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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

Tracking Information
First Submitted Date  ICMJE April 25, 2014
First Posted Date  ICMJE April 29, 2014
Last Update Posted Date May 5, 2014
Study Start Date  ICMJE May 2014
Estimated Primary Completion Date May 2015   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: April 28, 2014)
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.
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT02125409 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: May 2, 2014)
  • 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.
  • 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).
  • 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
  • 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.
  • 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.
  • 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.
  • 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.
Original Secondary Outcome Measures  ICMJE
 (submitted: April 28, 2014)
  • 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:
    • 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.
  • Cahnges 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).
  • 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
  • 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.
  • 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.
  • 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.
  • 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.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Acetylsalicylic Acid and Colorectal Cancer Prevention: Exploring the Platelet Function of Its Mechanism of Action
Official Title  ICMJE Acetylsalicylic Acid and Colorectal Cancer Prevention: Exploring the Platelet Function of Its Mechanism of Action.
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%).

Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Prevention
Condition  ICMJE Colorectal Cancer
Intervention  ICMJE
  • Drug: Acetylsalicylic acid
    One tablet of Adiro 100 mg will be administered daily for 7 days.
    Other Names:
    • Adiro 100
    • ASA
  • Procedure: Screening colonoscopy
Study Arms  ICMJE
  • 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.
    Interventions:
    • Drug: Acetylsalicylic acid
    • 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.
    Interventions:
    • Drug: Acetylsalicylic acid
    • Procedure: Screening colonoscopy
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Unknown status
Estimated Enrollment  ICMJE
 (submitted: April 28, 2014)
40
Original Estimated Enrollment  ICMJE Same as current
Study Completion Date  ICMJE Not Provided
Estimated Primary Completion Date May 2015   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 69 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Spain
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02125409
Other Study ID Numbers  ICMJE D-13-01
2013-004269-15 ( EudraCT Number )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Aragon Institute of Health Sciences
Study Sponsor  ICMJE Aragon Institute of Health Sciences
Collaborators  ICMJE
  • G. d'Annunzio University
  • Catholic University, Italy
Investigators  ICMJE
Principal Investigator: Angel Lanas Arbeloa, Physician Digestive disease service of Hospital Clinico Lozano Blesa
PRS Account Aragon Institute of Health Sciences
Verification Date May 2014

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP