Trial design
The protocol consists of an interventional, prospective, multicentre double-blind 1:1 randomised, placebo-controlled clinical trial with a medical food. The study will enroll eligible women who are healthy and within 1–6 years of menopause. Eligible participating women will be randomized to an oral medical food for the dietary management of postmenopausal bone loss or to placebo. The Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) was used to elaborate the study protocol and study statistical protocol see supplementary file 1 and supplementary file 2 respectively. Participants’ progression through the trial is presented in Fig. 1 (CONSORT diagram) [14]. The results of this study will be disseminated to study participants through peer-reviewed journals and at scientific conferences.
Recruitment process
The contract research organization (CRO), the primary study site managing the participant trial-phase (screening, recruitment, enrolment, including collection and storage of blood specimens, administration of the participant reported outcomes, adverse effects, use of rescue medication, progress and trial close out), the primary radiology site and microbiome testing site are located in Brisbane Queensland, Australia. The trial will be conducted using a purpose built E-Platform for participant management through the trial. Participants will be recruited (n = 300) in both Brisbane and Sydney, through social media channels, radio advertising and medical clinics. Participant screening and enrolment (Fig. 1) will be overseen by the principal and associate investigators and performed by trained study research associates holding certifications in Good Clinical Practice. A screening log will document all eligible and ineligible persons screened along with reasons for any exclusions. Those who are eligible and enrol in the trial will provide written informed consent prior to study enrolment.
Trial Status
Patient enrolment for the study commenced in March 2022 in Brisbane, QLD Australia, with the team including Evidence Sciences (New Farm), RDC Clinical (Newstead), the microbiome testing site, Microba (Brisbane city), a single radiology site (Newstead), with the radiology data (DXA and qCT) uploaded for independent analysis by Clario (USA). In February 2023, additional radiology sites in Brisbane and Sydney NSW (with an additional pathology site for collection of blood samples in Sydney) were included. The samples for the microbiome data are sent to Microba for storage and batch analysis at completion of the study. The blood samples taken at the set time points were also aliquoted and stored appropriately at −80°C and will be batch analysed at completion of the study.
Allocation
Eligible participants will be randomized to the SBD111 medical food formulation or placebo group without stratification using computer-generated random numbers (FileMarker Pro) in a parallel assignment scheme. All participant and study site personnel will be blinded to test article allocation, hence with quadruple masking (i.e., participant, care provider, investigators, outcomes assessors) and with documentation blinding. Participant unblinding will only be requested in a medical emergency, where knowledge of the study arm is essential for any treatment of the participant. The reason for unblinding will be documented and the study test article will not be revealed to any member of the study team.
Data Handling and Record Keeping
The data for the screening, enrolment, study progress and study completion including demographics, medical history, questionnaires and adverse reactions are collected in the E-platform by RDC Clinical. The radiology data is collected by the radiology site (with the body composition data collated by RDC Clinical) and the de-identified participant’s DXA/ qCT data (i.e., according to Best Practices for Dual-Energy X-ray Absorptiometry Measurement and Reporting) [15] uploaded to the Clario platform. All the study databases are password protected and backed up on their respective site servers. At completion of the study, a summary of results will be sent to participants by email.
Inclusion Criteria
To be eligible for inclusion in the trial, a participant must fulfill all of the following criteria:
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provide written informed consent;
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confirm availability throughout entire study period (12-months) and willingness to fulfill all details of the protocol; including DXA scan (x3), qCT scan (x2), provide stool samples for analysis of gut microbiome (x3), and have blood tests (x3);
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between 1–6 years post-menopause (at least 1 year but a maximum of 6-years since the last menstruation or since having a total hysterectomy);
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at least 6-months since the last intake of hormone replacement therapy (HRT);
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dual energy X-ray absorptiometry (DXA)-derived Bone mineral density (BMD) T-score of greater than −2.5 at the lumbar spine (L1-L4), femoral neck, and total hip but no site with BMD ≤ −2.5;
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body mass index between 18.5 and 35 kg/m2; normal levels of serum calcium (< 11mg/dL);
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normal cardiovascular parameters (systolic blood pressure ≤ 155 mm Hg, diastolic blood pressure ≤ 95 mm Hg), either healthy or medication controlled.
