Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT00484692 |
| Other study ID # |
EudraCT-Nr. 2005-006189-32 |
| Secondary ID |
FWF grant P16394 |
| Status |
Completed |
| Phase |
Phase 4
|
| First received |
June 8, 2007 |
| Last updated |
June 8, 2007 |
| Start date |
July 2005 |
| Est. completion date |
January 2007 |
Study information
| Verified date |
June 2007 |
| Source |
Medical University Innsbruck |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
Austria: Federal Ministry for Health and Women |
| Study type |
Interventional
|
Clinical Trial Summary
Background
Smokers often reject drugs as smoking cessation aids. Nonpharmacological interventions are
notoriously under-evaluated.
Methods
We conducted a randomized clinical trial in which we compared a medication, i.e.,
sustained-release bupropion (Zyban®; 413 subjects), at the time of the trial the most
efficacious pharmacological smoking cessation aid, with an ultrashort psychotherapeutic
intervention, Psychodynamic Model Training® (366 subjects), a manual-based psychodynamically
oriented 1 ½ day autosuggestion training. Outcome criterion was 12-month self-reported
continuous abstinence confirmed by urine cotinine levels below the level of detection (13
ng/ml) or, in an independent analysis, by exhaled carbon monoxide of 10 ppm or less at all
interviews conducted at 3, 6, and 12 months.
Description:
Study design
This randomized clinical trial was designed to compare the efficacy and safety of a
manual-based 1.5-day psychotherapeutic intervention, i.e., Psychodynamic Model Training®,
with a medication, i.e., sustained-release bupropion (Zyban®), as smoking cessation aids. In
order to render the data comparable to previously obtained bupropion data, the bupropion
treatment regimen and study protocol closely followed that by Jorenby et al. 1999.(3) As an
improvement over previous protocols(3-5), nonsmoking status was verified not only by
determination of exhaled carbon monoxide (CO) levels but also by tandem mass spectrometric
(LC/MS/MS) analysis of urine cotinine(6;7), a marker of higher sensitivity than CO.(8)
Subjects, screening, inclusion and exclusion criteria, and randomization
Female and male smokers were recruited between July 2005 and December 2005 by announcements
in the local media (press, local radio stations) and in the newsletter
(http://www.stgkk.at/mediaDB/104832.PDF) of the governmental Styrian Regional Health Care
System (Steiermaerkische Gebietskrankenkasse, STGKK), the sponsor of the present study.
Interested smokers were first screened by telephone interview and then scheduled for the
study intake interview. The first subject was enrolled in July 2005, and follow-up was
completed in January 2007. Of a total of 951 persons screened, 790 met the screening
criteria and were enrolled and randomized to one of two treatments according to a
randomization list in the care of the steering committee at the Medical University
Innsbruck. Great care was taken to preserve treatment allocation concealment: Only after the
subject had given his/her written consent, a sealed envelope containing the treatment
allocation was broken by the interviewer and presented to the subject. The study protocol
was registered with the European Medicines Agency (emea.europa.eu; EudraCT-Nr.
2005-006189-32) and was approved by the local governmental review board. The study was
conducted in compliance with the ethical principles of the Declaration of Helsinki
(www.wma.net/e/policy/b3.html ; accessibility verified May 16, 2007) and the standards on
good clinical practice developed by the International Conference on Harmonization
(www.ich.org/cache/compo/276-254-1.html ; accessibility verified May 16, 2007.)
Inclusion criteria were an age of at least 18 years, a cigarette consumption of at least 15
cigarettes per day in the last 3 months, and the willingness to contribute EUR 70 to the
treatment costs, regardless of the treatment modality. Exclusion criteria, as assessed by
the study-site physicians, were any psychiatric diagnosis except nicotine or caffeine
dependence, any current psychopharmacological treatment, known hypersensitivity to
bupropion, epilepsy, liver cirrhosis, brain tumor, pregnancy (verified by an immunological
test at the intake interview and 3 weeks after the first day of the first menses occurring
within treatment), lactation, any serious or unstable cardiac, renal, hypertensive,
pulmonary, endocrine, or neurologic disorder, ulcers, dermatologic disorders, current use of
other smoking cessation treatments, and regular use of any noncigarette tobacco product.
After induction of the first 620 subjects, it became apparent that more subjects randomized
to the bupropion group dropped out immediately after learning of their treatment allocation.
To compensate for this higher rejecter rate in the bupropion group, the remaining 170
subjects were randomized to bupropion vs psychotherapy at a ratio of 2:1. Seven of the 420
subjects randomly allocated to the bupropion group and 4 of the 370 to the psychotherapy
group were found to meet exclusion criteria by the study’s physicians only after the
randomization (bupropion: bulimia, 3 cases of major depression, 2 cases with antidepressant
medication, anticoagulant medication; psychotherapy: 4 cases with a previously undisclosed
psychiatric diagnosis) and had to be excluded before treatment started. Therefore, the final
intention-to-treat (ITT) sample consisted of 413 subjects in the bupropion and 366 subjects
in the psychotherapy group.
Treatments
The treatment period in the sustained-release bupropion (Zyban®) group was nine weeks(3),
following the protocol given in Zyban®’s product information as provided by its manufacturer
(GlaxoSmithKline, Vienna, Austria): After an initial medical consultation, a dose run-up
period of 1 week to a final 150 mg sustained-release bupropion twice daily on day 7, a
target quitting date was set for the second week, usually day 8. Subjects returned for a
second visit, scheduled between days 26 and 33 of the treatment, to the study’s physicians
for a medical checkup and to receive the second 60-tablet package of Zyban®. Failure to show
up for this second medical checkup was considered treatment failure.
