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Atorvastatin ± Aspirin in Lynch Syndrome Syndrome

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ClinicalTrials.gov Identifier: NCT04379999
Recruitment Status : Recruiting
First Posted : May 8, 2020
Last Update Posted : April 5, 2021
Sponsor:
Information provided by (Responsible Party):
Fox Chase Cancer Center

Brief Summary:
The goal of this study is to investigate that a common cholesterol lowering agent (atorvastatin) alone or combining with a nonsteroidal anti-inflammatory drug (aspirin) would reduce the risk of colorectal cancer (CRC) in high-risk individuals with Lynch syndrome.

Condition or disease Intervention/treatment Phase
Lynch Syndrome Drug: Atorvastatin 20mg Drug: Atorvastatin 20mg AND Aspirin 325 mg Early Phase 1

Detailed Description:
This is an exploratory biomarker trial to assess the ability of atorvastatin (common cholesterol lowering agent) alone or combining with aspirin (a nonsteroidal anti-inflammatory drug) to reduce the risk of colorectal cancer in high-risk individuals with Lynch Syndrome. Subjects will be stratified based on their prior history of polyps/cancer to receive atorvastatin without or with aspirin for 6 weeks. Blood and normal colon biopsies will be obtained at Day 0 and at 6 weeks on study. Tissue endpoints for analysis include cell proliferation, apoptosis and changes in gene expression. Circulating lipid profiles and metabolic function, and post-treatment questionnaires will be used to assess the acceptability of the study.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 46 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: One group receives atorvastatin 20 mg, and the other group receives atorvastatin 20 mg+ aspirin 325mg
Masking: None (Open Label)
Primary Purpose: Prevention
Official Title: Impact of Atorvastatin ± Aspirin on Colorectal Biomarkers in Patients With Lynch Syndrome: a Pilot Study
Actual Study Start Date : September 10, 2018
Estimated Primary Completion Date : September 1, 2022
Estimated Study Completion Date : September 10, 2023

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Active Comparator: Atorvastatin
Atorvastatin (LIPITOR) 20 milligram tablet daily for 6 weeks
Drug: Atorvastatin 20mg
No history of colorectal cancer and no colorectal adenomas within 5 years.
Other Name: Lipitor 20mg

Active Comparator: Atorvastatin and Aspirin
Atorvastatin (LIPITOR) 20 milligram tablet and Aspirin 325 mg tablet daily for 6 weeks
Drug: Atorvastatin 20mg AND Aspirin 325 mg
History of colorectal cancer and/or history of colorectal adenomas within 5 years.
Other Name: Lipitor 20mg AND Aspirin 325mg




Primary Outcome Measures :
  1. Proliferation (Ki-67) and apoptosis (active caspase 3) by immunohistochemical staining [ Time Frame: Changes from baseline to 6 weeks ]
    Effect of Atorvastatin or/and Aspirin on normal colonic proliferation and apoptosis will be evaluated by comparing of immunohistochemical staining of Ki-67 and active caspase 3 using formalin-fixed paraffin-embedded biopsies collected before and at the 6 weeks of drug treatments. Number of positive cells and total number of evaluated cells will be collected for both assays. Data of cells with positive Ki-67 or active caspase 3 will be expressed as % of positive cells (# positive cells/#total evaluated cells x 100). Statistical analyses will be performed to compare the difference between baseline and 6-weeks data.

  2. Genome-wide expression analyses using RNA-Seq [ Time Frame: Changes from baseline to 6 weeks ]
    Effect of Atorvastatin or/and Aspirin on gene expressions in normal colonic epithelial cells will be analyzed using RNA-Seq. Total RNA will be extracted from frozen biopsies. RNASeq libraries will be generated and sequenced on an Illumina platform and analyzed. Differential expression between samples at baseline and 6-weeks of drug treatment will be assessed for statistical significance. Genes with false discovery rat ≤ 0.05 and a fold-change ≥ 2 will be considered significant.


Secondary Outcome Measures :
  1. Rate of adherence of healthy patients with Lynch Syndrome to a 6-week of the treatment regimen (atorvastatin ± aspirin). [ Time Frame: 6 weeks ]
    Medication Adherence to the 6-week course of Atorvastatin or/and Aspirin preventive therapy will be assessed by one question in the follow -up survey which participants complete at the end of the study :"Over 6 weeks of preventive therapy, how many Atorvastatin/Aspirin pills did you forget to take?" In addition, participants will be asked to return medication bottle(s) with or without pills. RA will count pills and record number of missing pills in the system.

  2. Frequency of adverse events among patients administered atorvastatin ± aspirin for 6 weeks [ Time Frame: 6 weeks ]
    The adverse event assessment form is used to collect initial and follow-up information for non-serious and serious adverse events for patients participating in the study. Participants are contacted by RA every two weeks to assess side effects and toxicity. A grading scale from 1 to 5 (1-mild, 2-moderate, 3-severy, 4-life-threatining, 5- death related to AE) and causality (1-unrelated, 2-unlikly, 3-possible, 4-probable, 5-definite, NA- not assessed) are recorded for each adverse event (AE) term. Each AE is reviewed by principal investigator and entered into patient's electronic medical record (EMR)

  3. Acceptability of the pilot study intervention and the willingness of the subject to participate in a similar larger study. [ Time Frame: 6 weeks ]
    Acceptability of the study approach 6 Likert-type items (7 point scale) will assess participants' perceptions of various aspects of the study design as a measure of whether changes need to be made to the study methods or design prior to a larger multi-institutional trial. Participants' scores will be summed and a mean score generated. Mean scores > 4 will be considered in the acceptable range. Our threshold target is 75% of participants with a mean score in the acceptable range.



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Ages Eligible for Study:   18 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • Subjects who are 18 years of age or older
  • Able to read and sign an informed consent document in English
  • Eligible subjects will have molecular evidence of Lynch Syndrome (mutation in MLH1, MSH2, MSH6, EPCAM or PMS2)
  • History of colorectal cancer if surgically cured and > 1 year from completion of adjuvant chemotherapy

Exclusion Criteria:

  • Are <18 years of age
  • Unable to read and sign an informed consent document in English
  • Have active cancer or are less than 3 years post hormonal maintenance therapy for cancer
  • Have statin intolerance or contraindication for aspirin or atorvastatin use
  • Are pregnant or are actively breast feeding

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04379999


Contacts
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Contact: Yana Chertock, MA 215-214-3216 yana.chertock@fccc.edu

Locations
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United States, Pennsylvania
Fox Chase Cancer Center Recruiting
Philadelphia, Pennsylvania, United States, 19111
Contact: Yana Chertock, MA    215-214-3216    yana.chertock@fccc.edu   
Contact: Michael Hall, MD, MS    215-728-2791    michael.hall@fccc.edu   
Principal Investigator: Michael J Hall, MD, MS         
Sub-Investigator: Margie L Clapper, PhD         
Sub-Investigator: Minhhuyen T Nguyen, MD,AGAF,FACP         
Sub-Investigator: Harry S Cooper, MD         
Sub-Investigator: Wen-Chi L Chang, PhD         
Sponsors and Collaborators
Fox Chase Cancer Center
Investigators
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Principal Investigator: Michael J Hall, MD, MS Fox Chase Cancer Center
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Responsible Party: Fox Chase Cancer Center
ClinicalTrials.gov Identifier: NCT04379999    
Other Study ID Numbers: 18-1039
First Posted: May 8, 2020    Key Record Dates
Last Update Posted: April 5, 2021
Last Verified: April 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Individual participant data that underline the results reported in the article , after de-identification
Time Frame: beginning 9 months and ending 3 years following article publication
Access Criteria: Investigators whose proposed use of data has been approved by a review committee identified for this purpose.Proposals should be directed to Michael.Hall@fccc.edu. To gain access, data requestors will need to sign a data access agreement.

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Keywords provided by Fox Chase Cancer Center:
HNPCC
MLH1
MSH2
MSH6
PMS2
EPCAM
LYNCH
Additional relevant MeSH terms:
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Syndrome
Neoplastic Syndromes, Hereditary
Colorectal Neoplasms, Hereditary Nonpolyposis
Disease
Pathologic Processes
Colorectal Neoplasms
Intestinal Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Neoplasms
Digestive System Diseases
Gastrointestinal Diseases
Colonic Diseases
Intestinal Diseases
Genetic Diseases, Inborn
DNA Repair-Deficiency Disorders
Metabolic Diseases
Aspirin
Atorvastatin
Anti-Inflammatory Agents, Non-Steroidal
Analgesics, Non-Narcotic
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Anti-Inflammatory Agents
Antirheumatic Agents
Fibrinolytic Agents
Fibrin Modulating Agents