Exclusion Criteria
The presence of any of the following criteria will exclude a prospective participant from participating in the study:
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history of other bone disorders (i.e., Paget’s disease, or osteomalacia, osteogenesis imperfecta, osteopetrosis, etc.); bone or colorectal cancer; autoimmune disorders (i.e., rheumatoid arthritis, Hashimoto’s, Graves’ disease, etc), type 2 diabetes mellitus, specific gastrointestinal disorders (i.e., ulcerative colitis, Crohn’s disease, inflammatory bowel disease, irritable bowel syndrome), kidney disease or dysfunction or any other medical condition that could interfere with the conduct of the study; untreated hyperparathyroidism;
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women previously treated with calcitonin, estrogens, estrogen derivatives, selective estrogen receptor modulators (SERMs), tibolone, progestins, anabolic steroids, or daily glucocorticoids in the past 6 months; women treated with bisphosphonates or strontium in the past 5 years; women previously treated with parathyroid hormone, parathyroid hormone analogs, gallium nitrate, romosozumab or denosumab;
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history of cancer treatment with radiation therapy, anti-estrogen therapy, hormonal therapy, or aromatase inhibitors;
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history of bariatric surgery; partial colectomy; partial hysterectomy; hip joint replacement
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women with spine abnormalities that would prohibit assessment of BMD;
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per-oral use of corticosteroids;
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smoking or use of nicotine products within the past 6-months;
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any disease, that by the investigator’s judgement, could interfere with the intestinal barrier function;
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desire and/or plans on changing current diet and/or exercise regime during the participation of this trial; consumption of dietary supplements (probiotics, prebiotics) in the month prior to or during study (if participant is willing to stop taking these for 1-month, they can be enrolled after a 1-month washout period);
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pregnancy or lactation;
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prescribed antibiotics in the past 2 months (if participant is placed on an antibiotic after enrolment in the study, will be subject to a per protocol analysis) or history of chronic antibiotic use;
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participation in other bone, diet, autoimmune, or gastrointestinal related clinical trials in the last 6 months.
Intervention and compliance
Investigational product
The SBD111 medical food product is a constructed Defined Microbial Assemblage™ (DMA™) product composed of four strains of microorganisms isolated from various foods: Lactobacillus brevis (3 x 1010 CFU/day), Lactobacillus plantarum (3 x 1010 CFU/day), Leuconostoc mesenteroides (3 x 1010 CFU/day), and Pichia kudriavzevii (5 x 109 CFU/day), and prebiotics (oligofructose (300 mg/day), dried ground blueberry powder (300 mg/day). The probiotic amount is 9.5 x 1010 CFU/day in 4 x capsules/day, encased in Enteric coated Size zero white opaque capsules (Table 1). The comparative placebo is composed of maltodextrin (2,000 mg in 4 x capsules / day, and also encapsulated in identical enteric coated size zero white opaque capsules. Prior to particpant enrolment and study commencement the clinical study research associate will obtain written informed consent and randomize eligible participants to the SBD111 medical food or placebo groups.
Justification of concentration to be administered
For this study, a concentration of 9.5x1010 CFU/day was chosen according to the following rationale. A completed concentration response study of the SBD111 medical food in mice [12] demonstrated efficacy for the maintenance of BMD at the lumbar spine following estrogen depletion (ovariectomy) with a concentration of 5x108 CFU/administration. This concentration allometrically scales to a human equivalent concentration of 1.2x1011. A previous 28-day toxicity study of the medical food SBD111 in rats at a 20X human safety factor was shown to have no adverse reactions reported [16]. Further, a first in human placebo controlled safety and tolerability study in 32 healthy adults was completed in 2021, demonstrating no decernable difference in safety or gastrointestinal tolerability between placebo and SBD111 medical food [13].
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Table 1 Ingredients in Solarea Bio’s SBD111 Medical Food
Ingredient
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Amount per Capsule (CFU)*
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Daily Amount in Four Capsules (CFU)
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Ingredient in Each Capsule (mg)
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Lactobacillus brevis
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7.5x109
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3.0x1010
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25-50
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Lactobacillus plantarum
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7.5x109
|
3.0x1010
|
25-50
|
Leuconostoc mesenteroides
|
7.5x109
|
3.0x1010
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25-50
|
Pichia kudriavzevii
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1.25x109
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5.0x109
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100-200
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Oligofructose
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NA
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NA
|
150-200
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Dried ground blueberry powder
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NA
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NA
|
150-200
|
Magnesium stearate
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NA
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NA
|
5-10
|
Silicon dioxide
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NA
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NA
|
5-10
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Total
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2.375x1010
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9.5x1010
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500-560
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*CFU = colony forming units; NA = Not Applicable | not part of microorganism load
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Instructions to participants
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Take two capsules twice per day (with breakfast and dinner) with cold non-carbonated water;
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Store the study product in the refrigerator at 4–6°C;
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Bring all capsules remaining in the bottle to the next visit;
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Avoid consuming probiotic and prebiotic dietary supplements
Adjunct trial supplementation
Vitamin D (500IU, NanoCelle D3, Bioglan Medlab) will also be provided as adjunct supplementation to all participants for the duration of the trial, at a dose to prevent vitamin D deficiency.
