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| ID | Type | Description | Link |
|---|---|---|---|
| 1R61AT009622-01A1 | U.S. NIH Grant/Contract | View source |
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| Name | Class |
|---|---|
| National Center for Complementary and Integrative Health (NCCIH) | NIH |
| University of Maryland, Baltimore | OTHER |
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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.
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 (16 Svedberg) 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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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Control | Placebo Comparator | Yogurt without Bifidobacterium animalis subsp. lactis BB-12 (BB-12) and Amoxicillin-Clavulanate 875 Mg-125 Mg Oral Tablet |
|
| BB-12 | Experimental | Bifidobacterium animalis subsp. lactis BB-12 (BB-12)-supplemented yogurt and Amoxicillin-Clavulanate 875 Mg-125 Mg Oral Tablet |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Amoxicillin-Clavulanate 875 Mg-125 Mg Oral Tablet | Drug | Amoxicillin-Clavulanate 875 Mg-125 Mg Oral Tablet |
|
| Measure | Description | Time Frame |
|---|---|---|
| Level of Fecal Short-chain Fatty Acid (SCFA) Acetate | Level of fecal short-chain fatty acid acetate (SCFA) after administration of amoxicillin clavulanate | day 0 (post run-in), 7, 14, 21, 30 |
| Measure | Description | Time Frame |
|---|---|---|
| Level of Fecal SCFA Propionate | Level of fecal short-chain fatty acid propionate after administration of amoxicillin clavulanate | day 0 (post run-in), 7, 14, 21, 30 |
| Level of Fecal SCFA Butyrate |
| Measure | Description | Time Frame |
|---|---|---|
| Change in Community Diversity (Shannon Diversity Index) From Pre run-in Baseline | The Shannon diversity metric is a measure of community diversity and takes into account species richness (number of distinct taxa) and the relative abundance of each taxon. The Shannon diversity index was calculated for samples at each time point from subjects receiving control or BB-12 yogurt. The first of two baseline samples was collected from each subject at the time of enrollment (pre run-in) before a 30-day run-in period in which the consumption of dietary probiotics was stopped. A higher index indicates more diversity and a lower index indicates less diversity. |
Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Daniel Merenstein, MD | Georgetown University | Principal Investigator |
| Claire Fraser, PhD | University of Maryland, Baltimore | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Georgetown University Department of Family Medicine | Washington D.C. | District of Columbia | 20007 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 34444974 | Result | Merenstein D, Fraser CM, Roberts RF, Liu T, Grant-Beurmann S, Tan TP, Smith KH, Cronin T, Martin OA, Sanders ME, Lucan SC, Kane MA. Bifidobacterium animalis subsp. lactis BB-12 Protects against Antibiotic-Induced Functional and Compositional Changes in Human Fecal Microbiome. Nutrients. 2021 Aug 17;13(8):2814. doi: 10.3390/nu13082814. |
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| ID | Title | Description |
|---|---|---|
| FG000 | Control | Yogurt without Bifidobacterium animalis subsp. lactis BB-12 (BB-12) and Amoxicillin-Clavulanate 875 Mg-125 Mg Oral Tablet Amoxicillin-Clavulanate 875 Mg-125 Mg Oral Tablet: Amoxicillin-Clavulanate 875 Mg-125 Mg Oral Tablet Control: Yogurt without Bifidobacterium animalis subsp. lactis BB-12 (BB-12) |
| FG001 | BB-12 | Bifidobacterium animalis subsp. lactis BB-12 (BB-12)-supplemented yogurt and Amoxicillin-Clavulanate 875 Mg-125 Mg Oral Tablet Amoxicillin-Clavulanate 875 Mg-125 Mg Oral Tablet: Amoxicillin-Clavulanate 875 Mg-125 Mg Oral Tablet BB-12: Bifidobacterium animalis subsp. lactis BB-12-supplemented yogurt |
| FG002 | Not Randomized | Withdrawals prior to randomization |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
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| ID | Title | Description |