Psychodynamic Model Training® is a manual(9)-based psychodynamically oriented ultrashort
psychotherapeutic intervention, consisting of a very brief psychoeducation and an initial
training in autosuggestion techniques that are taught during a single 1.5-day program (day
1, 0900-2000 h; day 2, 0900 – 1300 h). Subjects, approximately 30 per group, were introduced
to five guided imagery scenarios aimed at strengthening the following psychotherapeutically
defined aspects of functioning: (1) self-worth, self-determination, self-assurance; (2)
self-acceptance; (3) health, vitality, relaxation, awareness of bodily functions; (4)
creativity, self-worth, remuneration and emotional reward for one’s work; and (5) ability to
sustain intimate personal relationship.
Follow-up period
Subjects of either group were contacted by telephone to schedule follow-up assessments in
the study physicians’ offices at the Institute for Clinical Psychology, Psychotherapy, and
Health Promontion, Graz, at the end of months 3, 6, and 12, and had to present for the
appointment within 36 h of the telephone call in order to facilitate the detection of any
smoking. During these assessments, subjects were asked about their non/smoking status, their
breathalyzer CO levels were determined by associates of the study’s sponsor, the STGKK, and
they had to provide a urine sample for cotinine analysis. Family members of randomly
selected subjects also received telephone calls from a staff member of the STGKK to confirm
their non/smoking status. No relapse-prevention counseling was administered during the
follow-up period.
Assessments
At baseline, demographic data, medical and smoking history were obtained, and vital signs
and exhaled CO levels were determined. The Beck Depression Inventory(10) was used to assess
depressive symptoms (scores of 0 to 9 are considered to be normal, scores of 10 to 18
indicated mild-to-moderate depression, scores of 19 to 29 indicated moderate-to-severe
derpession, and scores of 30 to 63 indicate severe depression). The Fagerström Tolerance
Questionnaire(11;12) was used to quantify the severity of nicotine dependence (scores of 0
to 11, with higher scores indicating more severe dependence). A separate questionnaire
contained the portion of the Structured Clinical Interview for the Diagnostic and
Statistical Manual version 4 (DSMIV)(13) concerning substance dependence disorders.
During follow-up interviews, CO levels were determined in the expired air by breathalyzer
(piCOsmokerlyzer®, www.bedfont.com). Urine samples were obtained and quantified for
cotinine, a major metabolite of nicotine with a urine elimination half-life around 20 h,(7)
by HPLC coupled with tandem mass spectrometry (LC/MS/MS) as previously described.(14) The
cotinine (mass transition 177 > 80 m/z) standard curve (internal standard, 50 ng/ml
d3-methadone) was essentially linear up to the highest concentration tested, i.e., 2000
ng/ml (quadratic equation fit, weighting 1/x, r>0.99). The level of detection (LOD) was 13
ng/ml at a signal/noise ratio of 2/1). The level of quantification (LOQ) in the actual urine
samples of the study was 30 ng/ml.
Measures of outcome
The primary outcome criterion was a biochemically/pharmacologically-confirmed 12-month
continuous abstinence as evidenced by self-reports of nonsmoking status in all interviews
(i.e., at 3, 6, and 12 months). Self-reports of nonsmoker status were confirmed by urine
cotinine levels below the level of detection (13 ng/mL at a signal/noise-ratio of 2/1 in the
LC/MS/MS analysis) at all 3 follow-up interviews. Subjects in the bupropion group had to
report abstinence from the target quitting date onwards, subjects in the psychotherapy group
had to report abstinence from the end of the 1.5-day program onwards. Subjects who
self-reported nonsmoker status but for which urine samples could not be collected or at any
of the 3 follow-up time points or which refused to provide a urine sample at any of the 3
follow-up time points were considered smokers. In order to better compare the data of the
present study with previously published bupropion data,(3;4) nonsmoker status was confirmed,
independently of the urine cotinine analysis, by exhaled carbon monoxide (CO) levels at or
below 10 parts per million (ppm) at all 3 follow-up interviews, following the nonsmoker
criterion of Jorenby and coworkers for low-frequency follow-ups.(3;4) The secondary outcome
was point prevalence of self-reported abstinence confirmed by urine cotinine levels below
the level of detection for each follow-up time point. Outcome criteria were assessed both in
the ITT- and the completer-sample.
Statistical analysis
The sample size of approximately 380 subjects per group was determined such that, under
standard conditions regarding power (80%) and two-sided alpha level (0.05), the following
differences between the two treatment groups may be detected: continuous abstinence rates of
17% in one group vs 10% in the other or 23% vs 15 % or 29% vs 20%. Baseline comparisons of
the two treatment groups were performed by the chi-square test for categorical data,
Student’s t-test for normally distributed and Mann-Whitney U-test for non-normally
distributed numerical variables. Differences between the two groups regarding primary
(12-month continuous abstinence rate) and secondary (point prevalence of abstinence) outcome
criteria, TEAE rates, and rejecter rates were analysed by means of the chi-square test
(two-sided). In order to quantify the differences between the two groups, the Odds Ratio
(OR), Relative Benefit (RB; in analogy to the Relative Risk), and the Number Needed to Treat
(NNT) were determined. Agreement between the two detection methods (cotinine level, CO
level) was evaluated by the kappa coefficient, significant differences in continuous
abstinence rates between the two detection methods were determined by means of the McNemar
test. All analyses were performed by a certified statistician using the SPSS® software
(www.spss.com). Measures of variance were either the standard deviation (S.D.) for the
treatment groups’ baseline characteristics or the 95 % confidence interval for OR, RB, and
NNT.
