Irritable Bowel Syndrome
Conditions
Keywords
Irritable Bowel Syndrome, Diarrhea, Small Intestinal Bacterial Overgrowth, Gut Microbiota
Brief summary
Diarrhea-predominant irritable bowel syndrome (IBS-D) is a highly prevalent but poorly understood condition with limited treatment options. Current therapies, including a nonabsorbable antibiotic rifaximin or diet low in fermentable oligosaccharides, disaccharides, monosaccharides, and polyols (FODMAP), show efficacy in 50% or less of patients. In this proposal, participants with IBS-D will be randomized to receive either rifaximin or low FODMAP dietary intervention.
Detailed description
Diarrhea-predominant irritable bowel syndrome (IBS-D) is a highly prevalent but poorly understood condition with limited treatment options. Recent evidence has established small intestinal bacterial overgrowth (SIBO) and alterations in fecal microbiota as potential etiologies in the pathogenesis of IBS-D. Current therapies, including a nonabsorbable antibiotic rifaximin or diet low in fermentable oligosaccharides, disaccharides, monosaccharides, and polyols (FODMAP), show efficacy in 50% or less of patients \[1-4\]. It has been postulated that limited responses to therapies may stem from failure to identify distinct subgroups in IBS-D stratified by gut microbial profiles. In this proposal, participants with IBS-D will be randomized to receive either rifaximin or low FODMAP dietary intervention. The results of fecal microbiota-derived data as well as hydrogen breath tests will then be longitudinally followed to define SIBO. These methods will be used to test the hypotheses that: (i) distinct IBS-D phenotypes can be generated by defining fecal microbial populations as well as delineating the presence or absence of SIBO; and (ii) longitudinal analyses using microbe-derived metrics and SIBO status may relate to response to treatment with rifaximin or low FODMAP dietary intervention.
Interventions
DRUGRifaximin 550 MG
Rifaximin 550 mg three times daily for 14 days
OTHERLow FODMAP Diet
Low FODMAP dietary intervention for 4 weeks
Sponsors
Michigan Institute for Clinical and Health Research (MICHR)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
University of Michigan
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Adult subjects greater than or equal to 18 years of age who meet Rome IV criteria for diarrhea-predominant irritable bowel syndrome (IBS-D). Prior colonoscopy or sigmoidoscopy within the past 2 years with random colon biopsies to exclude the presence of microscopic colitis. IBS medications, including anti-depressants, will be allowed if the dose has been stable for at least 1 month before inclusion. Medications will be carefully tracked to follow any potential confounding issues.
Exclusion criteria
Underlying celiac disease, inflammatory bowel disease, or other organic disease that could explain their symptoms. Subjects with a history of GI tract surgery, except for cholecystectomy or appendectomy, will also be excluded from the study. Women who are pregnant or breastfeeding Antibiotics taken within 3 months prior to enrollment will not be permitted. Subjects on probiotics must discontinue their use at least 1 month prior to enrollment. Subjects who have previously received formal dietary education for IBS, including a low FODMAP diet, or previously received antibiotics, including rifaximin, for treatment of IBS-D will be excluded from the study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Mean Daily Abdominal Pain | Baseline, Week 5 | Change in mean daily abdominal pain was measured using a visual analog scale (VAS) after intervention compared with baseline. VAS was a scale of 0 to 10, with higher numbers indicating a higher degree of pain; 0 indicated no pain and 10 indicated severe pain. |
| Change in Mean Daily Bloating | Baseline, Week 5 | Change in mean daily bloating was measured using a visual analog scale (VAS) after intervention compared with baseline. VAS was a scale of 0 to 10, with higher numbers indicating a higher degree of bloating; 0 indicated no bloating and 10 indicated severe bloating. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Gastrointestinal System Ratings Scale (GSRS) | Baseline, Week 5 | The GSRS was a disease-specific instrument of 15 items combined into five symptom clusters depicting Reflux, Abdominal Pain, Indigestion, Diarrhea, and Constipation. The GSRS had a seven-point graded Likert scale where 1 represents absence of troublesome symptoms and 7 represents very troublesome symptoms. The total range of the scale is 15 to 105 with 15 meaning low symptom burden and 105 meaning high symptom burden. |
| Change in Stool Form | Baseline, Week 5 | The Bristol Stool Form Scale was a diagnostic tool used to assess various digestive issues based on the type and shape of stool. The total range of the scale was 1 to 7, with 1 indicating hard stool and 7 indicating liquid stool. |
| Change in Irritable Bowel Syndrome Quality of Life Instrument (IBS-QOL) | Baseline, Week 5 | IBS-QOL was a condition-specific instrument for assessing health-related quality of life among persons with IBS. The IBS-QOL was comprised of 34 questions, each with a 5-point scale where the higher the value indicated the higher quality of life. The total range of the scale was 0 to 100, with 0 indicating no quality of life and 100 indicating extremely good quality of life. |
| 24-hour Diet Recall/Intake - Lactose | Baseline, Week 5 | Participants completed entries using the Nutrition Data System for Research (NDSR), which was a Windows-based dietary analysis program designed for the collection and analyses of 24-hour dietary recalls, food records, menus, and recipes. The NDSR was incapable of collecting data on all FODMAP-type foods, aside from lactose and gluten. The results represent data from lactose as a surrogate for all other FODMAP foods. |
| 24-hour Diet Recall/Intake - Gluten | Baseline, Week 5 | Participants completed entries using the Nutrition Data System for Research (NDSR), which was a Windows-based dietary analysis program designed for the collection and analyses of 24-hour dietary recalls, food records, menus, and recipes. The NDSR was incapable of collecting data on all FODMAP-type foods, aside from lactose and gluten. The results represent data from gluten as a surrogate for all other FODMAP foods. |
| Change in Psychological Function | Baseline, Week 5 | The PHQ-9 was a multipurpose instrument for screening, diagnosing, monitoring, and measuring the severity of depression. It is comprised of 9 questions, each ranging from 0 to 3 with higher values indicating more severe depression symptoms. The total range of the scale was 1 to 27, with 1 indicating no or minimal depression and 27 indicating severe depression. |
| Change in Irritable Bowel Syndrome (IBS) Symptom Severity Scale | Baseline, Week 5 | The IBS Symptom Severity Scale was comprised of 5 questions each of which was on a scale of 0 to 100, with higher scores indicating more severe symptoms. The total range of the scale was 0 to 500, with 0 meaning no IBS symptoms and 500 indicating severe IBS symptoms. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Glucose Breath Tests | 4 weeks | Glucose breath tests (GBT) will be performed at baseline and repeated after intervention |
| Fecal Microbiota | 4 weeks | Changes in fecal microbial diversity after intervention will be compared with baseline. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Rifaximin Rifaximin 550 mg three times daily for 14 days
Rifaximin 550 MG: Rifaximin 550 mg three times daily for 14 days | 38 |
| Low FODMAP Group Low FODMAP diet for 4 weeks
Low FODMAP Diet: Low FODMAP dietary intervention for 4 weeks | 36 |
| Total | 74 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 5 | 4 |
| Overall Study | Withdrawal by Subject | 4 | 4 |
Baseline characteristics
| Characteristic | Rifaximin | Low FODMAP Group | Total |
|---|---|---|---|
| Age, Continuous | 44.2 years STANDARD_DEVIATION 17.9 | 44.1 years STANDARD_DEVIATION 16.4 | 44.1 years STANDARD_DEVIATION 17 |
| Body Mass Index (BMI) | 29.7 kg/m^2 STANDARD_DEVIATION 8.72 | 29.8 kg/m^2 STANDARD_DEVIATION 8.18 | 29.8 kg/m^2 STANDARD_DEVIATION 8.41 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 3 Participants | 2 Participants | 5 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 35 Participants | 34 Participants | 69 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 2 Participants | 4 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 34 Participants | 33 Participants | 67 Participants |
| Region of Enrollment United States | 38 Participants | 36 Participants | 74 Participants |
| Sex: Female, Male Female | 30 Participants | 26 Participants | 56 Participants |
| Sex: Female, Male Male | 8 Participants | 10 Participants | 18 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 36 | 0 / 29 |
| other Total, other adverse events | 30 / 36 | 26 / 29 |
| serious Total, serious adverse events | 0 / 36 | 0 / 29 |
Outcome results
Primary
Change in Mean Daily Abdominal Pain
Change in mean daily abdominal pain was measured using a visual analog scale (VAS) after intervention compared with baseline. VAS was a scale of 0 to 10, with higher numbers indicating a higher degree of pain; 0 indicated no pain and 10 indicated severe pain.
