Constipation-predominant Irritable Bowel Syndrome
Conditions
Keywords
chenodeoxycholate, IBS, transit, colon, constipation
Brief summary
The study hypothesis is that the naturally occurring bile acid, chenodeoxycholic acid, induces acceleration of colonic transit in health and in patients with constipation-predominant Irritable Bowel Syndrome (IBS-C).
Detailed description
Hypothesis: A hydrophobic di-alpha hydroxy bile salt, sodium chenodeoxycholate (CDC), delivered in a delayed release capsule to the ileocolonic region of the colon induces acceleration of colonic transit in patients with constipation-predominant IBS. Methods: We shall study 36 patients with IBS-C, aged 18-65 years, and each treatment group will be balanced on gender and Body Mass Index (BMI) in the randomization. All patients will be assessed for symptoms of functional gastrointestinal disorder or psychological disturbance will be characterized in a standard fashion with questionnaires (Talley et al 1989), the Psychosomatic Symptom Checklist (SCL-90) and the Hospital Anxiety and Depression Inventory \[HAD (Zigmond and Snaith 1983)\]. With appropriate consent, a venous blood sample will be obtained from each participant for DNA extraction. Fasting Serum 7alpha-hydroxy-4-cholesten-3-one (7alpha-CHO) will be measured in all to ensure they do not have evidence of asymptomatic bile acid malabsorption. The normal range in our lab is \<61 ng/mL. Experimental design: A randomized, double blind, placebo controlled, dose-response parallel group design, with concealed allocation. Participants will undergo an initial baseline colonic transit for 24 hours to obtain Colonic Geometric Center (GC24). Sodium chenodeoxycholate (CDC) will be delivered to the ileocolonic region to assess ascending colon and whole colonic transit in participants with IBS-C; 12 participants per group will be randomized to placebo, 0.5 or 1 gram CDC each for a period of 4 days with the transit study conducted during the last 48 hours of drug ingestion. The CDC will be placed in gelatin capsules that are coated with methacrylate (EUDRAGIT-L®), a pH-sensitive polymer that will result in release of the active ingredient in the terminal ileum. Experimental procedure: At standardized times (hourly for first 8 hours, and at 12, 24 and 48 h), dual gamma camera scans will be obtained to measure ascending colon and overall colonic transit. Patients will fill daily diaries to evaluate stool, frequency, consistency and ease of passage. Gastrointestinal and Colonic Transit: A validated scintigraphic method to measure gastric, small bowel, and colonic transit will be used. A methacrylate-coated capsule dissolves in the alkaline pH of the distal ileum to release 111In-labeled activated charcoal particles to evaluate colonic transit on sequential scans. Meanwhile, orally ingested 99 mTc-labeled egg meal allows measurement of gastric and small bowel transit. (Technetium \[99mTc\] sestamibi (trade name Cardiolite) is a pharmaceutical agent used in nuclear medicine imaging.) We have previously shown that the gastric emptying (GE) at 2 and 4 hours, colonic filling (CF) at 6 hours, and colonic geometric center (GC, weighted average of isotopic counts) in colon at 4, 24 and 48 hours provide excellent summaries of gastric emptying and colonic transit with similar diagnostic accuracy as more detailed, costly, and time-consuming analyses. The normal values for these parameters have been previously published (Cremonini et al). Scintigraphic gastric emptying and intestinal/colonic transit analysis: A variable region of interest program will be used to measure transit, as in previous studies from our lab. Radioisotope content in each region (gastric, ascending, transverse, descending, rectosigmoid) will be corrected for decay and tissue attenuation or depth. Anticipated Result: CDC will accelerate whole colonic transit and loosen stool form in patients with constipation predominant IBS.
Interventions
DRUGSodium chenodeoxycholate (NaCDC)
500 or 1000 milligrams NaCDC per day each for a period of 4 days
OTHERPlacebo
Placebo capsules with identical appearance to the study drug were prepared by the Mayo Clinic research pharmacy.