|---|---|---|
| BG000 | Control | Yogurt without Bifidobacterium animalis subsp. lactis BB-12 (BB-12) and Amoxicillin-Clavulanate 875 Mg-125 Mg Oral Tablet Amoxicillin-Clavulanate 875 Mg-125 Mg Oral Tablet: Amoxicillin-Clavulanate 875 Mg-125 Mg Oral Tablet Control: Yogurt without Bifidobacterium animalis subsp. lactis BB-12 (BB-12) |
| BG001 |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Level of Fecal Short-chain Fatty Acid (SCFA) Acetate | Level of fecal short-chain fatty acid acetate (SCFA) after administration of amoxicillin clavulanate | Number of samples received | Posted | Mean | Standard Deviation | micromolar (μM) | day 0 (post run-in), 7, 14, 21, 30 |
|
Pre-run in baseline to day 30
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Control | Yogurt without Bifidobacterium animalis subsp. lactis BB-12 (BB-12) and Amoxicillin-Clavulanate 875 Mg-125 Mg Oral Tablet Amoxicillin-Clavulanate 875 Mg-125 Mg Oral Tablet: Amoxicillin-Clavulanate 875 Mg-125 Mg Oral Tablet Control: Yogurt without Bifidobacterium animalis subsp. lactis BB-12 (BB-12) |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Loose stool | Gastrointestinal disorders | Non-systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Daniel Merenstein, MD | Department of Family Medicine, Georgetown University Medical Center | 202-687-2745 | djm23@georgetown.edu |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | May 27, 2022 | Aug 3, 2022 | Prot_SAP_001.pdf |
| ICF | No | No | Yes | Informed Consent Form | Jun 22, 2019 | Mar 24, 2020 | ICF_000.pdf |
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| ID | Term |
|---|---|
| D019980 | Amoxicillin-Potassium Clavulanate Combination |
| ID | Term |
|---|---|
| D019818 | Clavulanic Acid |
| D002969 | Clavulanic Acids |
| D047090 | beta-Lactams |
| D007769 | Lactams |
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| BB-12 | Biological | Bifidobacterium animalis subsp. lactis BB-12-supplemented yogurt |
|
| Control | Other | Yogurt without Bifidobacterium animalis subsp. lactis BB-12 (BB-12) |
|
Level of fecal short-chain fatty acid butyrate (μM) after administration of amoxicillin clavulanate
| day 0 (post run-in), 7, 14, 21, 30 |
| day 0 (pre run-in), 7, 14, 21, 30 |
| Change in Community Diversity (Shannon Diversity Index) From Post run-in Baseline | The Shannon diversity metric is a measure of community diversity and takes into account species richness (number of distinct taxa) and the relative abundance of each taxon. The Shannon diversity index was calculated for samples at each time point from subjects receiving control or BB-12 yogurt. The second baseline sample was collected from each subject after a 30-day run-in period in which the consumption of dietary probiotics was stopped (post run-in). A higher index indicates more diversity and a lower index indicates less diversity. | day 0 (post run-in), 7, 14, 21, 30 |
| Bray-Curtis Dissimilarity | Community divergence over time with respect to the baseline sample (post run-in, day 0) | day 0, 7, 14, 21, 30 |
| Change in Diarrhea/Stool Frequency | Change in diarrhea/stool frequency from baseline | day 7, 14, 21, 30 |
| BB-12 |
Bifidobacterium animalis subsp. lactis BB-12 (BB-12)-supplemented yogurt and Amoxicillin-Clavulanate 875 Mg-125 Mg Oral Tablet Amoxicillin-Clavulanate 875 Mg-125 Mg Oral Tablet: Amoxicillin-Clavulanate 875 Mg-125 Mg Oral Tablet BB-12: Bifidobacterium animalis subsp. lactis BB-12-supplemented yogurt |
| BG002 | Not Randomized | Withdrawals prior to randomization |
| BG003 | Total | Total of all reporting groups |
| years |
|
| Sex/Gender, Customized | Count of Participants | Participants | No |
|
| Ethnicity (NIH/OMB) | Count of Participants | Participants | No |
|
| Race (NIH/OMB) | Count of Participants | Participants | No |
|
| Health insurance status | Count of Participants | Participants | No |
|
| Household smoking | Count of Participants | Participants | No |
|
| Marital status | Count of Participants | Participants | No |
|
| Annual gross total income | Count of Participants | Participants | No |
