Estrogen Receptor Beta Agonists (Eviendep) and Polyp Recurrence

Phase 1

Completed

• Conditions: Adenocarcinoma of Colon Recurrent
• Interventions: Dietary Supplement: Maltodextrins; Dietary Supplement: Eviendep (CM&D Pharma Limited, UK)

• Registration Number: NCT01402648
• Lead Sponsor: CM&D Pharma Limited

Brief Summary

The decreased Estrogen Receptor beta (ERβ) expression in the non adenomatous mucosa of ApcMin/+ mice favours intestinal neoproliferation. The dietary supplementation with a blend of ERβ agonists and lignin has been shown to recover ERβ to the healthy wild type levels, and a reduced polyp number and lower dysplasia was also observed in the adenomatous mucosa. In this randomised, double blind and placebo controlled study, we assessed if ERβ similarly guides the apoptotic control of cell proliferation in the non adenomatous colon mucosa of patients affected from sporadic adenopolyposis, prone to polyp recurrence. For 60 day in advance of the screening colonoscopy, patients were supplemented with a dietary blend of ERβ agonists and lignin (Eviendep, CM\&D Pharma Limited, London, UK) on top their common diet (left unchanged during the study period), to study if the pro-proliferative behavior of the non adenomatous mucosa was effected. Sixty patients naïve from previous and concomitant hormonal or anti-inflammatory CRC chemoprevention were sequentially 1:1 randomised to active or placebo supplementation. ERα and ERβ (mRNA, Western Blotting, Elisa, immunostaining), TUNEL, caspase-3 and Ki-67 (immunostaining) were assessed in bioptic normal colon mucosa samples. Study power: 80%, type 1 error: .05 (two-tails). Statistics: Non parametric Wilcoxon test for efficacy. MANOVA for proliferative and apoptotic biomarkers relationships to the common diet and to the 60 day supplementation.

Detailed Description

Enrolled patients were actively ongoing the surveillance program for the follow up of polyp recurrence and progression to CRC. Eligible patients should have undergone a polypectomy since 2003, affected by multiple polyps \< 10 mm or one-two adenomas \< 10 mm and/or with a grade of dysplasia to make them classified at intermediate risk for CRC, and scheduled to screening colonoscopy each 3-5 years. Patients were sequentially 1:1 randomly allocated to placebo or Eviendep at baseline (T0). The dietary supplements were administered twice a day for 60 days in advance of the screening colonoscopy, thus covering approximately eight complete colon epithelial turnover to occur. Five days in advance of T60 colonoscopy, patients refrained from fresh and cooked fruit and vegetable intake. Bowel cleansing was achieved by PEG 4000 oral administration (1120 g/4 L water solution). N=8 biopsy samples/patient were collected from the non adenomatous mucosa in the sigmoidal colon. Small polyps (diameter less or equal 0.5 cm) were topically electrocoagulated, whereas villous and tubulovillous polyps (diameter equal or higher than 0.5 cm) were submitted to the histological assessment.

Study Timeline

• Study Start: 2009-10
• Primary Completion: 2011-03
• Study Completion: 2011-04
• Status Verified: 2011-07
• Study First Submitted: 2011-07-25
• Study First Submitted QC: 2011-07-25
• Last Update Submitted: 2011-07-25
• Study First Posted: 2011-07-26
• Last Update Posted: 2011-07-26

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 60

Inclusion Criteria

• Men and women, age: 50-70 years
• Menopausal women since at least 2 years
• Diagnosed since 2003 for adenomas, underwent polypectomy and histological assessment
• Regularly inscribed and actively ongoing the surveillance program for the follow-up of adenoma recurrence and progression to advanced adenomas
• Screening colonoscopy every 3-5 years
• No previous or concomitant administration of ASA and NSAIDs
• No previous or concomitant administration of Hormonal Replacement Therapy (HRT)
• No previous or concomitant administration of other phytoestrogens

Exclusion Criteria

• Chronic inflammatory intestinal disease
• Intestinal and/or extraintestinal malignant neoplasms
• Acute or chronic renal disease
• Anemia
• Coagulation disorders,
• BMI > 30
• Systemic corticosteroids
• Anticoagulants or platelet antiaggregants
• Antibiotics within 30 days from enrollment

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Dietary supplement	Maltodextrins	900 mg Maltodextrins
Eviendep (CM&D Pharma Limited, UK)	Eviendep (CM&D Pharma Limited, UK)	175 mg milk thistle (fruit dry extract, 70% in silymarin)+ 20 mg flaxseed (dry extract, 40% in secoisolariciresinoldiglucoside) + 750 mg non starch, insoluble and indigestible fiber (6% in lignin).

Primary Outcome Measures

Name	Time	Method
Expression of ERβ, ERα, TUNEL, Caspase-3, Ki-67 in bioptic samples of non adenomatous mucosa in sporadic adenopolyposis	60 days following dietary oral supplementation, in advance of the screening colonoscopy as per the planning of the surveillance program	ERβ and ERα protein content (Elisa), mRNA and immunohistochemically stained cells (% over the total number of cells/field,ICH); TUNEL (%,ICH); caspase-3 (%,ICH), Ki-67 (%ICH), and comparison (mean, median, %ICH) between study groups. Safety assessed by no induction of ERα expression.

Secondary Outcome Measures

Name	Time	Method
Safety assessed by unchanged hematochemistry	30 and 60 days following dietary oral supplementation	Hemoglobin ≥ 12.0 g/dL; platelets ≥ 120,000/mm3; INR ≤ 1.5; AST or ALT ≤ 1.5 times the upper limit of normal values (ULN); Alkaline Phosphatase ≤ 1.5 times ULN; Bilirubin ≤ 1.5 times ULN; BUN ≤ 40 mg/dL; normal blood pressure or controlled hypertension
Urinary lignans	baseline (T0, 30 (T30) and 60 (T60) days during the study period	To verify comparability of phytoestrogens contributed from the common diet in the two arms at baseline, and to assess compliance to the active comparator during the study period.

Trial Locations

Locations (1)

Ospedale Policlinico Consorziale - Gastroenterology Unit; 🇮🇹 Bari, Italy