE - total score
Timepoint [8] 408764 0
Baseline and follow-up (within 7 days of completion of the 12-week intervention).
Secondary outcome [9] 408765 0
INTERPERSONAL REACTIVITY INDEX (PERSPECTIVE TAKING) - total score
Timepoint [9] 408765 0
Baseline and follow-up (within 7 days of completion of the 12-week intervention).
Secondary outcome [10] 408766 0
OVERALL HEALTH STATUS assessed by SF-36 - total score out of 100
Timepoint [10] 408766 0
Baseline and follow-up (within 7 days of completion of the 12-week intervention).
Secondary outcome [11] 408767 0
ASSESSMENT OF QUALITY OF LIFE 8D - total score
Timepoint [11] 408767 0
Baseline and follow-up (within 7 days of completion of the 12-week intervention).
Secondary outcome [12] 408768 0
SYDNEY PSYCHOSOCIAL REINTEGRATION SCALE - total score
Timepoint [12] 408768 0
Baseline and follow-up (within 7 days of completion of the 12-week intervention).
Secondary outcome [13] 408769 0
DISEASE STEPS SCALE (PATIENT DETERMINED) - level of disability selected from 9 possible 'steps'
Timepoint [13] 408769 0
Baseline and follow-up (within 7 days of completion of the 12-week intervention).
Secondary outcome [14] 408770 0
SHORT-FORM FOOD FREQUENCY QUESTIONNAIRE - change from baseline to follow up as a measure of dietary consistency.
Timepoint [14] 408770 0
Baseline and follow-up (within 7 days of completion of the 12-week intervention).
Secondary outcome [15] 408771 0
ALCOHOL USE DISORDERS IDENTIFICATION TEST - total score with of 8 or more recommended as indicators of hazardous and harmful alcohol use, as well as possible alcohol dependence.
Timepoint [15] 408771 0
Baseline and follow-up (within 7 days of completion of the 12-week intervention).
Secondary outcome [16] 408772 0
HOSPITAL ANXIETY AND DEPRESSION SCALE - total score with cut offs normal (0–7), mild (8–10), moderate (11–14) or severe (15–21).
Timepoint [16] 408772 0
Baseline and follow-up (within 7 days of completion of the 12-week intervention).
Secondary outcome [17] 408773 0
RELAPSE STATUS CHECKLIST - number of relapses in previous 3 months and characteristics of any relapse event/s
Timepoint [17] 408773 0
Baseline and follow-up (within 7 days of completion of the 12-week intervention).
Secondary outcome [18] 408774 0
TIMED 25-FOOT WALK - scored as the average time (seconds) of the two completed trials.
Timepoint [18] 408774 0
Baseline and follow-up (within 7 days of completion of the 12-week intervention).
Secondary outcome [19] 408775 0
KYNURENINE PATHWAY FUNCTION - total serum (nM) concentration of NAD, NADH, and upstream metabolites (tryptophan, kynurenine, anthranilic acid, kynurenic acid, 3-hydroxykynurenine, 3-hydroxyanthranilic acid, xanthurenic acid, picolinic acid, quinolinic acid).
Timepoint [19] 408775 0
Baseline and follow-up (within 7 days of completion of the 12-week intervention).
Secondary outcome [20] 408776 0
GUT MICROBIOME STRUCTURE (from stool) - taxonomic profiling (alpha diversity) and quantification of gene and pathway abundance.
Timepoint [20] 408776 0
Baseline and follow-up (within 7 days of completion of the 12-week intervention).
Secondary outcome [21] 408777 0
INFLAMMATORY MEDIATORS - quantification of multiplexing cytokines, chemokines and growth factors in blood plasma. Final readout of the sample concentration will be expressed as picogram per millilitre (pg/mL).
Timepoint [21] 408777 0
Baseline and follow-up (within 7 days of completion of the 12-week intervention).
Secondary outcome [22] 409041 0
VISUAL ANALOGUE SCALE (FATIGUE) - total score
Timepoint [22] 409041 0
Beginning and end of baseline assessment, and beginning and end of follow-up assessment (within 7 days of completion of the 12-week intervention).
Secondary outcome [23] 409042 0
SPIELBERGER STATE TRAIT ANXIETY INVENTORY (STATE) (5 ITEM) - total score
Timepoint [23] 409042 0
Baseline and follow-up (within 7 days of completion of the 12-week intervention).
Secondary outcome [24] 409043 0
MODIFIED FATIGUE IMPACT SCALE - subscale scores (physical, cognitive and psychosocial)
Timepoint [24] 409043 0
Baseline and follow-up (within 7 days of completion of the 12-week intervention).
Secondary outcome [25] 409137 0
PITTSBURGH SLEEP QUALITY INDEX - total score, with a global sum of 5 or greater indicating a “poor” sleeper.
Timepoint [25] 409137 0
Baseline and follow-up (within 7 days of completion of the 12-week intervention).
Secondary outcome [26] 409138 0
EPWORTH SLEEPINESS SCALE - total score, with a sum of 10 or more from the eight individual scores reflecting above normal daytime sleepiness.
Timepoint [26] 409138 0
Baseline and follow-up (within 7 days of completion of the 12-week intervention).
Secondary outcome [27] 409139 0
IMPACT OF VISUAL IMPAIRMENT SCALE - total score out of 15,
Timepoint [27] 409139 0
Baseline and follow-up (within 7 days of completion of the 12-week intervention).

