Effectiveness of Combined Treatment of Bupropion and Nicotine Replacement Therapy in Hospitalized Subjects With Active Smoking in a Reference Center
Phase: PHASE4
Conditions: Tobacco Smoking, Tobacco Withdrawal, Nicotine Addiction, Nicotine Withdrawal, Nicotine Replacement Therapy
Sponsor: National Institute of Respiratory Diseases, Mexico

DOCUMENT DATE: November 29, 2023 
UPLOADED: 02/01/24 
PROYECT TITLE: EFFECTIVENESS OF COMBINED TREATMENT FOR SMOKING 
CESSATION IN SUBJECTS HOSPITALIZED FOR LUNG DISEASE AND TOMOKING: 
AN OPEN RANDOMIZED CLINICAL TRIAL 
 
RESPONSIBLE INVESTIGATOR AND ASSIGNMENT 
 
Dr. Ireri Isadora Thirión Romero 
Smoking and COPD Research Department. 
 
PARTICIPANT RESEARCHERS AND ASSIGNMENTS 
 
Dr. Víctor Adrián Flores Aceves, National Institute of Respiratory Diseases. 
Dr. Arantxa Mariana Remigio Luna, National Institute of Respiratory Diseases. 
Dr. Ivan Centeno Saenz, Department of Smoking and COPD Research. 
Dr. José Rogelio Pérez Padilla, Department of Research in Smoking and COPD. 
Dr. Sebastián Rodríguez Llamazares, National Institute of Respiratory Diseases. 
Dr. Robinson Emmanuel Robles Hernández, Department of Research in Smoking and 
COPD. 
Dr. in Psych. Ma. Andrea Hernández Pérez, Department of Research in Smoking and 
COPD. 
Dr. in Psych. Leonor García Gómez, Department of Research on Smoking and COPD. 
Dr. in Psych. Ma. Jennifer Osio Echanove, Department of Research in Smoking and COPD. 
 
INTRODUCTION 
Smoking is an addictive disease that causes a chemical toxicosis caused by the inhalation 
of tobacco smoke, capable of causing acute or chronic harmful effects on different structures 
of the body. Various factors affect the damage this activity can generate in each individual, 
including clinical, biological, psychological, epidemiological, and socioeconomic.(7) 
Tobacco smoke increases the risk of health problems that lead to hospitalization, including 
Cardiovascular and respiratory diseases, increases the days of hospital stay, worsens 
postsurgical recovery, and increases the risks of cancer.(7) 

In Mexico, 14,820,107 people over 20 years of age currently smoke (18%); Of them, 
4,167,375 are women, and 10,652,720 are men.(8) 51.6 thousand deaths occur annually 
attributable to tobacco consumption, which represents 7.5% of deaths in Mexico.(7) 
The combination of psychological and pharmacological treatment for smoking cessation has 
been found to be more effective than separate treatments (9). Currently, the FDA has 
approved different medications as the first line of treatment: nicotine replacement treatments 
-NRT- (patches, gum, lozenges, nasal spray, and oral inhaler); and non-nicotinic treatment 
(bupropion and varenicline). (6)(9) 
Nicotine Replacement Therapy (NRT) helps combat nicotine withdrawal symptoms by 
providing users with nicotine in long-acting (patch) or short-acting (mask gum, lozenges, 
inhaler, nasal spray) form. Use of NRT in any form increases smoking abstinence by 60% 
compared to placebo (RR 1.60, 95% CI 1.53–1.68). To increase effectiveness, the nicotine 
patch can be combined with short-acting NRT, which is more effective than using a form of 
NRT (RR 1.34, 95% CI 1.18–1.51) (10 ). Bupropion increases norepinephrine and dopamine 
levels and is approved as an antidepressant for smoking cessation. Increases smoking 
cessation rates compared to placebo (OR 1·75, 95% CI 1·52 to 2·01) (8.9). Varenicline is a 
partial nicotinic receptor agonist that doubles smoking abstinence rates compared to 
placebo (RR 2.24, 95% CI 2.06–2.43). (10) These results have been obtained in smokers 
treated on an outpatient basis. Rhe study of the effectiveness of these different treatments 
in hospitalized subjects has been little and marginally analyzed.(6) Among the studies 
carried out, it shows that hospitalized subjects who received treatment for smoking cessation 
and support had abstinence rates greater than 6 months. The analysis carried out in this 
study does not differentiate by type of pharmacological treatment. The predominant 
pharmacological treatment was NRT. (11) Smoking cessation in hospitalized patients has 
been associated with lower rates of postsurgical complications, better tissue healing and 
proliferation, and reversibility of the attenuation of inflammation mechanisms. (12,13) 
Hospitalization is a vital scenario to address tobacco consumption for various reasons and 
benefits; among the most important are the prohibition of smoking on the hospital premises 
and the special availability for quitting that the smoker has during admission to a hospital 
admission promotes subsequent tobacco cessation because a severe illness, primarily if 
related to tobacco, can increase smokers' motivation to quit. 
 
