Clinical trial NCT02497820: Finding the Best Dose of Aspirin to Prevent Lynch Syndrome Cancers
Official title: A Randomised Double Blind Dose Non-inferiority Trial of a Daily Dose of 600mg Versus 300mg Versus 100mg of Enteric Coated Aspirin as a Cancer Preventive in Carriers of a Germline Pathological Mismatch Repair Gene Defect, Lynch Syndrome
Study type: INTERVENTIONAL
Overall status: NOT_YET_RECRUITING
Phase: PHASE3
Conditions: Lynch Syndrome I (Site-specific Colonic Cancer)
Lead sponsor: Tel-Aviv Sourasky Medical Center
Sponsor class: OTHER_GOV
Collaborators: name: Rambam Health Care Campus
name: Rabin Medical Center
name: Soroka University Medical Center
name: Sheba Medical Center
First posted: 2015-07-15
Enrollment: 1800
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: A randomised double blind dose non-inferiority trial of a daily dose of 600mg versus 300mg versus 100mg of enteric coated aspirin as a cancer preventive in carriers of a germline pathological mismatch repair gene defect, Lynch Syndrome. Project 3 in the Cancer Prevention Programme (CaPP3).

Detailed description: Study design: A randomised, double-blind, dose non-inferiority study.

Study Intervention: Enteric-coated aspirin 100mg, 300mg or 600mg blinded dose daily followed by daily 100mg open label dose daily.

Primary objective: To determine whether the cancer preventive properties of enteric coated aspirin in Lynch syndrome are dose sensitive by comparing overall cumulative Lynch syndrome cancer incidence rates after 5 years in people who took 100mg, 300mg or 600mg enteric coated aspirin for at least 2 years.

Secondary objectives: Compare overall cumulative incidence of primary colorectal cancers using Poisson regression to allow for multiple primaries in individual patients in the three treatment groups.

Compare overall cumulative incidence of primary endometrial cancers using Poisson regression to allow for multiple primaries in individual patients in the three treatment groups.

Compare overall cumulative incidence of cancers of all types, using Poisson regression to allow for multiple primaries in individual patients in the three treatment groups.

The burden of adverse events associated with the different aspirin doses in this relatively young and healthy population will be documented.

Primary outcome: The number of new primary mismatch repair deficient cancers ("Lynch syndrome cancers") at 5 years and beyond which develop in participants who remain on prescribed treatment for a minimum of 2 years.

Number of study sites: 4 ISRAEL sites. 20 sites all over the world.

Study population/size: 300 patients in ISRAEL. UK 1000-1500 patients. Total with International 3,000 patients.

Study duration: 7 years.

Eligibility criteria: Inclusion Criteria:

1. Male or female patients ≥ 18 years.
2. Confirmed germline pathological variant in one of the mismatch repair genes; MSH2, MLH1, PMS2 or MSH6 or a 3' EPCAM deletion associated with MSH2 silencing or be a carriers of a constitutional epimutation manifesting a classic Lynch syndrome phenotype.
3. Able to swallow tablets.
4. Provision of voluntary written informed consent.

Exclusion Criteria:

1. Regular use of a non-steroidal anti-inflammatory agent (except aspirin\*) on a prescription and/or long-term basis. Regular is defined as \> 3 doses per week.
2. Regular use of aspirin (\> 3 doses per week or on a prescription basis) that cannot be replaced with any one of the randomised arms of the study followed by 100mg dose.
3. Current methotrexate use at a weekly dose of ≥ 15mg.
4. Known aspirin intolerance or hypersensitivity, including aspirin-sensitive asthma.
5. Existing clinically significant liver impairment.
6. Existing renal failure.
7. Confirmed active peptic ulcer disease within the previous three months.
8. Known bleeding diathesis or concomitant warfarin therapy.
9. Inability to comply with study procedures and agents.
10. Women reporting that they are pregnant or actively planning to achieve a pregnancy within the next two years.
11. Women who are breastfeeding.
12. Any significant medical illness that would interfere with study participation.

    * Previous use of aspirin for medicinal purposes does not exclude enrolment but duration and quantity need to be documented in detail

Primary outcomes:
measure: cancer preventive properties of enteric coated aspirin in Lynch syndrome are dose sensitive by comparing overall cumulative Lynch syndrome cancer
timeFrame: 5 years
Secondary outcomes:
measure: Overall cumulative of new colorectal cancers incidence rates after 5 years
timeFrame: 5 years
measure: Overall cumulative of new endometrial cancers incidence rates after 5 years
timeFrame: 5 years
measure: Overall cumulative of new new cancers of all types incidence rates after 5 years
timeFrame: 5 years
measure: Overall cumulative of changes in the titre of frameshift peptide antibodies after 2 & 5 years
timeFrame: 5 years
measure: Overall cumulative of of new adenomas at five years
timeFrame: 5 years
Other outcomes:
Locations:
city: Tel Aviv
country: Israel
facility: Sourasky Medical Center
Study officials:
affiliation: Tel-Aviv Sourasky Medical Center
name: Nadir Arber, MD, MSc, MHA
role: PRINCIPAL_INVESTIGATOR
References: