Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12621001171808
Ethics application status
Approved
Date submitted
28/06/2021
Date registered
30/08/2021
Date last updated
17/01/2023
Date data sharing statement initially provided
30/08/2021
Type of registration
Prospectively registered

Titles & IDs
Public title
OsteoPreP: food supplements for postmenopausal bone health
Scientific title
OsteoPreP: The effect of probiotic supplementation on bone, muscle, and glucose metabolism in postmenopausal women: A randomised placebo-controlled trial
Secondary ID [1] 299831 0
None
Universal Trial Number (UTN)
Trial acronym
OsteoPreP
Linked study record

Health condition
Health condition(s) or problem(s) studied:
bone loss 315217 0
Condition category
Condition code
Musculoskeletal 313534 313534 0 0
Osteoporosis

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Participants will be randomized to one of the below arms and asked to consume the assigned supplement daily for a period of 12 months.
The active arm (probiotic capsule with prebiotic components [inulin]) and placebo control (magnesium stearate) will be taken twice daily.
• Probiotic treatment group (n = 80):
WBF-038; a proprietary formulation of the following strains: Akkermansia muciniphila, Clostridium butyricum, Clostridium beijerinckii, Anaerobutyricum hallii, Bifidobacterium infantis, plus chicory inulin and magnesium stearate. Exact doses will be disclosed after IP restrictions are met.
Adherence to the study supplementation will be recorded by participants checking a daily log/calendar for complete, partial and zero intake days.
Intervention code [1] 316091 0
Prevention
Comparator / control treatment
Placebo Control group (n = 80): placebo capsules consisting of magnesium stearate - 1 capsule twice daily
Control group
Placebo

