The following datasets contain the data available for EPPT UAZ2013-01-01. The description and documentation for each file is listed below. SAS7bdat and CSV versions of the actual data will be available to CDAS projects approved to use this study's data.

Analysis Datasets

Raw Datasets

These 20 datasets contain the raw form data received, excluding PII.

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Trial Summary

This randomized, double-blinded phase II trial studies the safety and effects of acetylsalicylic acid (aspirin) taken continuously or intermittently on gene expression in the nasal tissue of current smokers. ASA is suspected to be useful in preventing lung cancer. The change (if any) in gene expression as well as any difference between the results of each study arm is to be evaluated.

Randomized trial with two arms:

• Arm I: ASA (1 x 81mg capsule) daily.
• Arm II: Alternating weekly between ASA (1 x 81mg capsule daily) and Placebo (1 capsule daily).

Target Randomizable Enrollment: 56

Target Evaluable Enrollment: 40

Statistical Analysis:

The study planned to randomize 56 eligible participants to have at least 40 participants (20 per arm) with the complete set of evaluable specimens for biomarker analysis, based on an estimated attrition rate of 25%. A one-sided two-sample t test at a significance level of 5% was performed to evaluate whether intermittent ASA is non-inferior to continuous ASA in changes of the gene signature scores. Additional regression analysis was performed to adjust for baseline levels and/or potential confounders, for example, gender or BMI. A two-sided two-sample t test was used to compare the baseline values of gene signature scores between the intervention arms and the baseline values of PGEM and LTE4 and changes in PGEM and LTE4 levels between the intervention arms. A two-sided paired t test was performed to evaluate the changes in gene signature scores, PGEM and LTE4 overall, by intervention arm, and by gender. All of the secondary analyses are considered exploratory so no correction for multiple comparisons were used. The Fisher's exact test was used to compare the frequency of adverse events between the intervention arms.

Differential gene expression was calculated between sample collection time points: (i) baseline to end-of-intervention, (ii) baseline to one-week post intervention, and (iii) end-of-intervention to one-week post intervention in samples that passed quality control metrics (n = 109). These analyses reflect the genomic effects of ASA exposure, ASA exposure with persistence beyond one week, and ASA withdrawal, respectively. Differential gene expression was calculated for each comparison using linear modeling via the R package limma (28), adjusting for ASA dosing arm and blocking by subject. Adjusted p-values (FDR) <0.25 were considered significant. The EnrichR tool (29) was used to explore the functional role of significant genes. Additional pathway analyses were conducted using gene set enrichment analysis (GSEA; ref. 30) and genes rank ordered by t-statistic for each ASA effect from the linear modeling results. GSEA was used to assess enrichment of biology presumed to be modulated by aspirin exposure, and gene sets related to repair and wound healing from the Molecular Signatures Database (MSigDB; ref. 31). GSEA was also used to screen the curated Canonical Pathways (C2) within MSigDB and adjusted P values (FDR) <0.05 were considered significant. The most highly enriched genes from the significant gene sets were compiled using the Leading Edge Analysis tool. We also compared ASA-associated gene-expression alterations between the two dosing arms. Paired t tests were computed between baseline and end-of-intervention within each arm. The results of this analysis were used to construct dosing arm specific ranked lists of genes by t-statistic and gene sets (the top 100 most up- and down-regulated genes). GSEA was used to establish ASA-associated gene-expression changes between the two arms using these ranked lists and gene sets.

Enrollment Statistics

Actual Registration: 94

• 54 people randomized (54 of 94 registered)
• 27 in Arm I: ASA (27 of 54 randomized)
  • 20 participants completed study
  • 7 participants did not complete study
    • 5 lost to follow-up
    • 1 withdrew from study
    • 1 lost to protocol violation
• 27 in Arm II: ASA and Placebo (27 of 54 randomized)
  • 25 participants completed study
  • 2 participants did not complete study (lost to follow-up)
• 40 people not randomized (40 of 94 registered)

Final Analysis Population: 41

Eligibility Criteria

Inclusion Criteria

• Male or female current tobacco smokers with >= 20 pack years of self-reported smoking exposure and an average use of >= 10 cigarettes/day
• Karnofsky >= 70%
• Leukocytes >= 3,000/microliter
• Absolute neutrophil count >= 1,500/microliter
• Hematocrit within normal institutional limits
• Platelets within normal institutional limits
• Total bilirubin =< 1.5 × institutional upper limit of normal (ULN)
• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 1.5 × institutional ULN
• Creatinine =< the upper institutional limits
• Prothrombin time (PT)/partial thromboplastin time (PTT) within normal institutional limits
• Fertile subjects must use adequate contraception (abstinence, barrier methods, or birth control pills) prior to study entry and for the duration of study participation
• Participants may have a history of indeterminate pulmonary nodule(s) by chest imaging if nodule follow-up has been completed or the study procedures would not interfere with nodule follow-up
• Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria

• History of allergic reaction to aspirin or attributed to compounds of similar chemical or biologic composition to aspirin, including other nonsteroidal anti-inflammatory drugs (NSAIDs)
• Gastric intolerance attributable to ASA or NSAIDs
• History of gastric ulcer within the past 5 years (with or without bleeding)
• Use of ASA or NSAIDs for more than 5 days per month within 3 months of enrollment
• Not willing or are unable to refrain from use of any non-study ASA or NSAIDs during the study period
• Adult asthma
• Chronic, current or recent (within the past three months) use of leukotriene antagonists
• Require chronic anticoagulation or anti-platelet therapy
• History of bleeding disorder or hemorrhagic stroke
• Chronic, current or recent (within the past three months) use of glucocorticoids (systemic, topical and/or nasal sprays)
• History of chronic sinusitis or recent nasal polyps
• Not willing or are unable to limit alcohol consumption to =< 2 alcoholic beverages a day during the study period
• Pregnant or lactating women; breastfeeding should be discontinued if the mother is treated with aspirin; should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her study physician immediately
• Participants may not be receiving any other investigational agents
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
• Have a known history of inability to absorb an oral agent
• Invasive cancer within the past five years except non-melanoma skin cancer
• Urine cotinine level, if collected at screening, does not confirm active smoking status

The Schema is a timeline of the study. It indicates start/end points, visits expected, major testing to be done, and any other information that is crucial to understanding how the study was completed.

Study Schema

Results/Findings:

Overall, and for each dosing arm, a statistically significant modulation of the smoking, lung cancer, and COPD gene-expression signatures was not observed. LD ASA was effective in suppressing COX-mediated ARA metabolism in high risk smokers. Through the GSEA, it was found that LD ASA led to wide-ranging genomic changes in the nasal epithelium, with the continuous dosing resulting in a higher number of enriched gene sets than the intermittent dosing.