Efficacy and Safety of Plecanatide Comparing With Placebo in the Treatment of Functional Constipation

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.

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.

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)

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.

For weeks 4, 8, and 12 (EOT), the treatment satisfaction question on Patient Global Assessment(PAG) questionnaires will be analyzed separately at each visit using an ANCOVA with fixed effects for gender (stratification variable) and treatment. (Grade 1-5; 1=none, 2=mild, 3=moderate, 4=severe, 5=very severe)

Times to first CSBM and first SBM will be defined as the time from the first dose of study drug to the time of the first SBM and CSBM, respectively. Patients who have not had an SBM will be censored at the time of their first ingestion of rescue medication (not less than 72 hours after first dose of study drug) or at the time of Early Withdrawal, whichever is earlier. The primary analysis of time to first SBM will be to compare each plecanatide treatment versus placebo via a 2-sided log-rank test, stratified by gender. The functions of time to first SBM for each treatment group will be estimated using the K-M product-limit method. Two-sided, 95% CIs for median time to first SBM and other quartiles will be computed, by treatment group. A similar analysis will be done for time to first CSBM

The percentage of patients with a SBM ≤24 hours after first dose will be analyzed using a Cochran-Mantel-Haenszel(test) (CMH) test stratified by gender to test the difference between each plecanatide group and placebo.

The percentage of patients with a CSBM ≤24 hours after first dose will be analyzed using a Cochran-Mantel-Haenszel(test) CMH test stratified by gender to test the difference between each plecanatide group and placebo.

Patient-reported daily symptoms associated with constipation, measured using the 5-point score (0-4 rating), for the Treatment Period will be the average of non-missing patient scores by week, reported during that period. Comparisons will be made of changes from baseline for each parameter between each plecanatide treatment group and placebo, using a linear mixed-effect model under the assumption of normally distributed residuals with treatment group, week, interaction of treatment and week, gender and the corresponding baseline value as fixed effects and random intercept for patient.

Time to use of rescue medication will be defined as the time from the first dose of study drug to the time of the first use of provided rescue medication (Dulcolax®). Patients who haven't taken Dulcolax® will be censored at the time of their last rescue medication assessment or at the time of their Early Withdrawal, whichever is earliest.

Patient Global Assessments include constipation severity, change in constipation symptoms and treatment assessments will be reported at (where applicable) Day 1 Pre-dose, Weeks, 4, 8, and 12 or (End of treatment) EOT and (End of study) EOS. Data will be summarized using descriptive statistics on observed data and change from baseline (where applicable). In addition, each assessment will be analyzed separately at each visit using an ANCOVA with fixed effects for gender (stratification variable) and treatment. In addition, a responder analyses based on change in constipation symptoms will be performed: Patient's response is minimally improved or better (i.e., score ≤ 3), or Patient's response is much improved or better (i.e., score ≤ 2)

Patient's QOL, measured using the 28-item PAC-QOL© questionnaires will be reported at Weeks 4, 8, and 12/EOT, and at the end of the Post-Treatment Period. Comparisons will be made of changes from baseline for the overall average of the 28 items between each plecanatide treatment and placebo using an ANCOVA model with treatment group and gender as fixed-effect terms, and the corresponding baseline value of the parameter as a covariate. The subscale scores (i.e., physical discomfort, psychosocial discomfort, worries/concerns, and satisfaction) will also be analyzed separately. For the measurements reported at the end of the Post-Treatment Period, additional comparisons will be made of changes from Week 12/EOT.

Patient's symptoms, measured using the 12-item Patient Assessment of Constipation Symptoms（PAC-SYM© ）questionnaires will be reported at Weeks 4, 8, and 12 (EOT), and at the end of the Post-Treatment Period. Comparisons will be made of changes from baseline for the overall average of the 12 items between each plecanatide treatment and placebo using an ANCOVA model with treatment group and gender as fixed-effect terms, and the corresponding baseline value of the parameter as a covariate. The individual scores (e.g., discomfort in abdomen, pain in abdomen, etc.) will be also analyzed separately. For the measurements reported at the end of Post-Treatment Period, additional comparisons will be made of changes from Week 12/EOT.