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Mechanisms of Preventing Antibiotic-Associated Diarrhea and the Role for Probiotics (YOBIOTIC)

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ClinicalTrials.gov Identifier: NCT03755765
Recruitment Status : Not yet recruiting
First Posted : November 28, 2018
Last Update Posted : May 24, 2019
Sponsor:
Collaborators:
National Center for Complementary and Integrative Health (NCCIH)
University of Maryland
Information provided by (Responsible Party):
Daniel Merenstein, Georgetown University

Brief Summary:
The focus of the study is to better understand the mechanisms causing antibiotic-associated diarrhea (AAD) and how probiotics may prevent some of the iatrogenic effects of antibiotic medications. One of the most common indications for probiotics is for prevention of antibiotic-associated diarrhea. Clinically, different probiotic strains have demonstrated the ability to prevent AAD; however, the mechanism of action behind this effect has not been elucidated. Data from several studies suggest that antibiotic-induced disruption of commensal bacteria in the colon results in a significant (up to 50%) reduction in short chain fatty acid (SCFA) production and a concomitant reduction in Na-dependent fluid absorption resulting in AAD. Probiotics have been shown to ameliorate a variety of gastrointestinal disease states and thus, the study investigators hypothesize that administration of a probiotic yogurt will protect against the development of AAD.

Condition or disease Intervention/treatment Phase
Antibiotic-associated Diarrhea Drug: Amoxicillin-Clavulanate 875 Mg-125 Mg Oral Tablet Biological: BB-12 Other: Control Early Phase 1

Detailed Description:

Probiotics are live microorganisms that, when administered in adequate amounts, confer a health benefit on the host. One of the most common indications for probiotic treatment is the prevention of antibiotic-associated diarrhea (AAD). Unfortunately, the efficacy of many probiotic products used for AAD is not supported by rigorous independent research, and non-evidence-based clinical usage is common. Data from several studies are consistent with the notion that antibiotic-induced disruption of commensal bacteria in the colon results in a significant reduction of short chain fatty acid (SCFA) production and a concomitant reduction in Na-dependent fluid absorption resulting in AAD. The probiotic strain being studied, Bifidobacterium animalis subsp. lactis BB-12 (BB-12), has been shown to ameliorate a variety of gastrointestinal disease states and is known to produce acetate at concentrations up to 50 mM in vitro. Thus, the investigators hypothesize that administration of BB-12 at the same time as antibiotic consumption will protect against the development of AAD through its ability to generate acetate directly, and also increase other SCFAs through cross-feeding of certain bacteria in the Firmicutes phylum such Clostridium, Eubacterium and Roseburia, which use acetate to produce butyrate.

The primary aim of the R61 phase (N=60) is to determine the ability of BB-12 to impact antibiotic-induced reduction in SCFA as reflected by the levels of acetate, the most abundant primary colonic SCFA. The primary hypothesis is that antibiotics will result in a reduction in fecal SCFA, but BB-12 supplementation will protect against antibiotic-induced SCFA reduction and/or be associated with a more rapid return to baseline SCFA levels as compared to controls. Antibiotics also result in a decrease in total microbial counts and diversity in the gut microbiota, disrupting the homeostasis of the gut ecosystem and allowing colonization by pathogens. The secondary aim will be to determine the ability of BB-12 to impact antibiotic-induced disruption of the gut microbiota with 16S ribosomal ribonucleic acid (rRNA) profiling. The secondary hypothesis is that antibiotics will result in a decrease in the overall number and diversity of bacterial species present in the fecal microbiota, and further BB-12 supplementation will protect against antibiotic-induced shifts in the microbiota and/or will be associated with a more rapid return to a baseline microbiota composition as compared to controls. The long-term goal is to determine the impact of BB-12 on a variety of gastrointestinal disease states and ages, through high-level independent research. This mechanism elucidation is important for directing future translational and effectiveness research.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 60 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary Purpose: Other
Official Title: Exploratory Pilot Studies to Demonstrate Mechanisms of Preventing Antibiotic-Associated Diarrhea and the Role for Probiotics
Estimated Study Start Date : July 2019
Estimated Primary Completion Date : June 2020
Estimated Study Completion Date : December 2020

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Antibiotics Diarrhea

Arm Intervention/treatment
Placebo Comparator: Control
Yogurt without Bifidobacterium animalis subsp. lactis BB-12 (BB-12) and Amoxicillin-Clavulanate 875 Mg-125 Mg Oral Tablet
Drug: Amoxicillin-Clavulanate 875 Mg-125 Mg Oral Tablet
Amoxicillin-Clavulanate 875 Mg-125 Mg Oral Tablet
Other Name: Augmentin

Other: Control
Yogurt without Bifidobacterium animalis subsp. lactis BB-12 (BB-12)

Experimental: BB-12
Bifidobacterium animalis subsp. lactis BB-12 (BB-12)-supplemented yogurt and Amoxicillin-Clavulanate 875 Mg-125 Mg Oral Tablet
Drug: Amoxicillin-Clavulanate 875 Mg-125 Mg Oral Tablet
Amoxicillin-Clavulanate 875 Mg-125 Mg Oral Tablet
Other Name: Augmentin

Biological: BB-12
Bifidobacterium animalis subsp. lactis BB-12-supplemented yogurt




Primary Outcome Measures :
  1. Change from baseline levels of fecal short-chain fatty acid at day 7 [ Time Frame: day 7 ]
  2. Change from baseline levels of fecal short-chain fatty acid at day 14 [ Time Frame: day 14 ]
  3. Change from baseline levels of fecal short-chain fatty acid at day 21 [ Time Frame: day 21 ]
  4. Change from baseline levels of fecal short-chain fatty acid at day 30 [ Time Frame: day 30 ]

Secondary Outcome Measures :
  1. Change in baseline diversity of bacterial species in fecal microbiota as assessed by Shannon index [ Time Frame: day 7, 14, 21, 30 ]
  2. Change in baseline diversity of bacterial species in fecal microbiota as assessed by Bray-Curtis dissimilarity [ Time Frame: day 7, 14, 21, 30 ]
    Bray-Curtis dissimilarity is used to quantify the differences in species populations between two different sites and is defined as: BCij = 1 - [ 2Cij / Si + Sj ] Where: i & j are the two sites, Si is the total number of specimens counted on site i, Sj is the total number of specimens counted on site j, Cij is the sum of only the lesser counts for each species found in both sites. The Bray-Curtis dissimilarity is bounded between 0 and 1, where 0 means the two sites have the same composition (that is they share all the species), and 1 means the two sites do not share any species. It may expressed as a percentage: BCij x 100. The Bray-Curtis index (similarity between two sites) is (1 - BCij) x 100.

  3. Change in baseline diversity of bacterial species in fecal microbiota as assessed by Chao1 metric [ Time Frame: day 7, 14, 21, 30 ]
  4. Change in baseline number of bacterial species in fecal microbiota [ Time Frame: day 7, 14, 21, 30 ]


Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 65 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  1. Has the ability to read, speak, and write in English
  2. Has refrigerator (for proper storage of the study yogurt)
  3. Has reliable telephone access
  4. Is between ages of 18-65 years
  5. Agree to refrain from eating yogurts, yogurt drinks, and other foods specified in the provided What Not to Eat list
  6. Agree to collect stool samples and participate in follow-up calls as specified

Exclusion Criteria:

  1. Diabetes or asthma that requires medication
  2. Allergy to strawberry
  3. Active diarrhea (three or more loose stools per day for two consecutive days)
  4. Any gastrointestinal (or digestive tract) medications, i.e. medicines for irritable bowel syndrome, gastroesophageal (acid) reflux disease, inflammatory bowel disease, etc.
  5. History of heart disease, including valvulopathies or cardiac surgery, any implantable device or prosthetic
  6. History of gastrointestinal surgery or disease
  7. Lactose intolerance that prevents participant from eating yogurt
  8. Allergy to milk-protein
  9. Allergy to any component of the product or the yogurt vehicle
  10. Allergy to penicillin or cephalosporin class antibiotics
  11. Allergy to any of the following medications: a) Penicillin; b) Erythromycin; c) Tetracycline; d) Trimethoprim; e) Ciprofloxacin
  12. Women who are breastfeeding, pregnant, or planning to become pregnant during the study

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): NCT03755765


Contacts
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Contact: Daniel Merenstein, MD 202-687-2745 djm23@georgetown.edu

Sponsors and Collaborators
Georgetown University
National Center for Complementary and Integrative Health (NCCIH)
University of Maryland
Investigators
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Principal Investigator: Daniel Merenstein, MD Georgetown University
Principal Investigator: Claire Fraser, PhD University of Maryland

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Responsible Party: Daniel Merenstein, Director of Research Programs, Georgetown University
ClinicalTrials.gov Identifier: NCT03755765     History of Changes
Other Study ID Numbers: 2018-0736
1R61AT009622-01A1 ( U.S. NIH Grant/Contract )
First Posted: November 28, 2018    Key Record Dates
Last Update Posted: May 24, 2019
Last Verified: May 2019

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

Additional relevant MeSH terms:
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Diarrhea
Signs and Symptoms, Digestive
Signs and Symptoms
Anti-Bacterial Agents
Amoxicillin
Clavulanic Acid
Clavulanic Acids
Amoxicillin-Potassium Clavulanate Combination
Anti-Infective Agents
beta-Lactamase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action