Intermittent or Continuous Acetylsalicylic Acid and Gene Expression in the Nasal Tissue of Current Smokers

Phase 2

Completed

Conditions: Tobacco Use Disorder
Lung Carcinoma

Interventions: Drug: Aspirin
Other: Laboratory Biomarker Analysis
Other: Placebo

Registration Number: NCT02123849

Lead Sponsor: National Cancer Institute (NCI)

Brief Summary: This randomized 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. Smokers are at increased risk of developing lung cancer. Acetylsalicylic acid may be useful in preventing lung cancer.

Detailed Description: PRIMARY OBJECTIVES:

I. To analyze the impact of a 12-week intervention of intermittent and continuous acetylsalicylic acid (ASA) on a smoking-related gene expression signature in the nasal epithelium of current smokers and to analyze any difference between the intermittent and continuous ASA interventions.

SECONDARY OBJECTIVES:

I. To determine whether the change in the smoking-related gene expression signature of nasal epithelium persists one week off agent intervention.

II. To compare the change in urinary prostaglandin E metabolite (PGE-M) and leukotriene E (4) (LTE \[4\]) between the continuous and intermittent dosing arms and to determine whether the change persists one week off agent intervention.

III. To analyze the impact of intermittent and continuous ASA on a three lung cancer-related gene signatures (an 80-gene signature, a phosphoinositide 3-kinase \[PI3K\] gene signature, and a nasal epithelium cancer signature) in the nasal epithelium and to analyze any difference between the intermittent and continuous ASA interventions.

IV. To determine whether the change, if any, in the lung cancer-related gene expression signatures of nasal epithelium persists one week off agent intervention.

V. To compare the safety in current smokers of 12 week exposure to continuous versus intermittent ASA.

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

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

VIII. To analyze the impact of intermittent and continuous ASA on karyometric analysis of buccal cells and to analyze any difference between intermittent and continuous ASA interventions.

OUTLINE: Participants are randomized to 1 of 2 treatment arms.

ARM I (CONTINUOUS): Participants receive aspirin orally (PO) once daily (QD) for 12 weeks.

ARM II (INTERMITTENT): Participants receive placebo PO QD during weeks 1, 3, 5, 7, 9, and 11 and aspirin PO QD during weeks 2, 4, 6, 8, 10, and 12.

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

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 54

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Arm I (continuous aspirin)	Aspirin	Participants receive aspirin PO QD for 12 weeks.
Arm I (continuous aspirin)	Laboratory Biomarker Analysis	Participants receive aspirin PO QD for 12 weeks.
Arm II (intermittent aspirin)	Laboratory Biomarker Analysis	Participants receive placebo PO QD during weeks 1, 3, 5, 7, 9, and 11 and aspirin PO QD during weeks 2, 4, 6, 8, 10, and 12.
Arm II (intermittent aspirin)	Placebo	Participants receive placebo PO QD during weeks 1, 3, 5, 7, 9, and 11 and aspirin PO QD during weeks 2, 4, 6, 8, 10, and 12.
Arm II (intermittent aspirin)	Aspirin	Participants receive placebo PO QD during weeks 1, 3, 5, 7, 9, and 11 and aspirin PO QD during weeks 2, 4, 6, 8, 10, and 12.

Primary Outcome Measures

Name	Time	Method
Changes in Smoking-related Gene Expression Signature Score in Nasal Epithelium	Baseline to 12 weeks (End-of-Intervention)	Change in 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

Name	Time	Method
Changes in Urine Leukotriene E4 (LTE(4)) Levels	Baseline to 12 weeks (End-of-Intervention)	Urinary LTE(4) was used as a biomarker 5-lipoxygenase (5-LOX) mediated arachidonic acid metabolism. Decreased LTE4 implicated inhibition of the 5-LOX mediated pathway.
Persistence of the Change in the Lung Cancer-related Gene Expression Signature Score in the Nasal Epithelium One Week Off Agent Intervention	Baseline to 1 week post-intervention	Change in the lung cancer-related gene expression signature score from baseline to one week off agent intervention was compared between the two study arms. Prior research showed that higher scores were observed in lung cancer cases than healthy controls. A decreased score implicated a favorable intervention effect. There is no minimum or maximum score.
Persistence of the Change in the Smoking-related Gene Expression Signature Score in the Nasal Epithelium One Week Off Agent Intervention	Baseline to 1 week post-intervention	Change in nasal smoking-related gene expression signature score from baseline to 1 week post-intervention 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 Urine Prostaglandin E2 Metabolite (PGE-M) Levels	Baseline to 12 weeks (End-of-Intervention)	Urinary PGE-M was used as a biomarker of cyclooxygenase (COX) mediated arachidonic acid metabolism. Decreased PGE-M implicated inhibition of COX mediated pathway.
Number of Participants Experiencing Possibly/Probably/Definitely-related Adverse Events	Up to 2 weeks post-treatment
Whole-genome Gene Expression - Number of Canonical Pathways Differentially Expressed	Baseline to 12 weeks	Gene set enrichment analysis was performed on the MSigDB canonical pathways with the intent to discover differentially expressed genes after aspirin intervention.
Change in Buccal Cells Via Karyometric Analysis	Baseline to up to one week post-intervention
Gender Effect on Smoking-related Gene Expression Signature Score	Baseline to 12 weeks (End-of-Intervention)	Change in nasal smoking-related gene expression signature score was compared between male and female participants. The gender comparison was not stratified by arm because of the small sample size. 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 Lung Cancer-related Gene Expression Signature Score in the Nasal Epithelium	Baseline to 12 weeks (End-of-Intervention)	Change in lung cancer-related gene expression signature score derived from prior research was compared between the two study arms. Prior research showed that the score was higher in lung cancer cases than healthy controls. A decreased score implicated a more favorable intervention effect. There is no minimum or maximum score.

Trial Locations

Locations (2): Boston University School of Medicine
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Boston, Massachusetts, United States
The University of Arizona Medical Center-University Campus
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Tucson, Arizona, United States