Chronic Idiopathic Constipation
Conditions
Keywords
CIC, Constipation, Chronic Constipation, Synergy, Plecanatide
Brief summary
The purpose of this study is to confirm that the investigational medication, plecanatide, is safe and effective in treating chronic idiopathic constipation.
Detailed description
This is a national, randomized, 12-week, double-blind, placebo-controlled, study in approximately 1350 adult male and female patients with CIC comparing 2 doses of plecanatide to placebo. The study will be conducted at approximately 180 clinical study sites in the United States. The primary objective of the study is to evaluate the efficacy and safety of 3.0 and 6.0 mg of plecanatide administered once daily (QD) for 12 weeks in a population of patients with CIC. The study population will include only patients without other causes of constipation or other chronic conditions that could interfere with study assessments. Patients may not take laxatives (with the exception of the study-provided rescue medication, bisacodyl 5mg tablets), or a number of prohibited drugs that are known to cause constipation or diarrhea, during study participation. There are 6 scheduled study visits, including the screening and follow-up visits. The planned duration of participation in this study will be 112 days and up to 155 days, with washout and all visit windows considered.
Interventions
DRUGPlecanatide
DRUGPlacebo
Sponsors
Bausch Health Americas, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
* Male or female aged 18-80, inclusive * Meets modified Rome III criteria for functional chronic idiopathic constipation for at least 3 months with symptom onset for at least 6 months * Completed a colonoscopy in accordance with American Gastroenterological Association (AGA) colon cancer screening guidelines (5 years), with no clinically significant findings * Willing to maintain a stable diet during the study
Exclusion criteria
* Loose stool (mushy) or watery (Bristol score 6 or 7) stool in the absence of any laxative or prohibited medicine for \> 25% of Bowel Movements (BMs) during the 3 months prior to screening visit OR during the 14 day pre-treatment assessment * Active peptic ulcer disease, diabetes or hypertension 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: diseases or conditions associated with constipation (GI or CNS), 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, stroke or myocardial infarction (MI) within 60 days of screening * Participated in a previous plecanatide clinical trial
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Durable Overall CSBM Responders, Mean Replacement Approach | 12-Week Treatment Period | The primary efficacy endpoint was measured by the number of durable overall CSBM responders over the 12-week Treatment Period. A durable overall CSBM responder was defined as a weekly CSBM responder for at least 9 of the 12 treatment weeks, including at least 3 of the last 4 weeks. A CSBM weekly responder was defined as a patient who has ≥ 3 Complete Spontaneous Bowel Movements (CSBMs) per week and an increase from baseline of ≥1 CSBM for that week. A CSBM was a bowel movement that occurred in the absence of laxative use within 24 hours and was associated with the feeling of complete evacuation. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in CSBMs (CSBMs/Week) Over the 12-week Treatment Period , Mean Replacement Approach | Baseline and 12 weeks | The change from baseline in the number of Complete Spontaneous Bowel Movements (CSBMs) over the 12-week Treatment Period was analyzed. Baseline was the mean number of CSBMs recorded during the 2-week baseline diary assessment period prior to the first dose of study drug. A CSBM was a bowel movement that occurred in the absence of laxative use within 24 hours and was associated with the feeling of complete evacuation. |
| Change From Baseline in SBMs (SBMs/Week) Over the 12-week Treatment Period, Mean Replacement Approach | Baseline and 12 weeks | The change from baseline in the number of Spontaneous Bowel Movement (SBM) over the 12-week Treatment Period was analyzed. Baseline was the mean number of SBMs recorded during the 2-week baseline diary assessment period prior to the first dose of study drug. The weekly SBM totals were derived from the daily diary entries reported during the Treatment Period. |
| Change From Baseline in Average Weekly SBM Stool Consistency Over the 12-week Treatment Period, Mean Replacement Approach | Baseline and 12 weeks | The change from baseline in the stool consistency score (i.e. BSFS) over the 12-week Treatment Period was analyzed. Baseline was the mean BSFS score recorded during the 2-week baseline diary assessment period prior to the first dose of study drug. The weekly mean BSFS score per patient was derived from the BSFS entries reported during the Treatment Period in the Daily Symptom Diary. 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 Average Weekly Straining Score Over the 12-week Treatment Period, Mean Replacement Approach | Baseline and 12 weeks | The change from baseline in the straining score over the 12-week Treatment Period was analyzed. Baseline was the mean of non-missing straining scores recorded during the 2-week baseline diary assessment period prior to the first dose of study drug. The weekly average straining score was derived from the straining scores reported during the Treatment Period in the Daily Symptom Diary. The severity of straining during bowel movements was assessed on a 5-point Likert scale where 0 = none, 1 = mild, 2 = moderate, 3 = severe, and 4 = very severe. |
Countries
United States
Participant flow
Pre-assignment details
The data are correct and approved in the NDA. 1410 randomized subj.including 95 (index and non-index) duplicate subj. The index subj (22) were duplicate appeared the first time in the study and the same subject appeared in other studies or sites were non-index duplicate (73) who were excluded in the ITT population (1337).
Participants by arm
| Arm | Count |
|---|---|
| Placebo Matching placebo tablets QD for 12 weeks | 445 |
| Plecanatide 3 mg Plecanatide tablets 3 mg QD for 12 weeks | 443 |
| Plecanatide 6 mg Plecanatide tablets 6 mg QD for 12 weeks | 449 |
| Total | 1,337 |
Baseline characteristics
| Characteristic | Placebo | Plecanatide 3 mg | Plecanatide 6 mg | Total |
|---|---|---|---|---|
| Age, Continuous | 44.6 years STANDARD_DEVIATION 14.59 | 45.5 years STANDARD_DEVIATION 14.38 | 45.3 years STANDARD_DEVIATION 14.47 | 45.1 years STANDARD_DEVIATION 14.47 |
| Sex: Female, Male Female | 350 Participants | 345 Participants | 353 Participants | 1048 Participants |
| Sex: Female, Male Male | 95 Participants | 98 Participants | 96 Participants | 289 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 | 15 / 466 | 25 / 467 | 31 / 469 |
| serious Total, serious adverse events | 8 / 466 | 8 / 467 | 4 / 469 |
Outcome results
Primary
Number of Durable Overall CSBM Responders, Mean Replacement Approach
The primary efficacy endpoint was measured by the number of durable overall CSBM responders over the 12-week Treatment Period. A durable overall CSBM responder was defined as a weekly CSBM responder for at least 9 of the 12 treatment weeks, including at least 3 of the last 4 weeks. A CSBM weekly responder was defined as a patient who has ≥ 3 Complete Spontaneous Bowel Movements (CSBMs) per week and an increase from baseline of ≥1 CSBM for that week. A CSBM was a bowel movement that occurred in the absence of laxative use within 24 hours and was associated with the feeling of complete evacuation.
Time frame: 12-Week Treatment Period
Population: The modified ITT population (1310 subjects) for primary outcome was ITT population minus 27 subjects eliminated from two OAI sites. The ITT population (1337) as described in the Participate Flow consisted of the randomized subjects (1410) excluding 73 non-index subjects. Index subjects were duplicate subjects appeared once in the ITT population.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Number of Durable Overall CSBM Responders, Mean Replacement Approach | 57 Participants |
| Plecanatide 3 mg | Number of Durable Overall CSBM Responders, Mean Replacement Approach | 88 Participants |
| Plecanatide 6 mg | Number of Durable Overall CSBM Responders, Mean Replacement Approach | 88 Participants |
Secondary
Change From Baseline in Average Weekly SBM Stool Consistency Over the 12-week Treatment Period, Mean Replacement Approach
The change from baseline in the stool consistency score (i.e. BSFS) over the 12-week Treatment Period was analyzed. Baseline was the mean BSFS score recorded during the 2-week baseline diary assessment period prior to the first dose of study drug. The weekly mean BSFS score per patient was derived from the BSFS entries reported during the Treatment Period in the Daily Symptom Diary. 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: Baseline and 12 weeks
Population: A total of 1288 patients included in ITT-E population for secondary outcome which consisted of the randomized subjects (1410) excluding 95 duplicate subjects as described in the Participate Flow and 27 subjects eliminated from two OAI sites.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change From Baseline in Average Weekly SBM Stool Consistency Over the 12-week Treatment Period, Mean Replacement Approach | Baseline | 2.35 score on a scale | Standard Deviation 1.09 |
| Placebo | Change From Baseline in Average Weekly SBM Stool Consistency Over the 12-week Treatment Period, Mean Replacement Approach | 12 weeks | 1.02 score on a scale | Standard Deviation 1.346 |
| Plecanatide 3 mg | Change From Baseline in Average Weekly SBM Stool Consistency Over the 12-week Treatment Period, Mean Replacement Approach | Baseline | 2.16 score on a scale | Standard Deviation 1.036 |
| Plecanatide 3 mg | Change From Baseline in Average Weekly SBM Stool Consistency Over the 12-week Treatment Period, Mean Replacement Approach | 12 weeks | 1.71 score on a scale | Standard Deviation 1.475 |
| Plecanatide 6 mg | Change From Baseline in Average Weekly SBM Stool Consistency Over the 12-week Treatment Period, Mean Replacement Approach | Baseline | 2.27 score on a scale | Standard Deviation 1.113 |
| Plecanatide 6 mg | Change From Baseline in Average Weekly SBM Stool Consistency Over the 12-week Treatment Period, Mean Replacement Approach | 12 weeks | 1.59 score on a scale | Standard Deviation 1.497 |
Secondary
Change From Baseline in Average Weekly Straining Score Over the 12-week Treatment Period, Mean Replacement Approach
The change from baseline in the straining score over the 12-week Treatment Period was analyzed. Baseline was the mean of non-missing straining scores recorded during the 2-week baseline diary assessment period prior to the first dose of study drug. The weekly average straining score was derived from the straining scores reported during the Treatment Period in the Daily Symptom Diary. The severity of straining during bowel movements was assessed on a 5-point Likert scale where 0 = none, 1 = mild, 2 = moderate, 3 = severe, and 4 = very severe.
Time frame: Baseline and 12 weeks
Population: A total of 1288 patients included in ITT-E population for secondary outcome which consisted of the randomized subjects (1410) excluding 95 duplicate subjects as described in the Participate Flow and 27 subjects eliminated from two OAI sites.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change From Baseline in Average Weekly Straining Score Over the 12-week Treatment Period, Mean Replacement Approach | Baseline | 2.42 score on a scale | Standard Deviation 0.855 |
| Placebo | Change From Baseline in Average Weekly Straining Score Over the 12-week Treatment Period, Mean Replacement Approach | 12 weeks | -0.79 score on a scale | Standard Deviation 1.132 |
| Plecanatide 3 mg | Change From Baseline in Average Weekly Straining Score Over the 12-week Treatment Period, Mean Replacement Approach | Baseline | 2.46 score on a scale | Standard Deviation 0.859 |
| Plecanatide 3 mg | Change From Baseline in Average Weekly Straining Score Over the 12-week Treatment Period, Mean Replacement Approach | 12 weeks | -1.09 score on a scale | Standard Deviation 1.092 |
| Plecanatide 6 mg | Change From Baseline in Average Weekly Straining Score Over the 12-week Treatment Period, Mean Replacement Approach | Baseline | 2.47 score on a scale | Standard Deviation 0.888 |
| Plecanatide 6 mg | Change From Baseline in Average Weekly Straining Score Over the 12-week Treatment Period, Mean Replacement Approach | 12 weeks | -1.04 score on a scale | Standard Deviation 1.084 |
Secondary
Change From Baseline in CSBMs (CSBMs/Week) Over the 12-week Treatment Period , Mean Replacement Approach
The change from baseline in the number of Complete Spontaneous Bowel Movements (CSBMs) over the 12-week Treatment Period was analyzed. Baseline was the mean number of CSBMs recorded during the 2-week baseline diary assessment period prior to the first dose of study drug. A CSBM was a bowel movement that occurred in the absence of laxative use within 24 hours and was associated with the feeling of complete evacuation.
Time frame: Baseline and 12 weeks
Population: A total of 1288 patients included in ITT-E population for secondary outcome which consisted of the randomized subjects (1410) excluding 95 duplicate subjects as described in the Participate Flow and 27 subjects eliminated from two OAI sites.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change From Baseline in CSBMs (CSBMs/Week) Over the 12-week Treatment Period , Mean Replacement Approach | Baseline | 1.41 CSBMs per week | Standard Error 0.138 |
| Placebo | Change From Baseline in CSBMs (CSBMs/Week) Over the 12-week Treatment Period , Mean Replacement Approach | 12 weeks | 1.69 CSBMs per week | Standard Error 0.159 |
| Plecanatide 3 mg | Change From Baseline in CSBMs (CSBMs/Week) Over the 12-week Treatment Period , Mean Replacement Approach | Baseline | 2.34 CSBMs per week | Standard Error 0.139 |
| Plecanatide 3 mg | Change From Baseline in CSBMs (CSBMs/Week) Over the 12-week Treatment Period , Mean Replacement Approach | 12 weeks | 2.66 CSBMs per week | Standard Error 0.162 |
| Plecanatide 6 mg | Change From Baseline in CSBMs (CSBMs/Week) Over the 12-week Treatment Period , Mean Replacement Approach | Baseline | 2.19 CSBMs per week | Standard Error 0.138 |
| Plecanatide 6 mg | Change From Baseline in CSBMs (CSBMs/Week) Over the 12-week Treatment Period , Mean Replacement Approach | 12 weeks | 2.50 CSBMs per week | Standard Error 0.159 |
Secondary
Change From Baseline in SBMs (SBMs/Week) Over the 12-week Treatment Period, Mean Replacement Approach
The change from baseline in the number of Spontaneous Bowel Movement (SBM) over the 12-week Treatment Period was analyzed. Baseline was the mean number of SBMs recorded during the 2-week baseline diary assessment period prior to the first dose of study drug. The weekly SBM totals were derived from the daily diary entries reported during the Treatment Period.
Time frame: Baseline and 12 weeks
Population: A total of 1288 patients included in ITT-E population for secondary outcome which consisted of the randomized subjects (1410) excluding 95 duplicate subjects as described in the Participate Flow and 27 subjects eliminated from two OAI sites.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change From Baseline in SBMs (SBMs/Week) Over the 12-week Treatment Period, Mean Replacement Approach | Baseline | 1.55 SBMs per week | Standard Deviation 1.591 |
| Placebo | Change From Baseline in SBMs (SBMs/Week) Over the 12-week Treatment Period, Mean Replacement Approach | 12 weeks | 1.81 SBMs per week | Standard Deviation 2.879 |
| Plecanatide 3 mg | Change From Baseline in SBMs (SBMs/Week) Over the 12-week Treatment Period, Mean Replacement Approach | Baseline | 1.79 SBMs per week | Standard Deviation 2.084 |
| Plecanatide 3 mg | Change From Baseline in SBMs (SBMs/Week) Over the 12-week Treatment Period, Mean Replacement Approach | 12 weeks | 3.25 SBMs per week | Standard Deviation 3.938 |
| Plecanatide 6 mg | Change From Baseline in SBMs (SBMs/Week) Over the 12-week Treatment Period, Mean Replacement Approach | 12 weeks | 3.10 SBMs per week | Standard Deviation 4.164 |
| Plecanatide 6 mg | Change From Baseline in SBMs (SBMs/Week) Over the 12-week Treatment Period, Mean Replacement Approach | Baseline | 1.63 SBMs per week | Standard Deviation 1.673 |