Estrogen Receptor Beta Agonists (Eviendep) and Polyp Recurrence (CRC)

This study has been completed.
Sponsor:
Information provided by:
CM&D Pharma Limited
ClinicalTrials.gov Identifier:
NCT01402648
First received: July 25, 2011
Last updated: NA
Last verified: July 2011
History: No changes posted
  Purpose

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.


Condition Intervention Phase
Adenocarcinoma of Colon Recurrent
Dietary Supplement: Eviendep (CM&D Pharma Limited, UK)
Dietary Supplement: Maltodextrins
Phase 1
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Prevention
Official Title: Effects of the Dietary Supplementation With a Blend of ER Beta Agonists on the Expression of ER Beta and Related Biomarkers of Cell Proliferation and Apoptosis, in Sporadic Colon Adenopolyposis

Resource links provided by NLM:


Further study details as provided by CM&D Pharma Limited:

Primary Outcome Measures:
  • Expression of ERβ, ERα, TUNEL, Caspase-3, Ki-67 in bioptic samples of non adenomatous mucosa in sporadic adenopolyposis [ Time Frame: 60 days following dietary oral supplementation, in advance of the screening colonoscopy as per the planning of the surveillance program ] [ Designated as safety issue: Yes ]
    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:
  • Safety assessed by unchanged hematochemistry [ Time Frame: 30 and 60 days following dietary oral supplementation ] [ Designated as safety issue: Yes ]
    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 [ Time Frame: baseline (T0, 30 (T30) and 60 (T60) days during the study period ] [ Designated as safety issue: No ]
    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.


Enrollment: 60
Study Start Date: October 2009
Study Completion Date: April 2011
Primary Completion Date: March 2011 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Placebo Comparator: Dietary supplement
900 mg Maltodextrins
Dietary Supplement: Maltodextrins
900 mg maltodextrin+excipient as per the active comparator eviendep, up to 5 g/sachet
Active Comparator: 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).
Dietary Supplement: 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). Provided in 5 g sachets, to be dissolved in half glass water, administered twice a day for 60 days on top of the common diet.

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.

  Eligibility

Ages Eligible for Study:   50 Years to 70 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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
  Contacts and Locations
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Please refer to this study by its ClinicalTrials.gov identifier: NCT01402648

Locations
Italy
Ospedale Policlinico Consorziale - Gastroenterology Unit
Bari, Italy, 70124
Sponsors and Collaborators
CM&D Pharma Limited
  More Information

No publications provided

Responsible Party: Alfredo Di Leo, Head Gastroenterology Unit, D.E.T.O. - University Hospital, Bari (Italy)
ClinicalTrials.gov Identifier: NCT01402648     History of Changes
Other Study ID Numbers: CMD-CRC09(2)
Study First Received: July 25, 2011
Last Updated: July 25, 2011
Health Authority: Italy: Ministry of Health

Keywords provided by CM&D Pharma Limited:
Non adenomatous mucosa
Estrogen Receptor beta and apoptosis
Adenoma recurrence
Screening colonoscopy every 3-5 years
patients at intermediate risk for CRC

Additional relevant MeSH terms:
Adenocarcinoma
Recurrence
Colonic Neoplasms
Carcinoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Disease Attributes
Pathologic Processes
Colorectal Neoplasms
Intestinal Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Digestive System Diseases
Gastrointestinal Diseases
Colonic Diseases
Intestinal Diseases
Estrogens
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Pharmacologic Actions

ClinicalTrials.gov processed this record on July 20, 2014