Constipation, Irritable Bowel Syndrome
Conditions
Keywords
IBSC, irritable bowel syndrome, constipation
Brief summary
Irritable bowel syndrome (IBS) is a common disorder which presents with abdominal pain or discomfort in association with altered bowel habit. IBS is further subcategorized as three types according to the predominant bowel movement pattern: IBS with constipation (IBS-C), IBS with diarrhea (IBS-D), and mixed-IBS (IBS-M). The exact causes of IBS remain incompletely understood, but proposed mechanisms include abnormal motility, visceral hypersensitivity, abnormal brain-gut interactions, psychological distress, and altered GI tract motility. Lubiprostone, a novel drug that works by activating the colonic Chloride channel type 2(ClC-2), has been approved for use in patients with chronic idiopathic constipation and recently approved for the treatment of IBS-C in women aged 18 and older. By activating the ClC-2 chloride channel in the colon, lubiprostone allows more fluid secretion into the intestinal lumen which leads to softer stool consistency. In phase III clinical trials, patients with IBS-C receiving lubiprostone have reported improvements in many symptoms such as abdominal pain and constipation. However, there is limited physiologic data to explain how exactly lubiprostone improves IBS-C symptoms. The Smartpill is a novel non-digestible capsule that is capable of measuring intraluminal pH, pressure, and temperature in the gastrointestinal (GI) tract. Smartpill has been shown to accurately measure whole gut as well as regional (i.e. stomach, small bowel, colon) transit time. The primary aim of this study is to determine the effects of lubiprostone on whole GI tract transit, colonic transit, motility, and intraluminal pH in patients with IBS-C through evaluation with the Smartpill. The investigators propose to study the effect of lubiprostone vs. placebo on these parameters, and secondarily to evaluate changes in these parameters with differing doses of lubiprostone. The investigators hypothesize that lubiprostone will increase whole GI and colonic transit compared to placebo in patient with IBS. the investigators do not expect a change in intraluminal pH with lubiprostone compared to placebo.
Interventions
OTHERSmartpill wireless motility capsule
Ingestion of a small non-digestible capsule that measures temperature, pH and pressure of the immediate surrounds as it passes through the GI tract eventually exiting the body through the anus
DRUGLubiprostone
lubiprostone taken either at a dose of 8 mcg orally twice daily (BID) for 28 days or 24 mcg orally once daily (QD) for 28 days
DRUGPlacebo
taken orally for 28 days
Sponsors
Takeda Pharmaceuticals North America, Inc.
University of Michigan
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Males or females \>18 years of age * Meet Rome III criteria for IBS\[2\]: * Recurrent abdominal pain or discomfort at least 3 days per month in the last 3 months associated with 2 or more of the following: 1. Improvement with defecation 2. Onset associated with a change in frequency 3. Onset associated with a change in form (appearance) of stool * \*Criteria fulfilled for the last 3 months with symptom onset at least 6 months prior to diagnosis * Fulfill the Rome III stool consistency criteria for IBS-C\[2\] * Hard or lumpy stools for \>25% of bowel movements * Loose (mushy) or watery stools for \<25% of bowel movements * Capable of independently completing all requirements of the study including returning for required visits * Able to provide written informed consent for study participation * Willing to discontinue prohibited medications during study participation * Documentation of a normal colonoscopy within last 5 years if over age 50 years (or sigmoidoscopy if less than age 50) * Documentation of normal thyroid stimulating hormone(TSH) level, complet blood count (CBC) and electrolyte panel within prior 3 years * Females of childbearing potential must have a negative urine or serum pregnancy test at screening * Females of childbearing potential must use an effective means of contraception during the course of the study * Hormonal (oral, injectable, implantable, cervical/vaginal rings or patches) * Double-barrier (condoms and/or diaphragm with spermicides) or intrauterine devices provided under the care of a health care professional * Abstinence, in this case documentation of counseling will be recorded
Exclusion criteria
* Unable to understand or provide written informed consent * Pregnant or nursing * Patients with IBS-D, IBS-M or unsubtyped IBS by Rome III criteria\[2\] * IBS with diarrhea (IBS-D) 1. Loose (mushy) or watery stools for \>25% of bowel movements 2. Hard or lumpy stools for \<25% of bowel movements * Mixed IBS (IBS-M) 1. Hard or lumpy stools \>25% of bowel movements 2. Loose (mushy) or watery stools for \>25% of bowel movements * Unsubtyped IBS 1\. Insufficient abnormality of stool pattern to meet criteria for IBS-C, IBS-D or IBS-M * Documented allergy or intolerance to lubiprostone * Failure of balloon expulsion test * Inability to expel 50cc balloon within 1 minute * Use of drugs known to affect gastrointestinal motility 1. Laxatives (stable doses of fiber taken for minimum of 4 weeks will be allowed) Osmotic laxatives: Magnesium hydroxide, Polyethylene glycol,Lactulose, Sorbitol Stimulant laxatives: Bisacodyl, Anthraquinones (senna), Misoprostol 2. Prokinetic agents: Metoclopramide, domperidone, erythromycin 3. Anti-diarrheal agents: Loperamide, Diphenoxylate, Bismuth 4. Anti-spasmotics: Dicyclomine, Hyoscyamine 5. Opioid, narcotic, opioid/narcotic-containing analgesics: Morphine, Hydrocodone, Codeine, Methadone, Propoxyphene 6. Probiotics 7. Systemic antibiotics within last 3 months 8. Recently initiated antidepressants (stable dose for \>2 months for non-GI conditions will be allowed) 9. Benzodiazepines \* Subjects taking prohibited medications will be required to stop these at the screening visit and remain off of them until completion of the study. * Initiation of dietary changes potentially altering bowel transit within 4 weeks * Comorbid medical problems that may affect gastrointestinal transit or motility 1. Previous surgery involving the stomach, small bowel or colon (prior appendectomy, cholecystectomy, polypectomy allowed) 2. Previous history of small bowel obstruction for any reason 3. History of any gastrointestinal malignancy 4. History of dyssynergic defecation 5. Unexplained nausea and vomiting 6. History of inflammatory bowel disease (Crohn's or ulcerative colitis) 7. History of microscopic colitis (lymphocytic or collagenous colitis) 8. History of Hirschsprung's disease 9. Severe or complicated diverticular disease 10. Chronic pancreatitis 11. History of celiac disease 12. History of eating disorders (anorexia nervosa or bulimia) 13. Cirrhosis 14. Chronic hepatitis B or C infection 15. HIV infection 16. Diabetes 17. Systemic sclerosis (scleroderma) 18. Amyloidosis 19. Untreated thyroid disease 20. Chronic pulmonary disease 21. Severe renal insufficiency or renal failure 22. Current or recent history (within last 6 months) of: Diverticulitis, Duodenal or gastric ulcer, Acute pancreatitis, Ileus * Contraindications to SmartPill® (in addition to above): Cardiac pacemaker, defibrillator, or other implanted electromagnetic device, Known Zenker's diverticulum, Dysphagia
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Gastric Emptying Time, Small Bowel Transit Time, Colon Transit Time and Whole Gut Transit Time From Baseline | 21-28 days | Change in gastric emptying time, small bowel transit time, colon transit time and whole gut transit time measured in hours based on a measurement done at baseline and then again at 3 weeks into the intervention within each treatment arm |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Small Bowel pH and Colon pH From Baseline | 21-28 days | Change in the mean pH of the small intestine and colon based on a measurement done at baseline and then again at 3 weeks into the intervention. |
| Change in Motility Pattern of the Small Bowel and Colon From Baseline as Defined by the Motility Index | 21-28 days | Change in the motility index defined as the natural log \[(sum of pressure amplitudes times the number of contractions) + 1\] for the small bowel and colon based on a measurement done at baseline and then again at 3 weeks into the intervention. |
Countries
United States
Participant flow
Pre-assignment details
60 adults were screened of whom 4 were screen failures.Of the 56 remaining study participants, 2 were unable to swallow the wireless motility capsule and 2 more dropped out of the study prior to randomization yielding 52 randomized participants.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Placebo: taken orally for 28 days
Smartpill wireless motility capsule: Ingestion of a small non-digestible capsule that measures temperature, pH and pressure of the immediate surrounds as it passes through the GI tract eventually exiting the body through the anus | 17 |
| Lubiprostone 24 mcg QD Lubiprostone: lubiprostone taken either at a dose of 8 mcg orally twice daily for 28 days or 24 mcg orally once daily for 28 days
Smartpill wireless motility capsule: Ingestion of a small non-digestible capsule that measures temperature, pH and pressure of the immediate surrounds as it passes through the GI tract eventually exiting the body through the anus | 16 |
| Lubiprostone 8 mcg BID Lubiprostone: lubiprostone taken either at a dose of 8 mcg orally twice daily for 28 days or 24 mcg orally once daily for 28 days
Smartpill wireless motility capsule: Ingestion of a small non-digestible capsule that measures temperature, pH and pressure of the immediate surrounds as it passes through the GI tract eventually exiting the body through the anus | 17 |
| Total | 50 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 1 | 0 |
| Overall Study | Lack of Efficacy | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | Placebo | Lubiprostone 24 mcg QD | Lubiprostone 8 mcg BID | Total |
|---|---|---|---|---|
| Age, Customized mean age | 39.9 years STANDARD_DEVIATION 16.1 | 46.5 years STANDARD_DEVIATION 18.7 | 37.2 years STANDARD_DEVIATION 15.8 | 41.2 years STANDARD_DEVIATION 17.2 |
| Baseline Colon Motility Index | 16.26 units on a scale STANDARD_DEVIATION 1.57 | 16.9 units on a scale STANDARD_DEVIATION 2.14 | 16.17 units on a scale STANDARD_DEVIATION 1.79 | 16.43 units on a scale STANDARD_DEVIATION 1.83 |
| Baseline Colon pH | 6.56 units on pH scale STANDARD_DEVIATION 0.55 | 6.75 units on pH scale STANDARD_DEVIATION 0.34 | 6.47 units on pH scale STANDARD_DEVIATION 0.48 | 6.50 units on pH scale STANDARD_DEVIATION 0.51 |
| Baseline Colon Transit Time | 32.18 hours STANDARD_DEVIATION 16.46 | 44.61 hours STANDARD_DEVIATION 27.18 | 37.12 hours STANDARD_DEVIATION 30.04 | 38.15 hours STANDARD_DEVIATION 25.31 |
| Baseline gastric emptying time | 4.25 hours STANDARD_DEVIATION 5.52 | 3.18 hours STANDARD_DEVIATION 0.95 | 4.67 hours STANDARD_DEVIATION 3.47 | 4.01 hours STANDARD_DEVIATION 3.74 |
| Baseline Small Bowel Motility Index | 13.14 units on a scale STANDARD_DEVIATION 1.66 | 12.80 units on a scale STANDARD_DEVIATION 1.86 | 12.65 units on a scale STANDARD_DEVIATION 2.26 | 12.86 units on a scale STANDARD_DEVIATION 1.93 |
| Baseline Small Bowel pH | 6.82 units on pH scale STANDARD_DEVIATION 0.28 | 6.75 units on pH scale STANDARD_DEVIATION 0.34 | 6.77 units on pH scale STANDARD_DEVIATION 0.39 | 6.78 units on pH scale STANDARD_DEVIATION 0.33 |
| Baseline Small Bowel Transit time | 4.84 hours STANDARD_DEVIATION 1.69 | 4.01 hours STANDARD_DEVIATION 1.02 | 4.81 hours STANDARD_DEVIATION 2.13 | 4.63 hours STANDARD_DEVIATION 1.75 |
| Baseline Whole Gut Transit Time | 41.47 hours STANDARD_DEVIATION 16.26 | 51.81 hours STANDARD_DEVIATION 26.78 | 47.0 hours STANDARD_DEVIATION 30 | 47.0 hours STANDARD_DEVIATION 24.97 |
| Gender Female | 16 Participants | 15 Participants | 13 Participants | 44 Participants |
| Gender Male | 1 Participants | 1 Participants | 4 Participants | 6 Participants |
| Region of Enrollment United States | 17 participants | 16 participants | 17 participants | 50 participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 9 / 18 | 11 / 17 | 10 / 17 |
| serious Total, serious adverse events | 2 / 18 | 0 / 17 | 0 / 17 |
Outcome results
Primary
Change in Gastric Emptying Time, Small Bowel Transit Time, Colon Transit Time and Whole Gut Transit Time From Baseline
Change in gastric emptying time, small bowel transit time, colon transit time and whole gut transit time measured in hours based on a measurement done at baseline and then again at 3 weeks into the intervention within each treatment arm
Time frame: 21-28 days
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change in Gastric Emptying Time, Small Bowel Transit Time, Colon Transit Time and Whole Gut Transit Time From Baseline | Gastric emptying time | 5.49 hours | Standard Deviation 13.77 |
| Placebo | Change in Gastric Emptying Time, Small Bowel Transit Time, Colon Transit Time and Whole Gut Transit Time From Baseline | Small bowel transit time | 0.2 hours | Standard Deviation 2.04 |
| Placebo | Change in Gastric Emptying Time, Small Bowel Transit Time, Colon Transit Time and Whole Gut Transit Time From Baseline | Colon transit time | 5.75 hours | Standard Deviation 21.23 |
| Placebo | Change in Gastric Emptying Time, Small Bowel Transit Time, Colon Transit Time and Whole Gut Transit Time From Baseline | Whole gut transit time | 10.32 hours | Standard Deviation 27.3 |
| Lubiprostone 24 mcg QD | Change in Gastric Emptying Time, Small Bowel Transit Time, Colon Transit Time and Whole Gut Transit Time From Baseline | Whole gut transit time | -1.74 hours | Standard Deviation 42.67 |
| Lubiprostone 24 mcg QD | Change in Gastric Emptying Time, Small Bowel Transit Time, Colon Transit Time and Whole Gut Transit Time From Baseline | Gastric emptying time | 6.52 hours | Standard Deviation 15.33 |
| Lubiprostone 24 mcg QD | Change in Gastric Emptying Time, Small Bowel Transit Time, Colon Transit Time and Whole Gut Transit Time From Baseline | Colon transit time | -4.43 hours | Standard Deviation 44.6 |
| Lubiprostone 24 mcg QD | Change in Gastric Emptying Time, Small Bowel Transit Time, Colon Transit Time and Whole Gut Transit Time From Baseline | Small bowel transit time | 0.15 hours | Standard Deviation 1.78 |
| Lubiprostone 8 mcg BID | Change in Gastric Emptying Time, Small Bowel Transit Time, Colon Transit Time and Whole Gut Transit Time From Baseline | Whole gut transit time | 1.67 hours | Standard Deviation 29.73 |
| Lubiprostone 8 mcg BID | Change in Gastric Emptying Time, Small Bowel Transit Time, Colon Transit Time and Whole Gut Transit Time From Baseline | Small bowel transit time | -0.001 hours | Standard Deviation 2.68 |
| Lubiprostone 8 mcg BID | Change in Gastric Emptying Time, Small Bowel Transit Time, Colon Transit Time and Whole Gut Transit Time From Baseline | Colon transit time | 2.59 hours | Standard Deviation 31.15 |
| Lubiprostone 8 mcg BID | Change in Gastric Emptying Time, Small Bowel Transit Time, Colon Transit Time and Whole Gut Transit Time From Baseline | Gastric emptying time | -0.16 hours | Standard Deviation 3.17 |
Secondary
Change in Motility Pattern of the Small Bowel and Colon From Baseline as Defined by the Motility Index
Change in the motility index defined as the natural log \[(sum of pressure amplitudes times the number of contractions) + 1\] for the small bowel and colon based on a measurement done at baseline and then again at 3 weeks into the intervention.
Time frame: 21-28 days
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change in Motility Pattern of the Small Bowel and Colon From Baseline as Defined by the Motility Index | Small bowel motility index | 0.06 units on a scale | Standard Deviation 1.37 |
| Placebo | Change in Motility Pattern of the Small Bowel and Colon From Baseline as Defined by the Motility Index | Colon motility index | -0.34 units on a scale | Standard Deviation 1.96 |
| Lubiprostone 24 mcg QD | Change in Motility Pattern of the Small Bowel and Colon From Baseline as Defined by the Motility Index | Small bowel motility index | -0.01 units on a scale | Standard Deviation 1.89 |
| Lubiprostone 24 mcg QD | Change in Motility Pattern of the Small Bowel and Colon From Baseline as Defined by the Motility Index | Colon motility index | -1.32 units on a scale | Standard Deviation 1.97 |
| Lubiprostone 8 mcg BID | Change in Motility Pattern of the Small Bowel and Colon From Baseline as Defined by the Motility Index | Small bowel motility index | 0.6 units on a scale | Standard Deviation 2.36 |
| Lubiprostone 8 mcg BID | Change in Motility Pattern of the Small Bowel and Colon From Baseline as Defined by the Motility Index | Colon motility index | 0.17 units on a scale | Standard Deviation 1.72 |
Secondary
Change in Small Bowel pH and Colon pH From Baseline
Change in the mean pH of the small intestine and colon based on a measurement done at baseline and then again at 3 weeks into the intervention.
Time frame: 21-28 days
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change in Small Bowel pH and Colon pH From Baseline | Small bowel pH | 0.18 pH | Standard Deviation 0.37 |
| Placebo | Change in Small Bowel pH and Colon pH From Baseline | Colon pH | -0.03 pH | Standard Deviation 0.5 |
| Lubiprostone 24 mcg QD | Change in Small Bowel pH and Colon pH From Baseline | Small bowel pH | 0.23 pH | Standard Deviation 0.36 |
| Lubiprostone 24 mcg QD | Change in Small Bowel pH and Colon pH From Baseline | Colon pH | -0.07 pH | Standard Deviation 0.45 |
| Lubiprostone 8 mcg BID | Change in Small Bowel pH and Colon pH From Baseline | Small bowel pH | 0.24 pH | Standard Deviation 0.4 |
| Lubiprostone 8 mcg BID | Change in Small Bowel pH and Colon pH From Baseline | Colon pH | 0.27 pH | Standard Deviation 0.56 |