The following datasets contain the data available for EPPT UAZ2013-02-01. 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 relevant information from every dataset received (except ae dataset). 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 23 datasets contain the raw form data received, excluding PII.
8.
The Death Report dataset contains participant deaths that occurred during the study. *The 1 observation contains only missing values. There were no deaths during the study.
16.
The Outcome Of Pregnancy dataset contains outcome of any pregnancies during the study. * The 1 observation contains only missing values. There were no pregnancies during the study.
23.
The Verification dataset contains investigator verification.
Trial Summary
This randomized, double-blinded phase II trial studies the safety and effects of acetylsalicylic acid (aspirin) and Zileuton taken together on biomarkers of tobacco-related carcinogenesis in nasal tissue of current smokers. The change (if any) in biomarkers is to be evaluated.
Randomized trial with two arms:
Arm I: 1:1 to ASA 81 mg QD + zileuton (ZyfloCR) 2x600 mg BID.
Arm II: Matched Placebos BID.
Target Randomizable Enrollment: 44
Statistical Analysis:
A two-sided two-sample t test was used to test whether or not there are significant differences in changes in gene signature scores (changes from baseline) between the treatment and placebo groups. A two-sided two-sample t test was also 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.
Enrollment Statistics
Actual Registration: 123
63 people randomized(63 of 123 registered)
31 in Arm I: ASA+Zileuton (31 of 63 randomized)
21 participants completed study
21 participants completed study
1 due to adverse event
6 lost to follow-up
2 withdrew from study
1 for other reasons
32 in Arm II: Placebo (32 of 63 randomized)
22 participants completed study
10 participants did not complete study
1 due to adverse event
5 lost to follow-up
4 withdrew from study
60 people not eligible and not randomized (60 of 123 registered)
Total Study Population Demographics (54 Randomized and Eligible People):
Overall (N = 64)
ASA+Zileuton (N = 31)
Placebo (N = 32)
p
Ages(Years)
51.57 ± 9.85
49.55 ± 8.64
53.53 ± 10.67
0.11
BMI
28.23 ± 7.02
28.69 ± 6.60
27.78 ± 0.61
0.61
Pack-Years
35.67 ± 12.42
32.74 ± 12.52
36.53 ± 12.22
0.23
Male
36(57.14%)
18(58.06%)
18(56.25%)
1.00
Female
27(42.86%)
13(41.94%)
14(43.75%)
1.00
White
52(82.54%)
28(90.32%)
24(75.00%)
0.15
Hispanic
7(11.11%)
3(9.68%)
4(12.50%)
1.00
Final Analysis Population: 63
Eligibility Criteria
Inclusion Criteria
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 >= the lower institutional limit
Platelets >= the lower institutional limits
Total bilirubin within normal institutional limits
Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) within normal institutional limits
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; women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation; should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her study physician immediately
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, NSAIDs and leukotriene antagonists 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 or steroid topical creams to large body surface area); use of steroid topical creams for small body areas (=< 10% body surface) during study intervention is allowed
History of chronic sinusitis or recent nasal polyps
History of, or current, active or chronic liver disease even if transaminases have normalized
History of allergic reaction to zileuton or attributed to compounds of similar chemical or biologic composition to zileuton
Are taking drugs known to interact with zileuton, including theophylline, warfarin, and propranolol
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.
At the screening visit (visit 1), informed consent is to be given for admission to study. Clinical evaluation (medical history, vital signs, physical exam, Karnofsky performance status) 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, NSAIDS, or leukotriene antagonist 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, ASA, zileuton, 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 1 will take ASA (81mg) once a day and zileuton(ZyfloCR) (2x 600mg) twice a day. Participants in arm 2 will take matched placebos. At the first and second interim visit (week 4, visit 3 and week 8, visit 4), a hepatic panel will be taken, 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 (visit 5), 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, ASA, zileuton, AA oxylipins), and buccal cells (for banking and karyometric analysis) will all be collected. Study compliance is to be checked and adverse events are to be reported. At the follow-up visit (visit 6), final specimens are to be collected. A hepatic panel, a collection of nasal brushings (for gene expression), urine (for PGE-M, LTE(4)), blood (for plasma AA oxylipins), and buccal cells (for banking and karyometric analysis) will be collected.
Results/Findings:
Aspirin plus zilueton had minimal effects on the modulation of the nasal or bronchial gene expression signatures of smoking, lung cancer, and COPD but favorably modulated a bronchial gene expression signature of squamous dysplasia. Aspirin plus zileuton suppressed urinary leukotriene but not prostaglandin E2, suggesting shunting through the cyclooxygenase pathway when combined with 5-lipoxygenase inhibition. Continued investigation of leukotriene inhibitors is needed to confirm these findings, understand the long-term effects on the airway epithelium, and identify the safest, optimally dosed agents.
