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Trial registered on ANZCTR


Registration number
ACTRN12613000438752
Ethics application status
Approved
Date submitted
12/04/2013
Date registered
17/04/2013
Date last updated
30/01/2019
Date data sharing statement initially provided
30/01/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
Randomised clinical trial investigating the Efficacy of Probiotic Administration in ImpRoving depressive symptomatology - the REPAIR depression study.
Scientific title
An investigation of the effects of a probiotic supplement on symptoms of depression and related biomarkers: a double-blind randomized placebo controlled trial with open label extension in people with symptoms of moderate to very severe depression.
Secondary ID [1] 282267 0
None
Universal Trial Number (UTN)
Trial acronym
REPAIR depression study
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Depression 288796 0
Condition category
Condition code
Mental Health 289153 289153 0 0
Depression
Alternative and Complementary Medicine 289265 289265 0 0
Other alternative and complementary medicine

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Double-blind randomized controlled trial (RCT) comparing a probiotic supplement (Probio'Stick) with a placebo, followed by an open-label extension. The intervention requires the intake of a probiotic formula (Probio'Stick) containing two bacterial strains: Lactobacillus Helveticus R0052 and Bifidobacterium longum R0175 (3 x 10^9 colony-forming units/stick). More detailed information about the product can be found on the manufacturer's website, www.institut-rosell-lallemand.com. Participants consume 1 probiotic stick per day for a period of 8 weeks. The stick is in the form of an orodispersible powder which can be taken without water. Participants will be asked to record any sticks missed, as well as any unusual events in their life, in a study diary. Following the RCT, participants will be invited to enter an open-label trial for a further 8 week period with the same dose of Probio'Stick.
Intervention code [1] 286897 0
Treatment: Other
Comparator / control treatment
The placebo group receives a placebo formula of identical taste and appearance, consisting of the same excipients as are in Probio'Stick (xylitol, maltodextrin (maize-derived), plum flavour and malic acid) without any active cultures. Participants consume one placebo stick per day for a total of eight weeks. They will then be invited to enter the open-label trial for a further 8 week period with the same dose of Probio'Stick (ingredients described above).
Control group
Placebo

Outcomes
Primary outcome [1] 289265 0
MADRS score - Montgomery-Asberg Depression Rating Scale - clinician-rated measure of depression
Timepoint [1] 289265 0
Baseline, 8 weeks (end of RCT phase) and 16 weeks (end of open-label phase
Primary outcome [2] 289295 0
iCGI - Improved Clinical Global Impression scale - clinician-rated measure used for severity and improvement in the symptoms of depression
Timepoint [2] 289295 0
8 weeks (end of RCT phase) and 16 weeks (end of open-label phase
Primary outcome [3] 289296 0
QIDS - Quick inventory of depressive symptomatology - patient-rated depression measure
Timepoint [3] 289296 0
Baseline and every two weeks for the duration of the RCT and open-label phases
Secondary outcome [1] 302126 0
Patient-rated CGI
Timepoint [1] 302126 0
8 weeks (end of RCT phase) and 16 weeks (end of open-label phase
Secondary outcome [2] 302128 0
DASS - depression anxiety and stress scale - patient-rated
Timepoint [2] 302128 0
Baseline and every two weeks for the duration of the RCT and open-label phases
Secondary outcome [3] 302129 0
DAS - Dysfunctional Attitude Scale - measures cognitive distortions, particularly distortions that may relate to or cause depression.
Timepoint [3] 302129 0
Baseline and every two weeks for the duration of the RCT and open-label phases
Secondary outcome [4] 302130 0
ATQ - Automatic Thoughts Questionnaire - measures the frequency of automatic negative statements about the self.
Timepoint [4] 302130 0
Baseline and every two weeks for the duration of the RCT and open-label phases
Secondary outcome [5] 302132 0
IBS severity score questionnaire (IBS-SS)
Timepoint [5] 302132 0
Baseline and every two weeks for the duration of the RCT and open-label phases
Secondary outcome [6] 302133 0
Assessment of blood-based biomarkers:

C-reactive protein (CRP)
Vitamin D
Brain derived neurotrophic factor (BDNF)
Interleukin (IL)-1
Interleukin (IL)-6
Tumor necrosis factor (TNF)-alpha
Timepoint [6] 302133 0
Baseline and 8 weeks (end of RCT phase)

Eligibility
Key inclusion criteria
Participants are older than 16 years of age.

