Evaluation of Low-Dose Acetylsalicylic Acid for Chemoprevention of Colorectal Adenomas in Lynch Syndrome: A Randomized, Placebo-Controlled Trial

The primary objective of this study is to explore the **preventive effect** of low-dose aspirin (100 or 300 mg/day) compared with placebo on the occurrence of new or recurrent colorectal adenomas in patients with **Lynch syndrome**. This is clinically relevant as Lynch syndrome significantly increases the risk of colorectal cancer, and identifying effective preventive measures could reduce morbidity and mortality associated with this condition.

Secondary objectives include:

• Comparing the time to occurrence of the first adenoma between the treatment and placebo groups.
• Determining the recurrence or occurrence of colorectal neoplasms according to various germline alterations in mismatch repair genes.
• Assessing if there is a dose-response effect of aspirin on adenomatous polyp burden.
• Comparing the burden of serrated polyps detected by chromo-endoscopy between the two groups after 24 and 48 months.
• Comparing the frequency and time to occurrence of diagnosed colorectal cancers and interval colorectal cancers between treated and untreated groups.
• Evaluating the frequency of scheduled surveillance colonoscopies and the quality of colonoscopy preparation in Lynch syndrome.
• Determining compliance to chemoprevention in patients with Lynch syndrome.
• Studying tolerance, dietary habits, microbiota, and nucleotide polymorphisms in relation to neoplasia appearance in treated and untreated groups.
• Investigating the preventive effect of low-dose aspirin on the occurrence or recurrence of colorectal adenomas or hyperplastic polyps.

The clinical trial involves **participants** diagnosed with **Lynch syndrome**, a hereditary condition that increases the risk of colorectal adenomas. The study population includes both men and women aged between 18 and 75 years, with a specific focus on those over 25 years old unless there is an early familial history necessitating regular colonoscopies. Participants must have undergone a colonoscopy within 180 days prior to inclusion, with all polyps endoscopically resectable. The trial does not include a vulnerable population, and both genders are represented. Participants are required to refrain from regular aspirin use throughout the study duration. Women of childbearing age must use effective contraception. All participants are covered by French Social Security, excluding AME, and have provided informed consent. The sponsor has not provided information regarding the total number of participants in the trial.

The clinical trial is designed to evaluate the preventive effect of low-dose **aspirin** (100 mg or 300 mg daily) compared to placebo on the development of new or recurrent colorectal adenomas in patients with **Lynch syndrome**. This study is a randomized, double-blind, placebo-controlled trial, ensuring that neither the participants nor the researchers know which treatment the participants are receiving, thus minimizing bias. The trial is expected to last for approximately 10 years, with an estimated recruitment start date of November 14, 2017, and an estimated end date of March 14, 2027.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on specific criteria, such as age, genetic background, and recent colonoscopy results. Following the inclusion visit, participants will be randomly assigned to receive either aspirin or placebo. The trial includes regular follow-up visits to monitor the participants' health, adherence to the treatment regimen, and any side effects. These visits will also involve assessments such as chromoendoscopy to evaluate the presence of adenomas. The end-of-study visit will occur 48 months after the complete resection of polyps and the initiation of the investigational medicinal product (IMP).

The expected length of participant involvement is up to 48 months, during which they will be required to adhere to the study protocol, including not using aspirin outside the study parameters. Conditions that may lead to early termination from the study include non-compliance with the study protocol, withdrawal of consent, or the occurrence of significant adverse events. The primary endpoint of the study is the number of patients with at least one adenoma detected on chromoendoscopy 48 months after the complete withdrawal of polyps and initiation of the IMP. Secondary endpoints include the delay between the onset of adenomas and treatment start, adenomatous polyp burden, and the incidence of colon cancers diagnosed during scheduled surveillance colonoscopies.

The clinical trial involves the administration of **Aspirin® protect 100 mg** as an experimental medication. This medication is formulated as a **gastro-resistant tablet** containing **acetylsalicylic acid** as the active substance. The tablets are designed for **oral use** and are administered once daily. The maximum daily dose is 100 mg, with a total maximum dose of 146 grams over a treatment period of 48 weeks. The medication is manufactured by Bayer Vital GmbH and is classified under the ATC code B01AC06.

Another experimental medication used in the trial is **Aspirin® protect 300 mg**, also formulated as a **gastro-resistant tablet** with **acetylsalicylic acid** as the active ingredient. This medication is administered orally once daily, with a maximum daily dose of 300 mg and a total maximum dose of 438 grams over the same 48-week treatment period. This product is also manufactured by Bayer Vital GmbH and shares the same ATC classification as the 100 mg formulation.

The study includes a **placebo** group to serve as a comparator. The placebo is designed to mimic the appearance of the **Aspirin® protect 100 mg** and **300 mg** tablets but does not contain any active pharmaceutical ingredients. The placebo is administered orally, following the same dosing schedule as the active treatments, to ensure blinding and maintain the integrity of the trial results.

The efficacy of the clinical trial will be assessed by evaluating the preventive effect of low-dose **aspirin** (100 mg or 300 mg daily) compared to placebo on the development of new or recurrent colorectal adenomas in patients with Lynch syndrome. The primary endpoint for efficacy assessment is the number of patients with at least one adenoma detected via chromoendoscopy 48 months after the complete removal of polyps and the initiation of the investigational medicinal product (IMP). Only neoplastic polyps, which have the potential to progress to cancer, will be considered. These include adenoma not otherwise specified, tubular adenoma, tubulovillous adenoma, mixed or serrated adenoma (sessile serrated adenoma), and villous adenoma. Additionally, the occurrence of cancers will be included in the primary endpoint analysis.

Secondary endpoints will further evaluate efficacy by measuring various parameters, including the delay between the onset of an adenoma after complete polyp resection and the start of treatment, the number of patients presenting an adenoma during follow-up based on specific gene mutations (MLH1, MSH2, MSH6, PMS2, or without other identified anomalies), and the load of serrated polyps after 24 and 48 months of treatment. The adenomatous polyp burden will be assessed by chromoendoscopy, measuring the sum of the size of all adenomatous polyps as a function of the aspirin dose. Other secondary endpoints include the number of colon cancers diagnosed during scheduled surveillance colonoscopies, the time to onset of colon cancer, and the number of colonoscopies performed during the study follow-up. Additional assessments will include the quality of preparation before colonoscopy, chromoendoscopy execution, counting of remaining tablets, and the number of events or side effects. The distribution of bacterial populations and polymorphisms based on treatment groups and recidivism will also be analyzed.