Clinical trial NCT02125409: Acetylsalicylic Acid and Colorectal Cancer Prevention: Exploring the Platelet Function of Its Mechanism of Action
Official title: Acetylsalicylic Acid and Colorectal Cancer Prevention: Exploring the Platelet Function of Its Mechanism of Action.
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE3
Conditions: Colorectal Cancer
Lead sponsor: Aragon Institute of Health Sciences
Sponsor class: OTHER
Collaborators: name: G. d'Annunzio University
name: Catholic University, Italy
First posted: 2014-04-29
Enrollment: 40
Sex: ALL
Minimum age (years): 18
Maximum age (years): 69
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: In a preliminary study in healthy subjects, the investigators determined the pharmacokinetic and pharmacodynamic of enteric-coated acetylsalicylic acid (ASA) (Adiro 100 mg, Bayer), and the variability (coefficient of variation), accuracy and precision of a novel biomarker of ASA action, i.e., quantification of the extent of COX-1 acetylation at serine-529, using a stable isotope dilution liquid chromatography multiple reaction monitoring/mass spectrometry (LC-MS) technique.

Now, the investigators will perform a clinical study in individuals undergoing Colorectal cancer (CRC) to validate the hypothesis that that low-dose ASA given once daily is acting primarily by selectively acetylating platelet COX-1 and suppressing its activity throughout the 24-hour dosing interval. In contrast, it is expected that the inhibitory effect on extra-platelet sources of COX-1 will be short-lasting, if any, affecting only partially COX-1, and this effect will be completely reversed at 24 hours after dosing. This is an important point which will strengthen the platelet hypothesis underpinning the apparent adequacy of a 24-hour dosing interval of ASA administration for the anticancer effect detected in cardiovascular trials.

These patients will be stratified into individuals with adenomas/carcinomas (20 to 30%) and patients without clinically detected adenomas/carcinomas (about 70 to 80%).


Eligibility criteria: Inclusion Criteria:

1. Men and women, aged ≥ 18 and ≤ 69.
2. Patients should have an indication for screening colonoscopy

   1. First degree relative of patient with CRC.
   2. Personal history of adenomas.
   3. People older than 50 and FOBT positive
3. Routine hematological and biochemical parameters within the normal range.

Exclusion Criteria:

1. Allergy to ASA or other NSAIDs.
2. Previous use of ASA, NSAIDS, antiplatelet agents, corticosteroids or misoprostol in the previous 15 days and/or anticipated need for these drugs during the study period.
3. Peptic ulcer history or any other gastrointestinal disease that could be considered a contraindication for ASA use without the concomitant use of a proton-pump inhibitor.
4. Subjects with coagulation disorder or serious comorbid condition.
5. Malignancies, excluding CRC, diagnosed in the previous 5 years
6. Cigarette smoking, history of drug or alcohol abuse
7. Pregnant women or breast feeding

Primary outcomes:
measure: Assessment of the degree of COX-1 acetylation by ASA administered for 1 week.
timeFrame: 7 hours after the 7th daily dose (group 1) and 24 hours after the 7th daily dose (group 2)
Secondary outcomes:
measure: Changes from baseline in different biomarkers.
timeFrame: pre-drug on day 0 and after the 7th daily dose (6 hours for Group 1 and 24 hours for Group 2)
measure: Changes from baseline in eicosanoid generation in vivo by measuring urinary metabolites derived from COXs.
timeFrame: pre-drug on day 0 and after the 7th daily dose (6 hours for Group 1 and 24 hours for Group 2)
measure: Changes in baseline platelet COX-1
timeFrame: pre-drug on day 0 and after the 7th daily dose (6 hours for Group 1 and 24 hours for Group 2)
measure: Change from baseline in plasma proteins of markers of angiogenesis.
timeFrame: pre-drug on day 0 and after the 7th daily dose (6 hours for Group 1 and 24 hours for Group 2)
measure: Assessment of ASA plasma levels.
timeFrame: pre-drug on day 0 and after the 7th daily dose (6 hours for Group 1 and 24 hours for Group 2)
measure: Changes from baseline of proteomic profile of selected angiogenesis factors, ie VEGF, FGF2, TGFbeta, EGF, PDGF, MMP, angiogenin, and angiogenesis inhibitors, ie endostatin, PF4, thrombospondin 1, alpha-macroglobulin, PAI 1 and angiostatin.
timeFrame: pre-drug on day 0 and after the 7th daily dose (6 hours for Group 1 and 24 hours for Group 2)
measure: Change from baseline in eicosanoid biosynthesis and protein expression of markers of growth and progression of colorectal cancer (such as COX-2, NF-Kb and PI3K/Akt/mTOR pathway).
timeFrame: pre-drug on day 0 and after the 7th daily dose (6 hours for Group 1 and 24 hours for Group 2)
Other outcomes:
Locations:
city: Zaragoza
country: Spain
facility: Hospital Clínico Universitario Lozano Blesa
Study officials:
affiliation: Digestive disease service of Hospital Clinico Lozano Blesa
name: Angel Lanas Arbeloa, Physician
role: PRINCIPAL_INVESTIGATOR
References: