Chronic Constipation, Methanogenesis
Conditions
Brief summary
Lubiprostone, a chloride channel activator, has been shown to improve symptoms of chronic constipation, largely by enhancing chloride-rich intestinal fluid secretion. Whether Lubiprostone has effects on colonic methanogenesis is not known. The investigators hypothesize that the effects of Lubiprostone may in part be due to its effects on altering colonic flora, particularly methanogenic flora. By altering the colonic stasis of stool and through more efficient clearance of digestive residue, the investigators anticipate that Lubiprostone may either inhibit or promote better excretion of methanogenic flora, and thereby decrease the gut load of methane producing bacteria. In turn, this may lead to enhanced colonic smooth muscle contraction and an increased rate of spontaneous bowel movements and reduction of constipation symptoms. The aim is to investigate the effects of Lubiprostone on intestinal methane production and bowel symptoms in patients with chronic constipation, by performing a randomized, double blind, placebo controlled study.
Interventions
DRUGLubiprostone
Colonic transit study performed and stool/symptom diaries will be reviewed. Eligible subjects will be given a lactulose breath test and randomized to Lubiprostone or placebo. Treatment group receives 24 mcg Lubiprostone twice daily and placebo group receives pills (identical in appearance to the study drug) for one month. Subjects will be asked to maintain a daily stool/symptom diary for duration of the study. In the middle of the study a research coordinator will call the subjects to take questions/concerns and record adverse events. Lactulose breath test will be repeated, constipation questionnaire filled out, colon transit study performed.
DRUGLubiprostone Control
Colonic transit study performed and stool/symptom diaries will be reviewed. Eligible subjects will be given a lactulose breath test and randomized to Lubiprostone or placebo. Treatment group receives 24 mcg Lubiprostone twice daily and placebo group receives pills (identical in appearance to the study drug) for one month. Subjects will be asked to maintain a daily stool/symptom diary for duration of the study. In the middle of the study a research coordinator will call the subjects to take questions/concerns and record adverse events. Lactulose breath test will be repeated, constipation questionnaire filled out, colon transit study performed.
Sponsors
Takeda Pharmaceuticals North America, Inc.
Augusta University
Study design
Allocation
RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Constipation as defined by Rome III criteria13. Patients must have symptoms \> 3 days/month for the past three months and report at least two of the following symptoms ≥ 25% of the time: straining, lumpy or hard stool, sensation of incomplete evacuation, sensation of anorectal obstruction/blockage, use of manual maneuvers, \< 3 bowel movements/week. Also,they should have insufficient criteria for IBS, and only rarely loose stools without the use of laxatives. * ≥ 3 ppm methane value at baseline1, 2(before sugar load).
Exclusion criteria
* Patients taking drugs that are known to be constipating will be excluded or asked to discontinue medications for at least 2 weeks and reassessed. For example, we will recommend that patients taking calcium channel antagonists contact their respective primary care physicians to explore alternative medications for hypertension such as beta blockers or ACE-inhibitors. If the calcium channel antagonists are able to be discontinued, patients will be re-screened at least two weeks after the medications are discontinued. If patients no longer meet inclusion criteria, they will be excluded from the study. Patients who remain constipated will be eligible for enrollment. * Patients with co-morbid illnesses such as severe cardiovascular disease, chronic renal failure, or those with previous gastrointestinal surgery except cholecystectomy and appendectomy * Patients with neurologic diseases such as multiple sclerosis, strokes, spinal cord injuries, and those who have problems with cognizance, i.e. a mini-mental score of \<15 and/or are legally blind will be excluded. * Women who are pregnant or are likely to conceive during the course of the study will be excluded. Urinary pregnancy tests will be performed on all women of child-bearing potential prior to enrollment and before any x-ray of the abdomen. * Patients with Hirschsprung' s disease, or active local anorectal problems such as anal fissures, bleeding hemorrhoids, Crohn's, colitis, or colon cancer. * Patients with alternating constipation and diarrhea and those who fulfill the Rome-III criteria for irritable bowel syndrome. * Recent antibiotic use (last 6 weeks). * Patients using laxatives, PEG or Tegaserod and unwilling to discontinue these medications at least 2 weeks prior to the study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Methane Production | Baseline and 1 month | Change in the mean area under the curve of the breath hydrogen and methane gas profiles in parts per million, from time 0 to 120 minutes, between baseline versus mean area under the curve at the end of study. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Stool Frequency (Complete Spontaneous Bowel Movements) | Baseline and 1 month | change in mean stool frequency (delta) between baseline week and final week of study |
| Percentage Change in the Colonic Transit Time | Baseline and 1 month | Percentage change of colonic transit time between the baseline colonic transit study and the colonic transit study at the end of study |
| Peak Methane Value | Baseline and 1 month | The peak methane value measured during the baseline breath study will be compared with the peak methane obtained at the end of study breath test |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Lubiprostone | 29 |
| Placebo | 12 |
| Total | 41 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 2 | 0 |
| Overall Study | Lost to Follow-up | 2 | 0 |
| Overall Study | Withdrawal by Subject | 3 | 0 |
Baseline characteristics
| Characteristic | Placebo | Lubiprostone | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 1 Participants | 3 Participants | 4 Participants |
| Age, Categorical Between 18 and 65 years | 11 Participants | 26 Participants | 37 Participants |
| Age, Continuous | 47.3 years STANDARD_DEVIATION 22.5 | 42.8 years STANDARD_DEVIATION 11.9 | 43.7 years STANDARD_DEVIATION 13.7 |
| Region of Enrollment United States | 12 participants | 29 participants | 41 participants |
| Sex: Female, Male Female | 12 Participants | 25 Participants | 37 Participants |
| Sex: Female, Male Male | 0 Participants | 4 Participants | 4 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 4 / 29 | 0 / 12 |
| serious Total, serious adverse events | 0 / 29 | 0 / 12 |
Outcome results
Primary
Change in Methane Production
Change in the mean area under the curve of the breath hydrogen and methane gas profiles in parts per million, from time 0 to 120 minutes, between baseline versus mean area under the curve at the end of study.
Time frame: Baseline and 1 month
Population: patients who completed the study were analyzed
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Lubiprostone | Change in Methane Production | 10645 parts per million*minutes | Standard Error 1481 |
| Placebo | Change in Methane Production | 14635 parts per million*minutes | Standard Error 2330 |
Secondary
Peak Methane Value
The peak methane value measured during the baseline breath study will be compared with the peak methane obtained at the end of study breath test
Time frame: Baseline and 1 month
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Lubiprostone | Peak Methane Value | 51.3 parts per million | Standard Error 7.1 |
| Placebo | Peak Methane Value | 70.5 parts per million | Standard Error 11.2 |
Secondary
Percentage Change in the Colonic Transit Time
Percentage change of colonic transit time between the baseline colonic transit study and the colonic transit study at the end of study
Time frame: Baseline and 1 month
Population: subjects who completed the study
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Lubiprostone | Percentage Change in the Colonic Transit Time | 0.23 percent | Standard Error 0.06 |
| Placebo | Percentage Change in the Colonic Transit Time | 0.48 percent | Standard Error 0.1 |
Secondary
Stool Frequency (Complete Spontaneous Bowel Movements)
change in mean stool frequency (delta) between baseline week and final week of study
Time frame: Baseline and 1 month
Population: subjects who completed the study
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Lubiprostone | Stool Frequency (Complete Spontaneous Bowel Movements) | 3.71 bowel movements per week | Standard Error 0.84 |
| Placebo | Stool Frequency (Complete Spontaneous Bowel Movements) | 0.85 bowel movements per week | Standard Error 0.54 |