Linaclotide Acetate in Preventing Colorectal Cancer in Healthy Volunteers

Phase I, Randomized, Placebo-Controlled Trial of Linaclotide to Demonstrate Colorectal Bioactivity in Healthy Volunteers

This randomized phase I trial studies the side effects and best dose of linaclotide acetate in preventing colorectal cancer in healthy volunteers. Chemoprevention is the use of certain drugs to keep cancer from forming. The use of linaclotide acetate may prevent colorectal cancer.

Study Overview

• Status: Completed
• Conditions: Colorectal Cancer; Healthy, no Evidence of Disease
• Intervention / Treatment: Other: laboratory biomarker analysis; Other: pharmacological study; Other: placebo; Drug: linaclotide acetate

Detailed Description

PRIMARY OBJECTIVES:

I. To assess the pharmacodynamic effect (PD) of linaclotide (linaclotide acetate) (single daily dose x 7 days, stage I cohort dose= 0.870 mg/day) on cyclic guanosine monophosphate (cGMP) levels, based on biopsy samples obtained pre- and post-intervention from the rectum, until an effect is documented.

SECONDARY OBJECTIVES:

I. To confirm the safety and tolerability of linaclotide. II. To assess the pharmacodynamic effect of linaclotide on cGMP levels, analyzed sequentially from the transverse colon to the cecum, if no cGMP effect was observed in the rectum for the primary endpoint.

III. To compare the change in the cGMP levels from baseline to day 7 between all the assigned doses of linaclotide (including placebo), analyzed sequentially from the rectum, transverse colon, and cecum.

IV. If the study proceeds to stage II, the pharmacodynamic effect of linaclotide on cGMP levels will be assessed from day 6 rectal biopsies (un-prepped).

TERTIARY OBJECTIVES:

I. To assess the pharmacodynamic effect of linaclotide on an additional pathway-specific biomarkers relevant to guanylate cyclase C (GCC) signaling (i.e., vasodilator-stimulated phosphoprotein [VASP] phosphorylation) and a marker of general proliferation (Ki67 expression), based on intestinal mucosa biopsy samples obtained by colonoscopy pre- and post-exposure at the anatomical location (rectum, transverse colon, or cecum) in which cGMP is elevated following linaclotide exposure.

OUTLINE: This is a dose-escalation study. Participants are randomized to 1 of 2 treatment arms.

ARM I: Participants receive linaclotide acetate orally (PO) once daily (QD) on days 1-7.

ARM II: Participants receive placebo PO QD on days 1-7.

After completion of treatment, participants are followed up for 21-51 days.

• Study Type: Interventional
• Enrollment (Actual): 24
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19107
      • Thomas Jefferson University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• PRE-REGISTRATION INCLUSION CRITERIA
• 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 follicle-stimulating hormone (FSH), and/or documentation of surgical sterilization
• Body mass index < 35 kg/m^2
• Willingness to provide blood and tissue specimens for research purposes
• REGISTRATION INCLUSION CRITERIA
• 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

Exclusion Criteria:

• PRE-REGISTRATION EXCLUSION CRITERIA
• Previous personal 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., familial adenomatous polyposis [FAP], hereditary non-polyposis colorectal cancer [HNPCC]) or colorectal cancer (first degree relatives younger than 60 years old)
• History of gastroparesis
• History of surgery involving the luminal gastrointestinal (GI) tract, including bariatric surgery
• 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 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
• REGISTRATION 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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm I (linaclotide acetate); Participants receive linaclotide acetate PO QD on days 1-7.	Other: laboratory biomarker analysis; Correlative studies; Other: pharmacological study; Correlative studies; Other Names: pharmacological studies; Drug: linaclotide acetate; Given PO; Other Names: Linzess; MD-1100 Acetate; MM-416775
Placebo Comparator: Arm II (placebo); Participants receive placebo PO QD on days 1-7.	Other: laboratory biomarker analysis; Correlative studies; Other: pharmacological study; Correlative studies; Other Names: pharmacological studies; Other: placebo; Given PO; Other Names: PLCB

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Dose of linaclotide acetate that produces a 60% response rate for cGMP levels in rectal tissue by radioimmunoassay (RIA)	The pharmacological effect is measured by the arithmetic difference in mean cGMP levels before and after 7 days of linaclotide acetate in biopsies from the colonoscopy. The mean cGMP value will be calculated based on 2 biopsies from the rectum assessed at each time point. The PD response is measured by the difference in mean cGMP levels after 7 days.	Baseline to 7 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of adverse events associated with linaclotide acetate assessed using the Common Terminology Criteria for Adverse Events version 4.0	Summary statistics, frequency tables, and non-parametric tests will be used to describe the distributions of adverse events.	Up to 51 days
PD effect of linaclotide acetate on cGMP levels from the transverse colon to the cecum		Up to 7 days
Change in cGMP levels between all assigned doses, analyzed sequentially from the rectum, transverse colon, and cecum	Summary statistics and nonparametric tests will be used to compare the change in the cGMP levels between the different dose levels of linaclotide acetate and placebo.	Baseline to 7 days
PD effect on cGMP levels (Stage II)	Changes in cGMP levels from baseline to day 6 will also be assessed using summary statistics and nonparametric tests.	Up to 6 days

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
PD effect of linaclotide acetate on GCC signaling (i.e., VASP phosphorylation) and general proliferation (Ki67 expression)	Summary statistics, frequency tables, non-parametric tests, and graphical methods will be used to describe the distributions of cGMP levels relative to linaclotide acetate dose levels and biomarkers. Linear and logistic regression models may also be used as appropriate.	Up to 7 days

Collaborators and Investigators

• Sponsor: Mayo Clinic
• Collaborators: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Paul Limburg, Mayo Clinic

Study record dates

Study Major Dates

• Study Start (Actual): September 1, 2013
• Primary Completion (Actual): April 28, 2016
• Study Completion (Actual): February 22, 2018

Study Registration Dates

• First Submitted: September 23, 2013
• First Submitted That Met QC Criteria: September 23, 2013
• First Posted (Estimated): September 25, 2013

Study Record Updates

• Last Update Posted (Actual): December 9, 2024
• Last Update Submitted That Met QC Criteria: December 4, 2024
• Last Verified: May 1, 2018

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Intestinal Diseases; Gastrointestinal Neoplasms; Digestive System Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Colonic Diseases; Colorectal Neoplasms; Guanylyl Cyclase C Agonists; Molecular Mechanisms of Pharmacological Action; Gastrointestinal Agents; Enzyme Activators; Linaclotide
• Other Study ID Numbers: MAY2012-00-01 (Other Identifier: DCP); N01CN00042 (U.S. NIH Grant/Contract); NCI-2013-01788 (Registry Identifier: CTRP (Clinical Trial Reporting Program)); HHSN2512012000042I; 13-829