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

Primary Purpose

Lung Carcinoma, Tobacco Use Disorder

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

About this trial

This is an interventional prevention trial for Lung Carcinoma

Eligibility Criteria

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

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

Sites / Locations

  • The University of Arizona Medical Center-University Campus
  • Boston University School of Medicine

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Experimental

Arm Label

Arm I (continuous aspirin)

Arm II (intermittent aspirin)

Arm Description

Participants receive aspirin PO QD for 12 weeks.

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.

Outcomes

Primary Outcome Measures

Changes in Smoking-related Gene Expression Signature Score in Nasal Epithelium
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

Changes in Urine Leukotriene E4 (LTE(4)) Levels
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.
Changes in Urine Prostaglandin E2 Metabolite (PGE-M) Levels
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
Gender Effect on Smoking-related Gene Expression Signature Score
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
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.
Persistence of the Change in the Lung Cancer-related Gene Expression Signature Score in the Nasal Epithelium One Week Off Agent 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
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.
Whole-genome Gene Expression - Number of Canonical Pathways Differentially Expressed
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

Full Information

First Posted
April 24, 2014
Last Updated
July 31, 2018
Sponsor
National Cancer Institute (NCI)
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1. Study Identification

Unique Protocol Identification Number
NCT02123849
Brief Title
Intermittent or Continuous Acetylsalicylic Acid and Gene Expression in the Nasal Tissue of Current Smokers
Official Title
The Effect of Intermittent Versus Continuous Dose Aspirin (ASA) on Nasal Epithelium Gene Expression in Current Smokers
Study Type
Interventional

2. Study Status

Record Verification Date
July 2018
Overall Recruitment Status
Completed
Study Start Date
June 2014 (undefined)
Primary Completion Date
September 2016 (Actual)
Study Completion Date
February 2018 (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 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.

6. Conditions and Keywords

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

7. Study Design

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

8. Arms, Groups, and Interventions

Arm Title
Arm I (continuous aspirin)
Arm Type
Experimental
Arm Description
Participants receive aspirin PO QD for 12 weeks.
Arm Title
Arm II (intermittent aspirin)
Arm Type
Experimental
Arm Description
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.
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
Other Intervention Name(s)
placebo therapy, PLCB, sham therapy
Intervention Description
Given PO
Primary Outcome Measure Information:
Title
Changes in Smoking-related Gene Expression Signature Score in Nasal Epithelium
Description
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.
Time Frame
Baseline to 12 weeks (End-of-Intervention)
Secondary Outcome Measure Information:
Title
Changes in Urine Leukotriene E4 (LTE(4)) Levels
Description
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.
Time Frame
Baseline to 12 weeks (End-of-Intervention)
Title
Changes in Urine Prostaglandin E2 Metabolite (PGE-M) Levels
Description
Urinary PGE-M was used as a biomarker of cyclooxygenase (COX) mediated arachidonic acid metabolism. Decreased PGE-M implicated inhibition of COX mediated pathway.
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 Score
Description
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.
Time Frame
Baseline to 12 weeks (End-of-Intervention)
Title
Changes in Lung Cancer-related Gene Expression Signature Score in the Nasal Epithelium
Description
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.
Time Frame
Baseline to 12 weeks (End-of-Intervention)
Title
Persistence of the Change in the Lung Cancer-related Gene Expression Signature Score in the Nasal Epithelium One Week Off Agent Intervention
Description
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.
Time Frame
Baseline to 1 week post-intervention
Title
Persistence of the Change in the Smoking-related Gene Expression Signature Score in the Nasal Epithelium One Week Off Agent Intervention
Description
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.
Time Frame
Baseline to 1 week post-intervention
Title
Whole-genome Gene Expression - Number of Canonical Pathways Differentially Expressed
Description
Gene set enrichment analysis was performed on the MSigDB canonical pathways with the intent to discover differentially expressed genes after aspirin intervention.
Time Frame
Baseline to 12 weeks
Title
Change in Buccal Cells Via Karyometric Analysis
Time Frame
Baseline to up to one week post-intervention

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
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) 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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Linda Garland
Organizational Affiliation
The University of Arizona Medical Center-University Campus
Official's Role
Principal Investigator
Facility Information:
Facility Name
The University of Arizona Medical Center-University Campus
City
Tucson
State/Province
Arizona
ZIP/Postal Code
85724
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

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

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