Studie zur Vorbeugung von
Darmpolypen mit Grüntee-Extrakt

Side effects and contraindications

There are no known common side effects of green tea extract. A systematic review performed in 2008 by the United States Pharmacopeia, case reports and animal pharmacology/toxicology studies from 1966 to 2007 showed no clear evidence for EGCG-related toxicity, specifically liver enzyme elevation in a common dose range of up to 800 mg [28]. A total of 216 case reports on green tea products were analyzed, including 34 reports concerning liver damage. Twenty-seven reports pertaining to liver damage were categorized as possible causality and seven as probable causality [28]. Consumption of concentrated green tea extract on an empty stomach is more likely to lead to adverse effects than consumption in the fed state, since up to five-fold higher plasma concentrations have been observed with empty stomach compared to the fed state [29-31]. In our study, liver enzyme parameters will be tested prior to enrollment, after the one month run-in period and after 4, 12, 20 and 36 months, respectively. An increase of liver enzymes by 2.5-fold above the upper normal value will lead to discontinuation of the study medication. Participants will be urged to take the capsules at breakfast and dinner. There are no known contraindications for the intake of green tea extract. Nevertheless, we will test for hepatotoxicity after one month of EGCG intake.

Interactions

The potential of EGCG to induce drug-drug interactions by the inhibition of major human cytochrome P450 isoenzymes has been studied in vitro using isoform-selective probe substrates for the major human CYP450 isoforms involved in drug-metabolism (CYP1A2, 2C9, 2C19, 2D6 and 3A4) [32]. Based on these in vitro results, no significant interactions are expected in man for EGCG with concomitantly administered compounds mainly metabolized by CYP1A2, CY2C9, CYP2C19, CYP2D6 and CYP3A4. Interactions via inhibition of transporters such as P glycoprotein or Multidrug Resistance Protein (MRP) by EGCG is possible, but has not been reported so far.

Study visits

Every four months during the 36 months of the whole study, the participants will be asked to visit the gastroenterological centers to check for any adverse events and medication changes, and to confirm with the physician the regular intake of the study medication. Blood sampling for liver enzyme testing will be performed after run in, and at the 4, 12, 20 and 36 month visits, and at 4, 20 and 36 months for biomarker sampling.

Data on health status, medication, and complaints about the study substance will be collected and the study diary will be reviewed. After each clinical visit, the study medication for the next study period will be dispensed. In cases of non-compliance or any disruption longer than four months of intake of EGCG, the study investigators will decide whether the participant may continue in the study.

The final study visit will be for the control colonoscopy three years after the start of the study. If additional colonoscopies have been performed during the three year interval, the results of those will be documented as well. The results of the colonoscopy as well as the histological confirmation of potential metachronous colorectal adenomas will be documented, as well as clinical data on medication, health status, complaints and adherence to capsule intake.

Follow-up visits are planned for three and six years after the end of the study in order to assess the long term development of adenomas since we know that it may take years to see the effect of a preventive treatment. As an example, the effect of ASS chemoprevention on colon carcinoma was assessed 10 years after [33].

Drop-out criteria

In the following situations, no study enrollment after the run-in is foreseen:

• If the pill count after the run-in period contains more than 30 capsules (out of 70 capsules).

• If the liver enzyme parameters are elevated above 2.5-fold of the upper normal value.

• Study participation will be terminated in the following occasions:

• in the case of any severe adverse event impairing further participation in the study

• If the adherence to study medication is poor (if > 35% of the capsules were not taken during more than one study period)

• the regular intake of the capsules is not assured, for any reason

• it becomes evident after the enrollment that the inclusion criteria have not been fulfilled

• a continuous (longer than 3 months) intake of the following drugs has become necessary: Any NSAID including COX-2 selective NSAIDs and ASS in a dose higher than 100 mg

• the patients desires to exit the study

• The liver enzyme parameters are elevated more than 2.5-fold of the upper normal value.

It is intended to include the data of the follow-up colonoscopy in the subjects that have dropped out for the intention-to-treat analysis.

Biobanking

At time points prior to the run-in period, and after 4, 20 and 36 months, blood sampling for biobanking will be performed. The biobank will consist of pseudonymized (coded) plasma, serum and whole blood samples for biomarkers for adenoma development, as well as paraffin blocks of advanced adenomas detected in study participants at the 3 year colonoscopy. Participation in the clinical trial is independent from the biobanking project, and thus, separate informed consent will be given for the biobanking project.

Ethics

The MIRACLE study will be performed according to the study protocol, as well as the ICH-GCP criteria, the Declaration of Helsinki, EU directives and applicable legal requirements. The study has been approved by Ethical Review Boards of the Martin Luther University of Halle-Wittenberg and Ulm University (Application 68/09, approved on the 9th of April 2009).

Data collection

Information on each patient's age, gender, height, weight, waist-to-hip ratio, ethnicity, regular tea intake, sport and activity level, smoking state, alcohol intake, family history of colon cancer and current disease and medication will be obtained from the initial interview before the run-in phase. From the colonoscopy prior to study entry, data on the number, localization and size of the removed adenoma(s) as well as the histological subtype and history of prior colonoscopies will be assessed. The patients' attitudes towards medicine and herbal supplements will be assessed at the beginning of the study.

At the follow-up visits, data on changes in concurrent disease or drug therapy, data on regular intake of the study medication and green tea beverages, laboratory data on liver enzymes and any adverse events experienced during the study will be recorded.

At the final visit, weight, waist-to-hip ratio, regular tea intake, data on changes in disease and medication will be obtained as well as data from the follow-up colonoscopy on the number, localization and size of the removed adenoma(s) as well as the histological subtype.

Data management

Data management, query management and monitoring of the study will be done by the Coordination Center for Clinical Trials at the Martin Luther University of Halle-Wittenberg (KKSH). Data collection will be done on paper CRFs and will be entered and stored in a validated GCP conform database. Study monitoring will be performed with one on-site visit per study center and regular data-entry checks of the CRFs.

Statistical analysis

The trial results will be analyzed by intention-to-treat and the per-protocol analysis. In analogy to [15] a modified intention-to-treat approach will be performed including all randomized subjects with a follow-up colonoscopy, irrespective of adherence to the study medication. Lacking values will be estimated using the Multiple Imputation MCMC method [34].

The per-protocol analysis will be done in all subjects who completed the whole course of the study. Safety will be assessed in all patients who took at least one capsule of the study medication.

Statistical analysis of the primary outcome

The study's aim is to check the following hypothesis: the regular intake of green tea extract (at least 300 mg daily) over three years results in a decrease of the incidences of colorectal adenomas. This primary outcome based on the intention-to-treat-population will be tested confirmatively by the one-sided χ2-Test [35] with a significance level of 5%.

The impact of other variables (e. g. study center, intake of low-dose ASS) related to the recurrence of adenomas will be explorative controlled by the logistic regression model [36]. Concerning the time of the recurrence of adenomas, the impact of other variables will be explorative controlled with the Cox proportional hazard model [37].

With the help of this multivariate analysis both the relative risks and the 95% confidence-intervals can be calculated.

Statistical analyses of the secondary outcome

How much other impact factors affect the risk of the incidence of metachronous adenomas will be analyzed explorative.

In addition, genetic and biochemical biomarkers for the recurrence of adenomas or the development of dysplasia and carcinoma will be analyzed explorative in the blood samples entered into the biobanking subproject.

Time plan

Patient recruitment is planned for a period of three years starting in October 2011. The total duration of the trial will be six years, with the last patient out in fall 2017.

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