Randomized Trial of PEITC as a Modifier of NNK Metabolism in Smokers
21 Years
70 Years
Both
Lung Cancer, Tobacco Use Disorder
Trial Information
Randomized Trial of PEITC as a Modifier of NNK Metabolism in Smokers
OBJECTIVES:
Primary
- To determine whether oral phenethyl isothiocyanate (PEITC) affects urinary levels of
biomarkers of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) metabolism in
current smokers.
Secondary
- To determine the effect of GSTM1 genotype on PEITC's impact on urinary biomarkers of
NNK metabolism.
- To determine the effect of GSTM1 genotype on the metabolism and excretion of PEITC as
measured by urinary levels of its major metabolite.
- To determine whether oral PEITC affects molecular markers of cell proliferation (Ki-67)
and apoptosis (caspase-3 and TUNEL) in bronchial tissue.
OUTLINE: Patients are stratified according to GST genotypes (GSTM1 null-null genotype vs
GSTM1-positive genotype). All participants are initially enrolled in the short-term trial.
After the completion of the short-term trial, only those participants meeting certain
criteria may proceed to the long-term trial.
- Short-term trial: Participants are randomized to 1 of 2 treatment arms.
- Arm I: Participants are asked to smoke only deuterated NNK cigarettes (provided by
the study) and record the exact number of cigarettes smoked and alcoholic drinks
consumed each day for 1 month. Participants receive oral phenethyl isothiocyanate
(PEITC) four times daily for 5 days in week 2 and oral placebo four times daily
for 5 days in week 4. Participants keep a diary of all food and beverages consumed
on the days that PEITC or placebo are taken.
- Arm II: Participants receive oral placebo four times daily for 5 days in week 2
and oral PEITC four times daily for 5 days in week 4. Participants are also asked
to smoke only deuterated NNK cigarettes, record the number of cigarettes smoked
and alcoholic drinks consumed each day, and keep a food and beverage diary as in
arm I.
After completion of the short-term trial, participants undergo a wash-out period for 1 month
in which they are asked to resume smoking regular cigarettes. Participants are offered
smoking cessation assistance, if desired. Only those participants meeting certain criteria
may proceed to the long-term trial after the 1-month wash-out period.
- Long-term trial: Participants are randomized to 1 of 2 treatment arms.
- Arm I: Participants receive oral PEITC twice daily for 12 months.
- Arm II: Participants receive oral placebo twice daily for 12 months. Participants
in both arms complete a 3-day food diary monthly for 12 months and a
food-frequency questionnaire at baseline and at the completion of study treatment.
All participants undergo blood and urine sample collection periodically for laboratory
studies. Participants enrolled in the long-term trial also undergo bronchoscopy and tissue
biopsy at baseline and at the completion study treatment. Urine samples are examined by
liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-ESI-MS/MS) for
various biomarkers. Tissue samples are examined by IHC for Ki-67, TUNEL, and caspase-3
expression.
Inclusion Criteria
Inclusion criteria:
Initial from phone interview:
- Currently smoking 10-45 cigarettes per day for the past year;
- Between the ages of 21 and 70 years;
- In apparently good physical health with no unstable medical conditions including
seizures or cancer;
- In stable and good mental health, i.e., currently do not experience unstable or
untreated psychiatric diagnosis, including substance abuse, as determined by the
DSM-IV criteria, during the past six months;
- Not using any other tobacco or nicotine-containing products;
- Not on methadone maintenance or stimulants such as ephedra; not a regular user of
street drugs and if uses occasionally, willing to abstain during the study; not
taking any drugs known to be P4501A6 substrates such as phenobarbital, rifampicin,
dexamethasone, ketoconazole, methoxsalen, pilocarpine, or tranylcypromine due to
their role in NNK metabolism;
- Does not average more than 21 alcoholic drinks per week;
- Willing to perform study activities such as having blood sample drawn, urine
collection, multiple clinic visits;
- For female subjects of child bearing potential, not known to be pregnant or nursing,
or planning to become pregnant within next 12 months.
For enrollment in the Short-Term Trial:
- Subjects who are generally healthy with liver enzyme and blood count values within
the ranges shown below based on blood samples drawn at the second screening visit.
Specifically:
- White blood cells ≥ 3,000/mL
- Total bilirubin ≤ 1.5 x upper limits of normal (ULN)
- AST (SGOT)/ALT (SGPT) ≤ 2.5 x ULN
- BUN and serum creatinine ≤ 1.5 x ULN
For enrollment in the Long-Term Trial:
- Participated in the short-term trial and invited to participate in the long-term
trial;
- Possess the GSTM1 null-null genotype;
- Smoke 20 or more cigarettes/day with a cumulative smoking history of 20 or more
pack-years (one pack-year equals to smoking a pack of cigarettes a day for one year);
- Normal liver enzymes based on blood sample drawn during 1 month wash-out;
- Determined to be a good candidate for the bronchoscopy procedure by a primary care
physician.
Exclusion Criteria:
- Subjects with uncontrolled hypertension, uncontrolled diabetes mellitus, unstable
coronary artery disease, history of cancer other than non-melanoma skin cancer, and
pregnant or lactating women will not be eligible.
Type of Study:
Interventional
Study Design:
Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Crossover Assignment, Masking: Double Blind (Subject, Investigator), Primary Purpose: Prevention
Outcome Measure:
Urinary levels of biomarkers of NNK metabolism
Outcome Description:
Total NNAL, free NNAL, keto acid and hydroxyacids will be measured by liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-ESI-MS/MS).
Outcome Time Frame:
Baseline and Completion of Study Treatment
Safety Issue:
No
Principal Investigator
Jian-Min Yuan, PhD
Investigator Role:
Principal Investigator
Investigator Affiliation:
Masonic Cancer Center, University of Minnesota
Authority:
United States: Food and Drug Administration
Study ID:
2007NT127
NCT ID:
NCT00691132
Start Date:
February 2009
Completion Date:
January 2013
Related Keywords:
- Lung Cancer
- Tobacco Use Disorder
- non-small cell lung cancer
- small cell lung cancer
- tobacco use disorder
- Lung Neoplasms
- Tobacco Use Disorder
Name | Location |
|---|---|
| Masonic Cancer Center, University of Minnesota | Minneapolis, Minnesota 55455 |
