The following datasets contain the data available for EPPT MAY2012-00-01. The description and documentation for each file is listed below. SAS7bdat and CSV versions of the actual data will be available to CDAS projects approved to use this study's data.

Analysis Datasets

Raw Datasets

These 46 datasets contain the raw form data received, excluding PII.

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Trial Summary

Guanylate cyclase C (GUCY2C) is a tumor suppressing receptor silenced by loss of expression of its endogenous luminocrine hormones guanylin and uroguanylin early in colorectal carcinogenesis. This observation suggests oral replacement with a GUCY2C agonist may be an effective targeted chemoprevention agent. Linaclotide is a chemically synthesized, 14-amino acid peptide that is an oral GUCY2C agonist. It is FDA approved to treat different causes of chronic constipation. The approved marketed formulation was designed for gastric release, inducing fluid secretion into the small bowel

This study was performed to evaluate whether a 7-day treatment of oral linaclotide can to induce a pharmacodynamic response in epithelial cells of the colorectum. The study was a placebo controlled trial that was comprised of four stages.

Stage I evaluated whether a single oral daily dose of linaclotide (0.87mg), administered for seven days, would activate cGMP production in the entire length of the colon and rectum. Biopsy samples were obtained by full colonoscopy using a standardized oral bowel preparation.

Stage II explored the ability of that dose to activate rectal GUCY2C (the most distant site for chemoprevention). Biopsy samples were obtained by sigmoidoscopy using a standardized oral bowel preparation.

Stage III explored the ability of that dose to activate rectal GUCY2C in the absence of the oral bowel prep. There was concern that the oral bowel prep might have affected the colonic distribution of linaclotide by accelerating transit through the gastrointestinal tract. Biopsy samples were obtained by sigmoidoscopy using a tap water enema to cleanse the area prior to biopsy.

Stage IV was performed because there was concern that the use of a tap water enema may have adversely affected the analyses, due to its ability to disrupt rectal mucosa. Stage IV explored the ability of that dose to activate rectal GUCY2C in the absence of the oral bowel prep. Biopsy samples were obtained by sigmoidoscopy using a PEG enema to cleanse the area prior to biopsy.

Study Overview

Primary Endpoints

The primary endpoint for all stages was the ability of oral linaclotide to increase cGMP accumulation in colorectal mucosa. The primary endpoint of the study was to identify a dose of linaclotide that produced a 60% response rate for the pharmacodynamic (PD) endpoint (cGMP level) based on rectal samples obtained at screening and post-intervention. The pharmacological effect of linaclotide (or placebo) was calculated as the arithmetic difference in mean cGMP levels in biopsies from the endoscopy before and after 7 days of intervention (linaclotide or placebo) in biopsies from the endoscopy. This represents the change in cGMP stimulated by 7 days of linaclotide in an individual subject. The mean cGMP value was calculated based on 2 biopsies from the rectum assessed at each time point.

Each biopsy was analyzed in triplicate using a commercially available enzyme-linked immunosorbent assay (EIA) kit, so that each subject had 6 cGMP values at each time point. PD responses were calculated as difference in mean cGMP levels after 7 days (the Pharmacological Effect) which is ≥ 0.94 times the baseline pooled intra-subject standard deviation (SD) of cGMP. The intra-subject standard deviation (SD) was calculated based on the 6 cGMP values at baseline.

Cohort size calculations were based on mucosal cGMP data from studies with healthy volunteers(17, 18) and recommendations from a previous Phase 0 study design.(19) This design yielded approximately 89% power to detect a 60% PD response rate at the subject level assuming a 1-sided alpha level of 0.05.(19)

Randomized trial with two arms and 4 Stages (each person was in only 1 stage):

• Arms
  • Arm I: Linaclotide after overnight fast for 7 consecutive days.
  • Arm II: Placebo after overnight fast for 7 consecutive days.
• Stages
  • Stage I: (Colonoscopy) Full colonoscopy prep, Linaclotide/Placebo 0.87mg Days 1-7
  • Stage II: (Sigmoidoscopy) Full colonoscopy prep, Linaclotide/Placebo 0.87mg Days 1-7
  • Stage III: (Sigmoidoscopy) Tap Water Enema prep, Linaclotide/Placebo 0.87mg Days 1-7
  • Stage IV: (Sigmoidoscopy) Peg Enema prep, Linaclotide/Placebo 0.87mg Days 1-7

Expected Enrollment: 54

Enrollment Statistics

Actual Enrollment: 24

• 24 participants randomized (24 of 46 that were pre-registered)
  • 12 administered Linaclotide (12 of 24 randomized)
    • 12 participants completed study (12 of 12)
  • 12 administered Placebo (12 of 24)
    • 12 participants completed study (12 of 12)
• 22 screen failures (22 of 46 pre-registered)
  • 4 participant decision
  • 5 alternates*
  • 4 lost to follow-up**
  • 2 polyps found at baseline
  • 2 proctitis
  • 1 investigator decision
  • 4 other reasons

* Subjects not needed due to full stage accrual by time of eligibility assessment completion.
** Subjects did not show up for sigmoidoscopy

Total Study Population Demographics (24 Randomized and Eligible People):

• Age (years):
  • Median: 48
  • IQR: 45 - 52
• Height (cm):
  • Median: 169
  • IQR: 165 - 175
• Weight (kg):
  • Median: 81
  • IQR: 75 - 90
• Sex
  • Females: 5 (21%)
  • Males: 19 (79%)

Final Analysis Population: 24

Eligibility Criteria

Inclusion Criteria

• Volunteers
• Male and female participants with an age between 18 years and 65 years.
• Ability to understand and willingness to sign a written informed consent document and follow study procedures.
• Willingness to abstain from grapefruit juice, alcohol and concomitant medications during study.
• Willingness to employ adequate contraception for men and women of childbearing potential. Acceptable methods include double barrier methods, intrauterine device (IUD), postmenopausal status documented by serum FSH, and/or documentation of surgical sterilization.
• Willingness to provide blood and tissue specimens for research purposes.
• Body Mass Index <35 kg/m2.
• No personal or first-degree family history of CRC, inflammatory bowel disease or any diseases producing acute/chronic diarrhea
• Tolerated an oral bowel preparation (100g of MoviPrep) and a screening colonoscopy and participants were able to tolerate the bowel prep and anesthesia and no intestinal pathology was found.
• Screening laboratory values (comprehensive metabolic panel, CBC, complete urinalysis, a urinary drug screen, and, if applicable, FSH) within institutional normal range or judged to be not clinically significant by the site PI and medical monitor.
• No findings in the rectum of advanced adenoma, chronic inflammation, or cancer.

Exclusion Criteria

• Documented 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. Exception: Prior appendectomy is not an exclusion criterion.
• History of celiac disease.
• Inflammatory bowel disease (Crohn’s disease, ulcerative colitis).
• 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 sigmoidoscopy 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 of anti-platelet agents within two weeks of anticipated sigmoidoscopy.
• Use of anti-coagulants within two weeks of anticipated sigmoidoscopy.
• History of bleeding/coagulation problems.
• Any medical condition judged by the investigator to constitute a risk to safe participation.
• Sigmoidoscopy finding requiring clinical intervention.
• Use of any illicit or illegal substances detected by urinary drug screen.

The Schema is a timeline of the study. It indicates start/end points, visits expected, major testing to be done, and any other information that is crucial to understanding how the study was completed.

Study Schema

Results/Findings:

The data collected from this study shows that oral linaclotide can regulate guanylate cyclase C in the colorectum only when the GI transit time is decreased by the use of a bowel prep. In absence of the bowel prep, the linaclotide peptide drug is broken down before it reaches the colon. The study suggests that a guanylate cycles C-targeted agent that is formulated for release in the proximal should be evaluated in the next study.