GCC Agonist Signal in the Small Intestine

Pilot Study of GCC Agonists to Identify a Cyclic-GMP Signal in Duodenal Tissue of Volunteers

This early phase I trial studies the guanylyl cyclase C (GCC) agonist effect on cGMP signal in duodenal tissue. Plecanatide and linaclotide are drugs approved by the Food and Drug Administration for the treatment of conditions related to constipation. This trial aims to see the effects of taking either one of two drugs, plecanatide or linaclotide, or no drug, on a certain chemical found in the tissue collected from small intestine and how they compare.

Study Overview

• Status: Recruiting
• Conditions: Gastroesophageal Reflux Disease; Barrett Esophagus; Malignant Digestive System Neoplasm
• Intervention / Treatment: Procedure: Biopsy; Drug: Linaclotide; Procedure: Biospecimen Collection; Procedure: Esophagogastroduodenoscopy; Drug: Plecanatide

Detailed Description

PRIMARY OBJECTIVE:

I. To assess and compare participants randomly assigned 1:1:1 to one of three intervention arms (plecanatide 3 mg versus linaclotide 145 mcg versus no active agent) with respect to change in cyclic guanosine monophosphate (cGMP) accumulation in normal appearing duodenal mucosa specimens.

SECONDARY OBJECTIVES:

I. Characterization and comparison of the following outcomes (in prioritized order):

Ia. cGMP levels in luminal fluid from participants receiving either linaclotide or plecanatide to fluid from participants receiving no agent; Ib. Vasodilator stimulated phosphoprotein (VASP) phosphorylation in normal-appearing duodenal mucosa biopsy specimens from participants receiving either linaclotide or plecanatide to those specimens from participants receiving no agent.

EXPLORATORY OBJECTIVES:

I. Comparison of cGMP and VASP phosphorylation between the plecanatide and linaclotide arms.

II. Transcriptome analysis of cellular response (ribonucleic acid [RNA] sequencing analyses) to define whether GCC ligand exposure induces reproducible changes in duodenal messenger [m]RNA expression that can serve as a reliable biomarker of GCC-cGMP signaling in future studies.

OUTLINE: Patients are randomized to 1 of 3 arms.

ARM I: Patients receive a single dose of plecanatide (3 mg) orally (PO) 60-120 minutes prior to standard of care esophagogastroduodenoscopy (EGD) with biopsy and luminal fluid collection. Patients also undergo biopsy on study.

ARM II: Patients receive a single dose of linaclotide (145 mcg) PO 60-120 minutes prior to standard of care EGD with biopsy and luminal fluid collection. Patients also undergo biopsy on study.

ARM III: Patients undergo standard of care EGD with biopsy and luminal fluid collection. Patients also undergo biopsy on study.

After completion of study intervention, patients are followed up at day 7.

• Study Type: Interventional
• Enrollment (Estimated): 43
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Arizona
    • Scottsdale, Arizona, United States, 85259
      • Not yet recruiting
      • Mayo Clinic in Arizona
      • Principal Investigator: Niloy J. Samadder
      • Contact: Niloy J. Samadder; Phone Number: 480-342-6263; Email: sammader.jewel@mayo.edu
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19107
      • Recruiting
      • Thomas Jefferson University Hospital
      • Contact: Scott A. Waldman; Phone Number: 215-955-6086; Email: Scott.waldman@jefferson.edu
      • Principal Investigator: Scott A. Waldman
    • Philadelphia, Pennsylvania, United States, 19111
      • Recruiting
      • Fox Chase Cancer Center
      • Contact: David S. Weinberg; Phone Number: 215-444-1424; Email: David.Weinberg@fccc.edu
      • Principal Investigator: David S. Weinberg
  • Wisconsin
    • Madison, Wisconsin, United States, 53792
      • Not yet recruiting
      • University of Wisconsin Carbone Cancer Center
      • Contact: Howard H. Bailey; Phone Number: 608-263-8624; Email: hhbailey@medicine.wisc.edu
      • Principal Investigator: Howard H. Bailey

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Scheduled for clinically indicated esophagogastroduodenoscopy (EGD)
• Age >= 18 years of age. Note: Because no dosing or adverse event (AE) data are currently available on the use of plecanatide or linaclotide in participants < 18 years of age, children and adolescents are excluded from this study but will be eligible for future pediatric trials, if applicable
• Willing to provide mandatory biospecimens as specified in the protocol
• Eastern Cooperative Oncology Group (ECOG) performance status =< 2
• Not pregnant or breastfeeding, as determined by pregnancy test prior to EGD procedure. Note: The effects of plecanatide and linaclotide on the developing human fetus at the recommended therapeutic dose are unknown. For this reason, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for 2 weeks after discontinuing study agent. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her study physician immediately. Breastfeeding should be discontinued if the mother is treated with plecanatide or linaclotide
• Ability to understand and the willingness to sign a written informed consent document
• Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial
• For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated
• Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load
• Patients on chronic suppressive antiviral therapy for herpes simplex virus (HSV) are eligible

Exclusion Criteria:

• Prior treatment in the past week with plecanatide, linaclotide, or other agent whose primary mechanism of action is that of a GCC agonist
• History of allergic reactions attributed to compounds of similar chemical or biologic composition of plecanatide or linaclotide
• Use of any other investigational agents =< 12 weeks prior to registration
• Uncontrolled intercurrent illness, or psychiatric illness/social situations that would limit compliance with study requirements
• History of gastric bypass, gastric sleeve, or bariatric surgery

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm I (plecanatide, EGD); Patients receive a single dose of plecanatide (3 mg) PO 60-120 minutes prior to standard of care EGD with biopsy and luminal fluid collection.	Procedure: Biopsy; Undergo biopsy; Other Names: Bx; BIOPSY_TYPE; Procedure: Biospecimen Collection; Undergo collection of luminal fluid; Other Names: Biological Sample Collection; Biospecimen Collected; Specimen Collection; Procedure: Esophagogastroduodenoscopy; Undergo EGD; Other Names: EGD; Drug: Plecanatide; Given PO; Other Names: Trulance
Experimental: Arm II (linaclotide, EGD); Patients receive a single dose of linaclotide (145 mcg) PO 60-120 minutes prior to standard of care EGD with biopsy and luminal fluid collection.	Procedure: Biopsy; Undergo biopsy; Other Names: Bx; BIOPSY_TYPE; Drug: Linaclotide; Given PO; Other Names: Linzess; [9-L-tyrosine]heat-stable enterotoxin (Escherichia coli)-(6-19)-peptide; MD-1100; Procedure: Biospecimen Collection; Undergo collection of luminal fluid; Other Names: Biological Sample Collection; Biospecimen Collected; Specimen Collection; Procedure: Esophagogastroduodenoscopy; Undergo EGD; Other Names: EGD
Active Comparator: Arm III (EGD); Patients undergo standard of care EGD with biopsy and luminal fluid collection.	Procedure: Biopsy; Undergo biopsy; Other Names: Bx; BIOPSY_TYPE; Procedure: Biospecimen Collection; Undergo collection of luminal fluid; Other Names: Biological Sample Collection; Biospecimen Collected; Specimen Collection; Procedure: Esophagogastroduodenoscopy; Undergo EGD; Other Names: EGD

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cyclic guanosine monophosphate (cGMP) levels	Will compare cGMP levels measured in normal-appearing duodenal mucosa biopsy specimens from participants receiving linaclotide or plecanatide to cGMP levels in specimens from participants receiving no active treatment. Will evaluate the difference between the control and each treated arm in cGMP levels using two-tailed two-sample Student t-tests. If necessary, a log transformation or Wilcoxon rank-sum will be used, as appropriate.	Up to 2 years

Secondary Outcome Measures

Outcome Measure	Time Frame
cGMP levels in luminal fluid	Up to 2 years
Vasodilator-stimulated phosphoprotein (VASP) phosphorylation in normal appearing duodenal mucosa	Up to 2 years

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Comparison pf cGMP and VASP phosphorylation between the plecanatide and linaclotide arms		Up to 2 years
Cellular response	Transcriptome analysis of cellular response (ribonucleic acid [RNA] sequencing analyses), to define whether guanylyl cyclase C (GCC) ligand exposure induces reproducible changes in duodenal messenger (m)RNA expression that can serve as a reliable biomarker of GCC-cGMP signaling in future studies.	Up to 2 years

Collaborators and Investigators

• Sponsor: National Cancer Institute (NCI)
• Investigators: Principal Investigator: David S Weinberg, Fox Chase Cancer Center

Study record dates

Study Major Dates

• Study Start (Actual): November 30, 2022
• Primary Completion (Estimated): February 1, 2025
• Study Completion (Estimated): February 1, 2025

Study Registration Dates

• First Submitted: November 3, 2021
• First Submitted That Met QC Criteria: November 3, 2021
• First Posted (Actual): November 4, 2021

Study Record Updates

• Last Update Posted (Actual): April 16, 2024
• Last Update Submitted That Met QC Criteria: April 13, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Neoplasms by Site; Gastrointestinal Diseases; Esophageal Motility Disorders; Deglutition Disorders; Esophageal Diseases; Precancerous Conditions; Gastroesophageal Reflux; Gastrointestinal Neoplasms; Digestive System Neoplasms; Barrett Esophagus; Molecular Mechanisms of Pharmacological Action; Gastrointestinal Agents; Guanylyl Cyclase C Agonists; Enzyme Activators; Plecanatide; Linaclotide
• Other Study ID Numbers: NCI-2021-11620 (Registry Identifier: CTRP (Clinical Trial Reporting Program)); P30CA014520 (U.S. NIH Grant/Contract); UG1CA242635 (U.S. NIH Grant/Contract); UWI21-06-01 (Other Identifier: DCP)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: NCI is committed to sharing data in accordance with NIH policy. For more details on how clinical trial data is shared, access the link to the NIH data sharing policy page.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No