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| ID | Type | Description | Link |
|---|---|---|---|
| 001631-I |
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Background:
Many kinds of good or normal bacteria live on your skin and inside your stomach and intestines (gut). These bacteria are important to your health. What you eat, where you live, and what medicines you take can affect the bacteria in your gut. Bismuth subsalicylate (BSS) is an ingredient in common medicines for mild diarrhea and stomach pain. Products that contain BSS include Pepto-Bismol, Kao-Tin, and Pink Bismuth. But how BSS affects the bacteria in a person s gut is not fully understood.
Objective:
To see how BSS affects gut bacteria in healthy people.
Eligibility:
Healthy people aged 18 to 50 years.
Design:
Participants will have 6 clinic visits in up to 18 weeks. Only 1 visit must be at the NIH clinic; others may be either in-person or remote.
BSS is a liquid taken by mouth. Participants will take a dose of BSS 4 times a day for 2 days. They will take the same amount of BSS as a person would take to treat diarrhea or related problems.
Stool samples will be collected at each study visit. For remote visits, participants will be given a collection kit; they will collect the sample at home and send it in.
Participants will take surveys at each visit. They will answer questions about their diet and health.
Participants may also provide optional samples of blood, saliva, and urine.
Participants may have up to 2 optional colonoscopies. A long tube will be inserted via the rectum to collect tissue samples from the intestine. Participants will be sedated or placed under anesthesia for the procedure.
Study Description:
This is a single-site, single-arm, open-label study to evaluate the effect of bismuth subsalicylate (BSS) on the human gut microbiome and host immune response. Upon confirmation of eligibility, healthy adult volunteers will provide stool and optional blood, saliva, urine, and intestinal biopsy samples for a baseline assessment of gut microbiome and host immune response. Up to 18 weeks later, participants will undergo a 2-day/8-dose regimen of oral BSS. Stool will be collected at baseline, days 2 (+3), 8 (+/-3), 14 (-3/+7) and 28 (+/-7). Blood, saliva, and urine are also optional at these time points. Participants may also undergo a second optional colonoscopy at day 8 (+/-3) to provide colon biopsies for research analysis.
Primary Objective:
To evaluate the effect of BSS on the human gut microbiome.
Secondary Objective:
To evaluate the effect of BSS on the human gut metabolome.
Tertiary/Exploratory Objective:
To evaluate the effect of BSS on the systemic and intestinal host response (immune and inflammatory responses).
Primary Endpoint:
Differences in the relative abundance of taxa in stool samples pre-BSS and approximately 1 month post-BSS. Differences in microbiome metrics of alpha diversity and beta diversity will also be assessed.
Secondary Endpoint:
Differences in the stool metabolome (including short chain fatty acids, bile acids, and untargeted metabolomics) pre-BSS and approximately 1 month post-BSS.
Tertiary/Exploratory Endpoint:
Differences in systemic host immune and inflammatory responses, such as cytokines and immune cells, and host intestinal immune responses, such as specific T-cell populations in intestinal biopsies pre-BSS and approximately 1 month post-BSS.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Interventional | Experimental | The oral suspension formulation of BSS will be used in this study. It is self administered at 1050mg 4 times per day (1 to 6 hours apart) for 2 days. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Bismuth subsalicylate | Drug | BSS is a commonly used, widely available, OTC medication for a variety of gastrointestinal GI symptoms. It is available in the generic form, but also under the more commonly known brands: Bismatrol; Diotame; Geri-Pectate; Kao-Tin; Peptic Relief; Pepto-Bismol; Pink Bismuth and Stomach Relief. It received approval by the US Food and Drug Administration (FDA) in 1939. |
| Measure | Description | Time Frame |
|---|---|---|
| To Evaluate the Effect of BSS on the Human Gut Microbiome. | In the context of gut microbiome analysis, this measure represents the number of bacterial taxa that are significantly different between the two timepoints (baseline and 28 days post BSS) based on the read counts which represent abundance of taxa. We used shotgun metagenomic sequencing to analyze the gut microbiome. Sequenced reads were mapped to a reference database, and the read count abundance of each taxon was calculated. Statistical analysis was performed to identify the number of taxa that are significantly different between timepoints. | Through Day 28 |
| To Evaluate the Effect of BSS on the Human Gut Microbiome. | Difference of alpha diversity stool samples by Shannon index at baseline (before study drug administration) and 28 days after BSS. In the context of gut microbiome analysis, the Shannon Index represents a measure of alpha diversity (measure of diversity of a microbial community). The Shannon Index is a value greater than 0 with lower values indicating lower diversity and higher values indicating higher diversity, generally between 1.5 and 3.5, and usually < 4.5. To evaluate changes in the gut microbiome, we compared the mean change in the Shannon Index at baseline and 28 days post-BSS. Shotgun metagenomic sequencing was performed, and sequenced reads were mapped to a reference database to identify and enumerate based on read count unique taxa present in each sample. Statistical analysis was then used to determine whether there were significant differences in the Shannon Index between the two timepoints, providing insight into shifts in microbial diversity following BSS administration. | Through Day 28. |
