Irritable Bowel Syndrome
Conditions
Keywords
Irritable bowel syndrome, Antidepressant, IBS, Serotonin-reuptake inhibitor, SSRI, Visceral sensitivity, Barostat, Quality of life, Depression
Brief summary
Hypotheses: 1. Primary null hypothesis: The rate of clinical response, assessed as patient-reported global symptom rating and adequate relief of IBS symptoms, does not differ between non-depressed IBS patients treated with the SSRI citalopram and patients treated with placebo. 2. Secondary null hypotheses: 1. Changes in disease-related quality of life, assessed with the IBS-QOL instrument, do not differ between patients treated with the SSRI citalopram and patients treated with placebo. 2. Changes in rectosigmoid visceral sensitivity, assessed by barostat balloon distention, do not differ between patients treated with the SSRI citalopram and patients treated with placebo.
Detailed description
Irritable bowel syndrome (IBS) affects an estimated 15 million Americans at a cost of $1.7 billion per year. Visceral hypersensitivity is present in many patients with IBS, but its contribution to clinical symptoms is unclear. Tricyclic antidepressants may be beneficial in IBS, but their side effects can be unacceptable. Because they are better tolerated, selective serotonin reuptake inhibitors (SSRIs) are often used to treat IBS, but their efficacy in IBS has not been examined in controlled studies. We propose a randomized, placebo-controlled trial of SSRI treatment in IBS. Non-depressed patients will be studied in order to assess SSRI effects on IBS independent of depression. Our specific aims are: 1) To determine whether the SSRI citalopram is superior to placebo in improving clinical symptoms, disease-related quality of life, and tolerance to rectal balloon distension; 2) To assess whether symptomatic improvement is correlated with improvement in quality of life and/or visceral sensitivity. Subjects will fulfill Rome II IBS criteria, will have normal screening studies, and will not be depressed or on antidepressants. Global and specific symptoms, and satisfaction will be rated daily during a 1-week baseline. Subjects will then be randomized in concealed, double-blind fashion to citalopram or placebo, will complete the validated IBS-QOL instrument, and will undergo rectal compliance and sensory testing with a barostat. Subjects will be treated and will rate symptoms and satisfaction weekly for a total of 8 weeks, and also daily during the final week for comparison with the baseline. At study end, subjects will again complete the IBS-QOL and undergo a barostat study. For the primary outcome, we estimate that to detect a standardized effect size of 0.9 in global symptom rating with 2-sided α=0.05 and β=0.1, 54 subjects are needed. We plan to enroll 60 subjects, which will allow detection of an odds ratio for response (adequate relief) of 4.5 with 2-sided α=0.05 and β=0.2. If the odds ratio for this dichotomous outcome is smaller, this study will provide pilot data for a larger trial. Clinical symptoms are expected to fluctuate. Even if citalopram is not superior to placebo, prospectively collected data will illuminate the relationship between symptoms and visceral sensitivity, and the placebo effect.
