Trial of Linaclotide to Demonstrate Colorectal Bioactivity in Health Volunteers

Study Design Healthy volunteers 18-65 years old, without personal or family (first degree
relative) history of colorectal neoplasia, inflammatory bowel disease or other recent (<3
months prior to day 0) or ongoing disease states producing acute or chronic diarrhea will be
pre-registered in the study. Pre-registered participants will receive a colonoscopy
procedure before receiving the test drug. Only those who have satisfactory anesthesia and
intestinal preparation and who have no significant intestinal pathology will be formally
registered (accrued). During the pre- and post-intervention colonoscopies, 8 biopsies from
each of 3 anatomic sections of intestine, including cecum, transverse colon, and rectum,
will be taken (24 total per participant) at each time point. In stage I, during the
intervention phase, registered participants will receive placebo or linaclotide at doses of
0.870 mg daily for 7 days. If required, in stage II, registered participants will receive
linaclotide at doses of 0.870 mg daily for 6 days followed by 2.900 mg on day 7. There will
be additional rectal biopsies collected on day 6 before bowel preparation for colonoscopy in
stage II patients. Post intervention physical exams, laboratory safety examination, Adverse
Event (AE) monitoring, and questionnaire data will be performed or collected 14 days (+/- 3
days) after the last dose of the assigned study agent.

Target Population Healthy male and female volunteers 18-65 years old, without personal
history of colorectal neoplasia, inflammatory bowel disease or other recent (≤3 months prior
to day 0) or ongoing disease states producing acute or chronic diarrhea will be enrolled.

Sample Size and Duration of Accrual It is expected that up to six participants will be
required in each cohort - five (5) evaluable participants, plus one (1) additional
participant for each cohort to replace participants who drop out or are otherwise not
evaluable. Therefore, it is anticipated that for a maximum enrollment of 18 participants the
study will be completed in approximately 12 months.

Dose Regimen and Dose Groups Each participant will receive a single, oral dose of
linaclotide or placebo for 7 days. It is acceptable to have a single missed dose, with the
exception of the final two doses (Days 6 or 7) since the anoscopy (Day 6, Stage II only)
and colonoscopy (both stages) need to be performed approximately 6 hours after the dose
administration.

Inclusion Criteria:

• Males and Females 18-65 years of age

- Able to understand and willing to sign informed consent and follow study procedures

- Participants must have normal organ function and have normal laboratory findings
without clinically significant findings

- Satisfactory anesthesia and intestinal preparation, with no findings of advanced
adenoma, chronic inflammation, or cancer

- Willing to abstain from grapefruit juice, alcohol, and concomitant medications during
the study

- Willing to employ adequate contraception during the study.

- Body Mass Index (BMI) less than 35 kg/m3

- Willing to provide blood and tissue specimens for research purposes.

Exclusion Criteria:

- Colonoscopic finding requiring clinical intervention

- Use of any illicit or illegal substances detected by urinary drug screen

- Inadequate pre-intervention bowel preparation, as determined by the study physician

- Previous medical history of advanced adenomas (≥1 cm in maximal diameter, ≥ 3 in
total number, villous morphology, or high-grade dysplasia) or colorectal cancer)

- Family history of polyposis syndrome (e.g., FAP, HNPCC) or colorectal cancer (first
degree relatives younger than 60 years old)

- History of gastroparesis

- History of surgery involving the luminal GI tract, including bariatric surgery

- History of celiac disease

- Inflammatory bowel disease

- Irritable bowel syndrome, chronic constipation, functional bowel disorders, or
colonic motility disorder

- Any malignancy within 3 years of baseline. Participants with a history of basal cell
or squamous cell skin cancer may be enrolled at the discretion of the investigator

- Participants may not be receiving any other investigational agents

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to linaclotide

- History of difficulty with colonoscopy or abnormal colorectal anatomy

- Uncontrolled current illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situations that would limit compliance with
study requirements

- Pregnant or lactating women

- Use of laxatives more than 3 times per week

- Intestinal motility agents, histamine-2 inverse agonists (H-2 blockers), or proton
pump inhibitors

- Current use of ≥ 5 cigarettes/day

- Current use of ≥ 3 alcoholic drinks/day

- Use anti-platelet agents within two weeks of anticipated colonoscopy

- Use of anti-coagulants within two weeks of anticipated colonoscopy

- History of bleeding/coagulation problems

- Prior intolerance of or contraindications for the use of sedation or anesthetic
agents, which would prevent the safe use of sedation for colonoscopy. This includes
allergies to eggs and soy products

- Any medical condition judged by the investigator to constitute a risk to safe
participation