Clinical trial NCT00912301: Cheno Effect on Transit in Health and IBS-C
Official title: Effect of Chenodeoxycholic Acid on Gastrointestinal Transit and Colonic Functions in Health and Constipation-predominant Irritable Bowel Syndrome (IBS-C)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Constipation-predominant Irritable Bowel Syndrome
Keywords: chenodeoxycholate, IBS, transit, colon, constipation
Lead sponsor: Mayo Clinic
Sponsor class: OTHER
Collaborators: name: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
name: National Center for Research Resources (NCRR)
First posted: 2009-06-03
Enrollment: 36
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: 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

Primary outcomes:
measure: Colonic Geometric Center at 24 Hours (GC24)
timeFrame: after 4 days of treatment
Secondary outcomes:
measure: Colonic Transit at 48 Hours (GC48)
timeFrame: after 4 days of treatment
measure: Ascending Colon Emptying (AC t_1/2)
timeFrame: after 4 days' treatment
measure: Stool Consistency
timeFrame: after 4 days' treatment
measure: Colonic Filling at 6 Hours
timeFrame: after 4 days' treatment
Other outcomes:
Locations:
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
Study officials:
affiliation: Mayo Clinic
name: Michael L. Camilleri, M.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Cremonini F, Mullan BP, Camilleri M, Burton DD, Rank MR. Performance characteristics of scintigraphic transit measurements for studies of experimental therapies. Aliment Pharmacol Ther. 2002 Oct;16(10):1781-90. doi: 10.1046/j.1365-2036.2002.01344.x.
citation: Rao AS, Wong BS, Camilleri M, Odunsi-Shiyanbade ST, McKinzie S, Ryks M, Burton D, Carlson P, Lamsam J, Singh R, Zinsmeister AR. Chenodeoxycholate in females with irritable bowel syndrome-constipation: a pharmacodynamic and pharmacogenetic analysis. Gastroenterology. 2010 Nov;139(5):1549-58, 1558.e1. doi: 10.1053/j.gastro.2010.07.052. Epub 2010 Aug 4.