Interventions
DRUGCitalopram
20mg/day for 4 weeks, then 40 mg/day for 4 weeks
DRUGPlacebo
Identical to citalopram 20mg capsules; 1 capsule/day for 4 weeks, then 2 capsules/day for 4 weeks
Sponsors
Stanford University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Inclusion criteria are: 1. Fulfilling Rome II IBS definition; 2. Age ≥18 yrs and able to give informed consent; 3. Normal sigmoidoscopy, colonoscopy or barium enema within 5 years, normal complete blood count and thyroid studies, and negative stool ova and parasite exam for patients with diarrhea.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Count of Participants Who Self-reported Adequate Relief | Baseline, weekly for 8 weeks | Participants were asked weekly to answer subjectively whether weekly adequate relief from IBS symptoms was achieved. Overall response was defined as having achieved adequate relief in at least 3 of the past 6 weeks. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in IBS-QOL Score at Week 8 | Baseline; Week 8 | The IBS-QOL is a self-report quality-of-life measure specific to Irritable Bowel Syndrome (IBS) that can be used to assess the impact of IBS and its treatment. The IBS-QOL consists of 34 statements about bowel problems, each with a five-point response scale ranging from 1 (no problems) to 5 (most problems). The individual scores are summed and averaged for a total score, then transformed to a 0-100 scale for ease of interpretation with higher scores indicating better IBS-specific quality of life. |
| Mean Sensation Score as a Function of Distending Pressure at the End of the Study | Week 8 | A 500mL polyethylene bag was passed into the rectum, with tubing connected to a barostat, which was controlled by a computer that recorded bag pressure, volume, and corrected volume every second. After 5 minutes, the bag was unfurled with 100mL of air and deflated; with inflations lasting 45 seconds from 0 up to 60 mmHg, increasing by 3 mmHg, and separated by 45-second deflations, subjects rated sensation 30 seconds into each inflation. Sensation score scale: 0=no inflation sensation, 1-5=increasing painless sensation, 6=threshold pain, 10=worst imaginable pain. |
| Urgency Score as a Function of Distending Pressure at the End of the Study | Week 8 | A 500mL polyethylene bag was passed into the rectum, with tubing connected to a barostat, which was controlled by a computer that recorded bag pressure, volume, and corrected volume every second. After 5 minutes, the bag was unfurled with 100mL of air and deflated; with inflations lasting 45 seconds from 0 up to 60 mmHg, increasing by 3 mmHg, and separated by 45-second deflations, subjects rated urgency for bowel movement 30 seconds into each inflation. Urgency score scale: 0=no urgency, 1=threshold urgency, 5=worst imaginable urgency. |
Countries
United States
Participant flow
Pre-assignment details
A total of 234 potentially eligible subjects were identified. Of these, 180 were excluded and 54 enrolled in the study, with 27 each randomized to citalopram and placebo.
Participants by arm
| Arm | Count |
|---|---|
| Cialopram One 20mg capsule per day for 4 weeks, then 2 capsules per day (40mg) for 4 weeks | 27 |
| Placebo Identical to citalopram 20mg capsule. One capsule per day for 4 weeks, then 2 capsules per day for 4 weeks | 27 |
| Total | 54 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 7 | 2 |
Baseline characteristics
| Characteristic | Cialopram | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 53 years | 51 years | 52 years |
| Region of Enrollment United States | 27 participants | 27 participants | 54 participants |
| Sex: Female, Male Female | 21 Participants | 23 Participants | 44 Participants |
| Sex: Female, Male Male | 6 Participants | 4 Participants | 10 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 7 / 27 | 2 / 27 |
| serious Total, serious adverse events | 0 / 27 | 0 / 27 |
Outcome results
Primary
Count of Participants Who Self-reported Adequate Relief
Participants were asked weekly to answer subjectively whether weekly adequate relief from IBS symptoms was achieved. Overall response was defined as having achieved adequate relief in at least 3 of the past 6 weeks.
Time frame: Baseline, weekly for 8 weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Citalopram | Count of Participants Who Self-reported Adequate Relief | 12 Participants |
| Placebo | Count of Participants Who Self-reported Adequate Relief | 15 Participants |
Comparison: Null hypothesis: number of patients achieving adequate relief is the same in both Citalopram and Placebo groupsp-value: 0.5995% CI: [0.687, 1.196]t-test, 2 sided
Secondary
Change From Baseline in IBS-QOL Score at Week 8
The IBS-QOL is a self-report quality-of-life measure specific to Irritable Bowel Syndrome (IBS) that can be used to assess the impact of IBS and its treatment. The IBS-QOL consists of 34 statements about bowel problems, each with a five-point response scale ranging from 1 (no problems) to 5 (most problems). The individual scores are summed and averaged for a total score, then transformed to a 0-100 scale for ease of interpretation with higher scores indicating better IBS-specific quality of life.
