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Trial registered on ANZCTR


Registration number
ACTRN12620000928910
Ethics application status
Approved
Date submitted
16/06/2020
Date registered
17/09/2020
Date last updated
17/09/2020
Date data sharing statement initially provided
17/09/2020
Date results information initially provided
17/09/2020
Type of registration
Retrospectively registered

Titles & IDs
Public title
A practice based trial of a combination of nutritional interventions: probiotics, glutamine and fish oils in patients experiencing psychological distress.

Scientific title
Investigating the effect of a novel nutritional intervention (probiotics, glutamine and fish-oil) on mild-moderate psychological distress in adults: a concurrent multiple baseline design
Secondary ID [1] 301248 0
None
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Psychological distress 317557 0
Mild digestive discomfort 317558 0
Condition category
Condition code
Alternative and Complementary Medicine 315645 315645 0 0
Other alternative and complementary medicine
Mental Health 316314 316314 0 0
Other mental health disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
The intervention consisted of 3 nutritionally based supplements or their matched placebos. In this multiple baseline study design participants were randomised into 3 groups based on the duration of their exposure to the verum intervention. Group 1 took 6 weeks of placebos followed by 12 weeks of verum supplements, Group 2 had 8 weeks of placebos followed by 10 weeks of verum supplements and group 3 took placebo for 12 weeks and then 6 weeks of verum supplements. Each participant took two doses of each supplement/placebo supplement each day of the trial. The doseage form and contents of the verum supplements are detailed below per dose.

a) Metagenics Ultra Flora Intensive Care (ARTG 286746) 600mg maroon (00 size Vcap with cream coloured powder) clear capsule for oral consumption containing Lactobacillus rhamnosus (LGG®) (10 x 109CFU), Saccharomyces cerevisiae (boulardii) (7.5 x 109 CFU) and Bifidobacterium animalis ssp lactis (BB-12®) (5 x 109 CFU).
Participants swallowed one capsule of this probiotic supplement morning and evening.

b) Metagenics Glutagenics (ARTG 213315) Powder for oral consumption after dissolving in water.
Each 4.33g dose contains: Aloe vera 3.25mg/g (equiv. fresh herb 649.35mg/g); Boswellia serrata 19.48mg/g (equiv. fresh herb 194.8mg/g); Cholecalciferol 1.6233mcg/g; Glutamine 285.71mg/g; Larix arabinogalactan 259.74mg/g; Retinol palmitate 178.57mcg/g; Zinc amino acid chelate 9.74mg/g.
Participants took one dose: 7.7g (two scoops - scooop included) of this oral powder supplement in 200ml water morning and evening.

All practitioner researchers were qualified naturopathic practitioners, apart from one who was a qualified nutritionist. It was beyond the scope of this practitioner reseracher to prescribe herbal medicines so the two participants that she monitored were given the same total daily dose of glutamine (571 mg) as used in the above supplement, encapsulated into 3 opaque capsules which were taken twice a day, by these two participants or a matched placebo.

c) Metagenics Metapure EPA/DHA oral liquid (ARTG 227557). Each ml
contains: concentrated fish Omega-3 triglycerides 952.38 mg/mL. Participants took 2.1ml twice daily with meals (breakfast and dinner).

Supplements were returned at each study clinic and the quantity remaining was rmeasured and recorded by the practitioner reserachers as a) the number of capsules, b) the weight of the powder and c) the volume of the liquid.
Intervention code [1] 317649 0
Treatment: Drugs
Intervention code [2] 317650 0
Treatment: Other
Comparator / control treatment
Placebo a: (matching the probiotic) 400mg maroon (00 size Vcap containing off-white coloured powder) clear capsule containing microcrystalline cellulose (MCC).

Placebo b: (matching the powdered glutamine based nutritional formula) powder for oral liquid consisting of maize maltodextrin IT 19 AGGLOM 4.497g, Malic acid 0.3g, Flavor lemon lime 0.1g, silicon dioxide (Syloid 244) 0.039g, Steviol glycosides, Reb A 0.034g, lemon Encapsulate 0.03g.
Placebo b for the participants of the practitioner researcher who could not prescribe herbal medicine: The placebo contained only maize maltodextrin.

Placebo c: (matching the fish oil) oral liquid consisting of safflower, Steviol glycosides, Reb A 0.034g, lemon Encapsulate 0.03g, 10% fish oil as a masking agent (positive placebo)
Control group
Placebo

Outcomes
Primary outcome [1] 323898 0
Kessler-10 scale of psychological distress (K-10); a 10 item validated and reliable scale of the risk of severe mental disorder.
Change in total score as estimate of change in risk of mental disorder.
Timepoint [1] 323898 0
Seven time points; the initial screening clinic (week -2) and 6 subsequent clinics (week 0, week 4, week 8, week 12, week 16 and week 18).
Secondary outcome [1] 383244 0
Percieved Stress Scale-10 (PSS-10); a 10-item self-reported measure of perceived stress.
Timepoint [1] 383244 0
Baseline clinic (week 0) and 5 subsequent study clinics (week 4, week 8, week 12, week 16 and week 18).
Secondary outcome [2] 383245 0
A 25 item Abbreviated Profile of Mood States (POMS) Short Form. This was a measure of total mood disturbance.
Timepoint [2] 383245 0
Weekly from the baseline clinic at week 0 to the final clinic in week 18: 18 timepoints
Secondary outcome [3] 383246 0
Gastrointestinal Symptom Rating Scale (GSRS): 15 items evaluating common symptoms of gastrointestinal disorders using a four point response scale from no discomfort to sufficent discomfort to impair social activities.
Timepoint [3] 383246 0
Six timepoints, at the Baseline clinic (week 0) and 5 subsequent study clinics (week 4, week 8, week 12, week 16 and week 18).
Secondary outcome [4] 383247 0
Change in gut microflora was measured using Complete Digestive Stool Analysis (CDSA) to assess numbers of colony forming units (CFU) of Bifidobacterium spp. at baseline and post intervention.
Timepoint [4] 383247 0
Two timepoints: week 0 and week 18 study clinic.
Secondary outcome [5] 383249 0
C-reactive protein (CRP) mg/L a biomarker for inflammation. Change in level at baseline compared with post intervention measured by serum assay.
Timepoint [5] 383249 0
Two timepoints: week 0 and week 18
Secondary outcome [6] 384781 0
'Change in gut microflora was measured using Complete Digestive Stool Analysis (CDSA) to assess numbers of colony forming units (CFU) of Lactobacillus spp. at baseline and post intervention'
Timepoint [6] 384781 0
Two time points: week 0 and Week 18.
Secondary outcome [7] 384782 0
Change in gut microflora was measured using Complete Digestive Stool Analysis (CDSA) to assess numbers of colony forming units (CFU) of Escherichia spp. (E. coli) at baseline and post intervention.
Timepoint [7] 384782 0
Two time points: week 0 and week 18.
Secondary outcome [8] 384783 0
Change in gut microflora was measured using Complete Digestive Stool Analysis (CDSA) to assess numbers of colony forming units (CFU) of Enterococcus spp. at baseline and post intervention

Timepoint [8] 384783 0
Two time points: week 0 and week 18
Secondary outcome [9] 384784 0
Change in GIT function was measured using Complete Digestive Stool Analysis (CDSA) to assess levels of faecal calprotectin ug/g.
Timepoint [9] 384784 0
At two timepoints: week 0 and week 18
Secondary outcome [10] 384785 0
Change in GIT function was measured using Complete Digestive Stool Analysis (CDSA) to assess levels of faecal zonulin ng/g.
Timepoint [10] 384785 0
At two timepoints: week 0 and week 18.
Secondary outcome [11] 384786 0
Change in GIT function was measured using Complete Digestive Stool Analysis (CDSA) to assess levels short chain fatty acids in umol/g.
Timepoint [11] 384786 0
Two timepoints: week 0 and week 18.
Secondary outcome [12] 384838 0
Patient perspectives on patient outcomes. This will be assessed by a one-on-one interview between the patient and the practitioner.
Timepoint [12] 384838 0
One-off interview within 9 months after Week 18. This timeframe is to align with individual participant feedback on all outcome measures, including pathology and stool tests results. In this interview the practitioner researcher will discuss and interpret individual results. Patients will then reflect on their experience in the trial. This timeframe will also accommodate return to routine clinical practice where appointments are negotiated between patients and practitioners as needed.

Eligibility
Key inclusion criteria
Individuals with:
- a score of greater than or equal to 16 and less than 30 on the K-10 scale
- symptoms of mild gut dysfunction (e.g. abdominal cramps or sharp pains, recurrent diarrhoea or constipation, excessive wind, abdominal bloating)
- agree to comply with the study protocols
- willing to have blood taken on two occasions during the study
Minimum age
18 Years
Maximum age
65 Years
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Individuals
- taking immunosuppressive medication
- taking Warfarin or other anticoagulant medication
- who have major surgery within the last 6 months
- diagnosed with chronic mental health conditions and taking prescribed medication for same (unless their condition has been stable for a minimum of 12 months)
- with diabetes
- with BMI greater than or equal to 35
- unexplained weight loss
- Females who are lactating, pregnant or planning to become pregnant


