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出境医 / 临床实验 / Assessment of Direct Biomarkers of Aspirin Action to Develop a Precision Chemoprevention Therapy of Colorectal Cancer

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

Study Description
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

Study Design
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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
Arms and Interventions
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
Outcome Measures
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 ]

Eligibility Criteria
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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.
Contacts and Locations

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
Tracking Information
First Submitted Date  ICMJE May 13, 2019
First Posted Date  ICMJE May 21, 2019
Last Update Posted Date May 21, 2019
Actual Study Start Date  ICMJE May 6, 2019
Estimated Primary Completion Date May 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: May 20, 2019) 		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 ]
Original Primary Outcome Measures  ICMJE Same as current
Change History No Changes Posted
Current Secondary Outcome Measures  ICMJE
 (submitted: May 20, 2019)
  • 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 ]
  • 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 ]
  • 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 ]
  • 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 ]
  • 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 ]
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Assessment of Direct Biomarkers of Aspirin Action to Develop a Precision Chemoprevention Therapy of Colorectal Cancer
Official Title  ICMJE Assessment of Direct Biomarkers of Aspirin Action to Develop a Precision Chemoprevention Therapy of Colorectal Cancer
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.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Prevention
Condition  ICMJE Colorectal Cancer
Intervention  ICMJE 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
Study Arms  ICMJE
  • Experimental: Arm 1 (100 mg/24h)
    Intervention: Drug: acetylsalicylic acid
  • Experimental: Arm 2 (300 mg/24h)
    Intervention: Drug: acetylsalicylic acid
  • Experimental: Arm 3 (100 mg/12h)
    Intervention: Drug: acetylsalicylic acid
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: May 20, 2019) 		60
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE May 2020
Estimated Primary Completion Date May 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 79 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 NCT03957902
Other Study ID Numbers  ICMJE PI17/01109
2018-002101-65 ( EudraCT Number )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
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
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Ángel Lanas Arbeloa, Instituto de Investigación Sanitaria Aragón
Study Sponsor  ICMJE Instituto de Investigación Sanitaria Aragón
Collaborators  ICMJE
  • Instituto de Salud Carlos III
  • G. d'Annunzio University
  • Hospital Clínico Universitario Lozano Blesa
Investigators  ICMJE
Principal Investigator: Ángel Lanas Arbeloa, MD Instituto de Investigación Sanitaria Aragón
PRS Account Instituto de Investigación Sanitaria Aragón
Verification Date May 2019

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

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