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

Primary Purpose

Tobacco Use Disorder

Status
Completed
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Aspirin
Laboratory Biomarker Analysis
Placebo Administration
Placebo Administration
Zileuton
Sponsored by
National Cancer Institute (NCI)
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional prevention trial for Tobacco Use Disorder

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesAccepts Healthy Volunteers

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

Sites / Locations

  • Banner University Medical Center - Tucson
  • Boston University School of Medicine

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Arm I (aspirin, zileuton)

Arm II (double placebo)

Arm Description

Patients receive aspirin PO QD and zileuton PO BID for 12 weeks in the absence of unacceptable toxicity.

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

Outcomes

Primary Outcome Measures

Changes in a Smoking-related Gene Expression Signature Score in the Nasal Epithelium of Current Smokers
Change in a nasal smoking-related gene expression signature score derived from prior research was compared between the two study arms. Prior research showed that a higher score was observed in never smokers compared to current smokers. An increased score implicated a more favorable intervention effect. There is no minimum or maximum score.

Secondary Outcome Measures

Changes in Three Lung Cancer Gene Signatures (an 80-gene Bronchial Signature, a PI3K Pathway Gene Signature and a Nasal Diagnostic Gene Signature) in the Nasal Epithelium of Current Smokers
Change in three lung cancer gene signatures (an 80-gene bronchial signature, a PI3K pathway gene signature and a nasal diagnostic gene signature) derived from prior research was compared between the two study arms. A decreased signature score implicated a more favorable intervention effect. There is no minimum or maximum score.
Changes in a Smoking-related Gene Expression Signature Score in the Nasal Epithelium of Current Smokers 10-14 Days Post Intervention
Change (from baseline to 10-14 days off intervention) in a nasal smoking-related gene expression signature score derived from prior research was compared between the two study arms. Prior research showed that a higher score was observed in never smokers compared to current smokers. An increased score implicated a more favorable intervention effect. There is no minimum or maximum score.
Changes in Three Lung Cancer Gene Signatures (an 80-gene Bronchial Signature, a PI3K Pathway Gene Signature and a Nasal Diagnostic Gene Signature) in the Nasal Epithelium of Current Smokers 10-14 Days Post Intervention
Change (from baseline to 10-14 days off intervention) in three lung cancer gene signatures (an 80-gene bronchial signature, a PI3K pathway gene signature and a nasal diagnostic gene signature) derived from prior research was compared between the two study arms. A decreased signature score implicated a more favorable intervention effect. There is no minimum or maximum score.
Change in Urinary PGE-M Levels
Change in Urinary LTE (4) Levels
Number of Participants Experiencing Possibly/Probably/Definitely-related Adverse Events
Gender Effect on Smoking-related Gene Expression Signature
Change in a nasal smoking-related gene expression signature score derived from prior research was analyzed by gender. Prior research showed that a higher score was observed in never smokers compared to current smokers. An increased score implicated a more favorable intervention effect. There is no minimum or maximum score.
Changes in the Metabolomics Profile of the Arachidonic Acid Pathway
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.
Number of Genes Differentially Expressed After Aspirin and Zileuton Intervention Compared to Placebo
Number of genes differentially expressed after aspirin and zileuton intervention compared to placebo using whole-genome gene expression data
Impact of ASA and Zileuton on Karyometric Analysis of Buccal Cells

Full Information

First Posted
January 27, 2015
Last Updated
June 1, 2022
Sponsor
National Cancer Institute (NCI)
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1. Study Identification

Unique Protocol Identification Number
NCT02348203
Brief Title
Aspirin and Zileuton and Biomarker Expression in Nasal Tissue of Current Smokers
Official Title
Clinical Study of the Effect of Combined Treatment of Aspirin and Zileuton on Biomarkers of Tobacco-Related Carcinogenesis in Current Smokers
Study Type
Interventional

2. Study Status

Record Verification Date
June 2022
Overall Recruitment Status
Completed
Study Start Date
January 13, 2016 (Actual)
Primary Completion Date
February 22, 2019 (Actual)
Study Completion Date
March 9, 2021 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
National Cancer Institute (NCI)

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

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.
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Tobacco Use Disorder

