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Assessment of Direct Biomarkers of Aspirin Action to Develop a Precision Chemoprevention Therapy of Colorectal Cancer

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ClinicalTrials.gov Identifier: NCT03957902
Recruitment Status : Recruiting
First Posted : May 21, 2019
Last Update Posted : May 21, 2019
Sponsor:
Collaborators:
Instituto de Salud Carlos III
G. d'Annunzio University
Hospital Clínico Universitario Lozano Blesa
Information provided by (Responsible Party):
Ángel Lanas Arbeloa, Instituto de Investigación Sanitaria Aragón

Brief Summary:
Acetylsalicylic acid (ASA) seems the ideal colorectal cancer (CRC) chemoprevention agent. Several ongoing trials are testing the effect of ASA as co-therapy in CRC. The mechanisms of action, the appropriate dose and the ideal target population are unknown. The investigators have demonstrated that doses of 100 mg of ASA induce direct and partial but persistent acetylation of the cyclooxygenase (COX) isoenzyme COX-1 in the normal colorectal mucosa. The primary objective is to perform a study of aspirin by using a proteomic assay for comparing platelet COX-1 and CRC mucosal COX-1 after different doses of ASA. Secondary objectives are: the measurement of prostaglandin E2 (PGE2) and phosphorylated S6 protein (p-S6) levels in CRC mucosa, the assessment of indirect biomarker of aspirin action (serum thromboxane B2 (TXB2) and urinary levels of 11-dehydro-TXB2 (TX-M)), the evaluation of systemic biomarkers of inflammatory/tumorigenic COX-2 by assessing urinary levels of major metabolite of PGE2 (PGE-M). Methods: Phase II randomized clinical trial in 60 patients with newly diagnosed CRC in 3 groups of 20 patients receiving 100 or 300 mg/day, or 100 mg/12 hours of enteric-coated ASA for 3±1 weeks, prior to definitive treatment by surgery. Main outcome: Acetylation of COX-1 and COX-2. Eicosanoid levels in target organs. Expected results: Evidence for the current uncertainty about the mechanisms of action and the dose required to obtain the best chemopreventive effect with ASA in CRC. Confirm acetylation of COX as a key biomarker of efficacy with ASA.

Condition or disease Intervention/treatment Phase
Colorectal Cancer Drug: acetylsalicylic acid Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 60 participants
Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Prevention
Official Title: Assessment of Direct Biomarkers of Aspirin Action to Develop a Precision Chemoprevention Therapy of Colorectal Cancer
Actual Study Start Date : May 6, 2019
Estimated Primary Completion Date : May 2020
Estimated Study Completion Date : May 2020

Resource links provided by the National Library of Medicine

Drug Information available for: Aspirin

Arm Intervention/treatment
Experimental: Arm 1 (100 mg/24h) Drug: acetylsalicylic acid
Different dosage effect over platelet COX enzymes, non- neoplastic and neoplastic colonic tissues used as biomarkers of clinical efficacy in CRC chemoprevention

Experimental: Arm 2 (300 mg/24h) Drug: acetylsalicylic acid
Different dosage effect over platelet COX enzymes, non- neoplastic and neoplastic colonic tissues used as biomarkers of clinical efficacy in CRC chemoprevention

Experimental: Arm 3 (100 mg/12h) Drug: acetylsalicylic acid
Different dosage effect over platelet COX enzymes, non- neoplastic and neoplastic colonic tissues used as biomarkers of clinical efficacy in CRC chemoprevention




Primary Outcome Measures :
  1. Assessment of changes in acetylation levels of COX enzymes in platelets and non-neoplastic and neoplastic colonic tissues [ Time Frame: before the beginning of the treatment and 3 ± 1 weeks of acetylsalicylic acid treatment ]

Secondary Outcome Measures :
  1. Assessment of changes in prostaglandin E2 (PGE2) levels in colorectal mucosa depending on drug dosis [ Time Frame: before the beginning of the treatment and 3 ± 1 weeks of acetylsalicylic acid treatment ]
  2. Assessment of changes in phosphorylated S6 protein (p-S6) levels in colorectal mucosa depending on drug dosis [ Time Frame: before the beginning of the treatment and 3 ± 1 weeks of acetylsalicylic acid treatment ]
  3. Assessment of changes in thromboxane B2 (TxB2) levels in urine as indirect systemic biomarker depending on drug dosis [ Time Frame: before the beginning of the treatment and 3 ± 1 weeks of acetylsalicylic acid treatment ]
  4. Assessment of changes in urinary metabolite 11-dehydro-TxB2 (TX-M) levels as indirect systemic biomarker depending on drug dosis [ Time Frame: before the beginning of the treatment and 3 ± 1 weeks of acetylsalicylic acid treatment ]
  5. Assessment of changes in major urinary metabolite of PGE2 (PEG-M) levels depending on drug dosis [ Time Frame: before the beginning of the treatment and 3 ± 1 weeks of acetylsalicylic acid treatment ]


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Ages Eligible for Study:   18 Years to 79 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • age ≥ 18 < 80 years old
  • recent diagnosis (< 48h) of rectum or colon cancer, established by endoscopy and later confirmed by anatomo-pathologic study
  • normal coagulation values and biochemical vales without clinically significant deviations that, at the discretion of the investigator, may interfere with the study procedures

Exclusion Criteria:

  • Allergy to ASA or to any other NSAID.
  • Rectal cancer requiring neoadjuvant treatment within the two weeks following the beginning of ASA treatment.
  • Previous use of ASA, NSAIDs, antiplatelet agents, corticosteroids or misoprostol within the 15 days prior to diagnosis and/or anticipation of need for treatment with any of these drugs during the study period. History of peptic ulcer disease or active peptic ulcer or any other gastrointestinal disease that may be considered a contraindication to the use of ASA, without the concomitant use of proton pump inhibitors.
  • Diagnosis of bleeding disorders.
  • Diagnosis of cancer (excluding non-melanoma skin cancer) within the previous 3 years.
  • Conditions supposing serious comorbidity, excluding diabetes, and including respiratory, cardiac, hepatic and renal diseases.
  • Active smoking.
  • Pregnancy or breastfeeding.
  • History of drug or alcohol abuse.

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): NCT03957902


Contacts
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Contact: Ángel Lanas Arbeloa, MD 0034976765786 angel.lanas@gmail.com

Locations
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Spain
Hospital Clínico Universitario Lozano Blesa Recruiting
Zaragoza, Spain, 50009
Contact: Ángel Lanas Arbeloa, MD    0034976765786    angel.lanas@gmail.com   
Sponsors and Collaborators
Instituto de Investigación Sanitaria Aragón
Instituto de Salud Carlos III
G. d'Annunzio University
Hospital Clínico Universitario Lozano Blesa
Investigators
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Principal Investigator: Ángel Lanas Arbeloa, MD Instituto de Investigación Sanitaria Aragón

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Responsible Party: Ángel Lanas Arbeloa, Head of Digestive Diseases Service, Instituto de Investigación Sanitaria Aragón
ClinicalTrials.gov Identifier: NCT03957902     History of Changes
Other Study ID Numbers: PI17/01109
2018-002101-65 ( EudraCT Number )
First Posted: May 21, 2019    Key Record Dates
Last Update Posted: May 21, 2019
Last Verified: May 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Additional relevant MeSH terms:
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Colorectal Neoplasms
Intestinal Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Neoplasms
Digestive System Diseases
Gastrointestinal Diseases
Colonic Diseases
Intestinal Diseases
Rectal Diseases
Aspirin
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
Platelet Aggregation Inhibitors
Cyclooxygenase Inhibitors
Enzyme Inhibitors
Antipyretics