|
|
|
| Secondary | Level of Fecal SCFA Propionate | Level of fecal short-chain fatty acid propionate after administration of amoxicillin clavulanate | Number of samples received | Posted | Mean | Standard Deviation | μM | day 0 (post run-in), 7, 14, 21, 30 |
|
|
|
| Secondary | Level of Fecal SCFA Butyrate | Level of fecal short-chain fatty acid butyrate (μM) after administration of amoxicillin clavulanate | Number of samples received | Posted | Mean | Standard Deviation | μM | day 0 (post run-in), 7, 14, 21, 30 |
|
|
|
| Other Pre-specified | Change in Community Diversity (Shannon Diversity Index) From Pre run-in Baseline | The Shannon diversity metric is a measure of community diversity and takes into account species richness (number of distinct taxa) and the relative abundance of each taxon. The Shannon diversity index was calculated for samples at each time point from subjects receiving control or BB-12 yogurt. The first of two baseline samples was collected from each subject at the time of enrollment (pre run-in) before a 30-day run-in period in which the consumption of dietary probiotics was stopped. A higher index indicates more diversity and a lower index indicates less diversity. | Number of samples received | Posted | Mean | Standard Deviation | Shannon Diversity Index | day 0 (pre run-in), 7, 14, 21, 30 |
|
|
|
| Other Pre-specified | Change in Community Diversity (Shannon Diversity Index) From Post run-in Baseline | The Shannon diversity metric is a measure of community diversity and takes into account species richness (number of distinct taxa) and the relative abundance of each taxon. The Shannon diversity index was calculated for samples at each time point from subjects receiving control or BB-12 yogurt. The second baseline sample was collected from each subject after a 30-day run-in period in which the consumption of dietary probiotics was stopped (post run-in). A higher index indicates more diversity and a lower index indicates less diversity. | Number of samples received | Posted | Mean | Standard Deviation | Shannon Diversity Index | day 0 (post run-in), 7, 14, 21, 30 |
|
|
|
| Other Pre-specified | Bray-Curtis Dissimilarity | Community divergence over time with respect to the baseline sample (post run-in, day 0) | Not Posted | day 0, 7, 14, 21, 30 | Participants |
| Other Pre-specified | Change in Diarrhea/Stool Frequency | Change in diarrhea/stool frequency from baseline | Not Posted | day 7, 14, 21, 30 | Participants |
| 0 |
| 20 |
| 0 |
| 20 |
| 15 |
| 18 |
| EG001 | BB-12 | Bifidobacterium animalis subsp. lactis BB-12 (BB-12)-supplemented yogurt and Amoxicillin-Clavulanate 875 Mg-125 Mg Oral Tablet Amoxicillin-Clavulanate 875 Mg-125 Mg Oral Tablet: Amoxicillin-Clavulanate 875 Mg-125 Mg Oral Tablet BB-12: Bifidobacterium animalis subsp. lactis BB-12-supplemented yogurt | 0 | 42 | 0 | 42 | 25 | 38 |
| Diarrhea | Gastrointestinal disorders | Non-systematic Assessment |
|
| Constipation | Gastrointestinal disorders | Non-systematic Assessment |
|
| Flatulence | Gastrointestinal disorders | Non-systematic Assessment |
|
| Lack/Loss of Appetite | General disorders | Non-systematic Assessment |
|
| Stomach Pain | Gastrointestinal disorders | Non-systematic Assessment |
|
| Rash | General disorders | Non-systematic Assessment |
|
| Vomiting | Gastrointestinal disorders | Non-systematic Assessment |
|
| Dyspepsia | Gastrointestinal disorders | Non-systematic Assessment |
|
| Nausea | General disorders | Non-systematic Assessment |
|
| Other | General disorders | Non-systematic Assessment |
|
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| D000577 |
| Amides |
| D009930 | Organic Chemicals |
| D000658 | Amoxicillin |
| D000667 | Ampicillin |
| D010400 | Penicillin G |
| D010406 | Penicillins |
| D013457 | Sulfur Compounds |
| D006574 | Heterocyclic Compounds, 2-Ring |
| D000072471 | Heterocyclic Compounds, Fused-Ring |
| D006571 | Heterocyclic Compounds |
| D004338 | Drug Combinations |
| D004364 | Pharmaceutical Preparations |
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