Clinical trial NCT01894685: Mesalazine Effects in Sporadic Colorectal Adenoma Patients
Official title: Chemopreventive Effects of Mesalazine in Patients at High Risk of Recurrent (Nonfamilial) Colorectal Adenomas
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Sporadic Colorectal Adenoma
Keywords: Colorectal
Adenoma
Recurrence
Mesalazine
Chemoprevention
Lead sponsor: UMC Utrecht
Sponsor class: OTHER
First posted: 2013-07-10
Enrollment: 74
Sex: ALL
Minimum age (years): 50
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: Several studies indicate that mesalazine might have a preventive effect on recurrence of adenomas in patients with and without inflammatory bowel disease. As mesalazine has limited adverse effects, it is an attractive candidate for chemoprevention. In this study we aim to investigate the antineoplastic properties of mesalazine in patients with sporadic colorectal adenomas.

Detailed description: Rationale: Patients with sporadic colorectal adenomatous polyps removed by polypectomy have a high rate of polyp recurrence and carry an increased risk for the development of colorectal carcinoma (CRC). Chemoprevention may lower the rate of adenoma recurrence after polypectomy, thereby reducing the risk of development or death from CRC. Mesalazine is an attractive candidate for chemoprevention, since even during long-term use it has only limited systemic adverse effects and no gastrointestinal toxicity. In a prospective trial a trend towards reduced adenoma recurrence has been observed in high risk patients with a history of at least 3 sporadic colorectal adenomas treated with mesalazine. Identification of biologically relevant antineoplastic properties of mesalazine in patients with sporadic adenomatous polyps will support further investigation of mesalazine as chemopreventive agent against colorectal neoplasia in the sporadic setting. Growth inhibition of colonic epithelial cells through induction of apoptosis and inhibition of proliferation is widely recognized as a potential mechanism for chemoprevention of colorectal cancer. In vivo data suggest that mesalazine exerts pro-apoptotic and anti-proliferative effects on normal colorectal epithelial cells. Furthermore, there is in vitro evidence in CRC cells that mesalazine inhibits Wnt/beta-catenin signalling, an early and common inappropriately activated pathway in colorectal carcinogenesis and molecular target for chemoprevention.

Objective: Evaluate the effects of mesalazine therapy on histologically normal sigmoid and rectal mucosa in patients at high risk of recurrent sporadic colorectal adenomas.

Primary endpoints:

* change in apoptotic index after treatment as compared to placebo
* change in proliferation index and distribution of proliferating cells in crypts after treatment as compared to placebo

Secondary endpoint:

• change in expression of beta-catenin signaling pathway components after treatment as compared to placebo

Study design: double-blind, randomized placebo-controlled study

Study population: 68 patients, aged 50-75 years, who underwent polypectomy within 6 months before study entry, for removal of 2 or more colorectal adenomas irrespective of size and/or 1 colorectal adenoma with at least 1 of the following features: a diameter of at least 1 cm at endoscopy, a proximal localization, high-grade dysplasia or villous histology.

Intervention: Patients will be randomized to receive 3.0 g mesalazine (n=34) or placebo (n=34) once daily for 6 months in a double-blinded way. At baseline and after 6 months of treatment, a sigmoidoscopy will be performed and five biopsies of normal appearing sigmoid and rectal mucosa will be collected.

Main study parameters/endpoints: The effect of treatment with mesalazine on apoptotic and proliferation indices relative to the placebo group.

Eligibility criteria: Inclusion Criteria:

* age: 50-75 years
* having undergone complete colonoscopy with polypectomy for removal of
* 2 or more colorectal adenomas, irrespective of size, and/or
* 1 colorectal adenoma:
* of at least 1 cm in diameter and/or
* located proximal to the splenic flexure and/or
* with high-grade dysplasia and/or villous histology

Exclusion Criteria:

* inflammatory bowel disease
* familial colorectal cancer syndrome
* history of colorectal carcinoma
* history of surgery to the large bowel (except appendectomy)
* chronic renal insufficiency
* chronic hepatic insufficiency
* allergy to salicylates
* diabetes mellitus (higher risk for developing renal disease)
* coagulation disorder or anticoagulant use, which cannot be temporarily discontinued (precludes biopsy taking)
* asthma
* prescription use of acetylsalicylic acid or calcium carbasalate (high- and low-dose) or other NSAIDs
* use of medicines which may interact with mesalazine: methotrexate, thiopurines, cyclosporine, coumarin anticoagulants and rifampicin

Primary outcomes:
measure: Apoptotic index
timeFrame: 6 months
measure: Proliferation index
timeFrame: 6 months
Secondary outcomes:
measure: Expression of β-catenin signaling pathway
timeFrame: 6 months
Other outcomes:
Locations:
city: Utrecht
country: Netherlands
facility: University Medical Center Utrecht
Study officials:
References: