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Trial registered on ANZCTR


Registration number
ACTRN12621000039886p
Ethics application status
Submitted, not yet approved
Date submitted
16/10/2020
Date registered
18/01/2021
Date last updated
18/01/2021
Date data sharing statement initially provided
18/01/2021
Type of registration
Prospectively registered

Titles & IDs
Public title
Probiotics and Palmitoylethanolamide (PEA) for Osteoarthritic Pain and Wellbeing
Scientific title
Probiotics and Palmitoylethanolamide (PEA) for Osteoarthritic Pain and Wellbeing: A Multiple Baseline Design Trial of Individual Effects
Secondary ID [1] 302514 0
None
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Osteoarthritis 319378 0
Wellbeing 319379 0
Condition category
Condition code
Alternative and Complementary Medicine 317348 317348 0 0
Other alternative and complementary medicine
Musculoskeletal 317811 317811 0 0
Osteoarthritis

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
The trial will be an 11 week multiple baseline design with two pathways. Both pathways commence with a baseline (placebo) phase followed by the treatment pathway. As a result there is no washout period between the placebo phase and the treatment phase. Each participant will be assigned to one of two pathways.

Pathway 1:
Active 1 (Metagenics Ultra Flora Intensive Care) will be taken as one capsule twice daily for 7 weeks AND Active 2 (Bioabsorb PEA) will be taken as one capsule twice daily for 7 weeks.

Pathway 2:
Active 1 (Metagenics Ultra Flora Intensive Care) will be taken as one capsule twice daily for 9 weeks AND Active 2 (Bioabsorb PEA) will be taken as one capsule twice daily for 9 weeks.

Please note that participants will be taking BOTH Active 1 and Active 2 at the same time during the active phases of their respective pathways.

Adherence to the intervention ill be through supplement capsule return, verbal questioning at scheduled consultations.

During the active phases, participants will take the following:
Active 1: Metagenics Ultra Flora Intensive Care (ARTG Entry: 286746) at a dose of one capsule twice daily. Each capsule is 600mg in a clear (00 size Vcap with cream coloured powder) capsule 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).

Active 2: Metagenics Bio Absorb PEA (ARTG Entry: 330607) at a dose of one capsule twice daily. Each capsule is 300mg with a dark green capsule (Vcap with cream coloured powder) containing palmidrol 299.99mg per capsule. Participants will be asked to take this dose (a total of 600mg daily for 6 – 8 weeks) as it represents the minimum ‘loading dose’ as well as the maximum ‘maintenance dose’ to ensure continuity.
Intervention code [1] 318806 0
Treatment: Other
Comparator / control treatment
Both placebos (1 and 2) will be taken at the same time during the placebo phase of the trial (at the start of the trial). For pathway one, this will last for four weeks. For pathway two, this will last for two weeks.

Placebo 1: During the placebo phases, participants will be taking one capsule twice daily of a 400mg (00 size Vcap containing off-white coloured powder) capsule containing microcrystalline cellulose (MCC) in matched clear capsules.

Placebo 2: During the placebo phase participants will be taking one capsule twice daily of a 300mg (00 size Vcap containing off-white coloured powder) capsule containing microcrystalline cellulose (MCC) in matched green capsules.
Control group
Placebo

Outcomes
Primary outcome [1] 325393 0
Difference in mean pain scores between placebo and active phases as measured daily on a 10cm Numerical Rating Scale (NRS)
Timepoint [1] 325393 0
This will be measured daily from the commencement of the trial (baseline measures in week 1) until the trial conclusion (primary endpoint in week 11).
Secondary outcome [1] 387752 0
Difference between placebo and active phases in mean scores of symptoms of functional mobility. Functional mobility will be represented by up to five daily activities nominated by the individual as important in tasks of daily living (Patient Specific Functional Scale (PSFS)).

Each task will be assessed on a 10 cm VAS scale from 0 (indicating no restriction on the activity) to 10 (indicating complete inability to undertake the activity).
Timepoint [1] 387752 0
This will be conducted at the commencement of the trial and every two weeks thereafter until the completion of the trial
(i.e. weeks 1, 3 5, 7, 9, 11).
Secondary outcome [2] 387753 0
Difference between placebo and active periods for negative emotional symptoms as measured by the total scores on the DASS21.
Timepoint [2] 387753 0
The DASS 21 is a self-administered scale of 21 questions that aims to determine perceptions of stress, anxiety and depression. As a shortened version of the original DASS 42 by Lovibond and Lovibond in 1995, the DASS 21 had demonstrated reliability and validity in elderly patients with persistent pain (Wood, Nicholas, Blyth, Asghari, & Gibson, 2010) whilst reducing participant burden as an outcome measure. Of the 21 questions, seven relate to symptoms of depression, seven relate to symptoms of anxiety and the remaining seven relate to symptoms of stress.