Time frame: Baseline, Week 5
Population: Some participants who were randomized to an arm withdrew or were lost to follow up before receiving an intervention. The number of participants analyzed at each time point is based on a modified intent to treat (mITT) analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Rifaximin | Change in Mean Daily Abdominal Pain | Baseline | 5.2 score on a scale | Standard Deviation 1.8 |
| Rifaximin | Change in Mean Daily Abdominal Pain | Week 5 | 3.9 score on a scale | Standard Deviation 2.5 |
| Low FODMAP Group | Change in Mean Daily Abdominal Pain | Week 5 | 3.8 score on a scale | Standard Deviation 2 |
| Low FODMAP Group | Change in Mean Daily Abdominal Pain | Baseline | 5.3 score on a scale | Standard Deviation 1.6 |
Comparison: Baselinep-value: 0.78Mixed Models Analysis
Comparison: Week 5p-value: 0.88Mixed Models Analysis
Primary
Change in Mean Daily Bloating
Change in mean daily bloating was measured using a visual analog scale (VAS) after intervention compared with baseline. VAS was a scale of 0 to 10, with higher numbers indicating a higher degree of bloating; 0 indicated no bloating and 10 indicated severe bloating.
Time frame: Baseline, Week 5
Population: Some participants who were randomized to an arm withdrew or were lost to follow up before receiving an intervention. The number of participants analyzed at each time point is based on a mITT analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Rifaximin | Change in Mean Daily Bloating | Baseline | 4.9 score on a scale | Standard Deviation 1.9 |
| Rifaximin | Change in Mean Daily Bloating | Week 5 | 4.0 score on a scale | Standard Deviation 2.4 |
| Low FODMAP Group | Change in Mean Daily Bloating | Baseline | 5.1 score on a scale | Standard Deviation 2.2 |
| Low FODMAP Group | Change in Mean Daily Bloating | Week 5 | 3.7 score on a scale | Standard Deviation 2.1 |
Comparison: Baselinep-value: 0.77Mixed Models Analysis
Comparison: Week 5p-value: 0.58Mixed Models Analysis
Secondary
24-hour Diet Recall/Intake - Gluten
Participants completed entries using the Nutrition Data System for Research (NDSR), which was a Windows-based dietary analysis program designed for the collection and analyses of 24-hour dietary recalls, food records, menus, and recipes. The NDSR was incapable of collecting data on all FODMAP-type foods, aside from lactose and gluten. The results represent data from gluten as a surrogate for all other FODMAP foods.
