Irritable Colon
Conditions
Keywords
mucosal blood flow d-IBS
Brief summary
This study will look at colonic mucosal blood flow in subjects who have taken alosetron vs placebo and healthy volunteers vs diarrhea-predominant Irritable Bowel Syndrome (d-IBS) patients.
Interventions
DRUGalosetron
Sponsors
GlaxoSmithKline
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
DOUBLE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 49 Years
Healthy volunteers
Yes
Inclusion criteria
* The subject signs and dates a written informed consent form prior to the initiation of any study-related activities. * The subject is between 18 and 49 years of age at the time of the Screening Visit. * The subject is female and either: * A healthy subject. Healthy subjects are defined as individuals who are free from clinically significant illness or disease as determined by their medical history (including family), physical examination, laboratory studies, and other tests. OR * A d-IBS patient per the Rome II criteria who has a normal result from a flexible sigmoidoscopy or colonoscopy, or flexible sigmoidoscopy plus barium enema, within 2 years of the Screening visit. * The subject demonstrates a negative urine pregnancy test result prior to investigational product administration and be either: * Of non-childbearing potential (i.e., physiologically incapable of becoming pregnant) * post-menopausal define as one year without menses in the absence of hormone replacement therapy. * sterilization (via hysterectomy or bilateral tubal ligation) * Of childbearing potential and agrees to one of the following acceptable non-hormonal contraceptive methods consistently and in accordance with both the product label and the instructions of a physician. Subjects will use effective contraceptive methods for at least one month prior to Screening and should continue to use the same contraceptive method throughout the study (Follow-up Visit). * Complete abstinence from intercourse * an intra-uterine device (IUD) inserted by a qualified physician, provided the IUD is not of the hormonal type and it has published data showing that the highest expected failure rate is less than 1% per year (not all IUDs meet this criterion) * double barrier method if comprised of a spermicide with either a condom or diaphragm * sterilization of partner The subject is ambulatory (defined as not depending exclusively on a wheelchair for mobility).
Exclusion criteria
* The subject is taking oral contraceptive or other hormonal therapy. * The subject has a concurrent illness or disability that may affect the interpretation of clinical data, or otherwise contraindicates participation in this clinical study (e.g., an unstable cardiovascular, autoimmune, renal, hepatic, pulmonary, endocrine, metabolic, gastrointestinal, hematologic, or neurological condition). * The subject has constipation-predominant IBS (c-IBS) or alternating IBS per the ROME II criteria. * The subject has current evidence of or history of chronic or severe constipation, or a history of sequelae from constipation. * Evidence of a biochemical or structural abnormality of the digestive tract. These conditions include (but not limited to): * Current evidence, or history of (at any time in the past): * GI/Bowel conditions: * inflammatory bowel disease (Crohn's disease or ulcerative colitis) * celiac disease * laxative abuse (in the clinical judgement of the physician) * gastrointestinal surgery (exceptions include ≥6 months post-surgery appendectomy, cholecystectomy, fundoplication without gas bloat, or hiatal hernia repair; ≥3 months post-surgery herniorrhaphy without bowel resection) * gastroparesis * GI malignancy * carcinoid syndrome * amyloidosis * gastrointestinal adhesions * ischemic colitis * toxic megacolon * impaired intestinal circulation * gastrointestinal perforation * gastrointestinal obstruction and/or stricture * Ischemic cardiovascular conditions: * coronary artery disease (CAD) * significant atherosclerosis * chronic pancreatitis * diabetes * thrombophlebitis or hypercoagulable state. * Current evidence of (within the past 6 months): * diverticulitis * ileus * symptomatic cholelithiasis * proctitis. * Current evidence of: * Hemoccult (+) stool. * The subject has a BMI of ≥27. * Mental impairment or inability or refusal to follow directions. * The subject has current evidence of, or has been treated for a malignancy within the past five years (other than localized basal cell, squamous cell skin cancer or cancer in situ that has been resected). * The subject exhibits evidence of hepatic dysfunction, viral hepatitis, or exhibits serum ALT (alanine aminotransferase) (SGPT), AST (aspartate aminotransferase) (SGOT) values \>2.5 times the upper limit of normal or alkaline phosphatase or bilirubin values \>2.0 times the upper limit of normal. * The subject displays renal impairment as evidenced by a serum creatinine value \>2.0 mg/dl. * The subject has used any medication within the seven days prior to dosing, unless approved by the investigator and GlaxoSmithKline (GSK) personnel. Section 9.1. * The subject has used an investigational drug, or participated in an investigational study, within 30 days of the Screening Visit. * The subject has a history of drug allergies (including but not limited to hypersensitivity responses to alosetron which, in the opinion of the investigator, contraindicates the subject's participation in this study. * Subjects who have made a blood donation (\>450mL) within 6 weeks prior to screening. * The subject has a history of alcohol and/or substance abuse within the past two years. * The subject is pregnant. The subject is breastfeeding.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Left Colon Mucosal Blood Flow (MBF) | Day 6 after each treatment period | On Day 6 of each treatment period; 1 hour after dosing, subjects underwent a flexible sigmoidoscopy with Laser Doppler Flowmetry (LDF) to measure Mucosal Blood Flow (MBF). There were no pre-treatment LDF procedure, MBF was compared between the Healthy volunteers and D-irritable bowel syndrome (IBS) cohorts using the flow rates from the placebo treatment period. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Rectal Mucosal Blood Flow (MBF) | Day 6 after each treatment period | On Day 6 of each treatment period approximately 1 hour after dosing, subjects underwent a flexible sigmoidoscopy with Laser Doppler Flowmetry (LDF) to measure Mucosal Blood Flow (MBF). There was no pre-treatment LDF procedure, MBF was compared between the Healthy and d-IBS cohorts using the flow rates from the placebo treatment period. |
| Left Colon and Rectal Mucosal Blood Flow Cohort Comparisons | Day 6 after each treatment period | On Day 6 of each treatment period approximately 1 hour after dosing, subjects underwent a flexible sigmoidoscopy with Laser Doppler Flowmetry (LDF) to measure Mucosal Blood Flow (MBF). There was no pre-treatment LDF procedure, MBF was compared between the Healthy and d-IBS cohorts using the flow rates from the placebo treatment period. |
Countries
United Kingdom
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| d-IBS Diarrhea-predominant irritable bowel syndrome. This group was randomize to EITHER 0.5 mb BID Alosetron or Placebo for 6 days followed by a flexible sigmoidoscopy; followed by a 7 day washout period; Then the subjects who were given study drug the first treatment period were given Placebo and vice versa for the next 6 days followed by another wash out period and a 7 day follow up period. | 22 |
| Healthy Volunteers Volunteers without clinical disease. This group was randomize to EITHER 0.5 mb BID Alosetron or Placebo for 6 days followed by a flexible sigmoidoscopy; followed by a 7 day washout period; Then the subjects who were given study drug the first treatment period were given Placebo and vice versa for the next 6 days followed by another wash out period and a 7 day follow up period. | 22 |
| Total | 44 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Follow-up Period | Withdrawal by Subject | 1 | 0 |
| Treatment Period 1 | Unable to perform sigmoidoscopy on Day 6 | 0 | 1 |
| Washout Period | Adverse Event | 1 | 0 |
| Washout Period | Lost to Follow-up | 0 | 1 |
| Washout Period | Withdrawal by Subject | 0 | 1 |
Baseline characteristics
| Characteristic | d-IBS | Healthy Volunteers | Total |
|---|---|---|---|
| Age, Continuous | 33.2 years STANDARD_DEVIATION 8.8 | 26.9 years STANDARD_DEVIATION 5.8 | 29.99 years STANDARD_DEVIATION 7.42 |
| Race/Ethnicity, Customized African American | 3 participants | 2 participants | 5 participants |
| Race/Ethnicity, Customized Central/South Asian | 1 participants | 1 participants | 2 participants |
| Race/Ethnicity, Customized East Asian | 1 participants | 0 participants | 1 participants |
| Race/Ethnicity, Customized Mixed Race | 0 participants | 1 participants | 1 participants |
| Race/Ethnicity, Customized South East Asian | 0 participants | 2 participants | 2 participants |
| Race/Ethnicity, Customized White/Caucasian/European | 17 participants | 16 participants | 33 participants |
| Sex: Female, Male Female | 22 Participants | 22 Participants | 44 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 12 / 24 | 10 / 23 | 11 / 24 | 11 / 23 |
| serious Total, serious adverse events | 0 / 24 | 0 / 23 | 0 / 24 | 0 / 23 |
Outcome results
Primary
Left Colon Mucosal Blood Flow (MBF)
On Day 6 of each treatment period; 1 hour after dosing, subjects underwent a flexible sigmoidoscopy with Laser Doppler Flowmetry (LDF) to measure Mucosal Blood Flow (MBF). There were no pre-treatment LDF procedure, MBF was compared between the Healthy volunteers and D-irritable bowel syndrome (IBS) cohorts using the flow rates from the placebo treatment period.
Time frame: Day 6 after each treatment period
Population: Per Protocol Population - the population used for the primary and secondary outcome analyses. The population consisted of all randomized subjects who completed the study with MBF measurements for both treatment periods.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| d-IBS Placebo | Left Colon Mucosal Blood Flow (MBF) | 125.6 ml per minute per 100 grams of tissue | Standard Deviation 38.6 |
| d-IBS Alosetron | Left Colon Mucosal Blood Flow (MBF) | 117.5 ml per minute per 100 grams of tissue | Standard Deviation 37.71 |
| Healthy Volunteers Placebo | Left Colon Mucosal Blood Flow (MBF) | 130.7 ml per minute per 100 grams of tissue | Standard Deviation 40.12 |
| Healthy Volunteers Alosetron | Left Colon Mucosal Blood Flow (MBF) | 121.6 ml per minute per 100 grams of tissue | Standard Deviation 51.26 |
p-value: 0.13195% CI: [-18.4, 2.157]paired t-test Hommel-Simes
p-value: 0.13195% CI: [-21.2, 2.997]paired t-test Hommel-Simes
Secondary
Left Colon and Rectal Mucosal Blood Flow Cohort Comparisons
On Day 6 of each treatment period approximately 1 hour after dosing, subjects underwent a flexible sigmoidoscopy with Laser Doppler Flowmetry (LDF) to measure Mucosal Blood Flow (MBF). There was no pre-treatment LDF procedure, MBF was compared between the Healthy and d-IBS cohorts using the flow rates from the placebo treatment period.
Time frame: Day 6 after each treatment period
Population: Population: modified per protocol to include placebo information only.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| d-IBS Placebo | Left Colon and Rectal Mucosal Blood Flow Cohort Comparisons | 135.1 ml per minute per 100 grams of tissue | Standard Deviation 38.6 |
| d-IBS Alosetron | Left Colon and Rectal Mucosal Blood Flow Cohort Comparisons | 178.9 ml per minute per 100 grams of tissue | Standard Deviation 45.52 |
| Healthy Volunteers Placebo | Left Colon and Rectal Mucosal Blood Flow Cohort Comparisons | 149.9 ml per minute per 100 grams of tissue | Standard Deviation 40.12 |
| Healthy Volunteers Alosetron | Left Colon and Rectal Mucosal Blood Flow Cohort Comparisons | 166.6 ml per minute per 100 grams of tissue | Standard Deviation 39.82 |
Secondary
Rectal Mucosal Blood Flow (MBF)
On Day 6 of each treatment period approximately 1 hour after dosing, subjects underwent a flexible sigmoidoscopy with Laser Doppler Flowmetry (LDF) to measure Mucosal Blood Flow (MBF). There was no pre-treatment LDF procedure, MBF was compared between the Healthy and d-IBS cohorts using the flow rates from the placebo treatment period.
Time frame: Day 6 after each treatment period
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| d-IBS Placebo | Rectal Mucosal Blood Flow (MBF) | 173 ml per minute per 100 grams of tissue | Standard Deviation 45.52 |
| d-IBS Alosetron | Rectal Mucosal Blood Flow (MBF) | 159.1 ml per minute per 100 grams of tissue | Standard Deviation 51.73 |
| Healthy Volunteers Placebo | Rectal Mucosal Blood Flow (MBF) | 149.1 ml per minute per 100 grams of tissue | Standard Deviation 39.82 |
| Healthy Volunteers Alosetron | Rectal Mucosal Blood Flow (MBF) | 140.3 ml per minute per 100 grams of tissue | Standard Deviation 56 |