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Linaclotide

Participants receive linaclotide acetate PO QD on days 1-7.

Participants receive placebo PO QD on days 1-7.

linaclotide acetate

placebo

pharmacological study

laboratory biomarker analysis

Paul Limburg

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.

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.

Linaclotide Acetate in Preventing Colorectal Cancer in Healthy Volunteers

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

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.

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.

Summary statistics, frequency tables, and non-parametric tests will be used to describe the distributions of adverse events.

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.

Changes in cGMP levels from baseline to day 6 will also be assessed using summary statistics and nonparametric tests.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Linaclotide Acetate in Preventing Colorectal Cancer in Healthy Volunteers	NCT01950403	Colorectal Canc... Healthy, no Evi...	linaclotide ace... placebo pharmacological... laboratory biom...	18 Years - 65 Years	Mayo Clinic
Linaclotide Acetate in Preventing Colorectal Cancer in Healthy Volunteers	NCT01950403	Colorectal Canc... Healthy, no Evi...	linaclotide ace... placebo pharmacological... laboratory biom...	18 Years - 65 Years	Mayo Clinic

Spots Global Cancer Trial Database for linaclotide acetate