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Aspirin Intervention for the Reduction of Colorectal Cancer Risk (ASPIRED): a Study Protocol for a Randomized Controlled Trial David A

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Aspirin Intervention for the Reduction of Colorectal Cancer Risk (ASPIRED): a Study Protocol for a Randomized Controlled Trial David A Drew et al. Trials (2017) 18:50 DOI 10.1186/s13063-016-1744-z STUDYPROTOCOL Open Access ASPirin Intervention for the REDuction of colorectal cancer risk (ASPIRED): a study protocol for a randomized controlled trial David A. Drew1,2, Samantha M. Chin1,2, Katherine K. Gilpin1,2, Melanie Parziale1,2, Emily Pond1,2, Madeline M. Schuck1,2, Kathleen Stewart2, Meaghan Flagg3, Crystal A. Rawlings3, Vadim Backman4, Peter J. Carolan2, Daniel C. Chung2, Francis P. Colizzo III2, Matthew Freedman5, Manish Gala1,2, John J. Garber2, Curtis Huttenhower6, Dmitriy Kedrin2, Hamed Khalili1,2, Douglas S. Kwon3, Sanford D. Markowitz8, Ginger L. Milne9, Norman S. Nishioka2, James M. Richter2, Hemant K. Roy10, Kyle Staller1,2, Molin Wang6,7,11 and Andrew T. Chan1,2,5,11,12* Abstract Background: Although aspirin is recommended for the prevention of colorectal cancer, the specific individuals for whom the benefits outweigh the risks are not clearly defined. Moreover, the precise mechanisms by which aspirin reduces the risk of cancer are unclear. We recently launched the ASPirin Intervention for the REDuction of colorectal cancer risk (ASPIRED) trial to address these uncertainties. Methods/design: ASPIRED is a prospective, double-blind, multidose, placebo-controlled, biomarker clinical trial of aspirin use in individuals previously diagnosed with colorectal adenoma. Individuals (n = 180) will be randomized in a 1:1:1 ratio to low-dose (81 mg/day) or standard-dose (325 mg/day) aspirin or placebo. At two study visits, participants will provide lifestyle, dietary and biometric data in addition to urine, saliva and blood specimens. Stool, grossly normal colorectal mucosal biopsies and cytology brushings will be collected during a flexible sigmoidoscopy without bowel preparation. The study will examine the effect of aspirin on urinary prostaglandin metabolites (PGE-M; primary endpoint), plasma inflammatory markers (macrophage inhibitory cytokine-1 (MIC-1)), colonic expression of transcription factor binding (transcription factor 7-like 2 (TCF7L2)), colonocyte gene expression, including hydroxyprostaglandin dehydrogenase 15-(NAD) (HPGD) and those that encode Wnt signaling proteins, colonic cellular nanocytology and oral and gut microbial composition and function. Discussion: Aspirin may prevent colorectal cancer through multiple, interrelated mechanisms. The ASPIRED trial will scrutinize these pathways and investigate putative mechanistically based risk-stratification biomarkers. Trial registration: This protocol is registered with the U.S. National Institutes of Health trial registry, ClinicalTrials.gov, under the identifier NCT02394769. Registered on 16 March 2015. Keywords: Aspirin, Colorectal cancer, Biomarker, Chemoprevention * Correspondence: [email protected] 1Clinical and Translational Epidemiology Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA 2Division of Gastroenterology, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA Full list of author information is available at the end of the article © The Author(s). 2017 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Drew et al. Trials (2017) 18:50 Page 2 of 11 Background Aspirin at 81 mg/day or 325 mg/day impairs binding Background and rationale of transcription factor 7-like 2 (TCF7L2)/T-cell factor Colorectal cancer (CRC) remains the second leading cause 4(TCF4)atthe8q24 CRC risk locus in colonic epithe- of cancer-related deaths in the United States despite the lium, particularly among individuals with the 8q24 increasing adoption of screening [1]. Thus, the develop- CRC susceptibility allele ment of alternative strategies for prevention remains a Aspirin at 81 mg/day or 325 mg/day lowers expression high priority. Aspirin (acetylsalicylic acid) has emerged as of Wnt signaling genes (CTNNB1, AXIN-2 and MYC) perhaps the most promising chemopreventive agent to and hydroxyprostaglandin dehydrogenase 15-(NAD) date with numerous basic, epidemiological and clinical (HPGD) in colonic epithelium studies supporting its anticancer effects, especially against Aspirin at 81 mg/day or 325 mg/day is associated with CRC [2]. In view of this compelling evidence, the United less neoplastic nanomorphological cellular signatures States Preventive Services Task Force recently recom- from brushings of normal colorectal