Outcomes
Primary outcome [1] 321987 0
Relative change (%) in total volumetric bone density of the distal tibia measured using high resolution peripheral quantitative computed tomography (HR-pQCT)
Timepoint [1] 321987 0
Baseline and 12 months
Secondary outcome [1] 376910 0
Lumbar spine (L1-L4) bone mineral density (BMD) measured using dual energy X-ray absorptiometry (DXA)
Timepoint [1] 376910 0
Baseline and 12 months
Secondary outcome [2] 376911 0
Total hip BMD (DXA)
Timepoint [2] 376911 0
Baseline and 12 months
Secondary outcome [3] 376912 0
Tibia and radius trabecular bone volume fraction (HR-pQCT)
Timepoint [3] 376912 0
Baseline and 12 months
Secondary outcome [4] 376913 0
Tibia and radius cortical area (HR-pQCT)
Timepoint [4] 376913 0
Baseline and 12 months
Secondary outcome [5] 376914 0
Tibia and radius cortical volumetric BMD (HR-pQCT)
Timepoint [5] 376914 0
Baseline and 12 months
Secondary outcome [6] 376916 0
Total volumetric bone density of the distal radius (HRpQCT)
Timepoint [6] 376916 0
Baseline and 12 months
Secondary outcome [7] 376917 0
Serum bone turnover markers including procollagen type 1 N-terminal propeptide (P1NP), osteocalcin (OC), and C-terminal cross-linking telopeptide of type I collagen (ßCTX-I)
Timepoint [7] 376917 0
Baseline, 6 and 12 months
Secondary outcome [8] 376918 0
Short chain fatty acid (SCFA) stool levels (including butyrate)
Timepoint [8] 376918 0
Baseline, 6 months, 12 months, and 2 weeks post intervention
Secondary outcome [9] 376920 0
Stool gut microbiota composition
Timepoint [9] 376920 0
Baseline, 6 months, 12 months, and 2 weeks post intervention
Secondary outcome [10] 377887 0
Fasting blood glucose
Timepoint [10] 377887 0
Baseline, 6 and 12 months
Secondary outcome [11] 377888 0
Glycated haemoglobin (HbA1c) in blood
Timepoint [11] 377888 0
Baseline, 6 and 12 months
Secondary outcome [12] 377889 0
Lower leg muscle area (HR-pQCT)
Timepoint [12] 377889 0
Baseline and 12 months
Secondary outcome [13] 379092 0
Appendicular lean body mass (DXA)
Timepoint [13] 379092 0
Baseline and 12 months
Secondary outcome [14] 380238 0
Grip strength measured with hand dynamometer
Timepoint [14] 380238 0
Baseline, 6 and 12 months
Secondary outcome [15] 380376 0
High-sensitivity C-reactive protein (hs-CRP) in serum
Timepoint [15] 380376 0
Baseline, 6 and 12 months
Secondary outcome [16] 380377 0
Circulating number of regulatory T lymphocytes (Tregs) in blood
Timepoint [16] 380377 0
Baseline and 12 months
Secondary outcome [17] 380379 0
Oral glucose tolerance, assessed by OGTT
Timepoint [17] 380379 0
Baseline, 6 and 12 months
Secondary outcome [18] 380380 0
Muscle tissue composition (glycogen and triglyceride content, type 1 fibre proportion) from muscle biopsy
Timepoint [18] 380380 0
Baseline, 6 and 12 months
Secondary outcome [19] 380381 0
Lipocalin2 [intestinal inflammation] in stool
Timepoint [19] 380381 0
Baseline, 6 months, 12 months and 2 weeks post intervention
Secondary outcome [20] 380382 0
Cogstate (cognitive performance questionnaire)
Timepoint [20] 380382 0
Baseline, 6 and 12 months
Secondary outcome [21] 395207 0
Depression, anxiety and stress (DASS-21)
Timepoint [21] 395207 0
Baseline, 6 and 12 months
Secondary outcome [22] 395208 0
Gastrointestinal symptoms (GSRS)
Timepoint [22] 395208 0
Baseline, 3, 6, 9 and 12 months
Secondary outcome [23] 395210 0
Gut hormones (glucagon-like peptide 1 [GLP-1], peptide tyrosine-tyrosine [PYY]) and adiponectin in plasma
Timepoint [23] 395210 0
Baseline, 6 and 12 months
Secondary outcome [24] 395379 0
Quality of life (EQ-5D)
Timepoint [24] 395379 0
Baseline, 6 and 12 months
Secondary outcome [25] 395380 0
Social anxiety (SIAS)
Timepoint [25] 395380 0
Baseline, 6 and 12 months
Secondary outcome [26] 395381 0
Mental wellbeing (WEMWBS)
Timepoint [26] 395381 0
Baseline, 6 and 12 months
Secondary outcome [27] 396129 0
Blood glucose regulation (via continuous glucose monitoring)
Timepoint [27] 396129 0
Baseline, 6 and 12 months
Secondary outcome [28] 396130 0
Fasting blood insulin
Timepoint [28] 396130 0
Baseline, 6 and 12 months
Secondary outcome [29] 396131 0
Fat mass (DXA)
Timepoint [29] 396131 0
Baseline and 12 months
Secondary outcome [30] 396132 0
Blood metabolomics
Timepoint [30] 396132 0
Baseline and 12 months
Secondary outcome [31] 396185 0
Office blood pressure by sphygmomanometer
Timepoint [31] 396185 0
Baseline, 6 and 12 months
Secondary outcome [32] 396186 0
Pain intensity (VAS)
Timepoint [32] 396186 0
Baseline, 6 and 12 months
Secondary outcome [33] 399429 0
Calprotectin [intestinal inflammation] in stool
Timepoint [33] 399429 0
Baseline, 6 months, 12 months and 2 weeks post intervention
Secondary outcome [34] 399431 0
Muscle mass (DXA)
Timepoint [34] 399431 0
Baseline and 12 months

Eligibility
Key inclusion criteria
• Postmenopausal women
• Caucasian (due to significant differences in BMD and bone remodeling between ethnicities)
• Between 1 and 4 years since final menses
• Signed informed consent
• Stated availability throughout the entire study period
• Mental ability to understand and willingness to fulfill all the details of the protocol
• 'Up to date' vaccination status
• Able to walk without the use of an aid
Minimum age
40 Years
Maximum age
65 Years
Sex
Females
Can healthy volunteers participate?
Yes
Key exclusion criteria
• Diagnosis of osteoporosis
• Low trauma fracture after 50 years of age
• T-score of -2.5 or less at the femoral neck or lumbar spine (L1-L4) on the DXA scan at screening visit
• HbA1c equal to or greater than 6.5% at screening visit
• Blood pressure at screening visit of systolic >180 mmHg and/or diastolic >120 mmHg
• Untreated hyperthyroidism
• Rheumatoid arthritis
• Diagnosed with a disease causing secondary osteoporosis or malabsorption: chronic obstructive pulmonary disease, inflammatory bowel disease, celiac disease, type 1/type 2 diabetes, or chronic liver disease
• Bariatric surgery
• Recently diagnosed malignancy (within the last 5 years)
• Current or recent oral corticosteroid use (any dose within the last 3 months, or 5mg of Prednisolone (or equivalent) or a higher daily dose for 14 days or more 3-12 months prior to screening)
• Use of antiresorptive therapy, including systemic hormone replacement therapy, bisphosphonates, strontium ranelate (current or during the last 3 years)
• Use of teriparatide (current or during the last 3 years)
• Participation in other clinical intervention trials
• Antibiotics treatment 2 months prior to inclusion
• Unwilling to cease taking other probiotic or prebiotic supplements (current use)