Each participant must have a level of understanding sufficient to complete the questionnaires and examinations required by the protocol and be considered reliable and compliant with the protocol.

Participants meet at least one score above the cut-off of 11 on the QIDS or 14 on the DASS-42 depression subscale (moderate to very severe depression).

Participants are free of antidepressant and other psychiatric medications for at least four weeks prior to the trial.

Participants who have not recently, within the last 4 days, suffered illness or have signs of inflammation.
Minimum age
16 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Neurological disorder involving brain or other central function (e.g., epilepsy, MS, narcolepsy).

Any serious medical condition for which major medical interventions are anticipated during the duration of the trial.

Any patient known to be allergic to the ingredients of the intervention.

Pregnancy or breastfeeding.

Any other medication with primarily central nervous system activity, including mood stabilizers. Participants must have been off of these medications for a minimum of four weeks prior to the trial.

Patients will be excluded temporarily if they have taken an oral antibiotic in the previous 6 weeks. If an antibiotic is begun during the course of the trial, that patient will be withdrawn from the study.

Any subject judged clinically to be at serious risk for suicide or violence in the opinion of the researchers.

Participants will be asked to minimize their intake of colas, tea, coffee, alcohol, cigarettes and illicit drugs. These substances will be monitored as part of the trial.

Participants will be excluded if they take the antidepressant herbal supplement, St John’s Wort.

Renal, hepatic, cardiovascular and respiratory diseases

Participants will be asked to cease their use of any type of nutritional or herbal supplement known to enhance the immune system (e.g. vitamin C, vitamin E, Echinacea) for the duration of the study as these may affect the efficacy of the probiotics.

Any person whose immune system is known to be weakened (e.g. by HIV/AIDS, a genetic defect, long-term use of corticosteroids or taking immunosuppressive medications).

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)
If an individual meets the inclusion criteria and does not meet the exclusion criteria, he/she will be allocated to the next available number. All sticks (active ingredient or placebo) have been pre-packaged by a person outside of the study who holds the randomization code. A sealed envelope is kept at the lab for each participant, only to be opened in an emergency (i.e. a patient deteriorates significantly).
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
We will set up 4 tables of random numbers (mix of 1s and 2s representing the probiotic or placebo) using www.randomization.com which provides web-based deterministic software which uses the pseudo-random number generator of Wichmann and Hill (1982) to randomize each subject to a single treatment by using the method of randomly permuted blocks. Although the site may modify the appearance of the software, the algorithms remain unchanged over time and previous versions always remain available. We will give these four sets to a person outside of the study, who will select one of them. All persons involved in running the study will not know which randomization code has been chosen. The person outside the study will then prepare a participant kit in advance which contains all the probiotic sticks required over the eight weeks for each participant. These kits are sequentially numbered and allocated to placebo or probiotic based on the randomization list. Once a participant’s eligibility has been confirmed they will be allocated the next sequentially numbered kit. In this manner, no-one involved in the study (the participant, PI, clinician and observer assessing the participant’s outcomes) will be aware of the participant’s allocated study group.
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
The randomized phase is followed with an open-label trial
Phase
Not Applicable
Type of endpoint/s
Efficacy
Statistical methods / analysis
Due to the lack of any pilot data, the sample size (80) was selected based on similar studies in the literature. The largest human probiotics study to date is that of Diop, Guillou, and Durand (2008), which used a sample size of 75, who found that the consumption of probiotics significantly reduced 2 stress-induced gastrointestinal symptoms (abdominal pain and nausea/vomiting). Other studies more similar to the current trial have all used smaller sample sizes (e.g. Messaoudi, Lalonde, et al., 2011); therefore, we predict that recruiting 80 participants will be enough to give us a medium effect-size without overly straining our human and financial resources.