7. Study Design

Primary Purpose
Prevention
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
Participant
Allocation
Randomized
Enrollment
63 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Arm I (aspirin, zileuton)
Arm Type
Experimental
Arm Description
Patients receive aspirin PO QD and zileuton PO BID for 12 weeks in the absence of unacceptable toxicity.
Arm Title
Arm II (double placebo)
Arm Type
Placebo Comparator
Arm Description
Patients receive aspirin placebo PO QD and zileuton placebo PO BID for 12 weeks.
Intervention Type
Drug
Intervention Name(s)
Aspirin
Other Intervention Name(s)
Acetylsalicylic Acid, ASA, Aspergum, Ecotrin, Empirin, Entericin, Extren, Measurin
Intervention Description
Given PO
Intervention Type
Other
Intervention Name(s)
Laboratory Biomarker Analysis
Intervention Description
Correlative studies
Intervention Type
Other
Intervention Name(s)
Placebo Administration
Intervention Description
Given aspirin placebo PO
Intervention Type
Other
Intervention Name(s)
Placebo Administration
Intervention Description
Given zileuton placebo PO
Intervention Type
Drug
Intervention Name(s)
Zileuton
Other Intervention Name(s)
Zyflo
Intervention Description
Given PO
Primary Outcome Measure Information:
Title
Changes in a Smoking-related Gene Expression Signature Score in the Nasal Epithelium of Current Smokers
Description
Change in a nasal smoking-related gene expression signature score derived from prior research was compared between the two study arms. Prior research showed that a higher score was observed in never smokers compared to current smokers. An increased score implicated a more favorable intervention effect. There is no minimum or maximum score.
Time Frame
Baseline to 12 weeks (End-of-intervention)
Secondary Outcome Measure Information:
Title
Changes in Three Lung Cancer Gene Signatures (an 80-gene Bronchial Signature, a PI3K Pathway Gene Signature and a Nasal Diagnostic Gene Signature) in the Nasal Epithelium of Current Smokers
Description
Change in three lung cancer gene signatures (an 80-gene bronchial signature, a PI3K pathway gene signature and a nasal diagnostic gene signature) derived from prior research was compared between the two study arms. A decreased signature score implicated a more favorable intervention effect. There is no minimum or maximum score.
Time Frame
Baseline to 12 weeks (End of Intervention)
Title
Changes in a Smoking-related Gene Expression Signature Score in the Nasal Epithelium of Current Smokers 10-14 Days Post Intervention
Description
Change (from baseline to 10-14 days off intervention) in a nasal smoking-related gene expression signature score derived from prior research was compared between the two study arms. Prior research showed that a higher score was observed in never smokers compared to current smokers. An increased score implicated a more favorable intervention effect. There is no minimum or maximum score.
Time Frame
Baseline to 14 days post intervention
Title
Changes in Three Lung Cancer Gene Signatures (an 80-gene Bronchial Signature, a PI3K Pathway Gene Signature and a Nasal Diagnostic Gene Signature) in the Nasal Epithelium of Current Smokers 10-14 Days Post Intervention
Description
Change (from baseline to 10-14 days off intervention) in three lung cancer gene signatures (an 80-gene bronchial signature, a PI3K pathway gene signature and a nasal diagnostic gene signature) derived from prior research was compared between the two study arms. A decreased signature score implicated a more favorable intervention effect. There is no minimum or maximum score.
Time Frame
Baseline to 14 days post intervention
Title
Change in Urinary PGE-M Levels
Time Frame
Baseline to 12 weeks (End-of-intervention)
Title
Change in Urinary LTE (4) Levels
Time Frame
Baseline to 12 weeks (End-of-intervention)
Title
Number of Participants Experiencing Possibly/Probably/Definitely-related Adverse Events
Time Frame
Up to 2 weeks post-treatment
Title
Gender Effect on Smoking-related Gene Expression Signature
Description
Change in a nasal smoking-related gene expression signature score derived from prior research was analyzed by gender. Prior research showed that a higher score was observed in never smokers compared to current smokers. An increased score implicated a more favorable intervention effect. There is no minimum or maximum score.
Time Frame
Baseline to 12 weeks (End-of-intervention)
Title
Changes in the Metabolomics Profile of the Arachidonic Acid Pathway
Description
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.
Time Frame
Baseline to 12 weeks (End-of-intervention)
Title
Number of Genes Differentially Expressed After Aspirin and Zileuton Intervention Compared to Placebo
Description
Number of genes differentially expressed after aspirin and zileuton intervention compared to placebo using whole-genome gene expression data
Time Frame
Baseline to 12 weeks (End-of-intervention)
Title
Impact of ASA and Zileuton on Karyometric Analysis of Buccal Cells
Time Frame
Up to week 12

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Linda L Garland
Organizational Affiliation
The University of Arizona Medical Center-University Campus
Official's Role
Principal Investigator
Facility Information:
Facility Name
Banner University Medical Center - Tucson
City
Tucson
State/Province
Arizona
ZIP/Postal Code
85719
Country
United States
Facility Name
Boston University School of Medicine
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02118
Country
United States

12. IPD Sharing Statement

Learn more about this trial

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

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