Effect of a Cannabinoid Agonist on Colonic Sensory Functions in Patients With Irritable Bowel Syndrome

• Sponsor: Michael Camilleri (Other)
• Overall Status: Completed
• CT.gov ID: NCT01786109
• Collaborator: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (NIH), National Center for Research Resources (NCRR) (NIH)
• Enrollment: 75
• Location: 1
• Arms: 3
• Duration (Months): 27
• Patients Per Site Per Month: 2.8

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).

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 is 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 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.

All participants underwent the following procedures:

1. Documentation of eligibility, screening questionnaires and physical examination, including exclusion of rectal evacuation disorder by standard clinical evaluation within the past 12 months; this was important to ensure the diarrhea was not secondary to "retention with overflow".

2. Bowel preparation with PEG and electrolyte-containing oral colonic lavage solution, followed by a 12 hour fast.

3. Colonic testing of compliance, tone, motility and sensation measurement. Colonic compliance, fasting tone, sensory thresholds and sensory ratings in response to random-order phasic distensions were performed before treatment was administered. Then medication was ingested, and after 60 minutes, the same studies were performed that is compliance, fasting tone, sensory thresholds and sensory ratings in response to random-order phasic distensions. Participants also filled in responses to questionnaires (using 100 mm VAS scales) to describe their sense of tiredness, peace, worry and activity at the time of the measurements of sensation. Finally, participants ingested a standard chocolate 1000 kcal milkshake meal, and postprandial colonic tone and motility were measured for one hour.

4. With appropriate consent, a venous blood sample was obtained from each participant for DNA extraction; this will be used in ongoing pharmacogenomics studies.

Note: This study is related to NCT01253408, part A of the same protocol. Part A explored the effect of dronabinol on gastric and colonic motor functions.

Study Design

• Study Type: Interventional
• Actual Enrollment: 75 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Official Title: Study on the Effect of Cannabinoid Agonist on Gastrointestinal and Colonic Motor and Sensory Functions in Patients With Diarrhea-Predominant 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 One dose of dronabinol 2.5 mg was taken orally with water.	Drug: Dronabinol; Dronabinol is a synthetic delta-9-tetrahydrocannabinol, a nonselective cannabinoid agonist. Subjects received one dose of either 2.5 mg or 5 mg orally with water.; Other Names: Marimol
Experimental: Dronabinol 5 mg One dose of dronabinol 5 mg was taken orally with water.	Drug: Dronabinol; Dronabinol is a synthetic delta-9-tetrahydrocannabinol, a nonselective cannabinoid agonist. Subjects received one dose of either 2.5 mg or 5 mg orally with water.; Other Names: Marimol
Placebo Comparator: Placebo One dose of placebo was taken orally with water.	Drug: Placebo; Placebo will match study drug; taken as one dose orally with water.

Outcome Measures

Primary Outcome Measures

1. Colonic Compliance at Pressure at Half-Maximum Volume (Pr 1/2) [1 hour after drug was ingested]

   Colonic compliance is a measure of the "stiffness" of the colon, that is, what pressure was needed to reach half the maximum volume of the colon. After the barostat catheter was inserted in the colon, the catheter was connected to a barostat machine. After an initial conditioning distension to 20 mm Hg, colonic compliance was measured by step-wise inflation with increments of 4 mm Hg up to 64 mm Hg. Colonic compliance was analyzed by a validated linear interpolation method. The pressure at half maximum volume serves as a summary of colonic compliance.

Secondary Outcome Measures

1. Postprandial Change in Colonic Tone [1 hour after ingestion of standard meal]

   Colonic tone is a measurement of the volume of the colon. Colonic tone was assessed by noting the changes in the balloon volume in the presence of a constant operating pressure in the balloon (in the barostat-manometric assembly placed in the colon.)

2. Post-treatment Sensory Threshold for First Perception of Pain [1 hour after drug was ingested]

   The sensory threshold for first perception of pain was measured by stepwise inflation in increments of 4 mm Hg at 60 second intervals up to a maximum pressure of 64 mm Hg. During this assessment participants were asked to report when they had the first sensation. The investigator recorded the threshold pressure at which the participants reported this sensation.

3. Post-Treatment Overall Sensory Rating in Response to 16, 24, 32, and 40 mm Hg Distensions [1 hour after drug was ingested]

   The sensory rating was measured by a 100 mm long Visual Analog Scale (VAS). The VAS does not have any pre-set marks between the extremes of 0 for no pain and 100 mm for extreme pain. The investigator measures the mark made by the participant in mm and records this for the value of pain.

