Acetylsalicylic Acid and Colorectal Cancer Prevention: Exploring the Platelet Function of Its Mechanism of Action.
试验速览
- 阶段
- 3 期
- 发起方
- 入组人数
- 40
- 试验地点
- 1
- 主要终点
- Assessment of the degree of COX-1 acetylation by ASA administered for 1 week.
研究概览
简要总结
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%).
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Prevention
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 69 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Men and women, aged ≥ 18 and ≤
- •Patients should have an indication for screening colonoscopy
- •First degree relative of patient with CRC.
- •Personal history of adenomas.
- •People older than 50 and FOBT positive
- •Routine hematological and biochemical parameters within the normal range.
排除标准
- •Allergy to ASA or other NSAIDs.
- •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.
- •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.
- •Subjects with coagulation disorder or serious comorbid condition.
- •Malignancies, excluding CRC, diagnosed in the previous 5 years
- •Cigarette smoking, history of drug or alcohol abuse
- •Pregnant women or breast feeding
研究组 & 干预措施
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.
干预措施: Acetylsalicylic acid (Drug)
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.
干预措施: Screening colonoscopy (Procedure)
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.
干预措施: Acetylsalicylic acid (Drug)
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.
干预措施: Screening colonoscopy (Procedure)
结局指标
主要结局
Assessment of the degree of COX-1 acetylation by ASA administered for 1 week.
时间窗: 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.
次要结局
- 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.(pre-drug on day 0 and after the 7th daily dose (6 hours for Group 1 and 24 hours for Group 2))
- Assessment of ASA plasma levels.(pre-drug on day 0 and after the 7th daily dose (6 hours for Group 1 and 24 hours for Group 2))
- Changes from baseline in different biomarkers.(pre-drug on day 0 and after the 7th daily dose (6 hours for Group 1 and 24 hours for Group 2))
- Changes from baseline in eicosanoid generation in vivo by measuring urinary metabolites derived from COXs.(pre-drug on day 0 and after the 7th daily dose (6 hours for Group 1 and 24 hours for Group 2))
- Changes in baseline platelet COX-1(pre-drug on day 0 and after the 7th daily dose (6 hours for Group 1 and 24 hours for Group 2))
- Change from baseline in plasma proteins of markers of angiogenesis.(pre-drug on day 0 and after the 7th daily dose (6 hours for Group 1 and 24 hours for Group 2))
- 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).(pre-drug on day 0 and after the 7th daily dose (6 hours for Group 1 and 24 hours for Group 2))