Effect of Cannabinoid Agonist on Gastrointestinal and Colonic Motor Functions in Patients With Irritable Bowel Syndrome (IBS)

• Sponsor: Mayo Clinic (Other)
• Overall Status: Completed
• CT.gov ID: NCT01253408
• 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): 27
• Patients Per Site Per Month: 1.3

Study Details

Study Description

Brief Summary

Irritable bowel syndrome (IBS) affects about 15% of the U.S. population. There are still no effective and safe medications approved for the treatment of abdominal pain associated with bowel symptoms in IBS. This study will investigate the effects of an approved medication, Dronabinol, on the movement of food through the stomach and colon in subjects with a history of diarrhea-predominant Irritable Bowel Syndrome (D-IBS).

Dronabinol is a synthetic medication (a medication made in a laboratory) related to the active ingredient of "cannabinoid or marijuana". Dronabinol is approved by the Food and Drug Administration (FDA) for preventing nausea and vomiting in patients with cancers undergoing chemotherapy. It is also used in AIDS patients with excessive weight loss for improvement in appetite and weight gain.

The hypothesis in this study is that dronabinol will slow down the movement of food through the colon, and that this effect is regulated by the genes controlling the body messengers (receptors) that respond to medicinal marijuana or synthetic medicines that work on the same messengers that are present in the gastrointestinal tract and pain nerves.

Condition or Disease	Intervention/Treatment	Phase
Irritable Bowel Syndrome	Drug: Dronabinol; Drug: Placebo	Phase 2

Detailed Description

Irritable bowel syndrome (IBS) affects about 15% of the U.S. population. Despite increasing understanding of the pathophysiology of IBS, there are unmet clinical needs and no effective medication approved for the treatment of abdominal pain associated with IBS. Cannabinoid receptors (CBR) are on cholinergic neurons in the brain stem, stomach and colon. A cannabinoid receptor type 1 (CB1) antagonist, rimonabant, is effective in induction of weight loss; however, the mechanism of this benefit is unclear. Human studies from this lab show that a CBR agonist, dronabinol, inhibits gastric and colonic motility, which may alter appetite or satiation in obesity, and may have potential in the treatment of IBS. The overall focus of the study is on the mechanisms involved in the modulation of gastric and colonic motor and sensory functions by cannabinoid receptors (CBR) in health and in IBS. CB1 receptors are also involved in nociception and in mediating inflammation which are increasingly recognized as being potential pathophysiological mechanisms in IBS. The aims of the study are to compare the effects of two doses of the cannabinoid agonist, dronabinol (5 and 10 mg/day) and placebo on gastrointestinal and colonic motor and sensory functions in IBS. Also, to determine whether variations in the fatty acid amide hydrolase (FAAH) gene and the monoacylglycerol lipase (MGLL) gene (for the rate limiting enzyme, monoacylglycerol lipase, for another endocannabinoid, 2-arachidonyl glycerol) influence the pharmacological effect of cannabinoid modulation on gastrointestinal motor and sensory functions.

All participants underwent the following procedures:

1. Documentation of eligibility, screening questionnaires, and physical examination within the month prior to the study. The physical exam included standard rectal and pelvic floor examinations to exclude rectal evacuation disorder. This was necessary to ensure the diarrhea ws not secondary to "retention of stool with overflow."

2. Baseline colonic transit measurement (Geometric Center 24-h and 48-h), off treatment.

3. Treatment days corresponded to the scintigraphic transit testing days (days 1 and 2) with participants receiving the medication to which they were randomized. Scintigraphic measurements of gastric, small bowel, and colonic transit were conducted, using a previously validated method on days 1 and 2, and were completed with a fasting 48-h scan on day 3 when no medication was administered.

On days 1 and 2, the morning dose of medication was ingested in the research laboratory, with the participant fasting. On day 1, the morning dose of medication was administered together with the delayed release capsule containing an isotope labeled activated charcoal used to measure colonic transit. On day 2, the morning dose of medication was given after the 24-h scan. The evening doses on days 1 and 2 were ingested by participants at bed time in their homes.

1. With appropriate consent, a venous blood sample was to be obtained from all participants for DNA extraction and pharmacogenomic studies.

Study Design

• Study Type: Interventional
• Actual Enrollment: 36 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Official Title: Study of the Effect of Cannabinoid Agonist on Gastrointestinal and Colonic Motor and Sensory Functions in Patients With Irritable Bowel Syndrome
• Study Start Date: Sep 1, 2009
• Actual Primary Completion Date: Dec 1, 2011
• Actual Study Completion Date: Dec 1, 2011

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Dronabinol 2.5 mg bid Dronabinol 2.5 mg will be taken orally with water twice per day for two days.	Drug: Dronabinol; Dronabinol is a synthetic delta-9-tetrahydrocannabinol, a nonselective cannabinoid agonist. Subjects will receive either 2.5 mg bid, or 5 mg bid, taken orally with water for 2 days.; Other Names: Marinol
Experimental: Dronabinol 5 mg bid Dronabinol 5 mg will be taken orally with water twice per day for two days.	Drug: Dronabinol; Dronabinol is a synthetic delta-9-tetrahydrocannabinol, a nonselective cannabinoid agonist. Subjects will receive either 2.5 mg bid, or 5 mg bid, taken orally with water for 2 days.; Other Names: Marinol
Placebo Comparator: Placebo Placebo will be taken orally with water twice per day for two days.	Drug: Placebo; Placebo will match study drug; taken orally with water twice per day for two days.

Outcome Measures

Primary Outcome Measures

1. Colonic Transit Geometric Center at 24 Hours [24 hours]

   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 Geometric Center [28, 32, and 48 hours]

   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. Gastric Emptying Half-Time (t1/2) [Approximately 2 hours after radiolabel meal is ingested]

   The time for half of the ingested solids or liquids to leave the stomach.

3. Colonic Filling at 6 Hours [6 hours after radiolabeled meal was ingested]

   Percent of the radio-labeled meal that reached the colon at 6 hours, indirectly reflecting small bowel transit time.

4. Ascending Colon Emptying T 1/2 [48 hours after radiolabeled meal was ingested]

   Ascending colon emptying t1/2 will be estimated by power exponential analysis of the proportionate emptying over time of counts from the colon. The primary data for this analysis will be the proportion of decay and depth-corrected counts in the ascending colon on the hourly scans on the first day of transit measurement and the 48 hour data.

5. Gastric Emptying at 2 and 4 Hours [2, 4 hours]

   Proportion of stomach contents emptied at a 2 and 4 hours.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 75 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Age 18-75 years

• Positive for IBS symptoms by Rome III criteria

• No prior abdominal surgery (except appendectomy or cholecystectomy)

• Baseline Geometric Center at 24 hours is greater/equal to 2.0

• Baseline Geometric Center at 48 hours is greater/equal to 3.9

Exclusion Criteria:

• Patients with significant depression (score of greater than 10 on Hospital and Anxiety Inventory)

• Patients with anxiety (score of greater than 10 on Hospital and Anxiety Inventory) will not be allowed to participate. However, patients on stable doses of selective serotonin re-uptake inhibitors (SSRIs) or low dose of tricyclic antidepressants will be eligible.

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 Camilleri, MD, Mayo Clinic

Study Documents (Full-Text)

None provided.

More Information

Publications

• Wong BS, Camilleri M, Busciglio I, Carlson P, Szarka LA, Burton D, Zinsmeister AR. Pharmacogenetic trial of a cannabinoid agonist shows reduced fasting colonic motility in patients with nonconstipated irritable bowel syndrome. Gastroenterology. 2011 Nov;141(5):1638-47.e1-7. doi: 10.1053/j.gastro.2011.07.036. Epub 2011 Jul 29.

• ClinicalTrials.gov Identifier: NCT01253408
• Other Study ID Numbers: 08-008314 Part A; R01DK079866; UL1RR024150
• First Posted: Dec 3, 2010
• Last Update Posted: May 7, 2013
• Last Verified: Mar 1, 2013

• Keywords provided by , ,: anandamide; cannabinoid; fatty acid amide hydrolase; gastric; motility; small bowel
• Additional relevant MeSH terms: Irritable Bowel Syndrome; Syndrome; Dronabinol

Study Results

Participant Flow

Recruitment Details	All participants were recruited from a database of patients with irritable bowel syndrome (IBS) who reside within 150 miles of Rochester, Minnesota from October 2008 through April 2011.

Arm/Group Title	Dronabinol 2.5 mg Bid	Dronabinol 5 mg Bid	Placebo
Arm/Group Description	Dronabinol 2.5 mg will be taken orally with water twice per day for two days.	Dronabinol 5 mg will be taken orally with water twice per day for two days.	Placebo will be taken orally with water twice per day for two days.
Period Title: Overall Study
STARTED	10	13	13
COMPLETED	10	12	13
NOT COMPLETED	0	1	0

Baseline Characteristics

Arm/Group Title	Dronabinol 2.5 mg Bid	Dronabinol 5 mg Bid	Placebo	Total
Arm/Group Description	Dronabinol 2.5 mg will be taken orally with water twice per day for two days.	Dronabinol 5 mg will be taken orally with water twice per day for two days.	Placebo will be taken orally with water twice per day for two days.	Total of all reporting groups
Overall Participants	10	13	13	36
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	47.68 (25.08)	42.28 (16.36)	36.7 (11.02)	41.77 (17.74)
Sex: Female, Male (Count of Participants)
Female	10 100%	11 84.6%	13 100%	34 94.4%
Male	0 0%	2 15.4%	0 0%	2 5.6%
Region of Enrollment (participants) [Number]
United States	10 100%	13 100%	13 100%	36 100%
Body Mass Index (BMI) (kg/m^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg/m^2]	28.7 (1.5)	31.6 (3.9)	30.8 (1.8)	30.50 (9.46)

Outcome Measures

1. Secondary Outcome

Title	Colonic Transit Geometric Center
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	28, 32, and 48 hours

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Dronabinol 2.5 mg Bid	Dronabinol 5 mg Bid	Placebo
Arm/Group Description	Dronabinol 2.5 mg will be taken orally with water twice per day for two days.	Dronabinol 5 mg will be taken orally with water twice per day for two days.	Placebo will be taken orally with water twice per day for two days.
Measure Participants	10	13	13
28 hours	3.39 (1.28)	3.60 (1.04)	3.24 (1.18)
32 hours	3.78 (1.11)	4.05 (0.90)	3.54 (1.17)
48 hours	4.21 (0.94)	4.60 (0.65)	4.02 (0.99)

2. Secondary Outcome

Title	Gastric Emptying Half-Time (t1/2)
Description	The time for half of the ingested solids or liquids to leave the stomach.
Time Frame	Approximately 2 hours after radiolabel meal is ingested

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Dronabinol 2.5 mg Bid	Dronabinol 5 mg Bid	Placebo
Arm/Group Description	Dronabinol 2.5 mg will be taken orally with water twice per day for two days.	Dronabinol 5 mg will be taken orally with water twice per day for two days.	Placebo will be taken orally with water twice per day for two days.
Measure Participants	10	13	13
Mean (Standard Deviation) [minutes]	137.3 (33.53)	130.7 (42.13)	138.2 (45.18)

3. 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	6 hours after radiolabeled meal was ingested

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Dronabinol 2.5 mg Bid	Dronabinol 5 mg Bid	Placebo
Arm/Group Description	Dronabinol 2.5 mg will be taken orally with water twice per day for two days.	Dronabinol 5 mg will be taken orally with water twice per day for two days.	Placebo will be taken orally with water twice per day for two days.
Measure Participants	10	13	13
Mean (Standard Deviation) [percentage of meal]	48.60 (33.76)	51.62 (29.89)	57.46 (24.77)

4. Secondary Outcome

Title	Ascending Colon Emptying T 1/2
Description	Ascending colon emptying t1/2 will be estimated by power exponential analysis of the proportionate emptying over time of counts from the colon. The primary data for this analysis will be the proportion of decay and depth-corrected counts in the ascending colon on the hourly scans on the first day of transit measurement and the 48 hour data.
Time Frame	48 hours after radiolabeled meal was ingested

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Dronabinol 2.5 mg Bid	Dronabinol 5 mg Bid	Placebo
Arm/Group Description	Dronabinol 2.5 mg will be taken orally with water twice per day for two days.	Dronabinol 5 mg will be taken orally with water twice per day for two days.	Placebo will be taken orally with water twice per day for two days.
Measure Participants	10	13	13
Mean (Standard Deviation) [hours]	9.50 (4.62)	9.90 (5.44)	14.53 (8.36)

5. Secondary Outcome

Title	Gastric Emptying at 2 and 4 Hours
Description	Proportion of stomach contents emptied at a 2 and 4 hours.
Time Frame	2, 4 hours

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Dronabinol 2.5 mg Bid	Dronabinol 5 mg Bid	Placebo
Arm/Group Description	Dronabinol 2.5 mg will be taken orally with water twice per day for two days.	Dronabinol 5 mg will be taken orally with water twice per day for two days.	Placebo will be taken orally with water twice per day for two days.
Measure Participants	10	13	13
2 hours	0.38 (0.15)	0.49 (0.17)	0.45 (0.14)
4 hours	0.90 (0.09)	0.90 (0.13)	0.88 (0.16)

6. Primary Outcome

Title	Colonic Transit Geometric Center at 24 Hours
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	24 hours

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Dronabinol 2.5 mg Bid	Dronabinol 5 mg Bid	Placebo
Arm/Group Description	Dronabinol 2.5 mg will be taken orally with water twice per day for two days.	Dronabinol 5 mg will be taken orally with water twice per day for two days.	Placebo will be taken orally with water twice per day for two days.
Measure Participants	10	13	13
Mean (Standard Deviation) [units on a scale]	3.12 (1.29)	3.05 (1.02)	2.77 (1.23)

Adverse Events

Arm/Group Title	Dronabinol 2.5 mg Bid		Dronabinol 5 mg Bid		Placebo
Arm/Group Description	Dronabinol 2.5 mg will be taken orally with water twice per day for two days.		Dronabinol 5 mg will be taken orally with water twice per day for two days.		Placebo will be taken orally with water twice per day for two days.
All Cause Mortality
	Dronabinol 2.5 mg Bid		Dronabinol 5 mg Bid		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Dronabinol 2.5 mg Bid		Dronabinol 5 mg Bid		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/10 (0%)		0/13 (0%)		0/13 (0%)
Other (Not Including Serious) Adverse Events
	Dronabinol 2.5 mg Bid		Dronabinol 5 mg Bid		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	7/10 (70%)		9/13 (69.2%)		7/13 (53.8%)
General disorders
Headache	3/10 (30%)	3	2/13 (15.4%)	2	2/13 (15.4%)	2
Dizziness/lightheadedness	2/10 (20%)	2	4/13 (30.8%)	4	1/13 (7.7%)	1
Drowsiness/tiredness	4/10 (40%)	4	5/13 (38.5%)	5	4/13 (30.8%)	4
"Loopy," foggy thinking	1/10 (10%)	1	2/13 (15.4%)	2	0/13 (0%)	0
Skin and subcutaneous tissue disorders
Hot flushing	1/10 (10%)	1	0/13 (0%)	0	2/13 (15.4%)	2

Limitations/Caveats

This study included assessment of only four doses of dronabinol over 2 days.

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.