| To Evaluate the Effect of BSS on the Human Gut Microbiome. | Difference of beta diversity stool samples at baseline (before study drug administration) and 28 days after BSS. Beta diversity refers to the variation in bacterial composition among samples, which we measured utilizing the Bray-Curtis dissimilarity Index. The Bray-Curtis is a widely used metric to quantify beta diversity, reflecting the degree of dissimilarity between samples, and its range is from 0 to 1, with 0 meaning no differences and 1 meaning completely dissimilar. This measure is essential for understanding changes in the bacterial composition over time. We used shotgun metagenomic sequencing to analyze the gut microbiome. Sequenced reads were mapped to a reference database, and the abundance of each taxon was calculated. The Bray-Curtis dissimilarity index was then calculated using read counts per species per sample to quantify the differences in community composition between samples at baseline and 28 days post-BSS administration. |
| Measure | Description | Time Frame |
|---|---|---|
| To Evaluate the Effect of BSS on the Human Gut Metabolome. | In the context of stool metabolome analysis, the number of differentially abundant metabolites refers to the count of metabolites whose levels significantly differ between baseline and 28 days post-BSS. To determine this, we performed broad targeted metabolomic profiling of stool samples collected at both timepoints. Metabolites were identified and quantified, and significant changes in abundance were calculated. The total number of differentially abundant metabolites provides a measure of the metabolic shifts in the gut environment following BSS administration. |
| Measure | Description | Time Frame |
|---|---|---|
| To Evaluate the Effect of BSS on the Human Gut Microbiome. | In the context of gut microbiome analysis, this measure represents the number of bacterial taxa that are significantly different between the two timepoints (baseline and 2 days post BSS) based on the read counts which represent abundance of taxa. We used shotgun metagenomic sequencing to analyze the gut microbiome. Sequenced reads were mapped to a reference database, and the read count abundance of each taxon was calculated. Statistical analysis was performed to identify the number of taxa that are significantly different between timepoints. |
An individual must meet all the following criteria to be eligible for this study:
Aged 18 to 50 years.
In generally good health.
Able to provide informed consent.
Willing to allow samples and data to be stored and shared for future research.
Participants who can become pregnant must agree to use one effective method of contraception when engaging in sexual activities that can result in pregnancy, beginning at the signing of the informed consent form (as early as week -18) until the final study visit. Acceptable methods of contraception include the following:
EXCLUSION CRITERIA:
An individual who meets any of the following criteria will be excluded from participation in this study:
Co-enrollment in other studies is restricted. Consideration for co-enrollment in clinical trials evaluating the use of a licensed medication will require the approval of the principal investigator. Study staff should be notified of co-enrollment on any other protocol as it may require the approval of the principal investigator.
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| Name | Affiliation | Role |
|---|---|---|
| Suchitra K Hourigan, M.D. | National Institute of Allergy and Infectious Diseases (NIAID) | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| National Institutes of Health Clinical Center | Bethesda | Maryland | 20892 | United States |
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| Label | URL |
|---|---|
| NIH Clinical Center Detailed Web Page | View source |
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Baseline visits were completed after confirmation of eligibility. The overlap between the screening and baseline windows accounted for the required 30-day interval between the optional colonoscopies at baseline and day 8. Participants who did not undergo colonoscopy may have a shorter interval between screening, baseline, and day 0 once eligibility is confirmed. Some participants did not meet criteria to continue based on medication use, scheduling issues, and enrollment in other trials.
Participants were recruited from June 2023 through October 2024. All recruitment took place at the National Institute of Allergy and Infectious Disease.
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| ID | Title | Description |
|---|---|---|
| FG000 | Interventional | The oral suspension formulation of BSS will be used in this study. It is self administered at 1050mg 4 times per day (1 to 6 hours apart) for 2 days. |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
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34 Participants signed informed consent and began baseline procedures. Only 21 participants received intervention and entered the trial. 13 participants either screen failed, were unable to schedule, or were lost to follow up prior to study drug administration.