Study design
Purpose of the study
Prevention
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
The randomisation list will be computer generated by the company providing the supplements. The company, as well as an independent external statistician, will also hold the key to unblind the study at the end. The probiotic supplement and placebo capsule bottles will be provided to the researchers pre-coded and blinded to the study group, where each bottle will be uniquely coded according to the randomisation list.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
A block randomisation (80 blocks; 2 participants per block) will be used to allocate participants to one of the two intervention arms. In addition, alternating blocks in the randomisation will be allocated to have circulating T lymphocytes counted, such that 50% of participants (40 blocks) will have this measure performed. The musculoskeletal subgroup analysis will comprise the first 30 participants (15 in each arm) that consent to the additional optional assessments of an OGTT, muscle biopsy, and ambulatory blood pressure.
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
All study participants' measurements will be analysed in a blinded manner. A complete data analysis plan of the primary and secondary study objectives will be drawn up prior to the completion of the study. Upon completion of the study, the data analysis plan will be sent to independent statistical consultants, along with the cleaned de-identified dataset which will be followed by the statistical analysis as per the predefined data analysis plan. Once the statistical analysis has been completed the randomisation list will be unlocked and the study arms unblinded.
Phase
Not Applicable
Type of endpoint/s
Efficacy
Statistical methods / analysis
Categorical variables will be described by number and percentage and 95% confidence interval (CI) for percentages based on binomial distribution, and for continuous variables mean, standard deviation (SD), median, minimum and maximum, and 95% CI for the mean. Main comparisons will be made separately for the intervention (probiotic supplementation) vs. placebo. For tests between two groups with respect to dichotomous variables Fisher’s exact test will be used, and for continuous variables Fisher’s non-parametric permutation test will be used. The primary variable will be analysed as percent change from baseline to 12 months comparing the active treatment group with placebo. The study will be considered positive if the comparison vs placebo is significant at 0.05 significance level. The primary variable is expected to be normally distributed and analysis will be performed applying analysis of covariance (ANCOVA) with relative change from baseline to 12 months as dependent variable, treatment group as fixed effect and baseline value as covariate.
The difference in least square means with 95% CI for the treatment group vs placebo will be presented along with the associated p-value.
Secondary variables are all continuous and are not guaranteed to be normally distributed. For this reason, the change from baseline to 6 and 12 months will be tested by applying Fisher’s non-parametric permutation test. Mean difference between treatments will be presented along with the 95% CI based on the same permutation test. Primary and secondary analyses will be performed both for intention to treat (ITT) and per protocol (PP) population. The differences in parameter estimates between the intervention and the placebo will be evaluated for its clinical relevance. The secondary analyses will be considered exploratory and alpha of 0.05 will be applied with no further multiple adjustments.
Statistical power analysis was performed in relation to the primary outcome of relative 12-month change (%) in total volumetric bone density of the distal tibia, assessed using HR-pQCT. Based on a similar probiotic intervention in older women (Nilsson et al., 2018) the expected decline in tibia volumetric BMD is 1.85% in the placebo arm and 0.9% decrease at most in the treatment arm with a SD of 1.6%, an alpha of 0.05, 46 individuals are required in each arm to achieve > 80% power. However, in order to be able to detect smaller group-to-group differences and to account for a 20-30% attrition rate and due to multiple secondary outcomes, we will aim to recruit at least 80 individuals into each arm.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
1/04/2022
Actual
1/04/2022
Date of last participant enrolment
Anticipated
30/06/2023
Actual
Date of last data collection
Anticipated
30/06/2024
Actual
Sample size
Target
160
Accrual to date
52
Final
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment postcode(s) [1] 29376 0
3000 - Melbourne
Recruitment postcode(s) [2] 29377 0
3001 - Melbourne
Recruitment postcode(s) [3] 29378 0
3002 - East Melbourne
Recruitment postcode(s) [4] 29379 0
3003 - West Melbourne
Recruitment postcode(s) [5] 29380 0
3004 - Melbourne
Recruitment postcode(s) [6] 29381 0
3006 - South Wharf
Recruitment postcode(s) [7] 29382 0
3050 - Royal Melbourne Hospital
Recruitment postcode(s) [8] 34465 0
3031 - Flemington
Recruitment postcode(s) [9] 34466 0
3031 - Kensington
Recruitment postcode(s) [10] 34467 0
3051 - North Melbourne
Recruitment postcode(s) [11] 34468 0
3052 - Parkville
Recruitment postcode(s) [12] 34469 0
3053 - Carlton
Recruitment postcode(s) [13] 34470 0
3054 - Carlton North
Recruitment postcode(s) [14] 34471 0
3057 - Brunswick East
Recruitment postcode(s) [15] 34472 0
3056 - Brunswick
Recruitment postcode(s) [16] 34473 0
3065 - Fitzroy
Recruitment postcode(s) [17] 34474 0
3066 - Collingwood
Recruitment postcode(s) [18] 34475 0
3067 - Abbotsford
Recruitment postcode(s) [19] 34476 0
3068 - Clifton Hill
Recruitment postcode(s) [20] 34477 0
3070 - Northcote
Recruitment postcode(s) [21] 34478 0
3071 - Thornbury
Recruitment postcode(s) [22] 34479 0
3101 - Kew
Recruitment postcode(s) [23] 34480 0
3102 - Kew East
Recruitment postcode(s) [24] 34481 0
3103 - Balwyn
Recruitment postcode(s) [25] 34482 0
3104 - Balwyn North
Recruitment postcode(s) [26] 34483 0
3121 - Richmond
Recruitment postcode(s) [27] 34484 0
3122 - Hawthorn
Recruitment postcode(s) [28] 34485 0
3123 - Hawthorn East
Recruitment postcode(s) [29] 34486 0
3124 - Camberwell
Recruitment postcode(s) [30] 34487 0
3141 - South Yarra
Recruitment postcode(s) [31] 34488 0
3142 - Toorak
Recruitment postcode(s) [32] 34489 0
3143 - Armadale
Recruitment postcode(s) [33] 34490 0
3144 - Malvern
Recruitment postcode(s) [34] 34491 0
3146 - Glen Iris
Recruitment postcode(s) [35] 34492 0
3145 - Malvern East
Recruitment postcode(s) [36] 34493 0
3181 - Prahran
Recruitment postcode(s) [37] 34494 0
3182 - St Kilda
Recruitment postcode(s) [38] 34495 0
3183 - Balaclava
Recruitment postcode(s) [39] 34496 0
3184 - Elwood
Recruitment postcode(s) [40] 34497 0
3185 - Elsternwick
Recruitment postcode(s) [41] 34498 0
3186 - Brighton
Recruitment postcode(s) [42] 34499 0
3205 - South Melbourne
Recruitment postcode(s) [43] 34500 0
3206 - Albert Park
Recruitment postcode(s) [44] 34501 0
3207 - Port Melbourne

Funding & Sponsors
Funding source category [1] 304291 0
University
Name [1] 304291 0
Australian Catholic University
Country [1] 304291 0
Australia
Primary sponsor type
University
Name
Australian Catholic University
Address
115 Victoria Parade, Fitzroy VIC 3065
Country
Australia
Secondary sponsor category [1] 309418 0
Commercial sector/Industry
Name [1] 309418 0
Pendulum Therapeutics, Inc.
Address [1] 309418 0
933 20th Street
San Francisco, CA 94107
Country [1] 309418 0
United States of America

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 304747 0
Australian Catholic University Human Research Ethics Committee
Ethics committee address [1] 304747 0
Ethics committee country [1] 304747 0
Australia
Date submitted for ethics approval [1] 304747 0
10/05/2021
Approval date [1] 304747 0
27/09/2021
Ethics approval number [1] 304747 0

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

Contacts
Principal investigator
Name 98066 0
Prof Mattias Lorentzon
Address 98066 0
Mary MacKillop Institute for Health Research
Level 5, 215 Spring St
Melbourne VIC 3000
Country 98066 0
Australia
Phone 98066 0
+61 3 92308056
Fax 98066 0
Email 98066 0
[email protected]
Contact person for public queries
Name 98067 0
Alisa Turbic
Address 98067 0
Mary MacKillop Institute for Health Research
Level 5, 215 Spring St
Melbourne VIC 3000
Country 98067 0
Australia
Phone 98067 0
+61 3 9953 3695
Fax 98067 0
Email 98067 0
[email protected]
Contact person for scientific queries
Name 98068 0
Liesbeth Vandenput
Address 98068 0
Mary MacKillop Institute for Health Research
Level 5, 215 Spring St
Melbourne VIC 3000
Country 98068 0
Australia
Phone 98068 0
+61 3 9230 8056
Fax 98068 0
Email 98068 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 participant data will not be publicly communicated; only summary statistics and aggregated data to ensure personal data protection.


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.