The Plecanatide Chronic Idiopathic Constipation (CIC) Study

This is a Phase IIb/III, randomized, double-blind, placebo-controlled, 12-Week, Repeat, Oral
Dose Ranging, study to determine the safety and efficacy of plecanatide in patients with
chronic idiopathic constipation (CIC). Subjects diagnosed with CIC via modified Rome III
criteria will be screened against the inclusion and exclusion criteria for the study and
enter a 2 Week pre treatment screening. During this phase patients will be required to call
in their bowel movements (BM diary) as they occur, and call at least once daily to complete a
patient diary of questions on their symptoms (Symptom Diary) associated with CC, as they will
throughout the trial. Patients who complete at least 5 days of dosing per week, 6 of each 7
day period of BM diary calls, and continue to have less than 3 complete spontaneous movements
per week (as well as meeting other inclusion and exclusion criteria) will be enrolled and
randomized to one of three plecanatide doses 0.3 mg, 1.0 mg, and 3.0 mg or placebo. 880
patients will be randomized with the intent of having 200 patients per treatment group (each
group the same size) included in efficacy analyses. All subjects receiving at least one dose
of plecanatide or matching placebo will be included in the safety analyses.

Inclusion Criteria:

- Male or female aged 18-75, inclusive

- Body Mass Index = 18-35 kg/m2, inclusive

- Meets modified Rome III criteria for functional chronic idiopathic constipation for at
least 3 months with symptom onset for at least 6 months. Note: For this trial,
patients with manual maneuvers required for >25% of defecations will not be eligible
for participation.

- Less than 3 CSBMs per week at baseline and during pretreatment

- Completed a colonoscopy in accordance with medical guidelines as appropriate, with no
clinically significant findings

- 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 (Bristol score- 6 or 7) 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 treatment period

- Patient meets the Rome III criteria for Irritable Bowel Syndrome (IBS-C)

- 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: 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 within 60 days of screening.