Irritable Bowel Syndrome Characterized by Constipation
Conditions
Brief summary
This is a randomized, 12-week, double-blind, placebo-controlled, dose-ranging study in patients with IBS-C.
Detailed description
This is a randomized, 12-week, double-blind, placebo-controlled, dose-ranging study in patients with IBS-C. Patients will undergo a Screening Period to determine eligibility. After completing a Screening Visit patients will undergo a 2-week Pre-Treatment assessment using the Interactive Voice Response System (IVRS) during which they will complete daily assessments of bowel movements (BMs), stool consistency (Bristol Stool Form Scale- BSFS), abdominal pain or abdominal discomfort and other symptoms associated with IBS-C. Data from the two-week IVRS Pre-treatment assessment are used to define the patient's baseline from which change will be determined. Patients who meet all entry criteria will be randomized to one of five treatment groups ( 0.3mg,1.0mg,3.0mg,9mg,or Placebo) on Day 1 of the Treatment Period. Patients will take an oral dose of study drug daily (QD) for 12 weeks and continue the daily IVRS diaries (BMs, abdominal pain, other symptoms). On Weeks 2, 4, 8, and 12, patients will return to the clinic to undergo safety and efficacy assessments. For 2 weeks after completing dosing, (i.e., Post-Treatment Period), patients will continue to complete daily IVRS diaries. Patients will then return to the clinical site for a final follow-up visit (End of Study Visit). The planned duration of participation in this study will be approximately 112 days from signing of informed consent through post-treatment or 145 days if 30 day washout of a prohibited concomitant medication or stabilization of a medical condition is required before Pre-Treatment (up to 148 days, with all windows considered).
Interventions
DRUGPlecanatide
DRUGPlacebo
Sponsors
Bausch Health Americas, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* Male or female aged 18-75, inclusive * Body Mass Index = 18-35 kg/m2, inclusive * Meets modified Rome III criteria for irritable bowel syndrome with constipation which includes abdominal pain or discomfort for at least 3 days/month in the last 3 months with symptom onset for at least 6 months. * Less than 3 CSBMs and less than 6 SBMs per week during the last 3 months. * Hard or lumpy stools ≥ 25 % of defecations * Patient has average abdominal pain intensity scores ≥ 3 (scale 0-10)for the combined 2 week pre-treatment period * Patient is willing to discontinue use of supplemental fiber, laxatives, prescription and nonprescription medications, herbal or dietary supplements intended to treat constipation during the screening, pre-treatment, treatment and 2-week post-treatment periods * Willing to maintain a stable diet during the study. * Patients with hemorrhoids and/or diverticulosis (NOT diverticulitis) CAN be entered into the study.
Exclusion criteria
* Loose stool (mushy) or watery stool in the absence of any laxative or prohibited medicine for \> 25% of BMs during the 3 months prior to screening visit OR during the 14 day pre-treatment period * Patient has diarrhea-predominant or mixed ( diarrhea and constipation cycling or diarrhea and normal cycling) IBS. * Active peptic ulcer disease not adequately treated or not stable * History of cathartic colon, laxative, enema abuse, or ischemic colitis. * Fecal impaction within 3 months of screening * Patient has had /has any: structural abnormality of the GI tract or gastric bypass surgery, pelvic floor dysfunction, pseudo-obstruction, active infectious gastritis, diverticulitis, anal fissures or any disease or condition that can affect GI motility or defecation or can be associated with abdominal pain * Unexplained and clinically significant alarm symptoms including lower GI bleeding, iron-deficiency anemia, weight loss or systemic signs of infection or colitis. * Major surgery within 60 days of screening.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Weekly CSBMs Frequency Over the 12-Week Treatment Period (mITT Population) | 12 weeks Treatment Period | The primary efficacy endpoint was the change from baseline in the weekly CSBM frequency (CSBMs per week minus CSBMs per week at baseline) over a 12-week Treatment Period. A Complete Spontaneous Bowel Movement (CSBM) is a Bowel Movement (BM) that occurs in the absence of laxative use within 24 hours of the BM and the patient reports a feeling of complete evacuation. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Abdominal Pain Intensity Scores Over 12-Week Treatment Period (mITT Population) | 12-Week Treatment Period | Abdominal Pain was assessed in the patient's daily response on a scale of 0 to 10 where 0 is did not experience the symptom at all and 10 is experienced the worst. |
| Change From Baseline in Stool Consistency (BSFS) Over 12-Week Treatment Period (mITT Population) | 12-Week Treatment Period | The stool consistency of each bowel movement (BM) was assessed by patients using the 7-point Bristol Stool Form Scale \[BSFS\] from 1 to 7. 1. = separate hard lumps like nuts (difficult to pass) 2. = sausage shaped but lumpy 3. = like a sausage but with cracks on its surface 4. = like a sausage or snake, smooth and soft 5. = soft blobs with clear-cut edges (passed easily) 6. = fluffy pieces with ragged edges, a mushy stool 7. = watery, no solid pieces (entirely liquid) |
| Change From Baseline in Straining Scores Over 12-Week Treatment Period (mITT Population) | 12-Week Treatment Period | The severity of straining (Straining Score) was rated by the patients using a 11-point scale (0-10) where 0 = none and 10 = very severe |
Countries
United States
Participant flow
Pre-assignment details
The Enrollment number in the Protocol Section was changed from 350 to 428 participants to reflect the actual enrollment number.