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| ID | Title | Description |
|---|---|---|
| BG000 | Interventional | The oral suspension formulation of BSS will be used in this study. It is self administered at 1050mg 4 times per day (1 to 6 hours apart) for 2 days. |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Sex: Female, Male | Count of Participants |
| 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 | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Other Pre-specified | To Evaluate the Effect of BSS on the Human Gut Microbiome. | In the context of gut microbiome analysis, this measure represents the number of bacterial taxa that are significantly different between the two timepoints (baseline and 2 days post BSS) based on the read counts which represent abundance of taxa. We used shotgun metagenomic sequencing to analyze the gut microbiome. Sequenced reads were mapped to a reference database, and the read count abundance of each taxon was calculated. Statistical analysis was performed to identify the number of taxa that are significantly different between timepoints. | One participant received only a partial dose of BSS, then withdrew from the study. Another participant was enrolled to ensure the analysis was populated with 20 participants who received the full dosing. | Posted | Number | Number of different bacterial taxa | Through Day 2 |
|
Adverse Events were collected from time of enrollment to end of follow-up, up to 23 weeks, to account for the pre-intervention colonoscopy.
Adverse events of special interest (AESIs) are AEs that will be handled in a protocol/study-specific manner that differs from statutory and general rules for reporting. For the purposes of this protocol, AESIs are limited to any grade 2+ AEs probably or definitely related to gastrointestinal research biopsy collection.
Study numbers include only participants who were given study drug.
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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 | Interventional | The oral suspension formulation of BSS will be used in this study. It is self administered at 1050mg 4 times per day (1 to 6 hours apart) for 2 days. |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Abdominal Cramps | Reproductive system and breast disorders | MedDRA 10.0 | Systematic Assessment | Not related as due to menstrual cycle |
The study had several limitations. Only Fecal samples were analyzed, which cannot characterize specific parts of the gut. Fecal sulfides couldn't be measured due to preservation issues. Dietary variations could not be controlled for, and the BSS formulation included food dyes and flavorings, as well as salicylate, which may have influenced results. The study only included healthy adults aged 18-50, and as with all read-based microbiome studies, taxonomic classification may have been suboptimal.
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Suchitra Hourigan | National Institute of Allergy and Infectious Disease | (240) 292-4552 | suchitra.hourigan@nih.gov |
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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 | Jul 5, 2024 | Dec 1, 2025 | Prot_SAP_000.pdf |
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| ID | Term |
|---|---|
| C015715 | bismuth subsalicylate |
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|
| Through Day 28. |
| Through Day 28 |
| Through Day 2 |
| To Evaluate the Effect of BSS on the Human Gut Microbiome. | Difference of alpha diversity stool samples by Shannon index at baseline (before study drug administration) and 2 days after BSS. In the context of gut microbiome analysis, the Shannon Index represents a measure of alpha diversity (measure of diversity of a microbial community). The Shannon Index is a value greater than 0 with lower values indicating lower diversity and higher values indicating higher diversity, generally between 1.5 and 3.5, and usually < 4.5. To evaluate changes in the gut microbiome, we compared the mean change in the Shannon Index at baseline and 2 days post-BSS. Shotgun metagenomic sequencing was performed, and sequenced reads were mapped to a reference database to identify and enumerate based on read count unique taxa present in each sample. Statistical analysis was then used to determine whether there were significant differences in the Shannon Index between the two timepoints, providing insight into shifts in microbial diversity following BSS administration. | Through Day 2 |
| To Evaluate the Effect of BSS on the Human Gut Microbiome. | Beta diversity refers to the variation in bacterial composition among samples, which we measured utilizing the Bray-Curtis dissimilarity Index. Bray-Curtis is used to quantify beta diversity, reflecting the degree of dissimilarity between samples, and its range is from 0 to 1, with 0 meaning no differences and 1 meaning completely dissimilar. This measure is essential for understanding changes in the bacterial composition over time. We used shotgun metagenomic sequencing to analyze the gut microbiome. Sequenced reads were mapped to a reference database, and the abundance of each taxon was calculated. Bray-Curtis was then calculated using read counts per species per sample to quantify the differences in community composition between samples at baseline and 2 days post-BSS administration. Bray-Curtis dissimilarities were calculated between samples and visualized using principal coordinates analysis (PCoA); values along the second ordination axis (PCoA2) used for downstream analysis. | Through Day 2. |
| To Evaluate the Effect of BSS on the Human Gut Metabolome. | In the context of stool metabolome analysis, the number of differentially abundant metabolites refers to the count of metabolites whose levels significantly differ between baseline and 2 days post-BSS. To determine this, we performed broad targeted metabolomic profiling of stool samples collected at both timepoints. Metabolites were identified and quantified, and significant changes in abundance were calculated. The total number of differentially abundant metabolites provides a measure of the metabolic shifts in the gut environment following BSS administration. | Through Day 2 |
| Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| Ethnicity (NIH/OMB) | Count of Participants | Participants |
|
| Age, Categorical | Count of Participants | Participants |
|
| Baseline Colonoscopy | Participants were eligible for colonoscopy if they were not pregnant, had no history of GI perforation, no prolonged bleeding time, no contraindications to anesthesia, and under age 30. | Number | Participants |
|
The oral suspension formulation of BSS will be used in this study. It is self administered at 1050mg 4 times per day (1 to 6 hours apart) for 2 days.
