Cheno Effect on Transit in Health and IBS-C (Chenotransit)

• ClinicalTrials.gov Identifier: NCT00912301
• Recruitment Status: Completed
• First Posted: June 3, 2009
• Results First Posted: July 2, 2012
• Last Update Posted: July 2, 2012
• Sponsor: Mayo Clinic
• Collaborators: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); National Center for Research Resources (NCRR)
• Information provided by: Mayo Clinic

Tracking Information

• First Submitted Date: May 29, 2009
• First Posted Date: June 3, 2009
• Results First Submitted Date: May 29, 2012
• Results First Posted Date: July 2, 2012
• Last Update Posted Date: July 2, 2012
• Study Start Date: April 2009
• Actual Primary Completion Date: November 2009 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: May 29, 2012)

Colonic Geometric Center at 24 Hours (GC24) [ Time Frame: 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.

• Original Primary Outcome Measures (submitted: June 2, 2009): Colonic Geometric Center at 24 Hours (GC24) [ Time Frame: after 4 days of treatment ]

Current Secondary Outcome Measures (submitted: May 29, 2012)

• Colonic Transit at 48 Hours (GC48) [ Time Frame: 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) [ Time Frame: after 4 days' treatment ]
• Stool Consistency [ Time Frame: 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 [ Time Frame: after 4 days' treatment ]
  Percent of the radio-labeled meal that reached the colon at 6 hours, indirectly reflecting small bowel transit time.

Original Secondary Outcome Measures (submitted: June 2, 2009)

• Colonic transit GC48 h [ Time Frame: after 4 days of treatment ]
• Ascending colon emptying T1/2 [ Time Frame: after 4 days' treatment ]
• Stool Consistency [ Time Frame: after 4 days' treatment ]
• Colonic Filling at 6 Hours [ Time Frame: after 4 days' treatment ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: 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)
• 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.

• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Condition: Constipation-predominant Irritable Bowel Syndrome

Intervention

• Drug: Sodium chenodeoxycholate (NaCDC)
  500 or 1000 milligrams NaCDC per day each for a period of 4 days
  Other Name: Chenodiol
• Other: Placebo
  Placebo capsules with identical appearance to the study drug were prepared by the Mayo Clinic research pharmacy.

Study Arms

• Experimental: NaCDC 500 mg
  Participants randomized to this arm received 500 mg NaCDC per day for 4 days.
  Intervention: Drug: Sodium chenodeoxycholate (NaCDC)
• Experimental: NaCDC 1000 mg
  Participants randomized to this arm received 1000 mg NaCDC per day for 4 days.
  Intervention: Drug: Sodium chenodeoxycholate (NaCDC)
• Placebo Comparator: Placebo
  Participants randomized to this arm received a placebo capsule each day for 4 days.
  Intervention: Other: Placebo

Publications *

• 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.
• 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.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: May 29, 2012): 36
• Original Estimated Enrollment (submitted: June 2, 2009): 120
• Actual Study Completion Date: December 2009
• Actual Primary Completion Date: November 2009 (Final data collection date for primary outcome measure)

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 65 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT00912301
• Other Study ID Numbers: 08-001003; R01DK054681 ( U.S. NIH Grant/Contract ); R01DK079866 ( U.S. NIH Grant/Contract ); UL1RR024150 ( U.S. NIH Grant/Contract ); 1RC1DK086182 ( U.S. NIH Grant/Contract )
• Has Data Monitoring Committee: No
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Responsible Party: Michael Camilleri, M.D., Mayo Clinic
• Study Sponsor: Mayo Clinic

Collaborators

• National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
• National Center for Research Resources (NCRR)

Investigators

• Principal Investigator: Michael L. Camilleri, M.D.; Mayo Clinic

• PRS Account: Mayo Clinic
• Verification Date: May 2012