This will be conducted at the commencement of the trial and every two weeks thereafter until the completion of the trial (i.e. weeks 1, 3 5, 7, 9, 11).
Secondary outcome [3] 387754 0
Differences between placebo and active periods in mean scores of personal wellbeing as measured by the Personal Wellness Index (PWI).

This is a scale to assess subjective wellbeing via seven domains: standard of living, health, life achievement, relationships, safety, community-connectedness, and future security.
Timepoint [3] 387754 0
This will occur at the commencement of the trial and at the conclusion of the trial (i.e. weeks 1 and 11).
Secondary outcome [4] 387755 0
Patient preference for the treatment condition.
The patient will be asked to try to identify which were the active and placebo periods during an interview with the practitioner at the end of the trial, before the blinding is broken
Timepoint [4] 387755 0
This will be conducted at the final clinic visit (i.e. week 11).
Secondary outcome [5] 387756 0
Changes in medication usage as recorded by the participant's daily usage of analgesic medication in addition to the list of concomitant medications recorded at baseline.
Timepoint [5] 387756 0
This will be recorded at each clinic visit (scheduled to be every 2 weeks after the commencement of the trial) (i.e. weeks 1, 3 5, 7, 9, 11).
Secondary outcome [6] 387757 0
This composite secondary outcome will measure any differences between inflammatory markers (CRP, ESR and fibrinogen) as measured through a blood test pre- and post-intervention.
Timepoint [6] 387757 0
The blood test will occur at the commencement of the trial and at the conclusion of the trial (i.e. weeks 1 and 11).
Secondary outcome [7] 387758 0
This will be an exploratory outcome measure to explore mechanisms of action for probiotics and PEA in the gastrointestinal system. Differences between placebo and active periods in gastrointestinal markers including zonulin will be measured by a stool analysis.
Timepoint [7] 387758 0
This will occur at the commencement of the trial and at the conclusion of the trial (i.e. weeks 1 and 11).
Secondary outcome [8] 387759 0
Differences between placebo and active periods in pain location and quality.

As part of the daily pain diary, participants will be asked to identify pain location(s) by making a mark on the relevant diagram. Participants will also be asked to describe the kind of pain experienced by circling from the following choices: shooting, aching, sharp, dull, burning, throbbing, radiating, gnawing, stabbing, numb and unbearable.
Timepoint [8] 387759 0
This will be measured daily from the commencement of the trial until its conclusion.
Secondary outcome [9] 389281 0
This composite secondary outcome will measure serum iron (Kell & Pretorius, 2014) and Vitamin D (Mousa, Misso, Teede, Scragg, & de Courten, 2016) as proxy biomarkers for mood pre- and post-intervention.
Timepoint [9] 389281 0
This will occur at the commencement of the trial and at the conclusion of the trial (i.e. weeks 1 and 11).

Eligibility
Key inclusion criteria
• Individuals aged between 18 and 85 years
• Medical diagnosis or clinical evidence of osteoarthritis in any site
• Individuals who describe chronic/symptomatic osteoarthritic pain in the affected joint
• In good general health
• Female participants of childbearing age who agree to continue using birth control measures for the duration of the study
Minimum age
18 Years
Maximum age
85 Years
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
• A history of trauma associated with the affected joint
• Rheumatoid arthritis or other inflammatory joint conditions
• Recent history gout
• Individuals with diabetes
• Individuals with a compromised immune system
• Individuals taking antidepressant medications for less than 6 months or who have experienced psychological side effects as a result of antidepressant medication in the last 6 months.
• Individuals taking Warfarin or other anti-coagulant medication
• Use of corticosteroids (intra-articular or systematic) within 4 weeks prior to baseline and throughout the study
• Female participants who are lactating, pregnant or planning to become pregnant
• Participants who have participated in another clinical trial in the last 30 days
• Participants unwilling to comply with the study protocol
• Any other condition, which in the opinion of the investigators could compromise the study

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)
Allocation involved random allocation by a third party who is not connected to the trial.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Simple randomisation as a result of a third party who is not connected to the trial.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s


