Linaclotide Acetate in Preventing Colorectal Cancer in Healthy Volunteers

This study is ongoing, but not recruiting participants.
Sponsor:
Collaborator:
Information provided by (Responsible Party):
Mayo Clinic
ClinicalTrials.gov Identifier:
NCT01950403
First received: September 23, 2013
Last updated: September 12, 2014
Last verified: September 2014
  Purpose

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.


Condition Intervention Phase
Colorectal Cancer
Healthy, no Evidence of Disease
Drug: linaclotide acetate
Other: placebo
Other: pharmacological study
Other: laboratory biomarker analysis
Phase 1

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Pharmacodynamics Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Investigator)
Primary Purpose: Basic Science
Official Title: Phase I, Randomized, Placebo-Controlled Trial of Linaclotide to Demonstrate Colorectal Bioactivity in Healthy Volunteers

Resource links provided by NLM:


Further study details as provided by Mayo Clinic:

Primary Outcome Measures:
  • Dose of linaclotide acetate that produces a 60% response rate for cGMP levels in rectal tissue by radioimmunoassay (RIA) [ Time Frame: Baseline to 7 days ] [ Designated as safety issue: No ]
    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.


Secondary Outcome Measures:
  • Incidence of adverse events associated with linaclotide acetate assessed using the Common Terminology Criteria for Adverse Events version 4.0 [ Time Frame: Up to 51 days ] [ Designated as safety issue: Yes ]
    Summary statistics, frequency tables, and non‐parametric tests will be used to describe the distributions of adverse events.

  • PD effect of linaclotide acetate on cGMP levels from the transverse colon to the cecum [ Time Frame: Up to 7 days ] [ Designated as safety issue: No ]
  • Change in cGMP levels between all assigned doses, analyzed sequentially from the rectum, transverse colon, and cecum [ Time Frame: Baseline to 7 days ] [ Designated as safety issue: No ]
    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.

  • PD effect on cGMP levels (Stage II) [ Time Frame: Up to 6 days ] [ Designated as safety issue: No ]
    Changes in cGMP levels from baseline to day 6 will also be assessed using summary statistics and nonparametric tests.


Other Outcome Measures:
  • PD effect of linaclotide acetate on GCC signaling (i.e., VASP phosphorylation) and general proliferation (Ki67 expression) [ Time Frame: Up to 7 days ] [ Designated as safety issue: No ]
    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.


Estimated Enrollment: 18
Study Start Date: September 2013
Estimated Primary Completion Date: March 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Arm I (linaclotide acetate)
Participants receive linaclotide acetate PO QD on days 1-7.
Drug: linaclotide acetate
Given PO
Other Names:
  • Linzess
  • MD-1100 Acetate
  • MM-416775
Other: pharmacological study
Correlative studies
Other Name: pharmacological studies
Other: laboratory biomarker analysis
Correlative studies
Placebo Comparator: Arm II (placebo)
Participants receive placebo PO QD on days 1-7.
Other: placebo
Given PO
Other Name: PLCB
Other: pharmacological study
Correlative studies
Other Name: pharmacological studies
Other: laboratory biomarker analysis
Correlative studies

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.

  Eligibility

Ages Eligible for Study:   18 Years to 65 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   Yes
Criteria

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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01950403

Locations
United States, Pennsylvania
Thomas Jefferson University
Philadelphia, Pennsylvania, United States, 19107
Sponsors and Collaborators
Mayo Clinic
Investigators
Principal Investigator: Paul Limburg Mayo Clinic
  More Information

No publications provided

Responsible Party: Mayo Clinic
ClinicalTrials.gov Identifier: NCT01950403     History of Changes
Obsolete Identifiers: NCT01912079
Other Study ID Numbers: NCI-2013-01788, NCI-2013-01788, HHSN2512012000042I, 13-829, MAY2012-00-01, MAY2012-00-01, N01CN00042, P30CA015083
Study First Received: September 23, 2013
Last Updated: September 12, 2014
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Colorectal Neoplasms
Intestinal Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Neoplasms
Digestive System Diseases
Gastrointestinal Diseases
Colonic Diseases
Intestinal Diseases
Rectal Diseases

ClinicalTrials.gov processed this record on September 30, 2014