Eligibility
Key inclusion criteria
(1) A diagnosis of clinically definite Relapsing Remitting MS, as defined by the McDonald criteria (as diagnosed by their treating neurologist).
(2) Aged between 18 and 70 years
(3) Able to speak and read English
(4) Not currently taking probiotic supplements
(5) Have not taken regular probiotic supplements within the previous 3 months or if so, willing to undertake an 8-week washout
Minimum age
18 Years
Maximum age
70 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
(1) A diagnosis of a psychotic, bipolar or related disorder
(2) A history of brain injury or other neurological illness (e.g., stroke, epilepsy)
(3) A significant history of alcohol or illicit drug abuse
(4) MS disease relapse (symptom flare-up) within 2 weeks of assessment
(5) Unable to speak and read English
(6) Uncorrected visual difficulties such that the participant is unable to read and undertake tasks
(7) Pregnant
(8) Currently taking or have taken regular probiotic supplements within the previous 3 months and unwilling to undertake an 8-week washout
(9) Active infection treated by antibiotic therapy at the time of screening
(10) Risky alcohol consumption in the previous 3 months, as defined by NHMRC guideline 1 (no more than 10 standard drinks a week and no more than 4 standard drinks on any one day).

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)
There is considerable heterogeneity in MS symptomology and variability in the degree of cognitive dysfunction experienced by people with MS – whilst commonly experienced by most, for some this may be a key symptom and for others, not so much. Given the small sample size due to the study being a pilot, quasi-randomisation will be undertaken to minimise the likelihood of systematic differences between the probiotic and placebo groups in regard to baseline cognitive functioning. Allocation to cognitively intact or cognitively non-intact groups will be determined based on a participant’s performance on the primary cognitive measures. In line with prior studies, we will use 5th percentile cut off on greater than 2 tests to determine the existence of cognitive impairment.

Allocation of participants in the cognitively intact and non-intact groups to either probiotic or placebo will however be random (using a computer generated random number list) and will be concealed from all parties actively involved in the study. The allocation sequence within the cognitively intact and cognitively non-intact groups will be organised in advance of baseline testing by two personnel external to the main research team. Treatments (probiotic/placebo) will be ordered accordingly in the refrigerator by the external personnel, ready for collection by the assessor once allocation to cognitive group has been determined from baseline performance.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
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
Based on a prior 12-week probiotic intervention to improve inflammatory cytokine markers (IL-8) of MS that found a very large treatment effect (d=1.7), 30 participants (with 15 participants in each group) will have >99% power to detect effects (a=.05) for this pilot examination.
To examine change in the primary and secondary outcome measures in this study, a maximum likelihood mixed models approach will be used with an alpha level of 0.05 to detect statistical significance and with effect sizes (e.g., Cohen’s d) also reported. More specifically, this will enable determination of whether the primary cognition variables, and secondary self-report cognitive fatigue and functional outcome measures, improve with the intervention compared to placebo, and whether this might differ across cognitively-intact vs cognitively non-intact groups. Additional maximum likelihood mixed models analyses will be conducted to examine whether probiotic supplementation is associated with changes in the gut microbiome (relative to baseline and placebo), and kynurenine pathway biomarker and inflammatory mediator concentrations. A preliminary examination will be conducted to identify covariates that need to be modelled into the mixed models analyses. Such covariates include age, gender, education level, disease duration, EDSS, disease modifying treatment, and diet.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
16/05/2022
Actual
23/08/2022
Date of last participant enrolment
Anticipated
31/08/2022
Actual
6/01/2023
Date of last data collection
Anticipated
7/12/2022
Actual
4/04/2023
Sample size
Target
30
Accrual to date
Final
28
Recruitment in Australia
Recruitment state(s)
TAS

Funding & Sponsors
Funding source category [1] 311266 0
Charities/Societies/Foundations
Name [1] 311266 0
Clifford Craig Foundation
Country [1] 311266 0
Australia
Funding source category [2] 311267 0
University
Name [2] 311267 0
University of Tasmania
Country [2] 311267 0
Australia
Funding source category [3] 311268 0
Charities/Societies/Foundations
Name [3] 311268 0
MS Australia
Country [3] 311268 0
Australia
Primary sponsor type
University
Name
University of Tasmania
Address
Newnham Drive,
Newnham TAS 7248
Country
Australia
Secondary sponsor category [1] 312626 0
None
Name [1] 312626 0
Address [1] 312626 0
Country [1] 312626 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 310777 0
University of Tasmania Human Research Ethics Committee
Ethics committee address [1] 310777 0
Ethics committee country [1] 310777 0
Australia
Date submitted for ethics approval [1] 310777 0
10/02/2022
Approval date [1] 310777 0
07/04/2022
Ethics approval number [1] 310777 0
26849

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

Contacts
Principal investigator
Name 118826 0
Dr Cynthia Honan
Address 118826 0
School of Psychological Sciences
College of Health and Medicine
University of Tasmania
Locked Bag 1342, Launceston TAS 7250
Country 118826 0
Australia
Phone 118826 0
+61 3 6324 3819
Fax 118826 0
Email 118826 0
[email protected]
Contact person for public queries
Name 118827 0
Terry Purton
Address 118827 0
School of Psychological Sciences
College of Health and Medicine
University of Tasmania
Locked Bag 1342, Launceston TAS 7250
Country 118827 0
Australia
Phone 118827 0
+61 3 6324 3129
Fax 118827 0
Email 118827 0
[email protected]
Contact person for scientific queries
Name 118828 0
Cynthia Honan
Address 118828 0
School of Psychological Sciences
College of Health and Medicine
University of Tasmania
Locked Bag 1342, Launceston TAS 7250
Country 118828 0
Australia
Phone 118828 0
+61 3 6324 3819
Fax 118828 0
Email 118828 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
This data will not be made publicly available alongside published articles due to the personal and medical information it contains.


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.