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Aspirin and Zileuton and Biomarker Expression in Nasal Tissue of Current Smokers

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ClinicalTrials.gov Identifier: NCT02348203
Recruitment Status : Active, not recruiting
First Posted : January 28, 2015
Last Update Posted : September 13, 2019
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)

Brief Summary:
This randomized phase II trial studies the effects of aspirin and zileuton on genes related to tobacco use in current smokers. Aspirin and zileuton may interfere with genes related to tobacco use and may be useful in preventing lung cancer in current smokers.

Condition or disease Intervention/treatment Phase
Tobacco Use Disorder Drug: Aspirin Other: Laboratory Biomarker Analysis Other: Placebo Drug: Zileuton Phase 2

Detailed Description:

PRIMARY OBJECTIVES:

I. To analyze the impact of combined treatment of acetylsalicylic acid (ASA) (aspirin) and zileuton on smoking-related gene expression signature in the nasal epithelium in current smokers and to analyze any difference between the ASA and zileuton intervention and placebo control.

SECONDARY OBJECTIVES:

I. To assess the impact of ASA and zileuton on three lung cancer gene signatures (an 80-gene bronchial signature, a phosphatidylinositol 3-kinase [PI3K] pathway gene signature and a nasal diagnostic gene signature) and to compare this to placebo control.

II. To determine whether the change in the smoking-related gene expression signature and the three lung cancer gene signatures of nasal epithelium persists 10-14 days off agent intervention.

III. To measure urinary prostaglandin E metabolite (PGE-M) and leukotriene E(4) (LTE[4]) levels in current smokers after ASA and zileuton.

IV. To assess the safety in current smokers of 12 week exposure to ASA and zileuton.

V. To evaluate a gender effect in the modulatory effects of ASA and zileuton on smoking related-gene expression signature.

VI. To explore the effect of ASA and zileuton on the metabolomics profile of the arachidonic acid pathway.

VII. To explore, in a discovery-driven fashion, the effect of ASA and zileuton on whole-genome gene expression.

VIII. To analyze the impact of ASA and zileuton on karyometric analysis of buccal cells.

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM I: Patients receive aspirin orally (PO) once daily (QD) and zileuton PO twice daily (BID) for 12 weeks in the absence of unacceptable toxicity.

ARM II: Patients receive aspirin placebo PO QD and zileuton placebo PO BID for 12 weeks.

After completion of study treatment, patients are followed up for 2 weeks.


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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 62 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single (Participant)
Primary Purpose: Prevention
Official Title: Clinical Study of the Effect of Combined Treatment of Aspirin and Zileuton on Biomarkers of Tobacco-Related Carcinogenesis in Current Smokers
Actual Study Start Date : January 13, 2016
Actual Primary Completion Date : February 22, 2019

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Arm I (aspirin, zileuton)
Patients receive aspirin PO QD and zileuton PO BID for 12 weeks in the absence of unacceptable toxicity.
Drug: Aspirin
Given PO
Other Names:
  • Acetylsalicylic Acid
  • ASA
  • Aspergum
  • Ecotrin
  • Empirin
  • Entericin
  • Extren
  • Measurin

Other: Laboratory Biomarker Analysis
Correlative studies

Drug: Zileuton
Given PO
Other Name: Zyflo

Placebo Comparator: Arm II (double placebo)
Patients receive aspirin placebo PO QD and zileuton placebo PO BID for 12 weeks.
Other: Laboratory Biomarker Analysis
Correlative studies

Other: Placebo
Given aspirin placebo PO
Other Names:
  • placebo therapy
  • PLCB
  • sham therapy

Other: Placebo
Given zileuton placebo PO
Other Names:
  • placebo therapy
  • PLCB
  • sham therapy




Primary Outcome Measures :
  1. Changes in a smoking-related gene expression signature score in the nasal epithelium of current smokers after acetylsalicylic acid (ASA) and zileuton intervention [ Time Frame: Baseline up to week 12 ]
    A two-sided two-sample t test will be used to test whether or not there are significant differences in changes in smoking gene signature score (changes from baseline) between the treatment and placebo groups. Exploratory analyses will be performed to evaluate whether the effect of ASA and zileuton on smoking-related gene expression signature is modulated by gender and whether gene expression changes are associated with ASA and zileuton exposure and changes in PGE-M and LTE(4) levels.


Secondary Outcome Measures :
  1. Impact of ASA and zileuton on three lung cancer gene signatures (an 80-gene bronchial signature, a PI3K pathway gene signature and a nasal diagnostic gene signature) [ Time Frame: Up to week 12 ]
    Analysis of variance will be performed to evaluate whether ASA and zileuton has significantly different impact on changes in the three lung cancer gene signatures and the changes are significantly different from the placebo group.

  2. Change in the smoking-related gene expression signature [ Time Frame: Baseline to 14 days post intervention ]
  3. Change in the three lung cancer gene signatures of nasal epithelium [ Time Frame: Baseline to 14 days post intervention ]
  4. Change in urinary PGE-M levels [ Time Frame: Baseline up to week 12 ]
    Two sample t tests will be performed to evaluate whether or not there are significant differences in changes in PGE-M between the treatment and placebo groups.

  5. Change in urinary LTE (4) levels [ Time Frame: Baseline up to week 12 ]
    Two sample t tests will be performed to evaluate whether or not there are significant differences in changes in LTE(4) between the treatment and placebo groups.

  6. Incidence of adverse events graded using the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 [ Time Frame: Up to 2 weeks post-treatment ]
    Descriptive statistics of the type and frequency of all adverse events will be generated, including 95% confidence intervals. For each type of the adverse events, a Fisher's exact test will be performed to compare the frequency of the adverse event between the two groups.

  7. Gender effect on smoking-related gene expression signature [ Time Frame: Up to week 12 ]
    Exploratory analyses will be performed to evaluate whether the effect of ASA and zileuton on smoking-related gene expression signature is modulated by gender.

  8. Changes in the metabolomics profile of the arachidonic acid pathway [ Time Frame: Baseline to week 12 ]
    Two sample t tests will be performed to evaluate whether or not there are significant differences in changes in oxylipin metabolome between the treatment and placebo groups. In addition, system biology methods will also be used to analyze the oxylipin metabolome data.

  9. Whole-genome gene expression [ Time Frame: Up to week 12 ]
    Pair-wise comparisons based on two-sample t tests will be performed to whole-genome gene expression data to identify the genes for which ASA and zileuton has a significantly different expression level from the placebo group. Multivariate statistical techniques such as principle component analysis (PCA) will be used to reduce complexity of the whole-genome expression data.

  10. Impact of ASA and zileuton on karyometric analysis of buccal cells [ Time Frame: Up to week 12 ]


Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02348203


Locations
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United States, Arizona
Banner University Medical Center - Tucson
Tucson, Arizona, United States, 85719
United States, Massachusetts
Boston University School of Medicine
Boston, Massachusetts, United States, 02118
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Linda L Garland The University of Arizona Medical Center-University Campus
  Study Documents (Full-Text)

Documents provided by National Cancer Institute (NCI):

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Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT02348203     History of Changes
Other Study ID Numbers: NCI-2015-00061
NCI-2015-00061 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
N01-CN-2012-00031
1403269898 ( Other Identifier: Banner University Medical Center - Tucson )
UAZ2013-02-01 ( Other Identifier: DCP )
N01CN00031 ( U.S. NIH Grant/Contract )
P30CA023074 ( U.S. NIH Grant/Contract )
First Posted: January 28, 2015    Key Record Dates
Last Update Posted: September 13, 2019
Last Verified: April 2019
Additional relevant MeSH terms:
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Tobacco Use Disorder
Substance-Related Disorders
Chemically-Induced Disorders
Mental Disorders
Aspirin
Zileuton
Hydroxyurea
Anti-Inflammatory Agents, Non-Steroidal
Analgesics, Non-Narcotic
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Anti-Inflammatory Agents
Antirheumatic Agents
Fibrinolytic Agents
Fibrin Modulating Agents
Molecular Mechanisms of Pharmacological Action
Platelet Aggregation Inhibitors
Cyclooxygenase Inhibitors
Enzyme Inhibitors
Antipyretics
Lipoxygenase Inhibitors
Leukotriene Antagonists
Hormone Antagonists
Hormones, Hormone Substitutes, and Hormone Antagonists
Antineoplastic Agents
Antisickling Agents
Nucleic Acid Synthesis Inhibitors