Clinical trial NCT02060396: Study of Biochemical Markers to Determine the Acetylsalicylic Acid Chemopreventive Effect Through Antiplatelet Action
Official title: Study of Biochemical Markers to Determine the Acetylsalicylic Acid Chemopreventive Effect Through Antiplatelet Action
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Healthy Volunteers
Lead sponsor: Aragon Institute of Health Sciences
Sponsor class: OTHER
First posted: 2014-02-12
Enrollment: 24
Sex: ALL
Minimum age (years): 18
Maximum age (years): 45
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: PREVENTION

Brief summary: This study in healthy volunteers is the first step in developing a collaborative research program, which seeks to test the hypothesis that chemopreventive effect of acetylsalicylic acid (ASA) on colon cancer is due predominantly to its antiplatelet effect.

The following features of the clinical evidence are consistent with the platelet-mediated hypothesis:

1. The apparent saturability of the chemopreventive effect of ASA at low doses given once daily, found in long-term analyses of cardiovascular and adenoma recurrence randomized clinical trial, as well as in the vast majority of observational studies performed in different settings and with different methodology. A remarkably similar saturability of the cardioprotective effect of low dose ASA given once daily is explained by the irreversible nature of cyclooxygenase (COX)-1 inactivation in platelets, and limited capacity of human platelets for de novo protein synthesis.
2. Given the short half-life of ASA in the human circulation (approximately 20 min) and the capacity of nucleated cells to resynthesize the acetylated COX-isozyme(s), it seems unlikely that a nucleated target could be suppressed throughout the 24-h dosing interval.
3. One of the cardiovascular randomized clinical trial (Thrombosis Prevention Trial) in which the chemopreventive effect of ASA was detected on long-term follow-up, involved the administration of a controlled-release formulation of ASA (75 mg) with negligible systemic bioavailability.
4. Enhanced platelet activation and thromboxane (TX)A2 generation in vivo has been demonstrated in patients with colorectal cancer and in Familial Adenomatous Polyposis patients.

So, the main objective of this study is to assess the extent of acetylation at serine-529 of platelet COX-1 after the 1st and 7th dose of low-doseof enteric-coated ASA 100 mg daily. Changes of this novel biomarker of ASA action will be correlated to other known parameters of ASA PK and PD: i) Tmax, Cmax and AUC of ASA and salicylate in the peripheral circulation after oral dosing; ii) time to obtain the maximal antiplatelet effect by ASA and its persistence throughout the dosing interval as assessed by measuring the inhibition of platelet COX-1 activity in whole blood ex vivo, the inhibition of platelet aggregation in whole blood ex vivo and the inhibition of the systemic generation of TXB2.

Detailed description: This study will be performed in healthy subjects, under fasting conditions, and it will allow to acquire more information on the pharmacokinetics (PK) and pharmacodynamics (PD) of low-dose enteric-coated ASA, and to characterize 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. This biomarker will be then used in another clinical study in the target population, i.e. FAP patients, treated with low-dose ASA which that will be performed by Prof Angel Lanas (University of Zaragoza, Spain).

Twenty four healthy volunteers recruited among the hospital and laboratory personnel will be enrolled and treated with ASA (100 mg enteric-coated tablet per day, Adiro) for 1 week.

Blood samples will be collected at baseline (before treatment) and at 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12 and 24 h after the first and the last dose of ASA to assess the extent of inhibition of serum TXB2, as an index of platelet COX-1 activity, and plasma levels of ASA and salicylate and the extent of COX-1 acetylation in circulating platelets. Moreover, the investigators will assess the extent of inhibition of platelet aggregation in whole blood by the PFA-100 system. Twenty four hours urine samples will be also collected to measure 11-dehydro-TXB2 (TX-M), an index of systemic TXA2 biosynthesis in vivo.

Healthy subjects will take their daily ASA under fasting conditions and will abstain from the use of ASA and other NSAIDs for at least 2 weeks before enrolment.

All volunteers will be attended at the Clinical Research Unit of the University Hospital Lozano Blesa.

Eligibility criteria: Inclusion Criteria:

* Men and women, aged ≥ 18 and ≤ 45.
* No potential contraindication to ASA.
* Unaltered history and physical examination.
* Unchanged hematological and biochemical laboratory parameters.
* Hematological parameters consistent with the current rules for blood donation.
* Negative urine pregnancy test.
* Negative serology for HIV, hepatitis B and C, alcohol intake and drug abuse.

Exclusion Criteria:

* Active cigarette smokers.
* Coagulation disorders.
* Allergy to ASA or any other NSAID.
* History of any gastrointestinal disorder.
* Pregnant women

Primary outcomes:
measure: Assessment of the extenet of acetylation at serine-529 of platelet COX-1 during 1 week
timeFrame: 3 days before the 1st dose and at 0.5, 2, 4, 8 and 24 h after the 1st and the 7th daily dose of enteric-coated aspirin, blood samples will be collected to assess: - platelet COX-1 acetylation - serum TXB2 levels - whole blood aggregation
Secondary outcomes:
measure: Change from baseline in quantification acetylation COX-1 in the circulating platelets during 1 week
timeFrame: 3 days before the 1st dose and at 0.5, 2, 4, 8 and 24 h after the 1st and the 7th dose of aspirin, blood samples will be collected to assess: - platelet COX-1 acetylation - serum TXB2 levels - whole blood aggregation
measure: Change from baseline in urinary levels of 11-dehydro-TXB2 (TX-M) during 1 week
timeFrame: 1 day before the 1st dose aspirin administration and after the 6thdose of aspirin, all subjects will perform a 24 h urine collection.
measure: Change from baseline in whole blood platelet aggregation during 1 week
timeFrame: 3 days before the 1st dose and at 0.5, 2, 4, 8 and 24 h after the 1st and the 7th dose of aspirin, blood samples will be collected to assess: - platelet COX-1 acetylation - serum TXB2 levels - whole blood aggregation
measure: Change from baseline in plasma levels of aspirin and salicylate during 1 week.
timeFrame: On day 1 and day 7, at pre-drug (baseline) and at 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12 and 24 h after dosing all subjects will undergo a blood sample collection to assess: - aspirin and salicylate plasma levels.
Other outcomes:
Locations:
city: Zaragoza
country: Spain
facility: Hospital clinico Universitario Lozano Blesa
Study officials:
affiliation: Digestive disease service of Hospital Clinico Lozano Blesa
name: Angel Lanas, Physician
role: PRINCIPAL_INVESTIGATOR
References: