GCC Agonist Signal in the Small Intestine
Study Details
Study Description
Brief Summary
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.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Early Phase 1 |
Detailed Description
PRIMARY OBJECTIVE:
- 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:
-
Comparison of cGMP and VASP phosphorylation between the plecanatide and linaclotide arms.
-
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 served 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).
ARM II: Patients receive a single dose of linaclotide (145 mcg) PO 60-120 minutes prior to standard of care EGD.
ARM III: Patients undergo standard of care EGD.
Study Design
Arms and Interventions
| 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. |
Procedure: Esophagogastroduodenoscopy
Undergo EGD
Other Names:
Drug: Plecanatide
Given PO
Other Names:
|
| Experimental: Arm II (linaclotide, EGD) Patients receive a single dose of linaclotide (145 mcg) PO 60-120 minutes prior to standard of care EGD. |
Procedure: Esophagogastroduodenoscopy
Undergo EGD
Other Names:
Drug: Linaclotide
Given PO
Other Names:
|
| Active Comparator: Arm III (EGD) Patients undergo standard of care EGD. |
Procedure: Esophagogastroduodenoscopy
Undergo EGD
Other Names:
|
Outcome Measures
Primary Outcome Measures
- Cyclic guanosine monophosphate (cGMP) levels [Up to 2 years]
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.
Secondary Outcome Measures
- 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
- Comparison pf cGMP and VASP phosphorylation between the plecanatide and linaclotide arms [Up to 2 years]
- Cellular response [Up to 2 years]
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.
Eligibility Criteria
Criteria
Inclusion Criteria:
-
Scheduled for clinically indicated esophagogastroduodenoscopy (EGD) for diagnosis of possible non-duodenal malignancies, for surveillance of Barrett's esophagus, or for reflux, abdominal pain, or unexplained nausea/vomiting
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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 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
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Eastern Cooperative Oncology Group (ECOG) performance status =< 1
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Not pregnant or breastfeeding, as determined by clinical administration of 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 childbearing 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
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Ability to understand and the willingness to sign a written informed consent document
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 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
-
History of gastric bypass, gastric sleeve, or bariatric surgery
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Thomas Jefferson University Hospital | Philadelphia | Pennsylvania | United States | 19107 |
| 2 | Fox Chase Cancer Center | Philadelphia | Pennsylvania | United States | 19111 |
Sponsors and Collaborators
- National Cancer Institute (NCI)
Investigators
- Principal Investigator: David S Weinberg, University of Wisconsin, Madison
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- NCI-2021-11620
- NCI-2021-11620
- Pending
- UWI21-06-01
- P30CA014520
- UG1CA242635