Concomitant medications
Additional medications for menopausal symptoms, including HRT, or osteoporosis, such as bisphosphonates and others will be excluded. Probiotics and prebiotics will also be excluded. (See Section Exclusion Criteria). All the medications/supplements which are prescribed to a participant for other reasons apart from study test article and short-term medication, including antibiotics, will be recorded.
Study product compliance
As an interventional study, the test product is to be used for study purposes only. For this reason, a log will be maintained of all study test product received and returned to the clinic. For individual participants, accountability will be maintained with respect to study test product dispensed, study test product consumed (by counting of the remaining capsules returned at final visit) in online GastroCRF. Once the data is recorded, and the bottles/contents verified (providing approved for disposal) by the investigator, the clinical staff will dispose the bottles and product as per Good Clinical Practice.
Outcome Measures
Primary outcome measure
The primary objective of the study, amongst participants randomized to the SBD111 medical food or placebo test article, is to determine the percent change in BMD at the lumbar spine (2–4 evaluable levels L1-L4) attributable to intervention (relative to placebo), computed at the participant level, over 12 months of administration.
Secondary outcome measure
The secondary objectives of participants randomized to active or placebo test article will be
Additional Bone Density testing using DXA, qCT, and Bone Turnover markers
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To compare the percent change in BMD measured by DXA at the lumbar spine (2–4 evaluable levels L1-L4) between baseline and 6-months
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To compare the percent change in trabecular volumetric BMD (vBMD) measured by qCT at the lumbar spine (L1 & L2) between baseline and completion of study period (12 months).
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To compare the change in biochemical markers of bone turnover (CTX, P1NP) between baseline, 6-months, and completion of study period (12-months).
Inflammatory marker assessments
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To compare the change in the circulating marker of inflammation (CRP) between baseline, 6-months, and completion of study period (12-months).
Other outcome measures
The other objectives of participants randomized to intervention or placebo test article will be
Additional Bone Density Outcomes
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To compare the percent change in BMD measured by DXA at the femoral neck and hip between baseline, 6-months, and completion of study period (12-months).
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To compare the percent change in total vBMD (L1-L2) measured by qCT at the lumbar spine between baseline and completion of study period (12 months).
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To compare other characteristics of lumbar spine architecture as measured by qCT between baseline and completion of study period (12 months).
Inflammatory marker assessments
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To compare the change in circulating inflammatory cytokines and markers of inflammation (IL-17, TNFα, IL-1β, IL-4, RANKL, IFNγ) between baseline, 6-months, and completion of study period (12 months).
Menopause symptoms
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To compare the change in global Menopause Rating Scale (MRS) from baseline to 3, 6, 9, and 12 months.
Intestinal microbiome assessment
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To assess the change in gut microbiome composition and function between baseline, 6-months, and completion of study period (12 months)
Body composition assessment
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To assess the change in DXA based lean mass and fat mass from baseline to 6-months, and completion of study period (12 months).
Safety Outcome Measures
Safety will be assessed using the incidence (total count and number of participants experiencing) of adverse events (AE) and serious adverse events (SAE). AE will also be characterized according to severity (mild, moderate, severe) and probability of relatedness (unlikely, possible, probable, certain; conditional, unassessible) to trial procedures. Time since test article administration and time to resolution of adverse events will be computed and displayed. Tolerability will be assessed via change in the total Gastrointestinal Tolerability Questionnaire (GITQ) to 12 months.
As appropriate, a comparison between arms of the incidence of gastrointestinal symptoms occurring within the first month of the intervention period, as well as incidence of dropout specifically attributed to intolerability of the intervention or control, may be considered.
Participant timeline
Screening, interventions, and assessment visits will be performed by a research associate. The schedule of visits and measurements is set out in Table 2 in compliance with SPIRIT guidelines.