Sponsors
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
National Center for Research Resources (NCRR)
Mayo Clinic
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
Yes
Inclusion criteria
Healthy volunteers: * Age (yr) 18-65 * Gender (F:M)3.5 :1 * Bowel Disease Questionnaire (BDQ) - IBS symptoms negative by Rome III criteria * Hospital Anxiety/Depression score \<8 IBS patients: * Age (yr) 18-65 * Gender (F:M) 5 :1 * BDQ - IBS symptoms: positive by Rome III criteria * Hospital Anxiety/Depression score: No restrictions
Exclusion criteria
* Abdominal surgery (except appendectomy or cholecystectomy) * GI medications during the 48h prior to transit measurement * Aspartate/Alanine transaminases \>2 X Upper Limit of Normal (ULN) * Other Medications except stable doses of estrogen, thyroid, low dose antidepressants of the dopaminergic or serotonergic class
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Colonic Geometric Center at 24 Hours (GC24) | after 4 days of treatment | The scintigraphic method is used to measure colonic transit. An isotope is adsorbed on activated charcoal particles and delivered to the colon in a delayed release capsule. Anterior and posterior gamma images are taken hourly. The geometric center (GC) is the weighted average of counts in the different colonic regions. The scale ranges from 1 to 5; a high GC implies faster colonic transit, a GC of 1 implies all isotope is in the ascending colon, and a GC of 5 implies all isotope is in the stool. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Colonic Transit at 48 Hours (GC48) | after 4 days of treatment | The scintigraphic method is used to measure colonic transit. An isotope is adsorbed on activated charcoal particles and delivered to the colon in a delayed release capsule. Anterior and posterior gamma images are taken hourly. The geometric center (GC) is the weighted average of counts in the different colonic regions. The scale ranges from 1 to 5; a high GC implies faster colonic transit, a GC of 1 implies all isotope is in the ascending colon, and a GC of 5 implies all isotope is in the stool. |
| Ascending Colon Emptying (AC t_1/2) | after 4 days' treatment | — |
| Stool Consistency | after 4 days' treatment | The subjects rated their stool consistency using the Bristol Stool Scale. The Bristol Stool Scale is a medical aid designed to classify the form of human feces into seven categories or types. Types 1 and 2 indicate constipation with 3 and 4 being the ideal stools especially the latter, as they are the easiest to defecate, and 5-7 tending towards diarrhea. |
| Colonic Filling at 6 Hours | after 4 days' treatment | Percent of the radio-labeled meal that reached the colon at 6 hours, indirectly reflecting small bowel transit time. |
Countries
United States
Participant flow
Recruitment details
Participants were enrolled between April 17 and November 20, 2009 from 150 mile geographical area around Mayo Clinic, Rochester, MN.
Pre-assignment details
40 patients signed informed consent, but 3 failed screening due to presence of evacuation disorder, and 1 withdrew prior to study due to illness.
Participants by arm
| Arm | Count |
|---|---|
| NaCDC 500 mg Participants randomized to this arm received 500 mg NaCDC per day for 4 days. | 11 |
| NaCDC 1000 mg Participants randomized to this arm received 1000 mg NaCDC per day for 4 days. | 12 |
| Placebo Participants randomized to this arm received a placebo capsule each day for 4 days. | 13 |
| Total | 36 |
Baseline characteristics
| Characteristic | NaCDC 500 mg | NaCDC 1000 mg | Placebo | Total |
|---|---|---|---|---|
| Age Continuous | 38.3 years STANDARD_DEVIATION 3.3 | 46.1 years STANDARD_DEVIATION 2.6 | 40.8 years STANDARD_DEVIATION 2.3 | 42 years STANDARD_DEVIATION 10 |
| Region of Enrollment United States | 11 participants | 12 participants | 13 participants | 36 participants |
| Sex: Female, Male Female | 11 Participants | 12 Participants | 13 Participants | 36 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 6 / 11 | 8 / 12 | 2 / 13 |
| serious Total, serious adverse events | 0 / 11 | 0 / 12 | 0 / 12 |
Outcome results
Primary
Colonic Geometric Center at 24 Hours (GC24)
The scintigraphic method is used to measure colonic transit. An isotope is adsorbed on activated charcoal particles and delivered to the colon in a delayed release capsule. Anterior and posterior gamma images are taken hourly. The geometric center (GC) is the weighted average of counts in the different colonic regions. The scale ranges from 1 to 5; a high GC implies faster colonic transit, a GC of 1 implies all isotope is in the ascending colon, and a GC of 5 implies all isotope is in the stool.
