Chenotransit: Cheno Effect on Transit in Health and IBS-C

• Sponsor: Mayo Clinic (Other)
• Overall Status: Completed
• CT.gov ID: NCT00912301
• Collaborator: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (NIH), National Center for Research Resources (NCRR) (NIH)
• Enrollment: 36
• Location: 1
• Arms: 3
• Duration (Months): 8
• Patients Per Site Per Month: 4.5

Study Details

Study Description

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).

Condition or Disease	Intervention/Treatment	Phase
Constipation-predominant Irritable Bowel Syndrome	Drug: Sodium chenodeoxycholate (NaCDC); Other: Placebo	Phase 2

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 Design

• Study Type: Interventional
• Actual Enrollment: 36 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Effect of Chenodeoxycholic Acid on Gastrointestinal Transit and Colonic Functions in Health and Constipation-predominant Irritable Bowel Syndrome (IBS-C)
• Study Start Date: Apr 1, 2009
• Actual Primary Completion Date: Nov 1, 2009
• Actual Study Completion Date: Dec 1, 2009

Arms and Interventions

Arm	Intervention/Treatment
Experimental: NaCDC 500 mg Participants randomized to this arm received 500 mg NaCDC per day for 4 days.	Drug: Sodium chenodeoxycholate (NaCDC); 500 or 1000 milligrams NaCDC per day each for a period of 4 days; Other Names: Chenodiol
Experimental: NaCDC 1000 mg Participants randomized to this arm received 1000 mg NaCDC per day for 4 days.	Drug: Sodium chenodeoxycholate (NaCDC); 500 or 1000 milligrams NaCDC per day each for a period of 4 days; Other Names: Chenodiol
Placebo Comparator: Placebo Participants randomized to this arm received a placebo capsule each day for 4 days.	Other: Placebo; Placebo capsules with identical appearance to the study drug were prepared by the Mayo Clinic research pharmacy.

Outcome Measures

Primary Outcome Measures

1. 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 Outcome Measures

1. 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.

2. Ascending Colon Emptying (AC t_1/2) [after 4 days' treatment]

3. 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.

4. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 65 Years
• Sexes Eligible for Study: All
• Accepts 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Mayo Clinic	Rochester	Minnesota	United States	55905

Sponsors and Collaborators

• Mayo Clinic
• 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

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Mayo Clinic Clinical Trials

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.

• ClinicalTrials.gov Identifier: NCT00912301
• Other Study ID Numbers: 08-001003; R01DK054681; R01DK079866; UL1RR024150; 1RC1DK086182
• First Posted: Jun 3, 2009
• Last Update Posted: Jul 2, 2012
• Last Verified: May 1, 2012

• Keywords provided by , ,: chenodeoxycholate, IBS, transit, colon, constipation
• Additional relevant MeSH terms: Irritable Bowel Syndrome; Syndrome; Constipation; Chenodeoxycholic Acid

Study Results

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 Detail	40 patients signed informed consent, but 3 failed screening due to presence of evacuation disorder, and 1 withdrew prior to study due to illness.

Arm/Group Title	NaCDC 500 mg	NaCDC 1000 mg	Placebo
Arm/Group Description	Participants randomized to this arm received 500 mg NaCDC per day for 4 days.	Participants randomized to this arm received 1000 mg NaCDC per day for 4 days.	Participants randomized to this arm received a placebo capsule each day for 4 days.
Period Title: Overall Study
STARTED	11	12	13
COMPLETED	11	12	13
NOT COMPLETED	0	0	0

Baseline Characteristics

Arm/Group Title	NaCDC 500 mg	NaCDC 1000 mg	Placebo	Total
Arm/Group Description	Participants randomized to this arm received 500 mg NaCDC per day for 4 days.	Participants randomized to this arm received 1000 mg NaCDC per day for 4 days.	Participants randomized to this arm received a placebo capsule each day for 4 days.	Total of all reporting groups
Overall Participants	11	12	13	36
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	38.3 (3.3)	46.1 (2.6)	40.8 (2.3)	42 (10)
Sex: Female, Male (Count of Participants)
Female	11 100%	12 100%	13 100%	36 100%
Male	0 0%	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
United States	11 100%	12 100%	13 100%	36 100%

Outcome Measures

1. Primary Outcome

Title	Colonic Geometric Center at 24 Hours (GC24)
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	NaCDC 500 mg	NaCDC 1000 mg	Placebo
Arm/Group Description	Participants randomized to this arm received 500 mg NaCDC per day for 4 days.	Participants randomized to this arm received 1000 mg NaCDC per day for 4 days.	Participants randomized to this arm received a placebo capsule each day for 4 days.
Measure Participants	11	12	13
Mean (Standard Deviation) [units on a scale]	3.1 (0.4)	3.5 (0.4)	2.2 (0.2)

2. Secondary Outcome

Title	Colonic Transit at 48 Hours (GC48)
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	NaCDC 500 mg	NaCDC 1000 mg	Placebo
Arm/Group Description	Participants randomized to this arm received 500 mg NaCDC per day for 4 days.	Participants randomized to this arm received 1000 mg NaCDC per day for 4 days.	Participants randomized to this arm received a placebo capsule each day for 4 days.
Measure Participants	11	12	13
Mean (Standard Deviation) [units on a scale]	4.1 (0.3)	4.3 (0.3)	3.8 (0.3)

3. Secondary Outcome

Title	Ascending Colon Emptying (AC t_1/2)
Time Frame	after 4 days' treatment

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	NaCDC 500 mg	NaCDC 1000 mg	Placebo
Arm/Group Description	Participants randomized to this arm received 500 mg NaCDC per day for 4 days.	Participants randomized to this arm received 1000 mg NaCDC per day for 4 days.	Participants randomized to this arm received a placebo capsule each day for 4 days.
Measure Participants	11	12	13
Mean (Standard Deviation) [hours]	9.5 (2.9)	8.2 (1.8)	15.8 (2.5)

4. Secondary Outcome

Title	Stool Consistency
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	NaCDC 500 mg	NaCDC 1000 mg	Placebo
Arm/Group Description	Participants randomized to this arm received 500 mg NaCDC per day for 4 days.	Participants randomized to this arm received 1000 mg NaCDC per day for 4 days.	Participants randomized to this arm received a placebo capsule each day for 4 days.
Measure Participants	11	12	13
Mean (Standard Deviation) [units on a scale]	4.4 (0.5)	4.4 (0.4)	2.9 (0.3)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	NaCDC 500 mg, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.031
	Comments
	Method	Dunnett's test
	Comments	pairwise comparison low dose NaCDC against placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	NaCDC 1000 mg, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.010
	Comments
	Method	Dunnett's test
	Comments	pairwise comparison high dose NaCDC against placebo

5. Secondary Outcome

Title	Colonic Filling at 6 Hours
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	NaCDC 500 mg	NaCDC 1000 mg	Placebo
Arm/Group Description	Participants randomized to this arm received 500 mg NaCDC per day for 4 days.	Participants randomized to this arm received 1000 mg NaCDC per day for 4 days.	Participants randomized to this arm received a placebo capsule each day for 4 days.
Measure Participants	11	12	13
Mean (Standard Deviation) [percentage of the radio-labeled meal]	52.6 (6.7)	54.8 (7.1)	50.6 (6.7)

Adverse Events

Time Frame	Adverse events were collected during the 4 days of the study.
Arm/Group Title	NaCDC 500 mg		NaCDC 1000 mg		Placebo
Arm/Group Description	Participants randomized to this arm received 500 mg NaCDC per day for 4 days.		Participants randomized to this arm received 1000 mg NaCDC per day for 4 days.		Participants randomized to this arm received a placebo capsule each day for 4 days.
All Cause Mortality
	NaCDC 500 mg		NaCDC 1000 mg		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	NaCDC 500 mg		NaCDC 1000 mg		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/11 (0%)		0/12 (0%)		0/12 (0%)
Other (Not Including Serious) Adverse Events
	NaCDC 500 mg		NaCDC 1000 mg		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	6/11 (54.5%)		8/12 (66.7%)		2/13 (15.4%)
Gastrointestinal disorders
Lower abdominal cramping/pain	5/11 (45.5%)	5	5/12 (41.7%)	5	0/13 (0%)	0
Diarrhea	2/11 (18.2%)	2	2/12 (16.7%)	2	0/13 (0%)	0
Nausea	1/11 (9.1%)	1	3/12 (25%)	3	0/13 (0%)	0
Gas	1/11 (9.1%)	1	2/12 (16.7%)	2	0/13 (0%)	0
Heartburn	2/11 (18.2%)	2	0/12 (0%)	0	0/13 (0%)	0
General disorders
Headache	2/11 (18.2%)	2	2/12 (16.7%)	2	2/13 (15.4%)	2
Light-headedness	1/11 (9.1%)	1	2/12 (16.7%)	2	0/13 (0%)	0

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.