MAIN OBJECTIVE 
 

Our objective will be to analyze the effectiveness of the combination of bupropion and 
nicotine versus nicotine replacement therapy to quit smoking in hospitalized subjects 12 
months after discharge. 
SPECIFIC OBJECTIVES 
 
1. Analyze the effectiveness of the combination of pharmacological therapies to quit smoking 
in hospitalized subjects 3, 6 and 12 months after discharge. 
2. Evaluate the symptoms and signs of withdrawal in the different groups throughout their 
follow-up. 
3. Record the adverse effects of the different pharmacological therapies reported in the 
different groups throughout their follow-up. 
4. Evaluate the lung function of the different groups at 3 months after discharge, 6 months 
and 12 months after discharge. 
 
METHODS 
a) Location of the study. 
National Institute of Respiratory Diseases, Ismael Cosío Villegas México. 
Smoking and COPD Research Department. 
 
b) Description of the population: 
Inclusion criteria: 
1. Over 18 years of age. 
2. Active smokers (smoking more than 100 cigarettes in their entire life and having 
consumed cigarettes in the last 30 days) 
3. Hospitalized subjects with acute or chronic lung disease. 
4. Signing of informed consent. 

Exclusion criteria: 
1. Subjects with pharmacological treatment to stop smoking during recruitment or in the last 
month. 
2. Contraindications to the use of pharmacological therapy. (Annex is attached the 
contraindications for the use of medications) 
3. Subjects who cannot maintain follow-up. 
Elimination criteria: 
1. In an analysis by intention to treat, there will be no elimination of subjects after 
randomization. 
Sample size: 
The sample size calculation is carried out by difference between proportions, with a 
confidence level of 95%, power of 80%, unilateral, with an observed proportion of 65% and 
an expected proportion of 80% for the combination of pharmacological therapy; 50 subjects 
are required for each group; If a loss of participants is estimated at 25%, 67 subjects are 
required for each group. The sample size was carried out in the WinEpi 2006 program. 
c) Outcome variables and description of other study variables. 
Outcome variable: 
-Abstinence: abstinence from tobacco is defined as its suspension 12 months after hospital 
discharge, corroborated by detection of exhaled carbon monoxide less than 7 ppb and/or 
detection of cotinine in urine (positive). 
-Active smoker: defined as an active smoker who has consumed more than 100 cigarettes 
in his or her entire life and who has consumed cigarettes in the last 30 days. 
-CBT (cognitive behavioral therapy) is a model for treating problematic behaviors that 
focuses primarily on identifying and changing maladaptive patterns of behavior and 
thoughts, including problem-solving and coping skills rooted in relapse prevention theory, 
along with the cognitive restoration of maladaptive thoughts to regulate emotions and is 
combined with the recommendations of the Clinical Practice Guideline (CPG) for tobacco. 
(14) 

