Sb-705498 Rectal Pain Study

Study Overview
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Brief Summary
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SB-705498 has demonstrated efficacy in several preclinical and human experimental pain models. This study will investigate the efficacy of SB-705498 in patients with rectal pain. This will be a double-blind, placebo-controlled, two-way crossover study. 21 patients with faecal urgency (Group 1), and 21 patients with IBS (Group 2) will complete this study.

Official Title
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A Double-blind, Randomised, Placebo Controlled, Single Dose, Two-period Crossover Study to Investigate the Therapeutic Potential of the TRPV1 Antagonist SB-705498 in Treatment of Subjects With Rectal Hypersensitivity Including Irritable Bowel Syndrome.

Conditions
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Irritable Colon

Intervention / Treatment
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* Drug: SB-705498


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Female/male aged 18-65. Women of child bearing potential must use an effective method of contraception Faecal urgency as defined by Chan ECG, which has no abnormalities Normal Clinical labs Informed consent and understand protocol requirements IBS subjects: Has irritable bowel syndrome (IBS) as defined by Rome II criteria Rectal hyperalgesia Exclusion Criteria: Any clinical or biological abnormality found at screen (other than those related to the disease under investigation) History of alcohol, substance or drug abuse Uncontrolled hypertension A history or presence of cardiovascular risk factors Participation in a trial within 3 months before the start of the study History of allergy Unable to withdraw from analgesic medications for their rectal hyperalgesia (opioid-dependent patients can be included if they are willing to withdraw from their opiate medication

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: SB-705498|nan|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Visual Analogue Scale (VAS) Pain Score to Rectal Distensions at Pre-dose and up to 6 Hours (h) Post-dose of Each Treatment Period | This analysis was performed at 12, 24, 36 and 48 millimeters of mercury (mmHg) which was above the baseline operating pressure threshold. Participants assessed the cough severity and urge to cough using VAS immediately prior to capsaicin challenge. No results were reported since the study objectives were not met due to the early study termination and withdrawal of participant. Average of Day -1 and pre-dose was planned as Baseline for VAs assessment. The VAS score was planned to be analyzed on Day-1, Day 1, 2 hours, and 24 hours. Average daily pain scores as captured in participant diary cards were planned to be summarized descriptively and planned to be analyzed. The 11 point pain intensity numerical rating scale ranging from 0 to 10, where 0 represents No pain and 10 represents Worst pain imaginable was planned to be used for the subjective assessment of the pain. | Baseline (Pre-dose) and up to 6 hours post-dose of each treatment period | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Visual Analogue Scores for Rectal Distensions for Gas, Urgency to Defecate and Discomfort at Pre-dose and 6 h Post-dose of Each Treatment Period | The VAS scores for assessment of rectal sensation for pain, gas, urgency and discomfort were analyzed separately. Participants assessed the cough severity and urge to cough using VAS immediately prior to capsaicin challenge. No results were reported since the study objectives were not met due to the early study termination and withdrawal of participant. Average of Day -1 and pre-dose was planned as Baseline for VAs assessment. The VAS score was planned to be analyzed on Day-1, Day 1, 2 hours, and 24 hours. Average daily pain scores as captured in participant diary cards were planned to be summarized descriptively and planned to be analyzed. The 11 point pain intensity numerical rating scale ranging from 0 to 10, where 0 represents No pain and 10 represents Worst pain imaginable was planned to be used for the subjective assessment of the pain. No results were reported since the study objectives were not met due to the early study termination and withdrawal of participant. | Baseline (pre-dose) and up to 6 h post-dose of each treatment period | 
| Rectal Sensory Thresholds to Thermal Stimulation (Contact Heat Device, Values Reported as in Study) at Pre-dose and 6h Post-dose of Each Treatment Period | Visceral hypersensitivity is defined as reduced pain and discomfort threshold to rectal stimuli. Rectal hypersensitivity was correlated with the degree of rectal hypersensitivity (up-regulation of TRPV-1 receptors) as measured by rectal thermal stimulation. Ongoing rectal pain intensity scale is 11-point numeric rating scale, where 0=Unnoticeable/No Pain, 10=Unbearable/Worst Pain. An average of daily scores over 1 week pre-dose and 1 week post-dose was recorded. Single measurements pre-dose and at hourly intervals within 6 hours post-dose were also recorded. Participants were planned to stay in the hospital for 6h post-dose and were planned to be discharged when physician was satisfied with their medical condition. No results were reported since the study objectives were not met due to the early study termination and withdrawal of participant. Participants assessed the cough severity and urge to cough using VAS immediately prior to capsaicin challenge. | Baseline (pre-dose) and 6h post-dose of each treatment period | 
| Peak Pain Intensity Difference (PPID6), as Derived From Maximum Pain Intensity (NRS) Difference From Baseline (Pre-dose on Day 1) by Single Measurement Recorded Over 0-6h of Each Treatment Period | No results were reported since the study objectives were not met due to the early study termination and withdrawal of participant. Change from Baseline (pre-dose) is the value at indicated time-point minus the Baseline value. Average daily pain scores as captured in participant diary cards were planned to be summarized descriptively and planned to be analyzed. The 11 point pain intensity numerical rating scale ranging from 0 to 10, where 0 represents No pain and 10 represents Worst pain imaginable was planned to be used for the subjective assessment of the pain. | Baseline (pre-dose) and up to 0-6 h of each treatment period | 
| Pain Intensity Difference (SPID6), as Derived From Pain Intensity (NRS) Difference From Baseline (Pre-dose on Day 1) by Single Measurement Recorded Over 0-6h Post-dose of Each Treatment Period | Change from Baseline (pre-dose0 is the value at indicated time point minus the Baseline value. Average daily pain scores as captured in participant diary cards were planned to be summarized descriptively and planned to be analyzed. The 11 point pain intensity numerical rating scale ranging from 0 to 10, where 0 represents No pain and 10 represents Worst pain imaginable was planned to be used for the subjective assessment of the pain. No results were reported since the study objectives were not met due to the early study termination and withdrawal of participant. | Baseline (pre-dose) and up to 0-6 h post-dose of each treatment period | 
| Somatic Heat Pain Thresholds (Hand and Foot) Assessed Pre-dose and 6h Post-dose of Each Treatment Period | Evoked potentials were to be recorded from midline electrodes by placing a ground electrode on temporal lobe region. A low cut off filter with a time constant of 1.06103 and a frequency of 0.15 hertz (Hz) and a high cut off filter of 100Hz was to be applied. The impedance from all electrodes was maintained below 5 ohms (Ω) and the electroencephalogram (EEG) was recorded, digitized at a sampling rate of 500 Hz. Responses from ten stimuli were to be recorded from each participant with the thermode placed over foot and one hand (non-dominant side). The thermode heating rate was set at 70 degree Celsius per second (°C/s) and the cooling rate at 40°C/s. The baseline temperature was 32 °C, destination temperature 51 °C, and stimulus interval approximately of 7 seconds. The participants were allowed to withdraw any time. No results were reported since the study objectives were not met due to the early study termination and withdrawal of participant. | Baseline (pre-dose) and upto 0-6h post-dose for each treatment period | 
| Contact Heat-evoked Potentials (CHEPs) - Optional, Assessed Pre-dose and 6h Post-dose of Each Treatment Period | For heat pain threshold measurement, temperature of the thermode was gradually increased from the baseline (32°C) at a rate of 1°C/s. The ramp was stopped and the temperature of the thermode was returned to the Baseline. This was repeated three times. The threshold temperatures and the average value were recorded by the computer. If the thermode temperature reached 50°C without the participant responding, the ramp was stopped and the temperature was returned to baseline automatically to prevent skin injury. This test was performed within two minutes. The respective cut-off temperature is then recorded for that trial. No results were reported since the study objectives were not met due to the early study termination and withdrawal of participant. | Baseline (pre-dose) and 6h post-dose of each treatment period | 
| Number of Defecations Over 24h and Over 1 Week Following a Dose of SB-705498 (Monitored Using Bristol Stool Scoring Diary Kept 1 Week Pre- and 1 Week Post-dose) | Onset associated with change in the frequency and change in the appearance of stools, abnormal stool frequency (>3/day or < 3/week); abnormal stool form (lumpy/hard or loose/watery stool), abnormal stool passage (straining, urgency, or feeling of incomplete evacuation); passage of mucus, and bloating were analyzed over period. No results were reported since the study objectives were not met due to the early study termination and withdrawal of participant. | 7 days pre-dose and 7 days post-dose of each treatment period | 
| Irritable Bowel Syndrome Symptom Severity Score (IBS SSS) Calculated Over Approximately 10 Days Pre- and Post-dose | Participants were rated on a scale based on following parameters - Onset associated with change in the frequency and change in the appearance of stools, abnormal stool frequency (>3/day or < 3/week); abnormal stool form (lumpy/hard or loose/watery stool), abnormal stool passage (straining, urgency, or feeling of incomplete evacuation); passage of mucus, and bloating were analyzed over period. No results were reported since the study objectives were not met due to the early study termination and withdrawal of participant. | 10 days pre-dose and post-dose of each treatment period | 
| Symptom Scoring and Quality of Life Assessments Over Period | Different scales used in this study included HAD, BDI, SF36, Bristol Stool Scoring, IBS QOL and SSS that were used to rate different scores on respective scales. Untreated pain leads to a decrease in daily function capability, social stresses, loss of work, an overall poor quality of life and a burden on healthcare resources. No results were reported since the study objectives were not met due to the early study termination and withdrawal of participant. | Approximately up to 3 months | 
| Average Daily Pain Scores at Baseline (Pre-dose), 1, 2, 3, 4, 5 and 6h Post-dose for Each Treatment Period | Individual pain scores were collected at screening and pre and post dose during the anorectal physiological assessments. Average daily pain scores as captured in participants' diary cards were summarized descriptively and analyzed. The 11 point pain intensity numerical rating scale ranges from 0 to 10, where 0 represents No pain and 10 represents Worst pain imaginable. This was used for the subjective assessment of the pain over period. No results were reported since the study objectives were not met due to the early study termination and withdrawal of participant. | At Baseline (pre-dose) and each hour post-dose of each treatment period | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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TRPV1 antagonist, Fecal Urgency, rectal pain, IBS