Time frame: Baseline; Week 8
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Citalopram | Change From Baseline in IBS-QOL Score at Week 8 | 6.3 units on a scale |
| Placebo | Change From Baseline in IBS-QOL Score at Week 8 | 7.6 units on a scale |
Secondary
Mean Sensation Score as a Function of Distending Pressure at the End of the Study
A 500mL polyethylene bag was passed into the rectum, with tubing connected to a barostat, which was controlled by a computer that recorded bag pressure, volume, and corrected volume every second. After 5 minutes, the bag was unfurled with 100mL of air and deflated; with inflations lasting 45 seconds from 0 up to 60 mmHg, increasing by 3 mmHg, and separated by 45-second deflations, subjects rated sensation 30 seconds into each inflation. Sensation score scale: 0=no inflation sensation, 1-5=increasing painless sensation, 6=threshold pain, 10=worst imaginable pain.
Time frame: Week 8
Population: Participants with available data were included in the analysis.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Citalopram | Mean Sensation Score as a Function of Distending Pressure at the End of the Study | Distending pressure 12mmHg | 1 units on a scale |
| Citalopram | Mean Sensation Score as a Function of Distending Pressure at the End of the Study | Distending pressure 36mmHg | 5 units on a scale |
| Citalopram | Mean Sensation Score as a Function of Distending Pressure at the End of the Study | Distending pressure 24mmHg | 4 units on a scale |
| Citalopram | Mean Sensation Score as a Function of Distending Pressure at the End of the Study | Distending pressure 48mmHg | 7 units on a scale |
| Placebo | Mean Sensation Score as a Function of Distending Pressure at the End of the Study | Distending pressure 36mmHg | 7 units on a scale |
| Placebo | Mean Sensation Score as a Function of Distending Pressure at the End of the Study | Distending pressure 12mmHg | 2 units on a scale |
| Placebo | Mean Sensation Score as a Function of Distending Pressure at the End of the Study | Distending pressure 24mmHg | 6 units on a scale |
| Placebo | Mean Sensation Score as a Function of Distending Pressure at the End of the Study | Distending pressure 48mmHg | 6 units on a scale |
Secondary
Urgency Score as a Function of Distending Pressure at the End of the Study
A 500mL polyethylene bag was passed into the rectum, with tubing connected to a barostat, which was controlled by a computer that recorded bag pressure, volume, and corrected volume every second. After 5 minutes, the bag was unfurled with 100mL of air and deflated; with inflations lasting 45 seconds from 0 up to 60 mmHg, increasing by 3 mmHg, and separated by 45-second deflations, subjects rated urgency for bowel movement 30 seconds into each inflation. Urgency score scale: 0=no urgency, 1=threshold urgency, 5=worst imaginable urgency.
Time frame: Week 8
Population: Participants with available data were included in the analysis.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Citalopram | Urgency Score as a Function of Distending Pressure at the End of the Study | Distending pressure 12mmHg | 1 units on a scale |
| Citalopram | Urgency Score as a Function of Distending Pressure at the End of the Study | Distending pressure 24mmHg | 4 units on a scale |
| Citalopram | Urgency Score as a Function of Distending Pressure at the End of the Study | Distending pressure 36mmHg | 4 units on a scale |
| Citalopram | Urgency Score as a Function of Distending Pressure at the End of the Study | Distending pressure 48mmHg | 5 units on a scale |
| Placebo | Urgency Score as a Function of Distending Pressure at the End of the Study | Distending pressure 48mmHg | 5 units on a scale |
| Placebo | Urgency Score as a Function of Distending Pressure at the End of the Study | Distending pressure 12mmHg | 2 units on a scale |
| Placebo | Urgency Score as a Function of Distending Pressure at the End of the Study | Distending pressure 36mmHg | 5 units on a scale |
| Placebo | Urgency Score as a Function of Distending Pressure at the End of the Study | Distending pressure 24mmHg | 5 units on a scale |