Study of Biochemical Markers to Determine the Acetylsalicylic Acid Chemopreventive Effect Through Antiplatelet Action
Condition: Healthy Volunteers
Study type: Interventional
Phase: Phase 1

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.
    

Intervention name(s): Acetylsalicylic acid
Intervention type(s): Drug
Intervention description(s): One tablet of Adiro 100 mg will be administered daily orally for 7 days.
Other intervention name(s): Adiro 100
Intervention MeSH terms: Aspirin
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Prevention