Healthy
Conditions
Keywords
lubiprostone, colon, motility, sensation
Brief summary
This study is being done to evaluate the effects of lubiprostone, a drug approved and used for constipation, on pattern of contractions of the colon and the colon's sensitivity to distension.
Detailed description
This was a trial of healthy adults to compare the effects of oral lubiprostone, 24 microgram per day and placebo for three days, on sensation and contractions of the colon using validated methods. On days 1 and 2, participants took the study medication with their breakfast and recorded the time. On day 2 starting at 4:00 pm, participants started a polyethylene glycol-based bowel preparation to cleanse the colon. After overnight bowl preparation, participants reported fasting to the study center at 7:00 am on day 3. Colonic sensorimotor functions were assessed by an endoscopically placed barostat-manometric assembly. After 30 minutes of rest following tube placement, fasting colonic tone, colonic compliance and colonic sensation were tested. The last dose of medication was ingested and 1 hour later the same colonic functions, as well as colonic response to a standardized meal of a 1,000-kilocalorie chocolate milkshake were assessed. The participant was able to leave the study center in the afternoon, after a meal had been ingested (if desired). Details on colonic tube placement: A flexible sigmoidoscopy was performed to evaluate the left side of the colon and to place a Teflon-coated guide wire beyond the splenic flexure. The colon was deflated as the sigmoidoscope was removed and a barostat catheter (constructed at Mayo Clinic, Rochester, MN) with six manometric point sensors and a polyethylene balloon was introduced into the colon over the guide wire. The barostat catheter was positioned in the mid-descending or upper sigmoid colon with the aid of fluoroscopy. The final position of the barostatically controlled balloon was confirmed by fluoroscopy. After the colonic tube placement, participants rested for 30 min. The catheter was connected to a rigid piston barostat machine. After transient inflation of the barostat bag to a volume of 75 ml to ensure it was unfolded, it was deflated. Thereafter, it was inflated in 2 mm Hg increments to baseline operating pressure, which was defined as 2 mm Hg above the minimal distension pressure at which respiratory excursions were clearly recorded by the barostat tracing.
Interventions
DRUGlubiprostone
Lubiprostone 24 micrograms, one dose daily for three days in 30 subjects
DRUGPlacebo
Placebo medication given for three days
OTHERBowel preparation
Polyethylene glycol-based bowel preparation
Sponsors
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
National Center for Research Resources (NCRR)
Takeda
Mayo Clinic
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
Yes
Inclusion criteria
* Healthy subjects * Body mass index (BMI): 18 to 32. * Negative pregnancy test for women of childbearing potential. * Absence of gastrointestinal symptoms (abridged Bowel Disease Questionnaire). * Signed informed consent.
Exclusion criteria
* Subjects with body mass index (BMI) of less than 18 or more than 32. * Structural or metabolic diseases/conditions that affect the gastrointestinal (GI)system, or functional gastrointestinal disorders. For screening, the Bowel Disease Questionnaire will be used to exclude subjects with irritable bowel syndrome. * Use of drugs or agents within the past 2 weeks that alter GI transit including laxatives, magnesium or aluminum-containing antacids, prokinetics, erythromycin, narcotics, anticholinergics, tricyclic antidepressants, SSRI and newer antidepressants. NOTE: Low stable doses of thyroid replacement, estrogen replacement, low dose aspirin for cardioprotection, and birth control pills or depot injections are permissible. * Use of drugs or agents within the 2 weeks prior to screening that may add drowsiness and central nervous system (CNS) depression such as barbiturates, benzodiazepines, ethanol, lithium, opioids, buspirone, antihistamines, muscle relaxants, other CNS depressants. * Female subjects who are pregnant or breast feeding. * Females must be either surgically sterilized, postmenopausal (\>12 months since last menses) or, if of childbearing potential, using reliable methods of contraception as determined by the physician (single-barrier methods alone and rhythm methods are not acceptable). * Clinical evidence (including physical exam and ECG) of significant cardiovascular, respiratory, renal, hepatic, gastrointestinal, hematological, neurological, psychiatric, or other disease that interfere with the objectives of the study. Any candidate participants with such disorder mentioned will be referred to their general physician. * The Hospital Anxiety and Depression Scale (HADS) will be used to exclude subjects with significant affective disorders, as well as to determine anxiety and depression scores at the start of the study. Any candidate participants with such disorder mentioned will be referred to their general physician. * Symptoms of a significant clinical illness in the two weeks prior to screening. * Participation in another clinical study within the 30 days prior to screening. * Subjects who are considered by the investigator to be alcoholics not in remission or known substance abusers.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Pain Sensation Ratings in Response to Colonic Distension at 32 mm HG Above Baseline Operating Pressure | approximately 1 hour after colonic tube placement, on Day 3 | Pain 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. |
| Colonic Compliance | 1 hour after third dose of lubiprostone or placebo, on Day 3 | 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. |
| Fasting Colonic Tone | 30 minutes after the colonic tube placement, on Day 3 | 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). |
| Postprandial Colonic Tone | 30 minutes after standard meal, on Day 3 | 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). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Gas Sensation Ratings in Response to Colonic Distensions at 32 mm Hg Above Baseline Operating Pressure | approximately 1 hour after colonic tube placement, on Day 3 | Gas sensation 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 gas sensation and 100 mm for extreme gas sensation. The investigator measures the mark made by the participant in mm and records this for the value of gas sensation. |
| Median Pressure When First Sensation Was Reported by 50% of Participants | approximately 45 min after colonic tube placement, on Day 3 | 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 mmg 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. |
| Median Pressure When Gas Sensation Was First Reported by 50% of Participants | approximately 45 min after colonic tube placement, on Day 3 | 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 mmg Hg. During this assessment participants were asked to report when they had the first perception of gas. The investigator recorded the threshold pressure at which the participants reported this sensation. |
| Median Pressure When Pain Sensation Was First Reported by 50% of Participants | approximately 45 min after colonic tube placement, on Day 3 | 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 mmg Hg. During this assessment participants were asked to report when they had the first perception of pain. The investigator recorded the threshold pressure at which the participants reported this sensation. |
Countries
United States
Participant flow
Recruitment details
The study was conducted between September 2007 and July 2008 at the Mayo Clinic, Rochester, Minnesota.