Intervention assignment
Other
Other design features
The design of this study is a variant of an N-of-1 trials design, known as a concurrent multiple baseline (MBD) or multiple phase design. Participants will be allocated into one of two treatment ‘pathways’, with each pathway commencing with a baseline (placebo) phase and followed by a treatment phase. The allocation to the pathways is randomised and will be conducted by an independent academic researcher not associated with the study and the schedule concealed from all investigators and practitioner. The trial will be single blinded (the patients are blinded to the allocation to pathway and the study design). The total duration of the trial is 11 weeks..
Phase
Not Applicable
Type of endpoint(s)
Efficacy
Statistical methods / analysis
Data will be entered in Excel, where it will be cleaned and checked prior to analysis. Scatter plots will be generated from daily VAS scores and PSFS to facilitate visual inspection of individual trajectories of pain over time for each individual.

Secondary outcomes and biomarkers will be explored to determine whether there are trends towards an effect for active compared to the placebo phases. Consistent effects over multiple outcomes will provide preliminary evidence of the potential effectiveness of active interventions in comparison with the placebo.

Statistical analysis using SPSS Statistics software (Arkkelin, 2014) and/or Stata v16 will include fitting a general linear model to the data to estimate the treatment effect on the primary outcome. Covariates, such as baseline values and indicator variables for pain medication (as noted by the participant on the pain score diaries) may be included in the final model if found to be significant.

A sensitivity analysis will be conducted on data collected after four weeks of supplementation (i.e. ignoring the first 3 weeks) to capture a potentially clearer the impact of supplementation. This is considered important as it is expected that the treatment effect is not constant but will be substantially delayed.

Recruitment
Recruitment status
Not yet 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

Funding & Sponsors
Funding source category [1] 306953 0
Commercial sector/Industry
Name [1] 306953 0
Metagenics Australia
Address [1] 306953 0
741 Nudgee Road,
Northgate QLD 4013
Country [1] 306953 0
Australia
Primary sponsor type
University
Name
Southern Cross University
Address
Southern Cross University,
Gold Coast Campus,
Southern Cross Drive,
Bilinga QLD 4225
Country
Australia
Secondary sponsor category [1] 307515 0
None
Name [1] 307515 0
Address [1] 307515 0
Country [1] 307515 0

Ethics approval
Ethics application status
Submitted, not yet approved
Ethics committee name [1] 307090 0
Southern Cross University Human Research Ethics Committee (HREC)
Ethics committee address [1] 307090 0
Ethics Manager
Office of Research
Southern Cross University
PO Box 157
Lismore NSW 2480
E: ethics.lismore@scu.edu.au
Ethics committee country [1] 307090 0
Australia
Date submitted for ethics approval [1] 307090 0
13/10/2020
Approval date [1] 307090 0
Ethics approval number [1] 307090 0

Summary
Brief summary
This study aims to investigate the efficacy of palmitoylethanolamide (PEA) and probiotics for wellbeing and osteoarthritic pain.

The primary hypothesis is that oral administration of PEA and probiotics will be associated with a decrease in pain, as measured by a numerical rating scale, in comparison with a placebo.

The active interventions include a probiotic (including three different strains) and a form of micronized PEA. Participants will be asked to take one capsule of each intervention in the morning after meals and another capsule of each intervention in the evening after meals.

Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 105994 0
Dr Joanne Bradbury
Address 105994 0
Southern Cross University,
Gold Coast Campus, Southern Cross Drive,
Bilinga QLD 4225
Country 105994 0
Australia
Phone 105994 0
+61 07 5589 3244
Fax 105994 0
Email 105994 0
joanne.bradbury@scu.edu.au
Contact person for public queries
Name 105995 0
Dr Joanne Bradbury
Address 105995 0
Southern Cross University,
Gold Coast Campus, Southern Cross Drive,
Bilinga QLD 4225
Country 105995 0
Australia
Phone 105995 0
+61 07 5589 3244
Fax 105995 0
Email 105995 0
joanne.bradbury@scu.edu.au
Contact person for scientific queries
Name 105996 0
Dr Joanne Bradbury
Address 105996 0
Southern Cross University,
Gold Coast Campus, Southern Cross Drive,
Bilinga QLD 4225
Country 105996 0
Australia
Phone 105996 0
+61 07 5589 3244
Fax 105996 0
Email 105996 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
Due to this trial being a trial of individual effects (4 participants), the risk of identification is high especially as all participants will be drawn from a single clinic.

What supporting documents are/will be available?
No other documents available
Summary results
No Results