-Acute or chronic lung disease: Acute or chronic lung disease will be considered by medical 
diagnosis. 
-Exhaled carbon monoxide: a value greater than or equal to 7 ppb is defined as positive 
(subject with active smoking). 
-Cotinine in urine: defined as positive (subject with active smoking) positive test (qualitative 
test) 
-Nicotine dependence (Fagerström Questionnaire): mild, moderate and severe. 
-Withdrawal symptoms questionnaire. 
-Nicotine Craving Questionnaire (Urge to smoke, understood as a physiological and 
motivational state that drives the desire to smoke tobacco). 
-Adverse reactions questionnaire. 
-Respiratory symptoms questionnaires (PLATINO). 
-Pulmonary function tests (pre- and post-bronchodilator spirometry, carbon monoxide 
diffusion, and 6-minute walk) 
-Beck Anxiety and Depression Questionnaires. 
Procedures for collecting information using instruments and data quality control methods. 
Data Capture. 
a)  
b) 1-Subject identification (inclusion/exclusion criteria) 
c) 2-Signature of informed consent 
d) 3-Randomization of the drug (2 groups: a-nicotine patches, b-combination: nicotine 
patches + bupropion) 
e) 4-Start hospitalization treatment 
f) - Processes: Medications are given in a personalized way during hospitalization; brief 
advice is given, and questionnaires and measurements of exhaled CO and cotinine 
in urine are performed (treatment start day is day 0). The pharmacological treatment 
given to the subject will be for at least 12 weeks. 
g) 5-Monitoring during hospitalization to provide medications 

h) 6-Upon discharge, an appointment is made at the Smoking Clinic within the first 14 
days of discharge, and anti-smoking treatment for home use and brief advice will be 
provided. 
i) 7-First appointment at the Smoking Clinic 
j) - Processes: brief advice; intake of exhaled CO and cotinine in urine). It is scheduled 
to begin cognitive behavioral therapy (CBT) in a group, which lasts ten sessions, two 
times a week, with mixed modality (online or in-person). 
k) 8-Start CBT in the next two weeks after discharge. 
l) 9- Second appointment at the Smoking Clinic at the end of therapy (3 months after 
discharge) 
m) - Processes: brief advice; questionnaires and measurement of exhaled CO and 
cotinine in urine are performed; pre- and post-bronchodilator spirometry, carbon 
monoxide diffusion, 6-minute walk. 
n) 10-Third appointment at the Smoking Clinic 6 months after discharge: 
o) - Processes: brief advice; questionnaires and measurement of exhaled CO and 
cotinine in urine are performed; pre- and post-bronchodilator spirometry, carbon 
monoxide diffusion, 6-minute walk. 
p) 11-Fourth appointment at the Smoking Clinic 12 months after discharge 
q) - Processes: brief advice; questionnaires and measurement of exhaled CO and 
cotinine in urine are performed; pre- and post-bronchodilator spirometry, carbon 
monoxide diffusion, 6-minute walk) 
r) The information collection will be carried out through the INER RedCAP platform, 
which has security mechanisms for the data obtained and methods for adequate 
control. The protocol researchers will carry out data capture. 
 
Results analysis plan. 
 
1- A retrospective analysis was carried out on hospitalized patients with a history of active 
smoking, with the following characteristics: 40% of the patients evaluated had low 
dependence on nicotine, and 60% had moderate and severe dependence. Of the patients 
evaluated, 72% were male, and 28% were female. Proportional allocation is carried out for 
stratified sampling, Stratified randomization for sex (man and woman), and for low and 
moderate/severe dependence 

2- Statistical analysis methods according to the type of variables: the variables will be 
analyzed according to their type of distribution and whether they are quantitative or 
qualitative, by student's t or chi2 as appropriate. A descriptive analysis will be carried out on 
each of the variables. Subsequently, a comparative analysis will be carried out between the 
2 groups included, using ANOVA or Kruskal Wallis, depending on their distribution. The 
analysis of the main objective will be carried out by intention to treat according to the 
treatment granted and randomization. Randomization was stratified by level of nicotine 
dependence and sex. There will be no blinding. The primary outcome will be abstinence at 
12 months, and its association with the randomized treatment group will be seen. As a 
complementary analysis, a per-protocol analysis will be performed according to the 
treatment received. Finally, through multivariate analysis by logistic regression, abstinence 
or non-abstinence at one year was analyzed depending on the treatment received, adjusted 
for the different covariates such as sex, age, smoking rate, and level of dependence. 
3-The statistical analysis will be carried out using the STATA V13 statistical package. 
 
ETHICAL CONSIDERATIONS 
 
The type of risk must be considered in accordance with the provisions of Art. 17 of the 
REGULATIONS of the General Health Law on Health Research: 
 
● Research with minimal risk. 
 
This protocol was approved by the institutional ethics committee under the approval opinion 
with code C80-23 on November 29, 2023. 
 
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