Baseline demographic and clinical variables will be examined for differences between the supplement group and the placebo group using analysis of variance (ANOVA) for continuous variables and chi square tests for categorical variables to ensure that the randomisation process was successful. If any significant differences are detected, subsequent analyses will involve controlling for possible confounding factors. Analysis of the outcome measures will involve conducting a series of mixed effect linear models, comparing randomized groups on the outcome measures at baseline, 8 weeks and 16 weeks. The second set of analyses will compare the two groups on the blood levels of measured biomarkers at baseline and at 8 weeks. A series of chi-square tests will be used to compare the supplement group to the placebo group. All analyses will be done on intent-to-treat basis - each patient who provides informed consent and is randomized to either supplement or placebo will be included in their randomization group for analysis, regardless of compliance with treatment. If any patient drops out before the final eight week follow-up visit, the ‘last-observation-carried-forward’ technique will be used to impute the missing values. Complete documentation will be kept on non-completers, and their reasons for dropping out of the study prematurely. The individual changes and the difference in the changes will be summarised with 95% confidence intervals derived from the ANCOVA. A two-sided p-value <0.05 will be taken to indicate statistical significance.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
29/04/2013
Actual
30/04/2013
Date of last participant enrolment
Anticipated
1/04/2014
Actual
30/05/2014
Date of last data collection
Anticipated
Actual
26/10/2014
Sample size
Target
80
Accrual to date
Final
80
Recruitment outside Australia
Country [1] 4993 0
New Zealand
State/province [1] 4993 0
Canterbury

Funding & Sponsors
Funding source category [1] 287045 0
University
Name [1] 287045 0
University of Canterbury
Country [1] 287045 0
New Zealand
Funding source category [2] 287046 0
Commercial sector/Industry
Name [2] 287046 0
Lallemand Health Solutions
Country [2] 287046 0
Canada
Primary sponsor type
Individual
Name
A/prof. Julia Rucklidge
Address
Mental Health and Nutrition Research Group
Psychology
University of Canterbury
Private Bag 4800
Chistchurch 8410
Country
New Zealand
Secondary sponsor category [1] 285820 0
University
Name [1] 285820 0
University of Canterbury
Address [1] 285820 0
Private Bag 4800
Chistchurch 8410
Country [1] 285820 0
New Zealand

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 289077 0
Southern Health and Disability Ethics Committee
Ethics committee address [1] 289077 0
Ethics committee country [1] 289077 0
New Zealand
Date submitted for ethics approval [1] 289077 0
Approval date [1] 289077 0
08/04/2013
Ethics approval number [1] 289077 0
URA/12/05/013

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

Contacts
Principal investigator
Name 39078 0
Mrs Amy Romijn
Address 39078 0
Mental Health and Nutrition Research Group
Psychology
University of Canterbury
Private Bag 4800
Christchurch 8140
Country 39078 0
New Zealand
Phone 39078 0
6433642987ext7705
Fax 39078 0
Email 39078 0
amy.romijn@pg.canterbury.ac.nz
Contact person for public queries
Name 39079 0
Amy Romijn
Address 39079 0
Mental Health and Nutrition Research Group
Psychology
University of Canterbury
Private Bag 4800
Christchurch 8140
Country 39079 0
New Zealand
Phone 39079 0
6433642987ext7705
Fax 39079 0
Email 39079 0
amy.romijn@pg.canterbury.ac.nz
Contact person for scientific queries
Name 39080 0
Julia Rucklidge
Address 39080 0
Mental Health and Nutrition Research Group
Psychology
University of Canterbury
Private Bag 4800
Christchurch 8140
Country 39080 0
New Zealand
Phone 39080 0
+64 3 3642987 ext. 7959
Fax 39080 0
Email 39080 0
julia.rucklidge@canterbury.ac.nz

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
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
SourceTitleYear of PublicationDOI
EmbaseNutrition-based interventions for mood disorders.2021https://dx.doi.org/10.1080/14737175.2021.1881482
N.B. These documents automatically identified may not have been verified by the study sponsor.