Time frame: Baseline, Week 5
Population: Some participants who were randomized to an arm withdrew or were lost to follow up before receiving an intervention. The number of participants analyzed at each time point is based on a mITT analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Rifaximin | 24-hour Diet Recall/Intake - Gluten | Baseline | 6.7 grams per day | Standard Deviation 6 |
| Rifaximin | 24-hour Diet Recall/Intake - Gluten | Week 5 | 7.2 grams per day | Standard Deviation 6.5 |
| Low FODMAP Group | 24-hour Diet Recall/Intake - Gluten | Baseline | 5.7 grams per day | Standard Deviation 5.6 |
| Low FODMAP Group | 24-hour Diet Recall/Intake - Gluten | Week 5 | 1.7 grams per day | Standard Deviation 4.2 |
Secondary
24-hour Diet Recall/Intake - Lactose
Participants completed entries using the Nutrition Data System for Research (NDSR), which was a Windows-based dietary analysis program designed for the collection and analyses of 24-hour dietary recalls, food records, menus, and recipes. The NDSR was incapable of collecting data on all FODMAP-type foods, aside from lactose and gluten. The results represent data from lactose as a surrogate for all other FODMAP foods.
Time frame: Baseline, Week 5
Population: Some participants who were randomized to an arm withdrew or were lost to follow up before receiving an intervention. The number of participants analyzed at each time point is based on a mITT analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Rifaximin | 24-hour Diet Recall/Intake - Lactose | Baseline | 4.1 grams per day | Standard Deviation 5.5 |
| Rifaximin | 24-hour Diet Recall/Intake - Lactose | Week 5 | 5.1 grams per day | Standard Deviation 6.7 |
| Low FODMAP Group | 24-hour Diet Recall/Intake - Lactose | Baseline | 7.3 grams per day | Standard Deviation 9.6 |
| Low FODMAP Group | 24-hour Diet Recall/Intake - Lactose | Week 5 | 1.4 grams per day | Standard Deviation 2.3 |
Secondary
Change in Gastrointestinal System Ratings Scale (GSRS)
The GSRS was a disease-specific instrument of 15 items combined into five symptom clusters depicting Reflux, Abdominal Pain, Indigestion, Diarrhea, and Constipation. The GSRS had a seven-point graded Likert scale where 1 represents absence of troublesome symptoms and 7 represents very troublesome symptoms. The total range of the scale is 15 to 105 with 15 meaning low symptom burden and 105 meaning high symptom burden.
Time frame: Baseline, Week 5
Population: Some participants who were randomized to an arm withdrew or were lost to follow up before receiving an intervention. The number of participants analyzed at each time point is based on a mITT analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Rifaximin | Change in Gastrointestinal System Ratings Scale (GSRS) | Baseline | 52.0 score on a scale | Standard Deviation 13.2 |
| Rifaximin | Change in Gastrointestinal System Ratings Scale (GSRS) | Week 5 | 40.7 score on a scale | Standard Deviation 11 |
| Low FODMAP Group | Change in Gastrointestinal System Ratings Scale (GSRS) | Baseline | 52.1 score on a scale | Standard Deviation 13.3 |
| Low FODMAP Group | Change in Gastrointestinal System Ratings Scale (GSRS) | Week 5 | 40.1 score on a scale | Standard Deviation 12.2 |
Secondary
Change in Irritable Bowel Syndrome (IBS) Symptom Severity Scale
The IBS Symptom Severity Scale was comprised of 5 questions each of which was on a scale of 0 to 100, with higher scores indicating more severe symptoms. The total range of the scale was 0 to 500, with 0 meaning no IBS symptoms and 500 indicating severe IBS symptoms.
Time frame: Baseline, Week 5
Population: Some participants who were randomized to an arm withdrew or were lost to follow up before receiving an intervention. The number of participants analyzed at each time point is based on a mITT analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Rifaximin | Change in Irritable Bowel Syndrome (IBS) Symptom Severity Scale | Baseline | 281.3 score on a scale | Standard Deviation 81 |
| Rifaximin | Change in Irritable Bowel Syndrome (IBS) Symptom Severity Scale | Week 5 | 209.3 score on a scale | Standard Deviation 81.8 |
| Low FODMAP Group | Change in Irritable Bowel Syndrome (IBS) Symptom Severity Scale | Baseline | 272.0 score on a scale | Standard Deviation 65.1 |
| Low FODMAP Group | Change in Irritable Bowel Syndrome (IBS) Symptom Severity Scale | Week 5 | 194.7 score on a scale | Standard Deviation 79.1 |
Secondary
Change in Irritable Bowel Syndrome Quality of Life Instrument (IBS-QOL)
IBS-QOL was a condition-specific instrument for assessing health-related quality of life among persons with IBS. The IBS-QOL was comprised of 34 questions, each with a 5-point scale where the higher the value indicated the higher quality of life. The total range of the scale was 0 to 100, with 0 indicating no quality of life and 100 indicating extremely good quality of life.