4. Fasting Colonic Tone [After 12 hour fast, before drug administered]

   Colonic tone is a measurement of the volume of the colon. Colonic tone was assessed by noting the changes in the balloon volume in the presence of a constant operating pressure in the balloon (in the barostat-manometric assembly placed in the colon.)

5. Postprandial Colonic Motility Index [1 hour after ingestion of standard meal]

   Colonic phasic pressure activity is summarized as a motility index (MI)=log_e[number of contractions * sum of amplitudes) + 1]. A normal fasting average motility index (MI) would be about 12. An increase in MI means an increase in the phasic contractions (in contrast to tone) which is measured as a change in volume of the barostat balloon. (Therefore, an increase in MI means that the meal is moving more quickly through the colon.)

6. Post-treatment Sensory Threshold for First Sensation [1 hour after drug was ingested]

   The sensory threshold for first sensation was measured by stepwise inflation in increments of 4 mm Hg at 60 second intervals up to a maximum pressure of 64 mm Hg. During this assessment participants were asked to report when they had the first sensation. The investigator recorded the threshold pressure at which the participants reported this sensation.

7. Post-Treatment Sensory Threshold for First Perception of Gas [1 hour after drug was ingested]

   The sensory threshold for first perception of gas was measured by stepwise inflation in increments of 4 mm Hg at 60 second intervals up to a maximum pressure of 64 mm Hg. During this assessment participants were asked to report when they had the first sensation. The investigator recorded the threshold pressure at which the participants reported this sensation.

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

• Score of 10 or less on either Anxiety or Depression on the Hospital Anxiety/Depression Inventory

Exclusion Criteria:

• Patients with significant depression (score of greater than 10 on Hospital Depression Inventory

• Patients with anxiety (score of greater than 10 on Hospital Anxiety Inventory. However, patients on stable doses of selective serotonin 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

• Michael Camilleri
• 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

Additional Information:

• Link to Part A of this study, results for GI and colonic motor functions, n=36

Publications

• Wong BS, Camilleri M, Eckert D, Carlson P, Ryks M, Burton D, Zinsmeister AR. Randomized pharmacodynamic and pharmacogenetic trial of dronabinol effects on colon transit in irritable bowel syndrome-diarrhea. Neurogastroenterol Motil. 2012 Apr;24(4):358-e169. doi: 10.1111/j.1365-2982.2011.01874.x. Epub 2012 Jan 30.

• Responsible Party: Michael Camilleri, Professor of Medicine, Mayo Clinic
• ClinicalTrials.gov Identifier: NCT01786109
• Other Study ID Numbers: 08-008314 Part B; R01DK079866; UL1RR024150
• First Posted: Feb 7, 2013
• Last Update Posted: Mar 14, 2013
• Last Verified: Mar 1, 2013

• Keywords provided by Michael Camilleri, Professor of Medicine, Mayo Clinic: anandamide; cannabinoid; fatty acid amide hydrolase; gastric; motility; small bowel; sensory; motor
• 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 120 miles of Rochester, Minnesota

Arm/Group Title	Dronabinol 2.5 mg	Dronabinol 5 mg	Placebo
Arm/Group Description	One dose of dronabinol 2.5 mg will be taken orally with water.	One dose of dronabinol 5 mg will be taken orally with water.	One dose of placebo will be taken orally with water.
Period Title: Overall Study
STARTED	24	24	27
COMPLETED	23	24	25
NOT COMPLETED	1	0	2

Baseline Characteristics

Arm/Group Title	Dronabinol 2.5 mg	Dronabinol 5 mg	Placebo	Total
Arm/Group Description	One dose of dronabinol 2.5 mg will be taken orally with water.	One dose of dronabinol 5 mg will be taken orally with water.	One dose of placebo will be taken orally with water.	Total of all reporting groups
Overall Participants	24	24	27	75
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	36.1 (2.5)	43.7 (2.1)	43.2 (2.5)	40.8 (11.935)
Sex: Female, Male (Count of Participants)
Female	22 91.7%	23 95.8%	24 88.9%	69 92%
Male	2 8.3%	1 4.2%	3 11.1%	6 8%
Region of Enrollment (participants) [Number]
United States	24 100%	24 100%	27 100%	75 100%
Body Mass Index (kg/m^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg/m^2]	26.7 (1.0)	29.7 (1.1)	28.9 (1.2)	28.3 (5.5)

Outcome Measures

1. Primary Outcome

Title	Colonic Compliance at Pressure at Half-Maximum Volume (Pr 1/2)
Description	Colonic compliance is a measure of the "stiffness" of the colon, that is, what pressure was needed to reach half the maximum volume of the colon. After the barostat catheter was inserted in the colon, the catheter was connected to a barostat machine. After an initial conditioning distension to 20 mm Hg, colonic compliance was measured by step-wise inflation with increments of 4 mm Hg up to 64 mm Hg. Colonic compliance was analyzed by a validated linear interpolation method. The pressure at half maximum volume serves as a summary of colonic compliance.
Time Frame	1 hour after drug was ingested

Outcome Measure Data

Analysis Population Description

Intention-to-treat analysis

Arm/Group Title	Dronabinol 2.5 mg	Dronabinol 5 mg	Placebo
Arm/Group Description	One dose of dronabinol 2.5 mg will be taken orally with water.	One dose of dronabinol 5 mg will be taken orally with water.	One dose of placebo will be taken orally with water.
Measure Participants	24	24	27
Mean (Standard Error) [mL/mm Hg]	17.57 (0.935)	16.2 (1.03)	18.76 (1.13)

2. Secondary Outcome

Title	Postprandial Change in Colonic Tone
Description	Colonic tone is a measurement of the volume of the colon. Colonic tone was assessed by noting the changes in the balloon volume in the presence of a constant operating pressure in the balloon (in the barostat-manometric assembly placed in the colon.)
Time Frame	1 hour after ingestion of standard meal

Outcome Measure Data

Analysis Population Description

Intention-to-treat analysis

Arm/Group Title	Dronabinol 2.5 mg	Dronabinol 5 mg	Placebo
Arm/Group Description	One dose of dronabinol 2.5 mg will be taken orally with water.	One dose of dronabinol 5 mg will be taken orally with water.	One dose of placebo will be taken orally with water.
Measure Participants	24	24	27
Mean (Standard Error) [mL]	30.34 (4.76)	27.41 (3.35)	26.31 (4.81)

3. Secondary Outcome

Title	Post-treatment Sensory Threshold for First Perception of Pain
Description	The sensory threshold for first perception of pain was measured by stepwise inflation in increments of 4 mm Hg at 60 second intervals up to a maximum pressure of 64 mm Hg. During this assessment participants were asked to report when they had the first sensation. The investigator recorded the threshold pressure at which the participants reported this sensation.
Time Frame	1 hour after drug was ingested

Outcome Measure Data

Analysis Population Description

Intention-to-treat analysis

Arm/Group Title	Dronabinol 2.5 mg	Dronabinol 5 mg	Placebo
Arm/Group Description	One dose of dronabinol 2.5 mg will be taken orally with water.	One dose of dronabinol 5 mg will be taken orally with water.	One dose of placebo will be taken orally with water.
Measure Participants	24	24	27
Mean (Standard Deviation) [mm Hg]	42.83 (12.73)	40.33 (17.17)	44.44 (13.05)

4. Secondary Outcome

Title	Post-Treatment Overall Sensory Rating in Response to 16, 24, 32, and 40 mm Hg Distensions
Description	The sensory rating was measured by a 100 mm long Visual Analog Scale (VAS). The VAS does not have any pre-set marks between the extremes of 0 for no pain and 100 mm for extreme pain. The investigator measures the mark made by the participant in mm and records this for the value of pain.
Time Frame	1 hour after drug was ingested

Outcome Measure Data

Analysis Population Description

Intention-to-treat analysis

Arm/Group Title	Dronabinol 2.5 mg	Dronabinol 5 mg	Placebo
Arm/Group Description	One dose of dronabinol 2.5 mg will be taken orally with water.	One dose of dronabinol 5 mg will be taken orally with water.	One dose of placebo will be taken orally with water.
Measure Participants	24	24	27
16 mm Hg Distension	38.18 (4.68)	38.71 (4.64)	37.0 (4.57)
24 mm Hg Distension	49.64 (5.83)	42.75 (5.16)	39.76 (5.06)
32 mm Hg Distension	58.36 (5.14)	45.35 (4.83)	46.76 (4.78)
40 mm Hg Distension	57.18 (5.42)	48.17 (4.97)	45.52 (4.44)

5. Secondary Outcome

Title	Fasting Colonic Tone
Description	Colonic tone is a measurement of the volume of the colon. Colonic tone was assessed by noting the changes in the balloon volume in the presence of a constant operating pressure in the balloon (in the barostat-manometric assembly placed in the colon.)
Time Frame	After 12 hour fast, before drug administered

Outcome Measure Data

Analysis Population Description

Intention-to-treat analysis

Arm/Group Title	Dronabinol 2.5 mg	Dronabinol 5 mg	Placebo
Arm/Group Description	One dose of dronabinol 2.5 mg will be taken orally with water.	One dose of dronabinol 5 mg will be taken orally with water.	One dose of placebo will be taken orally with water.
Measure Participants	24	24	24
Mean (Standard Error) [mL]	117.8 (7.97)	118.5 (6.41)	114.3 (5.50)

6. Secondary Outcome

Title	Postprandial Colonic Motility Index
Description	Colonic phasic pressure activity is summarized as a motility index (MI)=log_e[number of contractions * sum of amplitudes) + 1]. A normal fasting average motility index (MI) would be about 12. An increase in MI means an increase in the phasic contractions (in contrast to tone) which is measured as a change in volume of the barostat balloon. (Therefore, an increase in MI means that the meal is moving more quickly through the colon.)
Time Frame	1 hour after ingestion of standard meal

Outcome Measure Data

Analysis Population Description

Intention-to-treat analysis

Arm/Group Title	Dronabinol 2.5 mg	Dronabinol 5 mg	Placebo
Arm/Group Description	One dose of dronabinol 2.5 mg will be taken orally with water.	One dose of dronabinol 5 mg will be taken orally with water.	One dose of placebo will be taken orally with water.
Measure Participants	24	24	27
Proximal descending colon	11.24 (1.13)	11.22 (1.56)	10.70 (2.51)
Distal descending colon	9.97 (2.8)	10.23 (1.92)	10.50 (1.69)

7. Secondary Outcome

Title	Post-treatment Sensory Threshold for First Sensation
Description	The sensory threshold for first sensation was measured by stepwise inflation in increments of 4 mm Hg at 60 second intervals up to a maximum pressure of 64 mm Hg. During this assessment participants were asked to report when they had the first sensation. The investigator recorded the threshold pressure at which the participants reported this sensation.
Time Frame	1 hour after drug was ingested

Outcome Measure Data

Analysis Population Description

Intention-to-treat analysis

Arm/Group Title	Dronabinol 2.5 mg	Dronabinol 5 mg	Placebo
Arm/Group Description	One dose of dronabinol 2.5 mg will be taken orally with water.	One dose of dronabinol 5 mg will be taken orally with water.	One dose of placebo will be taken orally with water.
Measure Participants	24	24	27
Mean (Standard Deviation) [mm Hg]	15.83 (9.62)	15.5 (11.46)	18.37 (14.65)

8. Secondary Outcome

Title	Post-Treatment Sensory Threshold for First Perception of Gas
Description	The sensory threshold for first perception of gas was measured by stepwise inflation in increments of 4 mm Hg at 60 second intervals up to a maximum pressure of 64 mm Hg. During this assessment participants were asked to report when they had the first sensation. The investigator recorded the threshold pressure at which the participants reported this sensation.
Time Frame	1 hour after drug was ingested

Outcome Measure Data

Analysis Population Description

Intention-to-treat analysis

Arm/Group Title	Dronabinol 2.5 mg	Dronabinol 5 mg	Placebo
Arm/Group Description	One dose of dronabinol 2.5 mg will be taken orally with water.	One dose of dronabinol 5 mg will be taken orally with water.	One dose of placebo will be taken orally with water.
Measure Participants	24	24	27
Mean (Standard Deviation) [mm Hg]	28.83 (17.57)	27.33 (17.36)	29.04 (16.81)

Adverse Events

Arm/Group Title	Dronabinol 2.5 mg		Dronabinol 5 mg		Placebo
Arm/Group Description	One dose of dronabinol 2.5 mg will be taken orally with water.		One dose of dronabinol 5 mg will be taken orally with water.		One dose of placebo will be taken orally with water.
All Cause Mortality
	Dronabinol 2.5 mg		Dronabinol 5 mg		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Dronabinol 2.5 mg		Dronabinol 5 mg		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/24 (0%)		0/24 (0%)		0/27 (0%)
Other (Not Including Serious) Adverse Events
	Dronabinol 2.5 mg		Dronabinol 5 mg		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	10/24 (41.7%)		13/24 (54.2%)		10/27 (37%)
Cardiac disorders
Elevated heart rate	2/24 (8.3%)	2	1/24 (4.2%)	1	5/27 (18.5%)	5
General disorders
Drowsy/tired	5/24 (20.8%)	5	7/24 (29.2%)	7	5/27 (18.5%)	5
Flushing/hot	6/24 (25%)	6	4/24 (16.7%)	4	4/27 (14.8%)	4
Headache	4/24 (16.7%)	4	2/24 (8.3%)	2	4/27 (14.8%)	4
Dizzy/light-headed	2/24 (8.3%)	2	5/24 (20.8%)	5	1/27 (3.7%)	1
Loopy/foggy thinking	2/24 (8.3%)	2	6/24 (25%)	6	0/27 (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.