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

A

Assistance Publique - Hôpitaux de Paris

Status and phase

Enrolling
Phase 3

Conditions

Lynch Syndrome

Treatments

Drug: Acetylsalicylic acid lysinate 300 mg
Drug: Placebo (for Aspirin 300)
Drug: Placebo 100 (for Aspirin 100)
Drug: Acetylsalicylic acid lysinate 100 mg

Study type

Interventional

Funder types

Other

Identifiers

NCT02813824
P130937

Details and patient eligibility

About

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.

Full description

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.

Enrollment

852 estimated patients

Sex

All

Ages

18 to 75 years old

Volunteers

No Healthy Volunteers

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

Trial design

Primary purpose

Prevention

Allocation

Randomized

Interventional model

Parallel Assignment

Masking

Quadruple Blind

852 participants in 4 patient groups, including a placebo group

Aspirin300
Active Comparator group
Description:
Acetylsalicylic acid 300 mg tablet by mouth, daily dose during 4 years
Treatment:
Drug: Acetylsalicylic acid lysinate 300 mg
Placebo300
Placebo Comparator group
Description:
Placebo (like Acetylsalicylic acid 300 mg) tablet by mouth, daily dose during 4 years
Treatment:
Drug: Placebo (for Aspirin 300)
Aspirin100
Active Comparator group
Description:
Acetylsalicylic acid 100 mg tablet by mouth, daily dose during 4 years
Treatment:
Drug: Acetylsalicylic acid lysinate 100 mg
Placebo100
Placebo Comparator group
Description:
Placebo (like Acetylsalicylic acid 100 mg) tablet by mouth, daily dose during 4 years
Treatment:
Drug: Placebo 100 (for Aspirin 100)

Trial contacts and locations

1

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Central trial contact

Zahia BEN ABDESSELAM

Data sourced from clinicaltrials.gov

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