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)
Yes, allocation concealment involved contacting the holder of the allocation schedule who was at the central administration site and not otherwise involved with the trial.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
The sponsor agreed to take on the random sequence generation using a computer-generated sequence. Participants, practitioner reseracher and the N-of-1 trials unit were all blinded to the sequence which was held by an acedemic at the central administration site and not otherwise involved with the trial.
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
Other
Other design features
An N-of-1 trial with multiple base line design, such that participants in all groups started the intervention phase of the trial taking placebo supplements. Each group subsequently moved to the verum supplements and remained on these till the end of the study. This design was employed as hypothesiesed alterations to the microbiome could not be reliably and ethically 'washed out' , as required in a cross-over design.
Phase
Phase 2
Type of endpoint(s)
Efficacy
Statistical methods / analysis
The primary method of analysis will employ systematic visual graphing of the outcome measures over the placebo/verum conditions, as recommended by the CONSORT collaboration, extension for N-of-1 studies. Each trial will be analysed separately by the researchers. The results of all the trials will be aggregated to form an exploratory analysis using mixed modeling techniques.

Recruitment
Recruitment status
Active, not recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW,QLD,SA,VIC
Recruitment postcode(s) [1] 30364 0
5171 - Mclaren Vale
Recruitment postcode(s) [2] 30367 0
2830 - Dubbo
Recruitment postcode(s) [3] 30368 0
2000 - Sydney
Recruitment postcode(s) [4] 30370 0
4000 - Brisbane
Recruitment postcode(s) [5] 30554 0
3000 - Melbourne

Funding & Sponsors
Funding source category [1] 305695 0
Charities/Societies/Foundations
Name [1] 305695 0
Australian Traditional Medicine Society
Address [1] 305695 0
Suite 12/27 Bank St Meadowbank NSW 2114
Country [1] 305695 0
Australia
Primary sponsor type
University
Name
Southern Cross University
Address
Military Road
East Lismore NSW 2480
Country
Australia
Secondary sponsor category [1] 306111 0
None
Name [1] 306111 0
Not applicable
Address [1] 306111 0
Not applicable
Country [1] 306111 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 305973 0
Southern Cross Univeristy, Human Reserach Ethics Commitee
Ethics committee address [1] 305973 0
Military Road
East Lismore
NSW 2480
Ethics committee country [1] 305973 0
Australia
Date submitted for ethics approval [1] 305973 0
30/08/2018
Approval date [1] 305973 0
20/11/2018
Ethics approval number [1] 305973 0
ECN-18-192

Summary
Brief summary
Mental health problems affect one in five Australians every year. Psychological distress may be a risk factor for more serious mental health conditions. Recent research on the microbiome of the gastrointestinal tract suggests a complex interaction between this community of bacteria and the health and mental well-being of the host. Lack of balance in the microbiome is often indicated by mild digestive discomfort.
This study investigates a combination of nutrients that have been found to benefit the gastrointestinal tract (glutamine), the microbiome (probiotics) and support healthy mood balance (fish oil) in 10 individuals who suffer mild digestive symptoms and psychological distress. This study aims to investigate the effects of this combination of nutrients on perceptions of psychological distress in these 10 specific individuals. The data from the placebo phase and the ‘active treatment’ phase will be compared for each individual participant and will also be combined to explore some preliminary more general findings that will help with the design of future studies in this area.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 102266 0
Prof Sandra Grace
Address 102266 0
N-of-1 Clinical Trials Group
School of Health and Human Sciences
Southern Cross University
Military Rd
East Lismore
NSW 2480
Country 102266 0
Australia
Phone 102266 0
+61 2 6620 3646
Fax 102266 0
Email 102266 0
sandra.grace@scu.edu.au
Contact person for public queries
Name 102267 0
Prof Sandra Grace
Address 102267 0
N-of-1 Clinical Trials Group
School of Health and Human Sciences
Southern Cross University
Military Rd
East Lismore
NSW 2480
Country 102267 0
Australia
Phone 102267 0
+61 2 6620 3646
Fax 102267 0
Email 102267 0
sandra.grace@scu.edu.au
Contact person for scientific queries
Name 102268 0
Dr Joanne Bradbury
Address 102268 0
N-of-1 Clinical Trials Group
School of Health and Human Sciences
Southern Cross University
Southern Cross Drive
Bilinga QLD 4225
Country 102268 0
Australia
Phone 102268 0
+61 7 5589 3244
Fax 102268 0
Email 102268 0
joanne.bradbury@scu.edu.au

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 other documents available
Summary results
Have study results been published in a peer-reviewed journal?
No
Other publications
Have study results been made publicly available in another format?
No
Results – basic reporting
Results – plain English summary