Time frame: Baseline, Week 5
Population: Some participants who were randomized to an arm withdrew or were lost to follow up before receiving an intervention. The number of participants analyzed at each time point is based on a mITT analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Rifaximin | Change in Irritable Bowel Syndrome Quality of Life Instrument (IBS-QOL) | Baseline | 53.6 score on a scale | Standard Deviation 19.5 |
| Rifaximin | Change in Irritable Bowel Syndrome Quality of Life Instrument (IBS-QOL) | Week 5 | 62.6 score on a scale | Standard Deviation 20.4 |
| Low FODMAP Group | Change in Irritable Bowel Syndrome Quality of Life Instrument (IBS-QOL) | Baseline | 58.9 score on a scale | Standard Deviation 21.5 |
| Low FODMAP Group | Change in Irritable Bowel Syndrome Quality of Life Instrument (IBS-QOL) | Week 5 | 67.8 score on a scale | Standard Deviation 18.5 |
Secondary
Change in Psychological Function
The PHQ-9 was a multipurpose instrument for screening, diagnosing, monitoring, and measuring the severity of depression. It is comprised of 9 questions, each ranging from 0 to 3 with higher values indicating more severe depression symptoms. The total range of the scale was 1 to 27, with 1 indicating no or minimal depression and 27 indicating severe depression.
Time frame: Baseline, Week 5
Population: Some participants who were randomized to an arm withdrew or were lost to follow up before receiving an intervention. The number of participants analyzed at each time point is based on a mITT analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Rifaximin | Change in Psychological Function | Baseline | 8.6 score on a scale | Standard Deviation 6.5 |
| Rifaximin | Change in Psychological Function | Week 5 | 6.2 score on a scale | Standard Deviation 4.9 |
| Low FODMAP Group | Change in Psychological Function | Baseline | 8.3 score on a scale | Standard Deviation 6.2 |
| Low FODMAP Group | Change in Psychological Function | Week 5 | 5.8 score on a scale | Standard Deviation 4.3 |
Secondary
Change in Stool Form
The Bristol Stool Form Scale was a diagnostic tool used to assess various digestive issues based on the type and shape of stool. The total range of the scale was 1 to 7, with 1 indicating hard stool and 7 indicating liquid stool.
Time frame: Baseline, Week 5
Population: Some participants who were randomized to an arm withdrew or were lost to follow up before receiving an intervention. The number of participants analyzed at each time point is based on a mITT analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Rifaximin | Change in Stool Form | Baseline | 5.6 score on a scale | Standard Deviation 0.8 |
| Rifaximin | Change in Stool Form | Week 5 | 5.0 score on a scale | Standard Deviation 1.1 |
| Low FODMAP Group | Change in Stool Form | Baseline | 5.6 score on a scale | Standard Deviation 0.8 |
| Low FODMAP Group | Change in Stool Form | Week 5 | 5.3 score on a scale | Standard Deviation 0.9 |
Other Pre-specified
Fecal Microbiota
Changes in fecal microbial diversity after intervention will be compared with baseline.
Time frame: 4 weeks
Other Pre-specified
Glucose Breath Tests
Glucose breath tests (GBT) will be performed at baseline and repeated after intervention
Time frame: 4 weeks