Time frame: after 4 days of treatment
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| NaCDC 500 mg | Colonic Geometric Center at 24 Hours (GC24) | 3.1 units on a scale | Standard Deviation 0.4 |
| NaCDC 1000 mg | Colonic Geometric Center at 24 Hours (GC24) | 3.5 units on a scale | Standard Deviation 0.4 |
| Placebo | Colonic Geometric Center at 24 Hours (GC24) | 2.2 units on a scale | Standard Deviation 0.2 |
Secondary
Ascending Colon Emptying (AC t_1/2)
Time frame: after 4 days' treatment
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| NaCDC 500 mg | Ascending Colon Emptying (AC t_1/2) | 9.5 hours | Standard Deviation 2.9 |
| NaCDC 1000 mg | Ascending Colon Emptying (AC t_1/2) | 8.2 hours | Standard Deviation 1.8 |
| Placebo | Ascending Colon Emptying (AC t_1/2) | 15.8 hours | Standard Deviation 2.5 |
Secondary
Colonic Filling at 6 Hours
Percent of the radio-labeled meal that reached the colon at 6 hours, indirectly reflecting small bowel transit time.
Time frame: after 4 days' treatment
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| NaCDC 500 mg | Colonic Filling at 6 Hours | 52.6 percentage of the radio-labeled meal | Standard Deviation 6.7 |
| NaCDC 1000 mg | Colonic Filling at 6 Hours | 54.8 percentage of the radio-labeled meal | Standard Deviation 7.1 |
| Placebo | Colonic Filling at 6 Hours | 50.6 percentage of the radio-labeled meal | Standard Deviation 6.7 |
Secondary
Colonic Transit at 48 Hours (GC48)
The scintigraphic method is used to measure colonic transit. An isotope is adsorbed on activated charcoal particles and delivered to the colon in a delayed release capsule. Anterior and posterior gamma images are taken hourly. The geometric center (GC) is the weighted average of counts in the different colonic regions. The scale ranges from 1 to 5; a high GC implies faster colonic transit, a GC of 1 implies all isotope is in the ascending colon, and a GC of 5 implies all isotope is in the stool.
Time frame: after 4 days of treatment
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| NaCDC 500 mg | Colonic Transit at 48 Hours (GC48) | 4.1 units on a scale | Standard Deviation 0.3 |
| NaCDC 1000 mg | Colonic Transit at 48 Hours (GC48) | 4.3 units on a scale | Standard Deviation 0.3 |
| Placebo | Colonic Transit at 48 Hours (GC48) | 3.8 units on a scale | Standard Deviation 0.3 |
Secondary
Stool Consistency
The subjects rated their stool consistency using the Bristol Stool Scale. The Bristol Stool Scale is a medical aid designed to classify the form of human feces into seven categories or types. Types 1 and 2 indicate constipation with 3 and 4 being the ideal stools especially the latter, as they are the easiest to defecate, and 5-7 tending towards diarrhea.
Time frame: after 4 days' treatment
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| NaCDC 500 mg | Stool Consistency | 4.4 units on a scale | Standard Deviation 0.5 |
| NaCDC 1000 mg | Stool Consistency | 4.4 units on a scale | Standard Deviation 0.4 |
| Placebo | Stool Consistency | 2.9 units on a scale | Standard Deviation 0.3 |
p-value: 0.031Dunnett's test
p-value: 0.01Dunnett's test