mucosa mended the use of aspirin for the primary prevention of Aspirin at 81 mg/day or 325 mg/day is associated CRC as well as cardiovascular disease (CVD) in individ- with an increase in oral and gut microbial diversity, uals aged 50–69 years with elevated cardiovascular risk function, and genomic richness and inhibits microbial profiles [3]. pathways associated with CRC Nonetheless, aspirin is associated with harms, includ- ing gastrointestinal bleeding, for which the risk increases Methods/design with age, as well as dose and duration of use [2, 3]. The Trial design field is now at a critical juncture where broader adoption ASPIRED is a prospective, double-blind, placebo- of an aspirin-based chemoprevention strategy requires controlled, three-arm randomized controlled trial. We human data clarifying the optimal dose and mode of will target 180 individuals (60 per arm) for enrollment. action, which ultimately may help identify subgroups of individuals for whom the preventive benefits outweigh Participants, interventions and outcomes the harms. Carefully designed randomized clinical trials Study setting that examine a range of molecular biomarkers associated A single-center, academic hospital (MGH) with aspirin’s mechanisms will provide a cost-efficient means to illuminate the molecular underpinnings of as- Eligibility criteria pirin’s chemopreventive effects and validate putative Potential participants will be identified within the gastro- risk-stratification biomarkers. We have recently initiated enterology practice of MGH. Eligible adults (aged 18–80 the “ASPirin Intervention for the REDuction of colorec- years) will have had at least one adenoma removed during tal cancer risk” (ASPIRED) trial to achieve this goal. a qualifying endoscopy within 9 months of study enroll- ment, confirmed via official pathology reports. Full inclu- Objectives sion and exclusion criteria are included in Table 1. Within the gastroenterology practice of Massachusetts General Hospital (MGH), we will conduct a prospective, Interventions double-blind, placebo-controlled, randomized clinical trial The first dose of the study medication will be provided to measure the effects of daily low-dose (81 mg/day) and to participants immediately upon completing the initial standard-dose (325 mg/day) aspirin on urine, plasma, baseline flexible sigmoidoscopy (start of randomization). stool, and tissue biomarkers associated with CRC among Aspirin is an odorless, white, needle-like crystalline or patients with a prior adenoma history. This study is de- powdery substance. Generic aspirin is provided as an signed to advance the mechanistic understanding of aspi- oral tablet at an 81-mg or a 325-mg dose. To maintain rin’s anticancer mode of action with the goal of identifying blinding, we use specially designed formulations in individuals most likely to benefit from an aspirin-based which aspirin tablets are crushed into a powder. An chemoprevention regimen. Specifically, we hypothesize amount of powder that reflects the appropriate dose is that: then placed in a gel capsule with a lactose filler. In the case of placebo, an identically sized capsule filled only Aspirin at 81 mg/day or 325 mg/day reduces urinary with lactose is used. Participants will be instructed to prostaglandin metabolites (PGE-M), a biomarker of consume one study capsule per day with food and a full prostaglandin tone, to levels associated with low risk glass of water until they return for their final visit. The of colorectal neoplasia final visit will occur a minimum of 8 weeks, but no more Aspirin at 81 mg/day or 325 mg/day reduces plasma than 12 weeks after the initial visit. The study duration macrophage inhibitory cytokine-1 (MIC-1), an inflam- is designed to maximize feasibility and compliance. matory biomarker Moreover, in a pilot study, two doses of 650 mg of Drew et al. Trials (2017) 18:50 Page 3 of 11 Table 1 ASPIRED eligibility criteria Inclusion criteria Exclusion criteria • Adenoma removed during qualifying endoscopy • Any adenoma that was not completely removed during previous colonoscopy (as confirmed by pathology) • Known diagnosis of familial adenomatous polyposis (FAP) or hereditary • Not currently taking aspirin (any dose) non-polyposis colorectal cancer (HNPCC, Lynch syndrome) within the last 6 months • Diagnosis of inflammatory bowel disease, liver or kidney disease, or bleeding diathesis • Age 18–80 years • Any prior diagnosis of gastrointestinal cancer (including esophageal, small intestinal, • Able to swallow pills colon, pancreatic), or any diagnosis of other cancers (with the exception of • Ability to
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