Tobacco Use Disorder
Conditions
Keywords
Cancer Prevention, Smoking-related lung disease, Smoking, Celecoxib, Celebrex, Zileuton, Zyflo CR, Prevention
Brief summary
The goal of this clinical research study is to learn how zileuton alone or the combination of zileuton and celecoxib may affect certain chemicals in the body that may be linked with a risk for smoking-related lung disease. These effects will be measured by a urine test
Detailed description
PRIMARY OBJECTIVES: I. To determine whether short-term administration of zileuton, a 5-lipoxygenase (5-LO) inhibitor, in current smokers will suppress the formation of urinary leukotriene E4 (LTE4) and shunt arachidonic acid into the cyclooxygenase (COX) pathway, resulting in elevated urinary prostaglandin E-metabolite (PGE-M). SECONDARY OBJECTIVES: I. To determine whether short-term co-administration of celecoxib, a selective COX-2 inhibitor, and zileuton suppresses levels of both urinary LTE4 and PGE-M in current smokers. II. To evaluate the association between baseline levels of urinary LTE4 and magnitude of the arachidonic acid shunt induced by zileuton. OUTLINE: Patients are randomized to 1 of 2 treatment arms. ARM I: Patients receive zileuton orally (PO) twice daily (BID) on days 1-6. ARM II: Patients receive zileuton as in Arm I and celecoxib PO BID on days 1-6.
Interventions
DRUGZileuton
1200 mg twice daily given orally (PO) for 6 days
DRUGCelecoxib
200 mg twice daily given orally for 6 days
OTHERlaboratory biomarker analysis
Correlative studies
Sponsors
National Cancer Institute (NCI)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Male or female current tobacco smokers with more or equal to 10 pack years of self-reported smoking exposure and an average of more or equal to 10 cigarettes/day * Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 (Karnofsky 70-100%) * Total bilirubin less or equal to 2 \* upper limit of normal (ULN) * Direct bilirubin less or equal to 2 \* ULN * aspartate aminotransferase (AST)/(SGOT) less or equal to 2 \* ULN * alanine aminotransferase (ALT)/(SGPT) less or equal to 2 \* ULN * Alkaline phosphatase less or equal to 2 \* ULN * If the participant is female, of childbearing potential and not lactating, she has a documented negative serum pregnancy test within 14 days prior to randomization
Exclusion criteria
* The participant has active cancer (excluding non-melanoma skin cancer) * The participant has a history of curatively treated cancer with surgical therapy finished within 6 months prior to the Screening visit; or has had chemotherapy, cancer-related immunotherapy, hormonal therapy (other than Hormone replacement therapy (HRT) for menopause), or radiation therapy within 12 months of the screening visit * The participant has a chronic inflammatory condition, including but not limited to, ulcerative colitis, Crohn's disease, rheumatoid arthritis, psoriasis, gout and pancreatitis * The participant has an ongoing or active infection, including but not limited to HIV, pneumonia, urinary tract infection * The participant has a history of nonsteroidal anti-inflammatory drugs (NSAIDs) use, including aspirin (low-dose aspirin also prohibited) and selective COX-2 inhibitors within the previous 4 weeks * The participant has used zileuton or a leukotriene receptor antagonist within the previous 4 weeks * The participant has a history of corticosteroid use (excluding topical nasal sprays and dermal application) within the last 6 weeks * The participant has an acute or chronic kidney disorder * The participant exhibits clinical evidence of active liver disease or history of chronic liver disease * The participant has active cardiac disease, or a history of myocardial infarction, angina or coronary artery disease within the past 6 months * The participant has a history of a cerebrovascular accident (CVA) or transient ischemic attack (TIA) * The participant has a bleeding history * The participant is taking drugs known to interact with zileuton or celecoxib, including theophylline, warfarin, propranolol, fluconazole or lithium * The participant has received any investigational medication within 30 days of the screening visit or is scheduled to receive an investigational agent during the study * The participant is pregnant or nursing; women must not be pregnant or lactating * The participant is a female of child-bearing potential (women are considered not of childbearing potential if they are at least two years postmenopausal and/or surgically sterile) who has not used adequate contraception (abstinence; barrier methods such as intrauterine device (IUD), diaphragm with spermicidal gel, condom, or others; and hormonal methods such as birth control pills or others) since her last menses prior to study entry * The participant is a female of child-bearing potential or male who does not agree to use adequate contraception 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 * The participant has participated in the study previously and was withdrawn * 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 * Pregnant or nursing participants or those who are HIV-positive will be excluded from the study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Median Urinary PGE-M Levels (Pre and Post Treatment) | Baseline and Day 6 | Pre and Post treatment differences in urinary PGE-M levels measured in each treatment arm. PGE-M levels reported as median with full range (ng/mg creatinine) for Pre treatment versus Post treatment PGE-M levels among study participants compliant to treatment with evaluable urine samples at both time points (baseline and Day 6 +/- 1 day). |