Participants by arm
| Arm | Count |
|---|---|
| Plecanatide 0.3mg Plecanatide 0.3mg, one tablet by mouth daily for 12 weeks
Plecanatide | 84 |
| Plecanatide 1.0mg Plecanatide 1.0mg one tablet by mouth daily for 12 weeks
Plecanatide | 83 |
| Plecanatide 3.0mg Plecanatide 3.0mg, one tablet by mouth daily for 12 weeks
Plecanatide | 86 |
| Plecanatide 9.0mg Plecanatide 9.0mg, one tablet by mouth daily for 12 weeks
Plecanatide | 85 |
| Placebo Placebo, one tablet by mouth daily for 12 weeks
Placebo | 85 |
| Total | 423 |
Baseline characteristics
| Characteristic | Plecanatide 0.3mg | Plecanatide 1.0mg | Plecanatide 3.0mg | Plecanatide 9.0mg | Placebo | Total |
|---|---|---|---|---|---|---|
| Age, Continuous | 47.2 years STANDARD_DEVIATION 12.02 | 44.6 years STANDARD_DEVIATION 12.58 | 47.2 years STANDARD_DEVIATION 12.89 | 45.3 years STANDARD_DEVIATION 12 | 45.4 years STANDARD_DEVIATION 12.02 | 45.9 years STANDARD_DEVIATION 12.3 |
| Sex: Female, Male Female | 68 Participants | 67 Participants | 70 Participants | 70 Participants | 69 Participants | 344 Participants |
| Sex: Female, Male Male | 16 Participants | 16 Participants | 16 Participants | 15 Participants | 16 Participants | 79 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 18 / 85 | 29 / 85 | 19 / 86 | 31 / 85 | 12 / 86 |
| serious Total, serious adverse events | 1 / 85 | 0 / 85 | 1 / 86 | 2 / 85 | 0 / 86 |
Outcome results
Primary
Change From Baseline in Weekly CSBMs Frequency Over the 12-Week Treatment Period (mITT Population)
The primary efficacy endpoint was the change from baseline in the weekly CSBM frequency (CSBMs per week minus CSBMs per week at baseline) over a 12-week Treatment Period. A Complete Spontaneous Bowel Movement (CSBM) is a Bowel Movement (BM) that occurs in the absence of laxative use within 24 hours of the BM and the patient reports a feeling of complete evacuation.
Time frame: 12 weeks Treatment Period
Population: The Modified Intent-to-Treat (mITT) population included all randomized patients who received ≥ 1 dose of study drug and ≥ 1 post-baseline BM assessment was the primary analysis population analyzed for efficacy endpoints.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Plecanatide 0.3mg | Change From Baseline in Weekly CSBMs Frequency Over the 12-Week Treatment Period (mITT Population) | 1.28 CSBMs per week | Standard Error 0.26 |
| Plecanatide 1.0mg | Change From Baseline in Weekly CSBMs Frequency Over the 12-Week Treatment Period (mITT Population) | 2.12 CSBMs per week | Standard Error 0.265 |
| Plecanatide 3.0mg | Change From Baseline in Weekly CSBMs Frequency Over the 12-Week Treatment Period (mITT Population) | 2.74 CSBMs per week | Standard Error 0.26 |
| Plecanatide 9.0mg | Change From Baseline in Weekly CSBMs Frequency Over the 12-Week Treatment Period (mITT Population) | 2.44 CSBMs per week | Standard Error 0.262 |
| Placebo | Change From Baseline in Weekly CSBMs Frequency Over the 12-Week Treatment Period (mITT Population) | 1.27 CSBMs per week | Standard Error 0.26 |
Secondary
Change From Baseline in Abdominal Pain Intensity Scores Over 12-Week Treatment Period (mITT Population)
Abdominal Pain was assessed in the patient's daily response on a scale of 0 to 10 where 0 is did not experience the symptom at all and 10 is experienced the worst.