Data collection
Clinical examination
Medical history, prescribed and non-prescribed medications, and alcohol intake will be recorded during the screening visit. Blood draws and anthropometric measurements will be collected using standardized examination procedures and calibrated equipment at four time points (i.e., at Enrolment, Baseline, at 26-weeks and 52-weeks) [17] (Table 2).
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Table 2. Schedule of enrollments, interventions, and assessments.
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)
* qCT = Quantitative Computed Tomography; MRS = Menopause Rating Scale;
FFQ = Food Frequency Questionnaire; GITQ = Gastrointestinal Tolerability Questionnaire
Blood samples
Blood samples will be collected after fasting overnight at enrolment, baseline, 26-weeks and 52-weeks. Blood collection will be conducted by clinic staff at RDC Clinical (if recruited in Brisbane) or through Australian Clinical Laboratories (if recruited in Sydney). For blood collections, the FBC is performed at time of the blood draw. The blood will be spun, and plasma samples will be aliquoted in pyrogen free tubes using pyrogen-free pipette tips and stored at − 80°C. All remaining blood will be stored in 6 tubes of 1000 µL aliquots and stored in a −80°C freezer (temperature controlled) for analysis at completion of the study. The blood samples will be analysed by independent GLP certified laboratories.
Stool samples
Stool samples will be collected at baseline, 6-months and 12-months using a commercial kit (Microba Insight™ Sampling Kit, Microba, Brisbane, Australia) [18]. This kit includes a Coplan FLOQSwab brush in an active drying tube capable of preserving samples at room temperature. The stool kits are delivered to the study site by Microba Pty Ltd (Brisbane, Qld) and then these are provided to the participants with instructions for sample collections. Participants are instructed to avoid touching the brush and insert it into the tube immediately after sampling. Subsequently samples collected are sent directly to Microba in pre-paid/pre-labelled envelopes and the samples are then stored at −80°C until such time that the study is completed and then samples will be batch analysed. The collection kit includes an instruction booklet for the stool sample collection and transportation, gloves, a sterile container, sealed plastic pouch. Samples will be processed using the Illumina Novaseq 6000 sequencer to perform shotgun sequencing.
Radiology assessment
The radiology sites are certified independent laboratories and located in Brisbane (QLD) and Sydney (NSW). BMD of the lumbar spine, hip, and femur is collected by DXA (Lunar Prodigy, GE Medical Systems, or Hologic Horizon, Hologic, Inc) at baseline, 6-months, and 12-months. Trial-certified technicians acquire a Lumbar Spine and Left Femur DXA BMD. A standard Lumbar Spine DXA is acquired, with the L1-L4 vertebrae assessed. For the Left Femur, the Total Femur T-score is used. The Regions used for T-score cut-off are the L1-L4 average for the Lumbar Spine, and the Total Femur score for the Left Femur. Scans are uploaded to a central laboratory (Clario, USA) for QC and analysis by blinded technicians. If excluded due to T-score cut-off, no further imaging is performed and the patient returns to the Trial Labs for debriefing. A radiology report is generated, and patients are instructed to see a General Practitioner for further investigation and assessment.
QCT scans of the lumbar spine are collected at baseline and 12-month timepoints using whole-body CT scanners (Somatom Definition Edge, Seimens, Inc, Incisive, Philips Healthcare, or Lightspeed VCT, GE Medical Systems) via a custom scanning protocol as previously described [19]. Briefly, participants are scanned from mid-T12 to mid-L3, such that L1 and L2 can be analyzed. Participants are scanned while lying flat on top of a bone density calibration phantom (Siemens Syngo Osteo Phantom, Siemens or BDC phantom, QRM, Germany), accounting for subtle density variation and validating the analysis. Scans are performed at 120kV using 100 mAs and a pitch of 1. The data are uploaded to a central laboratory (CLARIO, USA) for QC and analysis by blinded technicians. The clinical trial technicians have dedicated training (provided by CLARIO) before conducting any radiology testing. All diagnostic equipment must pass the required benchmarks prior to participation and must undergo scheduled, consistent validation testing throughout the study. To maintain longitudinal quality control of each scanner, a QRM Spine Phantom (QSP) (QRM, Germany) is scanned monthly at each site. The participants in the trial will have their radiology tests completed on the same machine, and if possible, the same operator to also minimise errors due to machine differences or operator technique differences. Positioning, vertebral nomenclature, and acquisition technique is documented, consistent, and standardised. As with the DXA data, qCT data are uploaded to Clario for QC and analysis by blinded observers using Medical Imaging Analysis Framework (MIAF) Spine software as previously described [19].
