Effect of Chemoprevention by Low-dose Aspirin of New or Recurrent Colorectal Adenomas in Patients With Lynch Syndrome

Study Overview
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Brief Summary
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The proposed trial will evaluate the effect of aspirin 300 mg/d and 100 mg/d during 4 years vs placebo, in a 4 groups randomised parallel design in Lynch syndrome patients: patients with proven carriers of pathological mutations in mismatch repairs genes and patients with personal and family history characterizing Lynch syndrome according to modified Amsterdam criteria without proven mutation, aged more than 18 years with signed informed consent. The main hypothesis to be tested is that aspirin could decrease colorectal adenoma recurrence evaluated during high quality follow-up by colonic chromo-endoscopy in Lynch syndrome patients. The trial will also explore: (i) colorectal neoplasia recurrence according to different germline alteration in mismatch repair genes, (ii) observance to chemoprevention in Lynch syndrome patients, (iii) the burden of adverse events attributable to aspirin in Lynch syndrome patients, (iv) the dose-effect of aspirin on adenomatous polyp burden. All pathological samples will be reviewed using a centralized procedure. The INCA regional network organization and the HNPCC patient organization will allow the recruitment and the follow-up of a large number of patients with well characterised Lynch syndrome.

Detailed Description
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Lynch syndrome (LS) is the most common inherited colorectal cancer syndrome, and results from germline mutations in mismatch repair genes that confer a high lifetime risk of colorectal cancer (CRC) (60 to 70%). Most CRCs arise from asymptomatic polyps. Development of such polyps into cancer can be prevented if polyps are detected early by endoscopy and removed. Colonoscopy is proposed every 2 years in LS patients more than 25 years old, and every year when colonic neoplasia has been detected. Efficient chemoprevention has the potential to represent a cost-effective intervention in these patients and could allow a delay in colonoscopic surveillance. Several epidemiological studies have shown that regular use of low dose aspirin (75 to 300 mg/d) is associated with a 20 to 30 % reduction in the risk of sporadic colonic polyps and CRC. Four randomised controlled trials (RCT) have also shown a decrease in colorectal polyp recurrence. In a pooled analysis of cardio-vascular prevention RCTs, as well as in a meta-analysis, daily aspirin was associated with a reduced risk of CRC and CRC associated mortality. Aspirin preventive benefit is expected to outweigh its putative side effects in high risk patients. The CAPP2 study in Lynch syndrome patients showed that aspirin (300 mg x2/d) did not reduce significantly the risk of colorectal neoplasia after 29 months, but an extended follow-up (mean 56 months) showed a reduction in colorectal cancer in the aspirin group. In this study, the endoscopic follow-up was not optimal with a relatively low detection rate of colorectal neoplasia according to usual reported rate when chromo-endoscopy is performed. So, the real effect and clinical benefit of aspirin are still to be characterised in Lynch syndrome patients.

Official Title
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Assessment of the Effect of a Daily Chemoprevention by Low-dose Aspirin of New or Recurrent Colorectal Adenomas in Patients With Lynch Syndrome

Conditions
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Lynch Syndrome

Intervention / Treatment
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* Drug: Acetylsalicylic acid lysinate 300 mg
* Drug: Placebo (for Aspirin 300)
* Drug: Acetylsalicylic acid lysinate 100 mg
* Drug: Placebo 100 (for Aspirin 100)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patient with Lynch syndrome bearing an alteration of mismatch repair genes or,when no characteristic alteration has been found, with a personal or family history of Lynch syndrome according to modified Amsterdam criteria Aged more than 25 years, et aged more than 18 years with an early familial history and any reason to perform a colonoscopy every 2 years Aged less than 75 years Exclusion Criteria: Known allergy to aspirin (including a history of asthma induced by the administration of salicylates or substances with similar activity, including non-steroidal anti-inflammatory) Need for a prolonged treatment (prevention of cardio-vascular risk) or repeated treatments (recurring migraines) using aspirin or another non-steroidal anti-inflammatory drug (NSAID) Pregnancy or breast feeding Participation to another clinical trial during the 12 weeks before inclusion

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Aspirin300<br>Acetylsalicylic acid 300 mg tablet by mouth, daily dose during 4 years | Drug: Acetylsalicylic acid lysinate 300 mg<br>* Daily dose during 4 years<br>* Other names: Aspirin300;|
| Placebo Comparator: Placebo300<br>Placebo (like Acetylsalicylic acid 300 mg) tablet by mouth, daily dose during 4 years | Drug: Placebo (for Aspirin 300)<br>* Daily dose during 4 years<br>* Other names: Placebo300;|
| Active Comparator: Aspirin100<br>Acetylsalicylic acid 100 mg tablet by mouth, daily dose during 4 years | Drug: Acetylsalicylic acid lysinate 100 mg<br>* Daily dose during 4 years<br>* Other names: Aspirin100;|
| Placebo Comparator: Placebo100<br>Placebo (like Acetylsalicylic acid 100 mg) tablet by mouth, daily dose during 4 years | Drug: Placebo 100 (for Aspirin 100)<br>* Daily dose during 4 years<br>* Other names: Placebo100;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of patients with at least one adenoma seen on chromo-endoscopy 48 months after complete withdrawal of polyps and initiation of treatment (aspirin or placebo) | To look for a preventive effect of low-dose aspirin (100 or 300 mg/d) compared with placebo on new or recurrent colorectal adenomas in patients with Lynch syndrome | 4 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Delay between the onset of 1 adenoma after complete resection of polyps and date of start of treatment (aspirin vs placebo) |  | 24 and 48 months | 
| Number of patients who presented an adenoma during follow-up based on the gene reached (MLH1, MSH2, MSH6, PMS2, or without other identified anomalies) |  | 24 and 48 months | 
| Load serrated polyps after 24 and 48 months of treatment |  | 24 and 48 months |