Effects Of GW876008 On The Bowel In Patients With Irritable Bowel Syndrome

Study Overview
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Brief Summary
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The purpose of this study is to see if GW876008 in Irritable Bowel Syndrome patients will reverse stress-induced hypersensitivity, by looking at thresholds for perception and pain.

Official Title
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A Phase IIa Pharmacodynamic Study of Antagonism of Irritable Bowel Syndrome (IBS) Symptoms by GW876008, a Corticotrophin Releasing Factor 1 Receptor Antagonist (CRF1-RA)

Conditions
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Irritable Colon

Intervention / Treatment
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* Drug: GW876008


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Must have irritable bowel syndrome. Exclusion criteria: Subjects who have been taking any medication for the treatment of irritable bowel syndrome within 6 months prior to the start of the study.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment


Arms and Interventions

| Intervention/Treatment |
| --- |
|Drug: GW876008|nan|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent change from Baseline in Laser Doppler regional Rectal Mucosal Blood Flow (RMBF) measured in response to physiological stress (cold water pressor test) | Laser Doppler flowmetry measures changes in red cell flux using a probe that scans a fixed volume of tissue. Participants were examined in the left lateral position where DRT4 laser Doppler flow meter was placed against the rectal mucosa 10 centimeter (cm) above the lower limit of the anal margin, and pre-stress readings were taken after a period of 10 minutes of acclimatization in a room with an ambient temperature of 22 degrees Celsius. Physiological stress was evoked using the cold water pressor test. Participants were asked to place their hand and forearm into a container of ice-cold water at 0-4degree Celsius and were persuaded to maintain that position for as long as possible during the stress period of 10 minutes. Readings were then taken during pre-stress and at 5-minute intervals during the stress and recovery periods. Baseline was defined as the pre-dose assessment. Change from Baseline was calculated by subtracting the Baseline value minus the post-randomization value. | Baseline (pre-dose) and Study Days 1, 2 and 3 | 
| Percent Change from Baseline in Laser Doppler regional RMBF measured in response to psychological stress (dichotomous listening test) | Laser Doppler flowmetry measures changes in red cell flux using a probe that scans a fixed volume of tissue, an indirect measure of flow can be obtained. Participants were examined in the left lateral position with no prior bowel preparation. The laser Doppler probe (DRT4 laser Doppler flow meter) was then placed against the rectal mucosa 10 centimeter above the lower limit of the anal margin, and pre-stress readings were taken after a period of 10 minutes of acclimatization in a room with an ambient temperature of 22 degrees Celsius. The dichotomous listening test was used as a psychological stressor. At the onset of stress, folk music was played into one ear and rock music into the other ear for 10 minutes. Readings were then taken during pre-stress and at 5-minute intervals during the stress and recovery periods. Baseline was defined as the pre-dose assessment. Change from Baseline was calculated by subtracting the Baseline value minus the post-randomization value. | Baseline (pre-dose) and Study Days 1, 2 and 3 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from Baseline in RMBF at 90 minutes post-dose | RMBF was measured in response to both physiologic and psychological stress. Pre-stress readings were taken after 10 minutes of acclimatization. Readings were taken during pre-stress collections and at 5 minutes intervals during the stress and recovery period.Baseline was defined as the pre-dose assessment. Change from Baseline was calculated by subtracting the Baseline value minus the post-randomization value. | Baseline (pre-dose) and Study Days 1, 2 and 3 | 
| Number of participants with adverse events (AE) and serious adverse events (SAE) | An AE is defined as any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. An SAE is defined as any untoward medical occurrence that, at any dose, results in death, is life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, is a congenital anomaly/birth defect, may jeopardize the participant or require medical or surgical intervention to prevent one of the other outcomes listed in the definition above, or is an event of possible drug-induced liver injury. | Up to Week 14 | 
| Number of participants with abnormal clinical chemistry data of clinical concern | The clinical chemistry parameters included albumin, calcium low, creatinine, glucose, magnesium, phosphorus, potassium, sodium, and bicarbonate. The total number of participants with clinical chemistry data of clinical concern have been presented. | Up to Week 14 | 
| Number of participants with abnormal hematology data of clinical concern | The hematology parameters included white blood cell count, neutrophil count, hemoglobin, hematocrit, platelet count and lymphocytes. The total number of participants with hematology of clinical concern have been presented. | Up to Week 14 | 
| Participant perceived stress as assessed by a Visual Analogue Scale | The acute emotional response to stress during each study visit was assessed using a 10 cm description-anchored visual analogue scale, ranging from 0 to 10, where 0=no-stress and 10=Most stressed ever. Higher scores indicated significant stress. Participants were asked to mark this before onset of stress, after 10 minutes of stress and finally after 10 minutes of recovery. After the pre-stress recordings, the period of either physiological or psychological stress were commenced and continued for 10 minutes, followed by a period of recovery for a further 10 minutes. | Study Days 1, 2 and 3 | 
| Systemic autonomic nervous system response as assessed by systolic blood pressure (SBP) and diastolic blood pressure (SBP) | As an indicator of change in systemic autonomic activity, blood pressure was measured pre-stress, after 10 minutes of stress and after 10 minutes of recovery using a Dinamap. | Up to Week 14 | 
| Systemic autonomic nervous system response as assessed by heart rate (HR). | As an indicator of change in systemic autonomic activity, HR was measured pre-stress, after 10 minutes of stress and after 10 minutes of recovery using a Dinamap. | Up to Week 14 | 
| Percent change from Baseline in participant reported threshold for pain as a measure to assess Visceral (rectal) electro sensitivity | Visceral (rectal) sensitivity to pain was measured using previously validated techniques. In brief, a 1-cm bipolar electrode (21L10) mounted on a 14-gauge Foley catheter was placed initially into the anal canal before the period of acclimatization. The stimulation parameters were set at 0.5-millisecond pulse width and 10-Hertz frequency for rectal measurements. The current was then increased slowly and the participants were asked to report when they felt it was painful (pain). Rectal measurements were made 8 cm above the anal verge. Measurements were made pre-stress, after 10 minutes of stress, and then after 10 minutes of recovery. The catheter remained in situ throughout the study but was moved from anal to rectal sites for the 2 measurements. Baseline was defined as the pre-dose assessment. Change from Baseline was calculated by subtracting the Baseline value minus the post-randomization value. | Baseline (pre-dose) and Study Days 1, 2 and 3 | 
| Percent change from Baseline in participant reported threshold for perception of an electrical stimulus as a measure to assess Visceral (rectal) electro sensitivity | Visceral (rectal) sensitivity to perception was measured using previously validated techniques. In brief, a 1-cm bipolar electrode (21L10) mounted on a 14-gauge Foley catheter was placed initially into the anal canal before the period of acclimatization. The stimulation parameters were set at 0.5-millisecond pulse width and 10-Hertz frequency for rectal measurements. The current was then increased slowly and the participants will be asked to report when they were first aware of this (perception). Rectal measurements were made 8 centimeter above the anal verge. Measurements were made pre-stress, after 10 minutes of stress, and then after 10 minutes of recovery. The catheter remained in situ throughout the study but will be moved from anal to rectal sites for the 2 measurements. Baseline was defined as the pre-dose assessment. Change from Baseline was calculated by subtracting the Baseline value minus the post-randomization value. | Study Days 1, 2 and 3 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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IBS, stress, CRF1