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Effect of VSL#3 on Bone Mineral Density in Postmenopausal Women (ProBoneVSL)

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ClinicalTrials.gov Identifier: NCT03165747
Recruitment Status : Recruiting
First Posted : May 24, 2017
Last Update Posted : July 6, 2018
Sponsor:
Information provided by (Responsible Party):
Roberto Pacifici, Emory University

Brief Summary:

Osteoporosis has a devastating impact on quality of life of postmenopausal women, and is a significant cause of disability and morbidity. Many drugs are approved for the prevention and treatment of osteoporosis, but are associated with high costs and side effects. Some data from animal studies suggests that supplementation with probiotics can safely treat and prevent osteoporosis. The probiotic VSL#3 is commercially available, is safe for human consumption, and has been widely used in human clinical trials, and has known health-promoting effects in both children and adults.

The double-blind, randomized, placebo-controlled trial of VSL#3 will be conducted for 12 months in 40 postmenopausal women to determine if VSL#3 improves bone mineral density and related bone markers. Study visits will include all or some of the following procedures: a medical exam, urine collection, height and weight measurement, a blood draw to assess bone biomarkers, a DEXA (dual energy X-ray absorptiometry) scan to measure bone density, and health questionnaires.

This is one of the first clinical trials proposed to investigate the effects of probiotics in bone in humans. If successful, this proposal will provide the first evidence that nutritional supplementation with the probiotic VSL#3 is a safe and effective strategy for preventing postmenopausal bone loss.


Condition or disease Intervention/treatment Phase
Menopausal Osteoporosis Drug: VSL#3 Other: Placebo Phase 2

Detailed Description:

Osteoporosis has a devastating impact on quality of life of postmenopausal women, and is a significant cause of disability and morbidity. Many drugs are approved for the prevention and treatment of osteoporosis, but are associated with high costs and side effects. Some data from animal studies suggests that supplementation with probiotics can safely treat and prevent osteoporosis. The probiotic VSL#3 is commercially available, is safe for human consumption, and has been widely used in human clinical trials, and has known health-promoting effects in both children and adults.

The double-blind, randomized, placebo-controlled trial of VSL#3 will be conducted in a population of ambulatory, otherwise healthy, postmenopausal women for 12 months. Control and VSL#3-treated postmenopausal women will be matched by age (± 3 years). Study visits will include all or some of the following procedures: a medical exam, urine collection, height and weight measurement, a blood draw to assess bone biomarkers, a DEXA (dual energy X-ray absorptiometry) scan to measure bone density, and health questionnaires.

The primary endpoint is the change in bone mineral density (BMD) at the L1-4 lumbar spine over one year of study. Changes in BMD at the femoral neck and total hip area will be secondary endpoints. All BMD data will also be used as a tool for future studies power calculation and design. Additional endpoints will include changes in bone turnover markers and inflammatory/osteoclastogenic cytokines. Measurements of indices of bone turnover and cytokine levels will provide much needed mechanistic information.The data will allow to establish whether VSL#3 prevents bone loss and/or increases bone mass by regulating bone resorption, formation, or both.


Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 40 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description: Only the IDS pharmacy will know which dose of probiotic was given to the subject. The study team, parents, subjects, individuals entering the data, statistician, individuals performing laboratory tests and DEXA (dual energy X-ray absorptiometry) scans, research center nurses and investigators will remain blinded as to which treatment the subjects received. Each subject will be assigned a unique identifier, which will be used in the database. In addition, all lab specimens will only include the patient's unique identifier. Permuted block sizes will not be disclosed to the blinded study personnel to minimize the likelihood of their being able to predict the next randomization assignment in the series. Investigators and all study personnel will remain blinded until the final subject has completed her final visit and primary and secondary endpoints have been analyzed.
Primary Purpose: Prevention
Official Title: Effect of VSL#3 on Bone Mineral Density in Postmenopausal Women: a Pilot Randomized, Placebo-Controlled Trial
Actual Study Start Date : October 1, 2017
Estimated Primary Completion Date : December 2019
Estimated Study Completion Date : December 2019

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: VSL#3
VSL#3 two active sachets [containing 450x109 colony-forming units (CFU)/sachet], taken daily in a single administration.
Drug: VSL#3
8 strains of live bacteria: Bifidobacterium breve, B. longum, B. infantis, L. acidophilus, L. plantarum, L. paracasei, L. bulgaricus and Streptococcus thermophilus. 900 billion CFU taken orally daily in a single administration.