|
|
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| Secondary | To Evaluate the Effect of BSS on the Human Gut Metabolome. | In the context of stool metabolome analysis, the number of differentially abundant metabolites refers to the count of metabolites whose levels significantly differ between baseline and 28 days post-BSS. To determine this, we performed broad targeted metabolomic profiling of stool samples collected at both timepoints. Metabolites were identified and quantified, and significant changes in abundance were calculated. The total number of differentially abundant metabolites provides a measure of the metabolic shifts in the gut environment following BSS administration. | One participant received only a partial dose of BSS, then withdrew from the study. Another participant was enrolled to ensure the analysis was populated with 20 participants who received the full dosing. | Posted | Number | Number differently abundant metabolites | Through Day 28 |
|
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| Primary | To Evaluate the Effect of BSS on the Human Gut Microbiome. | In the context of gut microbiome analysis, this measure represents the number of bacterial taxa that are significantly different between the two timepoints (baseline and 28 days post BSS) based on the read counts which represent abundance of taxa. We used shotgun metagenomic sequencing to analyze the gut microbiome. Sequenced reads were mapped to a reference database, and the read count abundance of each taxon was calculated. Statistical analysis was performed to identify the number of taxa that are significantly different between timepoints. | One participant received only a partial dose of BSS, then withdrew from the study. Another participant was enrolled to ensure the analysis was populated with 20 participants who received the full dosing. | Posted | Number | Number of different bacterial taxa | Through Day 28 |
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| Primary | To Evaluate the Effect of BSS on the Human Gut Microbiome. | Difference of alpha diversity stool samples by Shannon index at baseline (before study drug administration) and 28 days after BSS. In the context of gut microbiome analysis, the Shannon Index represents a measure of alpha diversity (measure of diversity of a microbial community). The Shannon Index is a value greater than 0 with lower values indicating lower diversity and higher values indicating higher diversity, generally between 1.5 and 3.5, and usually < 4.5. To evaluate changes in the gut microbiome, we compared the mean change in the Shannon Index at baseline and 28 days post-BSS. Shotgun metagenomic sequencing was performed, and sequenced reads were mapped to a reference database to identify and enumerate based on read count unique taxa present in each sample. Statistical analysis was then used to determine whether there were significant differences in the Shannon Index between the two timepoints, providing insight into shifts in microbial diversity following BSS administration. | One participant received only a partial dose of BSS, then withdrew from the study. Another participant was enrolled to ensure the analysis was populated with 20 participants who received the full dosing. | Posted | Mean | Standard Error | Change in Shannon Index | Through Day 28. |
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| Primary | To Evaluate the Effect of BSS on the Human Gut Microbiome. | Difference of beta diversity stool samples at baseline (before study drug administration) and 28 days after BSS. Beta diversity refers to the variation in bacterial composition among samples, which we measured utilizing the Bray-Curtis dissimilarity Index. The Bray-Curtis is a widely used metric to quantify beta diversity, reflecting the degree of dissimilarity between samples, and its range is from 0 to 1, with 0 meaning no differences and 1 meaning completely dissimilar. This measure is essential for understanding changes in the bacterial composition over time. We used shotgun metagenomic sequencing to analyze the gut microbiome. Sequenced reads were mapped to a reference database, and the abundance of each taxon was calculated. The Bray-Curtis dissimilarity index was then calculated using read counts per species per sample to quantify the differences in community composition between samples at baseline and 28 days post-BSS administration. | One participant received only a partial dose of BSS, then withdrew from the study. Another participant was enrolled to ensure the analysis was populated with 20 participants who received the full dosing. | Posted | Mean | Standard Error | Bray-Curtis index | Through Day 28. |
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| Other Pre-specified | To Evaluate the Effect of BSS on the Human Gut Microbiome. | Difference of alpha diversity stool samples by Shannon index at baseline (before study drug administration) and 2 days after BSS. In the context of gut microbiome analysis, the Shannon Index represents a measure of alpha diversity (measure of diversity of a microbial community). The Shannon Index is a value greater than 0 with lower values indicating lower diversity and higher values indicating higher diversity, generally between 1.5 and 3.5, and usually < 4.5. To evaluate changes in the gut microbiome, we compared the mean change in the Shannon Index at baseline and 2 days post-BSS. Shotgun metagenomic sequencing was performed, and sequenced reads were mapped to a reference database to identify and enumerate based on read count unique taxa present in each sample. Statistical analysis was then used to determine whether there were significant differences in the Shannon Index between the two timepoints, providing insight into shifts in microbial diversity following BSS administration. | One participant received only a partial dose of BSS, then withdrew from the study. Another participant was enrolled to ensure the analysis was populated with 20 participants who received the full dosing. | Posted | Mean | Standard Error | Change in Shannon Index | Through Day 2 |