Menopause Symptoms Assessment
Assessments of the change from baseline in the global Menopause Rating Scale (MRS) at months 3, 6, 9, and 12 will be performed. The Menopause Rating Scale (MRS) [20] score assesses menopausal symptoms using a scale designed and standardized as a self-administered scale to (a) to assess symptoms/complaints of aging women under different conditions, (b) to evaluate the severity of symptoms over time, and (c) to measure changes pre- and post-menopause replacement therapy. It has 11 items on a scale from no complaints (0) to very severe symptoms (4). Sub-scores are added to create a composite or total score.
Assessments and Adverse events
Assessments to be conducted include safety and tolerability, menopause symptoms and gastrointestinal symptoms. Adverse events are defined as any unfavourable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of the study product, whether considered related to the medical food under investigation or not. The study investigator will monitor each participant for adverse events during the study. All adverse signs or symptoms reported between consent and final follow-up will be recorded. Adverse events are reported descriptively by the group and placed in MedDRA categories.
Safety and Gastrointestinal Tolerability Assessments
Safety will be assessed by incidence of AEs and SAEs, and tolerability will be assessed using the Gastrointestinal Tolerability Questionnaire (GITQ). The gastrointestinal tolerability questionnaire (GITQ) is a 12-item inventory of participant reported gastrointestinal related discomfort. It is a patient self-report questionnaire assessment of the frequency and severity of gastrointestinal symptoms, e.g., gas, abdominal pain, reported on a scale from Mild to Severe for all questions. As probiotics can induce gastrointestinal related symptoms such as gas and bloating, we have included a GITQ modified from Pereira et al., 2014 [21] to monitor these potential related symptoms to determine whether the SBD111 medical food causes gastrointestinal discomfort compared to placebo test product comparator.
Serious Adverse Events (SAEs)
All SAEs, related or not related to the study product, are recorded on electronic case report forms. Serious adverse events will be reported in compliance with the requirements of the National Institute of Integrative Medicine Human Research Ethics Committee. It is acknowledged that probiotic intake has not been associated with any major side effects and extensive safety data are available on their effects. However, participants will be discontinued from the study product if it is decided that a serious adverse event may be related to probiotic consumption.
Data analysis and statistical considerations
Sample size
The sample size computation was motivated to obtain 80% power to detect an absolute difference of 1% in BMD over 12-months under the assumption that the standard deviation of change was approximately 2.9%. Using a Student’s t-test, this would require an evaluable sample of 133 participants per study arm (266 participants in total). Anticipating approximately 10% loss of information to participant attrition and missing data, we therefore plan to enroll 300 participants (150 per arm). Owing to the fact that the analytic plan will exploit the repeated measures design, making use of outcomes measurements at 6 months and including all baseline and 6 month data on individuals who drop out between the 6 and 12 month visits, we expect the power to detect our motivating clinical difference of 1% to be greater than that anticipated by this computation.
Statistical Analysis
Safety
Total count of adverse and serious adverse events will be computed for each study arm, as will the proportion of participants experiencing one or more event. Limited hypothesis testing comparing proportions between arms may be conducted as appropriate.
BMD and other bone endpoints
Efficacy analysis will be conducted using the intention-to-treat principle and all available data on all randomized participants will be included. The primary analysis will be by mixed-effects linear regression in recognition of the repeated-measures design. The target estimand will be the population-level one-year difference in change in BMD attributable to the application of the intervention relative to control, as estimated by a regression contrast at 12 months. To support analyses of secondary and other endpoints, parallel approaches will be used, such as using generalized linear mixed effects models or generalized estimating equations as appropriate (e.g. for binary endpoints). Per-protocol analyses may be considered to account for variable levels of receipt of intervention and adherence to trial procedures.
Microbiome
All stool shotgun metagenome analysis will be performed by Microba Pty Ltd (Brisbane, QLD; microba.com) using the Microba Community Profiler (MCP) pipeline [22]. Taxonomic data will be obtained by mapping sequencing reads to genomes listed in the Microba Genome Database (MGDB) with the Microba Community Profiler, a validated pipeline for microbiota data analysis [22]. The MGDB is an expanded version of the GenBank, National Institute of Health (US) and the Genome Taxonomic Database (GTDB) of the Australian Centre for Ecogenomics at its core. This analysis will estimate the relative abundance of bacterial, archael, and eukaryotic community members, as well as the bacterial diversity within a sample (alpha diversity) and between all the samples (beta diversity). For functional annotation, genes will be clustered according to > 90% sequence similarity against representative proteins of the UniRef 90 database [23]. Identified sequences and pathways will be cross-referenced with established databases (GTDB – Genome Taxonomic Database and MetaCyc) [24]. Higher level metabolic pathway annotations will be quantified based on the MetaCyc database (https://metacyc.org). Functional analysis of metagenomes will evaluate identified functional pathway genes encoded for in the sample, providing information about gene families, abundances, and functional capabilities [25]. Differences in relative abundance of taxa and functional pathways between the intervention and placebo group will be determined using Analysis of Variance (ANOVA), using subject as a blocking factor. For all statistical tests, the Benjamini–Hochberg false discovery rate adjustment [20] will be used to correct for multiple hypothesis testing.
Withdrawals and Dropouts
A participant may be withdrawn from the study if: 1) the participant withdraws informed consent (with or without explanation, including those lost to follow-up); 2) AE(s) or SAE(s) (including pathology abnormalities) occur which, according to the investigator, makes study continuation not possible; 3) a concomitant condition is identified in which the prescribed additional therapy is prohibited by protocol as per the participant selection criteria; 4) protocol deviation, affecting the study results occurs; 5) a participant may also be withdrawn based on the discretion of the investigator for any reason, if it is felt that her further continuation in the study will adversely affect her, or, in the interests of the study.
If a participant withdraws, the reason of discontinuation will be documented, and all SAEs will be reported to the investigators. Once the participant has been enrolled for study participation and if the participant decides to withdraw from the study at any point time prior to study completion, all study procedures applicable at final assessment interview will be performed at the time of study withdrawal if the participant is agreeable. If the participant fails to complete the final visit assessments, they will be included in the modified intention-to-treat population analysis and not the per protocol population.
Unblinding and Poststudy Care
Following completion of the study, all participants will be offered the active test article for a period of 6-months, allowing those already experiencing benefit to continue with the SBD111 medical food and those on placebo to also have the same opportunity.
Ethical considerations
Ethics was sought from and approved by the National Institute of Integrative Medicine (NIIM) and ratified by additional radiology site ethics committees, in accordance with ICH Good Clinical Practice Guidelines. Protocol amendments are only made after consultation with trial management committee and approved for these protocol changes will be approved by the institutional Human Research Ethics Committees (HREC) prior to implementation. Tolerability and AEs will be recorded at regular intervals and reviewed at 3 monthly intervals by the independent medical practitioner. The medical practitioner will assess the rate of SAEs (graded ≥ 3 by CTCAE criteria) and accrual, with no pause in recruitment planned. Consideration will be given to altering aspects of the study if there is greater than 10% SAEs reported. Assessment of risk of osteopenia continues after enrolment in the trial. Bone density assessments at month 6 will flag results that show greater than 7% loss of bone density from the baseline assessment and patients will be referred by the medical practitioner/specialist for them to obtain medical advice to continuing in the study. Those participants with bone density scores indicative of osteopenia or osteoporosis on the subsequent 6-month scans will be deemed to have a condition requiring exclusion from the study (and recorded as a post-enrolment exclusion) and will be withdrawn. The trial medical practitioner will inform the participant of the result and refer them to relevant medical consultants/specialists to ensure the participant has access to required medical management of the condition. The clinical trial was registered at Clinicaltrials.gov ID: NCT05009875 on August 18, 2021.
Ethics and Dissemination
In Australia, the study will be conducted according to the Note for Guidance on Good Clinical Practice (CPMP/ ICH/135/95) annotated with Therapeutic Goods Administration Drug Safety and Evaluation Branch comments (July 2000) and in compliance with applicable laws and regulations. The study will be performed in accordance with the NHMRC Statement on Ethical Conduct in Research Involving Humans 2007 (updated May 2015), the NHMRC Australian Code for the Responsible Conduct of Research 2007 and the principles laid down by the World Medical Assembly in the Declaration of Helsinki 2008.
Participants will only be recruited to the study after all the necessary approvals have been obtained and the participant has provided written informed consent. Further, the investigator shall comply with the protocol, except when a protocol deviation is required to eliminate immediate hazard to a participant. In this circumstance the NHMRC CTC, principal investigator and HREC must be advised immediately.