AAS-Lynch - Assessment of the effect of a daily chemoprevention by aspirin low-dose of new or recurrent colorectal adenomas in patients with Lynch syndrome

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Assistance Publique Hopitaux De Paris

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

14 Nov 2017 → ongoing

Decision date (initial)

2024-09-25

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

External identifiers

EU CT number

2024-516601-23-00

EudraCT number

2014-001464-35

ClinicalTrials.gov

NCT02813824

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Prophylaxis, Efficacy

To explore a preventive effect of aspirin low-dose (100 or 300 mg/d) compared with placebo on apparition of a new or recurrent colorectal adenomas in patients with Lynch syndrome.

Secondary objectives 16

1. To compare the time to occurrence of the first adenoma between the treatment group and the placebo group
2. Determine the recurrence or occurrence of colorectal neoplasms according to various germline alterations in mismatch repair genes.
3. Determine if there is a dose-response effect of aspirin on adenomatous polyp burden.
4. Determine if there is a dose-response effect of aspirin on polyp burden.
5. Compare the burden of serrated polyps detected by chromo-endoscopy as the number of serrated polyps after 24 and 48 months between the two groups.
6. Compare the frequency and time to occurrence of diagnosed colorectal cancers between two groups (treated / untreated).
7. Compare the frequency and time to occurrence of interval colorectal cancers between two groups (treated / untreated).
8. Compare the frequency of scheduled surveillance colonoscopies between the two groups.
9. Evaluate the quality of colonoscopy preparation in Lynch syndrome.
10. Evaluate the frequency of chromoendoscopies performed.
11. Determine complaince to chemoprevention in patient with Lynch syndrome.
12. Study tolerance.
13. Study dietary habits of voluntarily enrolled subjects to complete a dietary frequency questionnaire.
14. Study the microbiota of subjects with Lynch syndrome.
15. Study nucleotide polymorphisms according to the appearance of neoplasia in treated and untreated groups.
16. Investigate the preventive effect of low-dose aspirin (100 or 300 mg/day) on the occurrence or recurrence of colorectal adenomas or hyperplastic polyps.

Conditions and MedDRA coding

Colorectal adenomas

Study design 1 period

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 8

1. Men and women 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
2. 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
3. Aged less than 75 years
4. A colonoscopy done within 180 days prior to inclusion, with removal of all polyps endoscopically resectable
5. Patients accept that not use aspirin regularly all along the study (during 7 consecutive days during at least 3 weeks per year or during more than 21 days per year)
6. Effective contraception for womens of childbearing age, defined by a hormonal method, an intrauterine device (IUD), or surgical sterilization of the patient or her partner
7. Patients covered by French Social Security (AME not accepted)
8. Patients signed informed consent

Exclusion criteria 22

1. History of total colectomy
2. Adenomatous polyposis related to a known alteration of the APC gene or the MYH gene
3. Allergy to aspirin (including a history of asthma induced by the administration of salicylates or substances with similar activity, including non-steroidal anti-inflammatory)
4. Allergy to one food coloring potentially used in a chromo-endoscopy (indigo carmine, for example)
5. 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)
6. Need for a prolonged and high-dose systemic glucocorticoid therapy
7. Known disease affecting primary hemostasis or coagulation (gastrointestinal bleeding, hemorrhagic stroke and thrombocytopenia history)
8. Need for a prolonged anticoagulant, antiplatelet agents, anagrelide, uricosurics, probenecid, ticagrelor, nicorandil, defibrotide, clopidogrel, ticlopidine, ticagrelor, ibrutinib, or cobimetinib
9. History of gastro-duodenal ulcer
10. Gastrointestinal bleeding linked to ulcerative disease in the previous 12 months before inclusion
11. Gastric pathology deemed significant by the investigator and not corrected by appropriate treatment
12. Uncontrolled hypertension
13. Kidney failure (creatinine clearance < 30 ml/mn)
14. Severe hepatic impairment (defined as TP <70%)
15. Severe uncontrolled heart failure
16. G6PD deficiency
17. Recent diagnosis of colorectal cancer implying a specific management
18. Menorrhagia deemed significant by the investigator and not corrected by appropriate treatment
19. Pregnancy or breast feeding
20. Any disease susceptible to interfere with protocol-defined follow-up or to impair the comprehension of the information provided by the protocol and informed consent
21. Patient waiting for or have been signified a justice decision
22. Participation to another clinical trial during the 12 weeks before inclusion

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Number of patients with at least 1adenoma on chromoendoscopy 48months after complete withdrawal of polyps and initiation of IMP. Only neoplastic polyps (progress to cancer), defined by the following histological types as determined by ACP result, will be considered: 1) Adenoma not otherwise specified 2) Tubular adenoma 3) Tubulovillous adenoma 4) Mixed or serrated adenoma (sessile serrated adenoma) 5) Villous adenoma. Additionally, cancers will also be considered for primary endpoint analysis

Secondary endpoints 18

1. Delay between the onset of 1 adenoma after complete resection of polyps and date of start of treatment (aspirin vs placebo)
2. Number of patients who presented an adenoma during follow-up based on the gene reached (MLH1, MSH2, MSH6, PMS2, or without other identified anomalies)
3. Load serrated polyps after 24 and 48 months of treatment
4. Adenomatous polyp burden, measured by chromoendoscopy as the sum of the size of all adenomatous polyps as a function of the dose of ASA (100 or 300 mg)
5. Load measured by polyps chromoendoscopy as the sum of the size of all polyps according to the aspirin dose (100 or 300mg)
6. Colon cancers diagnosed during the scheduled surveillance colonoscopies
7. Time to onset of colon cancer diagnosed during the scheduled surveillance colonoscopies
8. Cancers of the colon interval (diagnosed between 2 surveillance colonoscopies programmed)
9. Time to onset of interval colorectal cancer
10. Number of colonoscopies performed during follow-up in study
11. Quality of preparation before colonoscopy
12. Chromoendoscopy expected execution
13. Counting of remaining tablets in blisters
14. Number of events or side effects
15. Food frequency
16. Distribution of the bacterial population based on two groups (treated / untreated) and recidivism
17. Distribution of polymorphisms based on 2 groups (treated / untreated) and recidivism
18. Proportion of patients with at least one adenoma seen on chromo-endoscopy within 48 months after complete polyp resection and the start of treatment (aspirin vs placebo)

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 2

Placebo 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Assistance Publique Hopitaux De Paris

Sponsor organisation

Assistance Publique Hopitaux De Paris

Address

Porte 23, 1 Avenue Claude Vellefaux 1 Avenue Claude Vellefaux

City

Paris Cedex 10

Postcode

75475

Country

France

Scientific contact point

Organisation

Assistance Publique Hopitaux De Paris

Contact name

Pr. Robert BENAMOUZIG (Coordinating investigator)

Public contact point

Organisation

Assistance Publique Hopitaux De Paris

Contact name

Pr. Robert BENAMOUZIG (Coordinating investigator)

Locations

1 EU/EEA country · 29 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 9 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

2 submissions — initial application plus substantial / non-substantial modifications