Second Plecanatide Study In Irritable Bowel Syndrome With Constipation (IBS-C)

This study in patients with IBS-C is a randomized, double-blind, placebo-controlled,
parallel-group clinical trial with 12 weeks of study drug therapy.

Screening/Baseline: Patients will undergo an up to 28-day Screening/Baseline period to allow
for any necessary diagnostic procedures, allow for required washout of medications and to
determine study eligibility. If otherwise eligible based on screening criteria, patients will
undergo a 2-week baseline assessment using an electronic diary where they will record daily
assessments of bowel movements (BMs), stool consistency (Bristol Stool Form Scale-BSFS),
abdominal pain and other IBS-related symptoms. Data from the two-week electronic diary
assessment just prior to the randomization visit will be used to confirm IBS-C and study
eligibility as well as define the patient's baseline from which change will be determined.

Treatment: Patients who meet all entry criteria will be randomized (1:1:1) to one of three
blinded treatment groups on Day 1 of the Treatment period. Patients will take an oral dose of
study drug OD for 12 weeks and continue the daily electronic diaries (BMs, rescue medication
use, abdominal pain, and other symptoms). During treatment weeks 4, 8, and 12, patients will
return to the clinic to undergo safety and efficacy assessments.

Post-Treatment: For 2 weeks after completing dosing, patients will continue to complete daily
electronic diaries. Patients will then return to the clinical site for a final follow-up
visit during Week 14 following randomization.

The planned duration of participation in this study will be at least 116 days from signing of
informed consent through post-treatment or up to approximately 135 days with visit windows
considered.

Inclusion Criteria:

• Adult patients between the ages of 18 and 85 years (inclusive) with a diagnosis of IBS
based on ROME III diagnostic criteria and meeting criteria for diagnosis of the
constipation predominant subtype - IBS-C

Exclusion Criteria:

- Refusal or inability to sign informed consent for the trial

- Refusal or inability to complete daily Episodic (real-time) BM / RM calls, End of Day
daily Calls, and/or complete electronic questionnaires

- BMI ≥ 40 or < 18

- Women of child bearing potential who refuse to use an acceptable method of birth
control for the duration of the trial

- Women who are pregnant or lactating

- Diagnosis of IBS-D or IBS-M

- Organic or obstructive disease of the small or large intestine

- Use of laxatives other than the study-supplied rescue medication (Dulcolax®,
bisacodyl)

- Use of a prohibited concomitant medication within the time frame prior to screening
outlined in the study protocol for that medication

- Unstable medical illness

- Bilirubin > 3X ULN in the absence of a conjugation defect

- Any laboratory value > 3X ULN unless discussed and approved by the study Medical
Monitor