|
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|
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| Other Pre-specified | To Evaluate the Effect of BSS on the Human Gut Microbiome. | Beta diversity refers to the variation in bacterial composition among samples, which we measured utilizing the Bray-Curtis dissimilarity Index. Bray-Curtis is used to quantify beta diversity, reflecting the degree of dissimilarity between samples, and its range is from 0 to 1, with 0 meaning no differences and 1 meaning completely dissimilar. This measure is essential for understanding changes in the bacterial composition over time. We used shotgun metagenomic sequencing to analyze the gut microbiome. Sequenced reads were mapped to a reference database, and the abundance of each taxon was calculated. Bray-Curtis was then calculated using read counts per species per sample to quantify the differences in community composition between samples at baseline and 2 days post-BSS administration. Bray-Curtis dissimilarities were calculated between samples and visualized using principal coordinates analysis (PCoA); values along the second ordination axis (PCoA2) used for downstream analysis. | One participant received only a partial dose of BSS, then withdrew from the study. Another participant was enrolled to ensure the analysis was populated with 20 participants who received the full dosing. | Posted | Mean | Standard Error | Bray-Curtis index | Through Day 2. |
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| Other Pre-specified | To Evaluate the Effect of BSS on the Human Gut Metabolome. | In the context of stool metabolome analysis, the number of differentially abundant metabolites refers to the count of metabolites whose levels significantly differ between baseline and 2 days post-BSS. To determine this, we performed broad targeted metabolomic profiling of stool samples collected at both timepoints. Metabolites were identified and quantified, and significant changes in abundance were calculated. The total number of differentially abundant metabolites provides a measure of the metabolic shifts in the gut environment following BSS administration. | One participant received only a partial dose of BSS, then withdrew from the study. Another participant was enrolled to ensure the analysis was populated with 20 participants who received the full dosing. | Posted | Number | Number differently abundant metabolites | Through Day 2 |
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| 0 |
| 21 |
| 0 |
| 21 |
| 20 |
| 21 |
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| Diarrhea | Gastrointestinal disorders | MedDRA 10.0 | Systematic Assessment | Diarrhea specifically from colonoscopy preparation |
|
| Abdominal Pain | General disorders | MedDRA 10.0 | Systematic Assessment | Not related based on timeline. |
|
| Bloating | Gastrointestinal disorders | MedDRA 10.0 | Systematic Assessment | Possibly due to study intervention |
|
| Darkened Stool | Gastrointestinal disorders | MedDRA 10.0 | Systematic Assessment | Definitely related to study intervention. Known risk of BSS. |
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| Diarrhea | Gastrointestinal disorders | MedDRA 10.0 | Systematic Assessment | Probably related to study intervention, not related to colonoscopy prep. |
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| Eye Pain | Eye disorders | MedDRA 10.0 | Systematic Assessment | Unlikely related. |
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| Fatigue | General disorders | MedDRA 10.0 | Systematic Assessment | One participant reported fatigue post intervention. One was unlikely related, and one was not related based on the timeline. |
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| Heartburn | Gastrointestinal disorders | MedDRA 10.0 | Systematic Assessment | Probably related based on timeline. |
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| Joint or Muscle Ache | Musculoskeletal and connective tissue disorders | MedDRA 10.0 | Systematic Assessment | Unlikely related based on timeline. |
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| Loose Stools | Gastrointestinal disorders | MedDRA 10.0 | Systematic Assessment | One participant probably related and one unlikely related based on timeline. |
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| Nausea | Gastrointestinal disorders | MedDRA 10.0 | Systematic Assessment | One definitely, one probably, and one unlikely related to study intervention based on timeline. |
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| Sore throat | General disorders | MedDRA 10.0 | Systematic Assessment | Unlikely related based on timeline. |
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