Participants by arm
| Arm | Count |
|---|---|
| Lubiprostone Subjects randomized to this arm received 24 micrograms of lubiprostone per day for three days. | 30 |
| Placebo Subjects randomized to this arm received placebo medication for three days. | 30 |
| Total | 60 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Physician Decision | 0 | 2 |
| Overall Study | Withdrawal by Subject | 4 | 0 |
Baseline characteristics
| Characteristic | Lubiprostone | Placebo | Total |
|---|---|---|---|
| Age Continuous | 35.1 years STANDARD_DEVIATION 2.31 | 33.2 years STANDARD_DEVIATION 2.18 | 34.1 years STANDARD_DEVIATION 1.58 |
| Body Mass Index (BMI) | 25.3 kg/m^2 STANDARD_DEVIATION 0.54 | 25.5 kg/m^2 STANDARD_DEVIATION 0.74 | 25.4 kg/m^2 STANDARD_DEVIATION 0.45 |
| Region of Enrollment United States | 30 participants | 30 participants | 60 participants |
| Sex: Female, Male Female | 16 Participants | 15 Participants | 31 Participants |
| Sex: Female, Male Male | 14 Participants | 15 Participants | 29 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 1 / 26 | 2 / 28 |
| serious Total, serious adverse events | 0 / 26 | 0 / 28 |
Outcome results
Primary
Colonic Compliance
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 third dose of lubiprostone or placebo, on Day 3
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Lubiprostone | Colonic Compliance | 16.60 mm Hg | Standard Error 0.817 |
| Placebo | Colonic Compliance | 16.50 mm Hg | Standard Error 0.842 |
Primary
Fasting Colonic Tone
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: 30 minutes after the colonic tube placement, on Day 3
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Lubiprostone | Fasting Colonic Tone | 101.9 mL | Standard Error 7.479 |
| Placebo | Fasting Colonic Tone | 112.8 mL | Standard Error 6.068 |
Primary
Pain Sensation Ratings in Response to Colonic Distension at 32 mm HG Above Baseline Operating Pressure
Pain 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: approximately 1 hour after colonic tube placement, on Day 3
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Lubiprostone | Pain Sensation Ratings in Response to Colonic Distension at 32 mm HG Above Baseline Operating Pressure | 55.2 mm | Standard Error 4.38 |
| Placebo | Pain Sensation Ratings in Response to Colonic Distension at 32 mm HG Above Baseline Operating Pressure | 55.8 mm | Standard Error 4.16 |
Primary
Postprandial Colonic Tone
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: 30 minutes after standard meal, on Day 3
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Lubiprostone | Postprandial Colonic Tone | 78.69 mL | Standard Error 6.202 |
| Placebo | Postprandial Colonic Tone | 75.01 mL | Standard Error 3.492 |
Secondary
Gas Sensation Ratings in Response to Colonic Distensions at 32 mm Hg Above Baseline Operating Pressure
Gas sensation 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 gas sensation and 100 mm for extreme gas sensation. The investigator measures the mark made by the participant in mm and records this for the value of gas sensation.
Time frame: approximately 1 hour after colonic tube placement, on Day 3
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Lubiprostone | Gas Sensation Ratings in Response to Colonic Distensions at 32 mm Hg Above Baseline Operating Pressure | 51.4 mm | Standard Error 4.37 |
| Placebo | Gas Sensation Ratings in Response to Colonic Distensions at 32 mm Hg Above Baseline Operating Pressure | 54.6 mm | Standard Error 4.48 |
Secondary
Median Pressure When First Sensation Was Reported by 50% of Participants
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 mmg 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: approximately 45 min after colonic tube placement, on Day 3
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Lubiprostone | Median Pressure When First Sensation Was Reported by 50% of Participants | 16 mm Hg |
| Placebo | Median Pressure When First Sensation Was Reported by 50% of Participants | 12 mm Hg |
Secondary
Median Pressure When Gas Sensation Was First Reported by 50% of Participants
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 mmg Hg. During this assessment participants were asked to report when they had the first perception of gas. The investigator recorded the threshold pressure at which the participants reported this sensation.
Time frame: approximately 45 min after colonic tube placement, on Day 3
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Lubiprostone | Median Pressure When Gas Sensation Was First Reported by 50% of Participants | 28 mm Hg |
| Placebo | Median Pressure When Gas Sensation Was First Reported by 50% of Participants | 24 mm Hg |
Secondary
Median Pressure When Pain Sensation Was First Reported by 50% of Participants
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 mmg Hg. During this assessment participants were asked to report when they had the first perception of pain. The investigator recorded the threshold pressure at which the participants reported this sensation.
Time frame: approximately 45 min after colonic tube placement, on Day 3
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Lubiprostone | Median Pressure When Pain Sensation Was First Reported by 50% of Participants | 44 mm Hg |
| Placebo | Median Pressure When Pain Sensation Was First Reported by 50% of Participants | 40 mm Hg |