| Median Urinary LTE4 Levels (Pre and Post Treatment) | Baseline and day 6 | Pre and Post treatment differences in urinary LTE4 levels measured in each treatment arm compared using paired t-test should the data conform to the normality assumption or one-sample Wilcoxon rank-sum test. LTE4 levels reported as median with full range (pg/mg creatinine) for Pre treatment versus Post treatment LTE4 levels among study participants compliant to treatment with evaluable urine samples at both time points (baseline and Day 6 +/- 1 day). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of Cases With a Post-treatment Increase in Urinary PGE-M Levels | Baseline to Day 6 | Proportion of cases with a post-treatment increase in urinary PGE-M levels by comparing those treated with Zileuton and Celecoxib combined therapy compared to those treated with Zileuton alone. Pre/postchange in levels (Increase) derived from baseline level to Day 6 +/- 1 day. Differences in baseline levels between 2 treatment arms were examined using the Wilcoxon rank-sum test. |
Countries
United States
Participant flow
Recruitment details
Recruitment Period: May 5, 2010 to September 12, 2011. All recruitment done in medical clinics at Weill Cornell Medical College (WCMC), a Participating Organization within the MD Anderson Cancer Center (MDACC) Consortium.
Pre-assignment details
A total of 84 subjects were enrolled, four withdrew for different reasons before beginning study medication leaving 80 subjects started on the study medication(s).
Participants by arm
| Arm | Count |
|---|---|
| Arm I: Zileuton Zileuton 1200 mg twice orally twice a day on days 1-6. | 60 |
| Arm II: Zileuton and Celecoxib Combined Zileuton 1200 mg twice daily plus Celecoxib 200 mg twice daily on days 1-6. | 20 |
| Total | 80 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 3 | 0 |
Baseline characteristics
| Characteristic | Arm II: Zileuton and Celecoxib | Arm I: Zileuton | Total |
|---|---|---|---|
| Age, Continuous | 43 years | 45 years | 43 years |
| Age, Continuous, Compliant Participants | 43.1 years STANDARD_DEVIATION 7.6 | 43.8 years STANDARD_DEVIATION 9.6 | 43.6 years STANDARD_DEVIATION 9.1 |
| Baseline LTE4 (pg/mg CR) | 86.5 pg/mg CR | 107 pg/mg CR | 102.5 pg/mg CR |
| Baseline PGE-M (ng/mg Cr) | 10.2 ng/mg Cr | 12.8 ng/mg Cr | 12.6 ng/mg Cr |
| Gender, Male/Female: Compliant Participants Female | 8 participants | 19 participants | 27 participants |
| Gender, Male/Female: Compliant Participants Male | 10 participants | 33 participants | 43 participants |
| Race, Compliant Participants American Indian or Alaska Native | 0 participants | 0 participants | 0 participants |
| Race, Compliant Participants Asian | 2 participants | 0 participants | 2 participants |
| Race, Compliant Participants Black or African American | 7 participants | 28 participants | 35 participants |
| Race, Compliant Participants Native Hawaiian or Other Pacific Islander | 0 participants | 0 participants | 0 participants |
| Race, Compliant Participants Unknown or Not Reported | 0 participants | 0 participants | 0 participants |
| Race, Compliant Participants White | 9 participants | 24 participants | 33 participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 7 Participants | 28 Participants | 35 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) White | 10 Participants | 31 Participants | 41 Participants |
| Region of Enrollment United States | 20 participants | 60 participants | 80 participants |
| Sex: Female, Male Female | 8 Participants | 24 Participants | 32 Participants |
| Sex: Female, Male Male | 12 Participants | 36 Participants | 48 Participants |
| Smoking (Packs per Year) | 19.5 cigarette packs | 19.5 cigarette packs | 19.5 cigarette packs |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 26 / 60 | 13 / 20 |
| serious Total, serious adverse events | 0 / 60 | 0 / 20 |
Outcome results
Primary
Median Urinary LTE4 Levels (Pre and Post Treatment)
Pre and Post treatment differences in urinary LTE4 levels measured in each treatment arm compared using paired t-test should the data conform to the normality assumption or one-sample Wilcoxon rank-sum test. LTE4 levels reported as median with full range (pg/mg creatinine) for Pre treatment versus Post treatment LTE4 levels among study participants compliant to treatment with evaluable urine samples at both time points (baseline and Day 6 +/- 1 day).
