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Randomized, Phase II Trial of Atorvastatin, RAFTILOSE Synergy 1, and Sulindac Among Patients at Increased Risk for Sporadic Colorectal Neoplasia

Phase 2
40 Years
Not Enrolling
Colon Cancer, Precancerous Condition, Rectal Cancer

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Trial Information

Randomized, Phase II Trial of Atorvastatin, RAFTILOSE Synergy 1, and Sulindac Among Patients at Increased Risk for Sporadic Colorectal Neoplasia


I. Percent change in number of rectal aberrant cryptic foci (ACF) as measured by
magnification chromoendoscopy


I. Screening for possible phase III testing II. Effects on proliferation (Ki67 expression)
and apoptosis (caspase-3 expression) as measured by biopsy samples obtained from
normal-appearing rectal mucosa at baseline and after completion of study treatment III.
Correlation of endoscopic features with histologic characteristics of rectal ACF IV.
Observation of the natural history of rectal ACF in patients receiving placebo V. Adverse
events VI. Utilization of a biospecimen repository archive

OUTLINE: This is a multicenter, prospective, randomized, partially blinded,
placebo-controlled study. Patients are stratified according to history of prior surgical
resection of the colon (yes vs no) and number of rectal aberrant cryptic foci (ACF) (5-9 vs
>= 10). Patients are randomized to 1 of 4 treatment arms.

ARM I: Patients receive oral atorvastatin calcium once daily.

ARM II: Patients receive oral sulindac twice daily.

ARM III (blinded arm): Patients receive oral oligofructose-enriched inulin (Raftilose
Synergy 1) twice daily.

ARM IV (blinded arm): Patients receive an oral placebo twice daily.

In all arms, treatment continues for 6 months in the absence of unacceptable toxicity.

Tissue samples are collected at baseline and at the completion of study treatment. Tissue is
examined by immunohistochemistry for proliferation (Ki67) and apoptosis (cleaved caspase-3).

After completion of study treatment, patients are followed at approximately 30 days.

Inclusion Criteria


- ECOG performance status 0-2

- Platelet count >= 100,000/mm^3

- Fertile patients must agree to use effective contraception

- No history of inflammatory bowel disease (i.e., Crohn's disease or ulcerative

- No invasive malignancy within the past 5 years except nonmelanoma skin cancer or
colorectal cancer

- No history of endoscopically-confirmed peptic ulcer disease

- No history of allergic reactions attributed to compounds of similar chemical or
biological composition to the study agents

- No history of chronic liver disease or unexplained persistent elevations of serum

- No history of allergic-type reactions, including asthma or urticaria, to aspirin or

- No uncontrolled intercurrent illness including, but not limited to, any of the

- Ongoing or active infection

- Symptomatic congestive heart failure

- Unstable angina pectoris

- Cardiac arrhythmia

- Psychiatric illness or social situations that would preclude study compliance

- At least 6 weeks since prior oral corticosteroids

- Creatinine =< 1.5 times ULN

- Creatine phosphokinase =< 1.5 times ULN

- Not pregnant or nursing

- At least 6 weeks since prior statins

- At increased risk for developing sporadic colorectal neoplasia, as defined by 1 of
the following:

- History of colon cancer (excluding stage IV or Dukes' D tumors)

- Must have completed prior adjuvant therapy for colon cancer >= 12 months ago

- History of colorectal adenomas, meeting any of the following criteria:

- >= 1 cm in diameter

- >= 3 in total number

- Any component of villous morphology

- High-grade dysplasia

- At least 5 rectal aberrant cryptic foci (ACF), by magnification chromoendoscopy,
meeting both of the following criteria:

- At least 5 aggregated crypts in a single grouping (maximum spacing between
crypts must be =< 2 times the average crypt diameter)

- Crypt diameter >= 1.5 times the diameter of surrounding normal crypts

- No history of rectal cancer, familial adenomatous polyposis, or hereditary
nonpolyposis colorectal cancer

- Negative pregnancy test

- At least 6 months since prior and no concurrent regular use* of nonsteroidal
anti-inflammatory drugs** (NSAIDs) or statins

- Concurrent aspirin at cardioprotective doses (=< 162.5 mg/day or 325 mg every other
day) allowed

- No prior rectal surgery involving mucosal resection

- No prior pelvic radiation therapy

- No concurrent regular use* of cyclooxygenase-2 inhibitors

- No concurrent anticoagulant drugs (i.e., warfarin, heparin, clopidogrel bisulfate, or
extended-release dipyridamole)

- No concurrent use of any of the following:

- Fibrates (e.g., gemfibrozil or fenofibrate)

- Cyclosporine

- Erythromycin or macrolide antibiotics

- Protease inhibitors

- Azole antifungals

- Diltiazem

- Verapamil

- Compounds containing niacin or nicotinic acid

- Defined as 7 consecutive days for > 3 weeks OR > 21 days total during study

- Patients may be eligible for study treatment after discontinuing NSAIDs for
12 weeks, at the discretion of their health care provider

- No other concurrent investigational agents

- No planned (or likely to require) clinically indicated colonoscopy or flexible
sigmoidoscopy during study treatment

- Bilirubin =< 1.5 times ULN

- Hemoglobin >= lower limit of normal

- AST =< 1.5 times upper limit of normal (ULN)

- Alkaline phosphatase =< 1.5 times ULN

Type of Study:


Study Design:

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Investigator), Primary Purpose: Prevention

Outcome Measure:

Percent Change in Number of Rectal Aberrant Cryptic Foci (ACF) as Measured by Magnification Chromoendoscopy

Outcome Description:

At the Pre-Intervention Evaluation, rectal ACF will be classified with respect to ACF number, crypt number, crypt size, tissue plane, staining intensity, and (optional) lumen shape for each subject. At the Post- Intervention Evaluation, these same parameters will be recorded and incident vs prevalent rectal ACF status will also be recorded. Compare each non-placebo arms versus the placebo arm to screen the three active study agents for possible phase III testing.

Outcome Time Frame:

6 months

Safety Issue:


Principal Investigator

Paul Limburg

Investigator Role:

Principal Investigator

Investigator Affiliation:

Mayo Clinic


United States: Food and Drug Administration

Study ID:




Start Date:

March 2006

Completion Date:

Related Keywords:

  • Colon Cancer
  • Precancerous Condition
  • Rectal Cancer
  • Neoplasms
  • Colonic Neoplasms
  • Rectal Neoplasms
  • Precancerous Conditions



Mayo Clinic Rochester, Minnesota  55905