Placebo Comparator: Control
Placebo, no supplemental probiotics.
Other: Placebo
Two placebo sachets taken orally daily in a single administration.




Primary Outcome Measures :
  1. Change in bone mineral density (BMD) of the lumbar spine (L1-L4 segment) as measured by DEXA (dual energy X-ray absorptiometry). [ Time Frame: Baseline and 12-month visit. ]
    All DEXA scans will be performed on the same device using a GE Lunar iDEXA machine. Participants will be asked to lie still on a scanning table with their arms at their sides for approximately 10 minutes.


Secondary Outcome Measures :
  1. Change in bone density of the non-dominant hip (femoral neck and total hip area) as measured by DEXA (dual energy X-ray absorptiometry). [ Time Frame: Baseline and 12-month visit. ]
    All DEXA scans will be performed on the same device using a GE Lunar iDEXA machine. Participants will be asked to lie still on a scanning table with their arms at their sides for approximately 10 minutes.

  2. Change in serum collagen type 1 cross-linked C-telopeptide (CTX) concentrations (a marker of bone resorption). [ Time Frame: Baseline, 6-month, 12-month visits ]
    Up to approximately 50 mL of fasted blood will be collected at every visit from a peripheral vein.

  3. Change in serum procollagen type I N propeptide (PINP) - a marker of bone formation - concentrations. [ Time Frame: Baseline, 6-month, 12-month visits ]
    Up to approximately 50 mL of fasted blood will be collected at every visit from a peripheral vein.

  4. Change in serum free receptor activator of nuclear factor kappa-B ligand (RANKL) concentrations. [ Time Frame: Baseline, 6-month, 12-month visits ]
    Up to approximately 50 mL of fasted blood will be collected at every visit from a peripheral vein.

  5. Change in serum osteoprotegrin (OPG) concentrations. [ Time Frame: Baseline, 6-month, 12-month visits ]
    Up to approximately 50 mL of fasted blood will be collected at every visit from a peripheral vein.

  6. Change in serum tumor necrosis factor-TNF. [ Time Frame: Baseline, 6-month, 12-month visits ]
    Up to approximately 50 mL of fasted blood will be collected at every visit from a peripheral vein.

  7. Change in serum interleukin-17 (IL-17) concentrations. [ Time Frame: Baseline, 6-month, 12-month visits ]
    Up to approximately 50 mL of fasted blood will be collected at every visit from a peripheral vein.

  8. Number of unused study drug satchets. [ Time Frame: Every two weeks during the study 12-months ]
    This will be determined by contacts (twice monthly telephone or at research center visits) of the study coordinator with each subject and responses to three standardized question areas: 1) "Are you having any difficulty, problems or new symptoms with the study medication?" 2) If yes, "What has the problem been?" and 3) "Have you missed any of your study drug doses, and if so how many in the previous 2 week period?" Appropriate notations based on subject responses will be documented in the case report form (CRF). Subjects will be instructed at study entry and reminded via serial contacts to return all of their used and unused drug sachets at each research center visit. Unused and used study drug satchets will be tallied and recorded in the CRF by the study coordinator serially for the entire study.

  9. Gastrointestinal Symptom Rating [ Time Frame: Every two weeks during the study 12-months ]
    Study drug tolerance will be assessed by obtaining serial measures of the Gastrointestinal Symptom Rating Scale (GSRS). These will be obtained with in-person interviews at the baseline and month 6 and 12 visits and by telephone contact with all subjects by the study coordinator every 2 weeks. Data will be analyzed within the 5 symptom domains depicting symptoms related to gastric reflux, abdominal pain, indigestion, diarrhea, and constipation.The GSRS has a seven-point graded Likert-type scale where 1 represents absence of troublesome symptoms and 7 represents very troublesome symptoms. A GSRS total score, the sum of all 5 domains, will also be assessed.

  10. Study retention rate. [ Time Frame: Up to 12 months ]
    The number of participants who complete all study visits, phone calls, and maintain drug compliance. Retention will be documented via conventional Consolidated Standards of Reporting Trials (CONSORT) criteria and documentation of missed study visits, missed telephone communications and compliance with study drug administration. All data will be maintained in the CRFs.



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Ages Eligible for Study:   50 Years to 65 Years   (Adult, Older Adult)
Sexes Eligible for Study:   Female
Gender Based Eligibility:   Yes
Gender Eligibility Description:   Females
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Willing and able to give written informed consent for participation in the study,
  2. Age range 50-65 years,
  3. Menopausal status (defined by >1 yr since last menstrual period or FSH level in the postmenopausal range),
  4. Ambulatory,
  5. Body mass Index (BMI) must be ≥ 18 and ≤ 32 kg/m2 at screening,
  6. Bone mineral density (BMD), expressed as T-scores, must be > - 2.5 in the lumbar spine (L1-L4), the femoral neck, and the total hip, as measured by dual energy X-ray absorptiometry (DXA),
  7. Commitment not to use any products that may influence the study outcome (see below),
  8. Ability to understand and comply with the requirements of the study.

Exclusion Criteria:

  1. Premenopausal status,
  2. History of >1 previous atraumatic bone fractures after age 50;
  3. Presence of established osteoporosis (T-score ≤ - 2.5, in the lumbar spine, femoral neck or total hip as measured by screening DXA),
  4. History of immunological or bone-related disorders including: HIV infection, Type I diabetes mellitus, bone marrow or organ transplantation; Inflammatory bowel disease (ulcerative colitis, Crohn's disease); multiple myeloma; osteomalacia; osteosarcoma; Paget's disease; rheumatoid arthritis; systemic lupus erythematous; parathyroid disorders,
  5. Uncontrolled type II diabetes mellitus (HgbA1c ≥ 7% within the last 12 months),
  6. History of bariatric surgery or other forms of malabsorption (including documented celiac disease, or chronic diarrhea),
  7. Alcohol abuse,
  8. Clinically significant chronic kidney disease (stage ≥ 2, with total serum creatinine level > 2.5 mg/dL and calculated glomerular filtration rate (GFR) < 60 mL/min by the Modification of Diet in Renal Disease (MDRD equation),
  9. Clinically significant cardiovascular disease (myocardial infarction, cerebral vascular accident or acute congestive heart failure within the previous 12 months,
  10. Any malignancies, other than localized skin squamous cell carcinoma, diagnosed within the previous 5 years, or any history of metastatic cancer,
  11. History of use of oral supplement products containing probiotic bacteria (more than once per week) within four weeks prior to baseline,
  12. Current use (within the past 8 weeks) of any medication with known influences on the immune or skeletal system (e.g. immune modulation therapy, systemic glucocorticoids, systemic steroid hormones,
  13. Use of oral or injectable bisphosphonates for more than 1 year within the last 5 years,
  14. Current or past use (within 1 year) of Denosumab, Teriparatide, Raloxifene, hormone replacement therapy (HRT), calcitonin, or any other anti-resorptive agent other than bisphosphonates used for the prevention and treatment of osteoporosis,
  15. Use of antibiotics during the previous two months or frequent user of antibiotics (>2 courses during the previous 12 months) for any cause,
  16. Smoking or use of nicotine-containing products during the last six months,
  17. Known hypersensitivity to any of the ingredients in the VSL#3 or the placebo study drug,
  18. serum or plasma 25-hydroxyvitamin D [25(OH)D] concentration < 12 ng/mL,
  19. uncontrolled thyroid disease (abnormal blood TSH level within the last 12 months and/or changing dose of thyroid replacement therapy within the last 12 months).

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03165747


Contacts
Contact: Roberto Pacifici, MD (404) 7128420 roberto.pacifici@emory.edu
Contact: Jessica Alvarez, PhD 404-727-1300 jessica.alvarez@emory.edu

Locations
United States, Georgia
Emory University Hospital Clinical Research Network, Emory Clinic, Emory St. Joseph's Hospital, Emory University Hospital (non-CRN) Recruiting
Atlanta, Georgia, United States, 30322
Contact: Roberto Pacifici, MD    404-712-8420    roberto.pacifici@emory.edu   
Contact: Jessica Alvarez, Ph.D., R.D    404-727-1390    jessica.alvarez@emory.edu   
Sponsors and Collaborators
Emory University
Investigators
Principal Investigator: Roberto Pacifici Emory University

Responsible Party: Roberto Pacifici, Assistant Professor, Emory University
ClinicalTrials.gov Identifier: NCT03165747     History of Changes
Other Study ID Numbers: IRB00095798
First Posted: May 24, 2017    Key Record Dates
Last Update Posted: July 6, 2018
Last Verified: July 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Roberto Pacifici, Emory University:
Probiotics
Menopausal Osteoporosis

Additional relevant MeSH terms:
Osteoporosis
Osteoporosis, Postmenopausal
Bone Diseases, Metabolic
Bone Diseases
Musculoskeletal Diseases
Metabolic Diseases