Time frame: 12-Week Treatment Period
Population: The mITT population included all randomized patients who received at least 1 dose of study drug and who had at least 1 post-baseline Bowel Movement (BM) assessment was the primary analysis population for efficacy endpoints.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Plecanatide 0.3mg | Change From Baseline in Abdominal Pain Intensity Scores Over 12-Week Treatment Period (mITT Population) | -1.5 scores on a scale | Standard Error 0.2 |
| Plecanatide 1.0mg | Change From Baseline in Abdominal Pain Intensity Scores Over 12-Week Treatment Period (mITT Population) | -1.5 scores on a scale | Standard Error 0.2 |
| Plecanatide 3.0mg | Change From Baseline in Abdominal Pain Intensity Scores Over 12-Week Treatment Period (mITT Population) | -2.0 scores on a scale | Standard Error 0.2 |
| Plecanatide 9.0mg | Change From Baseline in Abdominal Pain Intensity Scores Over 12-Week Treatment Period (mITT Population) | -1.8 scores on a scale | Standard Error 0.2 |
| Placebo | Change From Baseline in Abdominal Pain Intensity Scores Over 12-Week Treatment Period (mITT Population) | -1.4 scores on a scale | Standard Error 0.2 |
Secondary
Change From Baseline in Stool Consistency (BSFS) Over 12-Week Treatment Period (mITT Population)
The stool consistency of each bowel movement (BM) was assessed by patients using the 7-point Bristol Stool Form Scale \[BSFS\] from 1 to 7. 1. = separate hard lumps like nuts (difficult to pass) 2. = sausage shaped but lumpy 3. = like a sausage but with cracks on its surface 4. = like a sausage or snake, smooth and soft 5. = soft blobs with clear-cut edges (passed easily) 6. = fluffy pieces with ragged edges, a mushy stool 7. = watery, no solid pieces (entirely liquid)
Time frame: 12-Week Treatment Period
Population: The Modified Intent-to-Treat (mITT) population included all randomized patients who received ≥ 1 dose of study drug and ≥ 1 post-baseline BM assessment was the primary analysis population analyzed for efficacy endpoints.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Plecanatide 0.3mg | Change From Baseline in Stool Consistency (BSFS) Over 12-Week Treatment Period (mITT Population) | 1.63 scores on a scale | Standard Error 0.143 |
| Plecanatide 1.0mg | Change From Baseline in Stool Consistency (BSFS) Over 12-Week Treatment Period (mITT Population) | 1.81 scores on a scale | Standard Error 0.144 |
| Plecanatide 3.0mg | Change From Baseline in Stool Consistency (BSFS) Over 12-Week Treatment Period (mITT Population) | 2.49 scores on a scale | Standard Error 0.143 |
| Plecanatide 9.0mg | Change From Baseline in Stool Consistency (BSFS) Over 12-Week Treatment Period (mITT Population) | 2.24 scores on a scale | Standard Error 0.145 |
| Placebo | Change From Baseline in Stool Consistency (BSFS) Over 12-Week Treatment Period (mITT Population) | 1.01 scores on a scale | Standard Error 0.143 |
Secondary
Change From Baseline in Straining Scores Over 12-Week Treatment Period (mITT Population)
The severity of straining (Straining Score) was rated by the patients using a 11-point scale (0-10) where 0 = none and 10 = very severe
Time frame: 12-Week Treatment Period
Population: The Modified Intent-to-Treat (mITT) population included all randomized patients who received ≥ 1 dose of study drug and ≥ 1 post-baseline BM assessment was the primary analysis population analyzed for efficacy endpoints.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Plecanatide 0.3mg | Change From Baseline in Straining Scores Over 12-Week Treatment Period (mITT Population) | -1.7 score on a scale | Standard Error 0.23 |
| Plecanatide 1.0mg | Change From Baseline in Straining Scores Over 12-Week Treatment Period (mITT Population) | -1.5 score on a scale | Standard Error 0.23 |
| Plecanatide 3.0mg | Change From Baseline in Straining Scores Over 12-Week Treatment Period (mITT Population) | -2.2 score on a scale | Standard Error 0.23 |
| Plecanatide 9.0mg | Change From Baseline in Straining Scores Over 12-Week Treatment Period (mITT Population) | -2.1 score on a scale | Standard Error 0.24 |
| Placebo | Change From Baseline in Straining Scores Over 12-Week Treatment Period (mITT Population) | -1.3 score on a scale | Standard Error 0.23 |