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Acetylsalicylic Acid and Colorectal Cancer Prevention: Exploring the Platelet Function of Its Mechanism of Action

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ClinicalTrials.gov Identifier: NCT02125409
Recruitment Status : Unknown
Verified May 2014 by Aragon Institute of Health Sciences.
Recruitment status was:  Not yet recruiting
First Posted : April 29, 2014
Last Update Posted : May 5, 2014
Sponsor:
Collaborators:
G. d'Annunzio University
Catholic University, Italy
Information provided by (Responsible Party):
Aragon Institute of Health Sciences

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%).


Condition or disease Intervention/treatment Phase
Colorectal Cancer Drug: Acetylsalicylic acid Procedure: Screening colonoscopy Phase 3

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 40 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Prevention
Official Title: Acetylsalicylic Acid and Colorectal Cancer Prevention: Exploring the Platelet Function of Its Mechanism of Action.
Study Start Date : May 2014
Estimated Primary Completion Date : May 2015

Resource links provided by the National Library of Medicine

Drug Information available for: Aspirin

Arm Intervention/treatment
Experimental: Group 1
Group 1, individuals will be treated with ASA for 1 week; then blood and tissue samples (during the screening colonoscopy) will be collected at from 6-7 h after the last dose of ASA.
Drug: Acetylsalicylic acid
One tablet of Adiro 100 mg will be administered daily for 7 days.
Other Names:
  • Adiro 100
  • ASA

Procedure: Screening colonoscopy
Experimental: Group 2
Group 2, individuals will be treated with ASA for 1 week; then blood and tissue samples (during the screening colonoscopy) will be collected at 24 hours after the last dose.
Drug: Acetylsalicylic acid
One tablet of Adiro 100 mg will be administered daily for 7 days.
Other Names:
  • Adiro 100
  • ASA

Procedure: Screening colonoscopy



Primary Outcome Measures :
  1. Assessment of the degree of COX-1 acetylation by ASA administered for 1 week. [ Time Frame: 7 hours after the 7th daily dose (group 1) and 24 hours after the 7th daily dose (group 2) ]
    It will be performed in platelets versus biopsies of the recto-colonic tissues.


Secondary Outcome Measures :
  1. Changes from baseline in different biomarkers. [ Time Frame: pre-drug on day 0 and after the 7th daily dose (6 hours for Group 1 and 24 hours for Group 2) ]

    It will be used a combining technique of liquid chromatography with mass spectrometry (LC-MS/MS) to quantify the level of acetylation of COX-1 in circulating platelets in subjects treated with ASA.

    Parameters of the composite measure:

    • haemochrome, AST, ALT, gamma-GT, alkaline phosphatase (AP), total bilirubin, total protein, glucose, creatinine, N, Na, K, Ca.
    • urine analysis: pH, protein, albumin, glucose, RBC, bilirubin, nitrites, leucocytes and sediment.

  2. Changes from baseline in eicosanoid generation in vivo by measuring urinary metabolites derived from COXs. [ Time Frame: pre-drug on day 0 and after the 7th daily dose (6 hours for Group 1 and 24 hours for Group 2) ]
    It will be performed by ultra-performance liquid chromatography tandem mass spectrometry-mass spectrometry (UPLC/MS/MS).

  3. Changes in baseline platelet COX-1 [ Time Frame: pre-drug on day 0 and after the 7th daily dose (6 hours for Group 1 and 24 hours for Group 2) ]
    By using human whole blood assay (serum TXB2) ex vivo

  4. Change from baseline in plasma proteins of markers of angiogenesis. [ Time Frame: pre-drug on day 0 and after the 7th daily dose (6 hours for Group 1 and 24 hours for Group 2) ]
    In blood sample by using an antibody array kit and Sphingosine-1 Phosphate (S1P) by immunoassay.

  5. Assessment of ASA plasma levels. [ Time Frame: pre-drug on day 0 and after the 7th daily dose (6 hours for Group 1 and 24 hours for Group 2) ]
    Will be performed whole blood aggregation test.

  6. 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. [ Time Frame: pre-drug on day 0 and after the 7th daily dose (6 hours for Group 1 and 24 hours for Group 2) ]
    It will be done in isolated platelets by using an antibody array kit and Sphingosine-1 Phosphate (S1P) by immunoassay.

  7. 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). [ Time Frame: pre-drug on day 0 and after the 7th daily dose (6 hours for Group 1 and 24 hours for Group 2) ]
    It will be done in normal tissues or pathological recto-colonic tissues.



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Ages Eligible for Study:   18 Years to 69 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02125409


Locations
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Spain
Hospital Clínico Universitario Lozano Blesa Not yet recruiting
Zaragoza, Spain, 50009
Contact: Angel Lanas Arbeloa, Physician    +34 976 765786    alanas@unizar.es   
Principal Investigator: Angel Lanas Arbeloa, Physician         
Sponsors and Collaborators
Aragon Institute of Health Sciences
G. d'Annunzio University
Catholic University, Italy
Investigators
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Principal Investigator: Angel Lanas Arbeloa, Physician Digestive disease service of Hospital Clinico Lozano Blesa

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Responsible Party: Aragon Institute of Health Sciences
ClinicalTrials.gov Identifier: NCT02125409     History of Changes
Other Study ID Numbers: D-13-01
2013-004269-15 ( EudraCT Number )
First Posted: April 29, 2014    Key Record Dates
Last Update Posted: May 5, 2014
Last Verified: May 2014

Additional relevant MeSH terms:
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Aspirin
Platelet Aggregation Inhibitors
Colorectal Neoplasms
Intestinal Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Neoplasms
Digestive System Diseases
Gastrointestinal Diseases
Colonic Diseases
Intestinal Diseases
Rectal Diseases
Anti-Inflammatory Agents, Non-Steroidal
Analgesics, Non-Narcotic
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Anti-Inflammatory Agents
Antirheumatic Agents
Fibrinolytic Agents
Fibrin Modulating Agents
Molecular Mechanisms of Pharmacological Action
Cyclooxygenase Inhibitors
Enzyme Inhibitors
Antipyretics