Time frame: Baseline and day 6
Population: Seventy-seven subjects completed the entire study, three withdrew for personal reasons. Seven of those participants were excluded from analysis as non-compliant (study medications were undetectable).
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Arm I: Zileuton | Median Urinary LTE4 Levels (Pre and Post Treatment) | Pre LTE4 levels | 107 pg/mg creatinine |
| Arm I: Zileuton | Median Urinary LTE4 Levels (Pre and Post Treatment) | Post LTE4 levels | 42 pg/mg creatinine |
| Arm II: Zileuton and Celecoxib | Median Urinary LTE4 Levels (Pre and Post Treatment) | Pre LTE4 levels | 86 pg/mg creatinine |
| Arm II: Zileuton and Celecoxib | Median Urinary LTE4 Levels (Pre and Post Treatment) | Post LTE4 levels | 30 pg/mg creatinine |
Primary
Median Urinary PGE-M Levels (Pre and Post Treatment)
Pre and Post treatment differences in urinary PGE-M levels measured in each treatment arm. PGE-M levels reported as median with full range (ng/mg creatinine) for Pre treatment versus Post treatment PGE-M levels among study participants compliant to treatment with evaluable urine samples at both time points (baseline and Day 6 +/- 1 day).
Time frame: Baseline and Day 6
Population: Seventy-seven subjects completed the entire study with seven of those excluded from analysis as non-compliant (study medications were undetectable). Urine of two participants contained interfering substances thus were excluded from PGE-M related analysis.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Arm I: Zileuton | Median Urinary PGE-M Levels (Pre and Post Treatment) | Pre PGE-M Levels | 12.8 ng/mg creatinine |
| Arm I: Zileuton | Median Urinary PGE-M Levels (Pre and Post Treatment) | Post PGE-M Levels | 10.5 ng/mg creatinine |
| Arm II: Zileuton and Celecoxib | Median Urinary PGE-M Levels (Pre and Post Treatment) | Pre PGE-M Levels | 13.4 ng/mg creatinine |
| Arm II: Zileuton and Celecoxib | Median Urinary PGE-M Levels (Pre and Post Treatment) | Post PGE-M Levels | 3.9 ng/mg creatinine |
Secondary
Proportion of Cases With a Post-treatment Increase in Urinary PGE-M Levels
Proportion of cases with a post-treatment increase in urinary PGE-M levels by comparing those treated with Zileuton and Celecoxib combined therapy compared to those treated with Zileuton alone. Pre/postchange in levels (Increase) derived from baseline level to Day 6 +/- 1 day. Differences in baseline levels between 2 treatment arms were examined using the Wilcoxon rank-sum test.
Time frame: Baseline to Day 6
Population: Analysis includes only number of participants in each treatment arm with post-treatment increase in urinary PGE-M levels as measured from baseline.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm I: Zileuton | Proportion of Cases With a Post-treatment Increase in Urinary PGE-M Levels | .37 proportion of participants |
| Arm II: Zileuton and Celecoxib | Proportion of Cases With a Post-treatment Increase in Urinary PGE-M Levels | .06 proportion of participants |