An official website of the United States government
Government Funding Lapse
Because of a lapse in government funding, the information on this website may not be up to date, transactions submitted via the website may not be processed, and the agency may not be able to respond to inquiries until appropriations are enacted. The NIH Clinical Center (the research hospital of NIH) is open. For more details about its operating status, please visit cc.nih.gov. Updates regarding government operating status and resumption of normal operations can be found at OPM.gov.
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.
1.
The Enhanced Person dataset contains all information relevant for most analyses. Each record represents one participant and contains updated variable names, formats, and labels. All information coming from non-person-based datasets has been converted into a person-based format.
2.
The Adverse Events dataset contains adverse event information, including onset date, grade of severity, attribution to the study agent, and outcome. This version of the dataset includes updated variable names, formats, and labels.
Raw Datasets
These 20 datasets contain the raw form data received, excluding PII.
20.
The tob_alc dataset contains cigarette and alcohol history (used to determine study eligibility).
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)
Total Study Population Demographics (54 Randomized and Eligible People):
Overall (N = 54)
Intermittent ASA (N = 27)
Continuous ASA (N = 27)
p
Ages(Years)
Gender(#):
1.00
Female
24
12
12
Male
30
15
15
Race(#):
0.46
White
45
21
24
Black or African American
5
3
2
Asian
1
0
1
American Indian or Alaskan Native
1
1
0
More than one race
2
2
0
Hispanic or Latino
10
4
6
0.73
Weight (kg)
83 ± 21.1
81.0 ± 20.2
85.9 ± 22.1
0.40
Height (cm)
171.9 ± 11.0
173.9 ± 12.3
170.2 ± 9.6
0.27
BMI (kg/m2)
28.0 ± 5.2
26.5 ± 4.6
29.4 ± 5.6
0.04
Pack-years
35.7 ± 12.9
33.7 ± 9.7
37.7 ± 15.3
0.25
Urinary cotinine levels (ng/mg Cr)
5,793.21 ± 4,519.80
5,538.03 ± 2,585.74
6,048.39 ± 5,900.98
0.68
Current Drinker (1-2 serving/d)
40(74.07%)
19(70.37%)
21(77.78%)
0.76
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)
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
At the screening visit (visit 1), informed consent is to be given for admission to study. Clinical evaluation (medical history, vital signs, physical exam) and clinical labs will be completed. Concomitant medications are to be reported and a tobacco use history questionnaire will be completed. If a participant has taken any ASA or NSAIDS in the preceding two weeks, a 4 week (minimum) washout of these drugs is to be done. At the next visit (visit 2), baseline specimens are to be collected. Nasal brushing (for gene expression analysis), urine (for PGE-M, LTE(4), and cotinine levels), blood (for plasma salicylate and ASA levels and for possible future analysis of plasma arachidonic acid (AA) oxylipins), and buccal cells (as a reserved specimen for gene expression analysis and karyometric analysis) will all be collected. Participants are to be randomized into either one of two study arms at a 1:1 ratio. Participants in arm 2 will take continuous ASA (81mg) daily. Participants in arm 1 will take intermittent ASA (81mg) daily for one week alternating with placebo daily one week. At the mid-study visit (week 6, visit 3), study compliance is to be checked and adverse events are to be reported. A current tobacco use assessment will also be completed. At the end-of-intervention visit (week 12, visit 4), participants will complete clinical labs, a current tobacco use assessment. Nasal brushing (for gene expression analysis), urine (for PGE-M, LTE(4), and cotinine levels), blood (for plasma salicylate and ASA levels and for possible future analysis of plasma arachidonic acid (AA) oxylipins), and buccal cells (as a reserved specimen for gene expression analysis and karyometric analysis) will all be collected. Study compliance is to be checked and adverse events are to be reported. At the post-intervention visit (week 13/14, visit 5), final specimens are to be collected. A collection of nasal brushings (for gene expression), urine (for PGE-M, LTE(4)), blood (for possible future analysis of plasma AA oxylipins), and buccal cells (for banking and karyometric analysis) will be collected.
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.
