TOBacco STOP in Chronic Obstructive Pulmonary Disease-Trial - Study Protocol
TOBacco STOP in Chronic Obstructive Pulmonary Disease-Trial - Study Protocol
Background:

 Cigarette smoking is the leading cause of chronic obstructive pulmonary disease (COPD) and it
 contributes to the development of many other serious diseases. Acute exacerbations of COPD
 (AECOPD) often lead to hospitalization. Severe hospitalization-requiring AECOPD carries very
 high economic costs for the healthcare system, and personal costs for patients. Smoking
 cessation in COPD for the healthcare system, and personal costs for patients. Smoking
 cessation in COPD patients is known to improve survival and reduce the number of AECOPD.
 However, smoking cessation interventions in these patients have only been successful for
 consistent smoking abstinence in 12 months in approximately 15-20%. Thus, more effective
 interventions are needed for this patient group.

 Aims:

 The aim of this study is to determine, among people with chronic obstructive pulmonary
 disease (COPD), whether a "high-intensive" smoking cessation intervention in comparison to a
 standard intervention can lead to permanent, >12 months, smoking cessation in a higher
 proportion.

 Methods:

 This study is a randomized trial in active smokers with COPD and who have lost less than 50%
 lung function. A total of 600 participants will be randomly assigned 1:1 to either a standard
 treatment (guideline-based municipal smoking cessation programme, "low intensity" group), or
 an intervention group ("high-intensity" group), which consists of group sessions, telephone
 consultations, behavior design, hotline, "buddy-matching" (smoker matched with COPD patient
 who stopped). Both groups will receive pharmacological smoking cessation.

 Discussion:

 The potential benefit of this project is to prevent smoking-related exacerbations of COPD and
 thereby reduce logistics and costs of hospitalization and treatment of COPD. In addition, the
 project can potentially benefit from increasing the quality of life and longevity of COPD
 patients and reducing the risk of developing lung cancer and other smoking-related diseases.
Hypothesis:

 A "high-intensity" smoking cessation intervention is superior in leading to permanent (>12
 months) smoking cessation in active smokers with COPD than does a standard, guideline-based
 municipal smoking cessation intervention.

 Secondary hypothesis: The progression of COPD will be reduced in the "high intensity group",
 and this will result in limited loss of lung function, a reduced number of exacerbations of
 COPD, improved mental health and self-rated health.

 Rationale:

 Smoking cessation in COPD patients improves survival and reduces the number of exacerbations.
 Unfortunately, relatively few COPD patients are successful in permanently stopping to smoke,
 even with pharmacological help.

 Primary aim: to determine if a high-intensity intervention in comparison to a low-intensity
 intervention can lead to persistent (>12 months) anamnestic and biochemical smoking cessation
 in more active smokers with COPD.

 Secondary aim 1: to investigate, within the randomized study design, long-term follow-up over
 2 years and 5 years, whether the occurrence of depressive symptoms and anxiety symptoms is
 different in the "high-intensity" and "low-intensity" group. This is estimated by means of a.
 Depression questionnaires and b. Consumption of pharmaceuticals that are primarily prescribed
 for these conditions.

 Secondary aim 2: to characterize changes in the respiratory microbiome between active smokers
 with COPD and COPD patients who have stopped smoking to find out whether the airway
 microbiome adapts/changes after smoking cessation.

 Background:

 COPD is a life-threatening and incurable lung disease characterized by persistent breathing
 problems and poor airflow in the lungs. Globally, it is estimated that approx. 250 million
 people have COPD and that approx. 3 million deaths annually, corresponding to 5% of all
 deaths worldwide, are caused by COPD. In Denmark, there are about 320,000 people with COPD,
 where approx. 5500 die due to COPD each year, making the disease the third most frequent
 cause of death in Denmark. Cigarette smoking is by far the most important cause of
 development of COPD by causing lung inflammation, which leads to release of oxidative
 radicals, and this in turn leads to destruction of lung tissue (both respiratory tissue and
 conductive tissue). Cigarette smokers have a higher incidence of respiratory symptoms and
 abnormal lung function, a greater annual decrease in FEV1 (forced expiratory volume for 1
 second) and a greater mortality rate than non-smokers.

 Acute exacerbations (worsening) of COPD (AECOPD) are associated with increased risk of
 mortality due to decreasing lung function and activity level and often lead to
 hospitalization. This is one of the biggest costs for the healthcare system for treatment of
 COPD. In addition, there is evidence that AECOPD increases the risk of myocardial infarction
 and strokes. In this way, smoking cessation will be the most effective intervention to stop
 the development of COPD, as well as increase survival and reduce morbidity. Overall, tobacco
 smoking thus increases mortality and serious morbidity as well as symptoms in COPD patients,
 and smoking cessation should be the top priority in treating COPD.

 Current evidence of smoking cessation:

 However, smoking cessation is only successful in a minority of patients with COPD. In an
 intervention study from 2011 (N = 499), after 12 months, only 18,6% of COPD patients treated
 with varenicline had still stopped smoking, while 5,6% of patients in the placebo group had
 obtained this. Despite a significant difference in absolute risk of 13% between the
 varenicline and placebo group, it is still >80% of COPD patients in the varenicline group who
 smoke after 12 months, which is not satisfactory.

 In an observational study from 2008 among patients with COPD who participated in a new 1 year
 smoking cessation programme (N = 247), smoking cessation rates were as high as 52% after 1
 year and 38% after 3 years. The results were compared with a group of COPD patients who
 received normal care (N = 231), in which smoking cessation rates were 7% after 1 year and 10%
 after 3 years. The smoking cessation program in the patients who participated in the new
 programme included a 2-week period of admission to hospitals, group sessions where nicotine
 replacement therapy (NRT) and exercise were recommended/advised in, and in addition telephone
 calls with specially trained staff who gave feedback and support for smoking cessation
 throughout the year. Although these results are very inspiring, the obvious weaknesses in the
 design leave open numerous possibilities for errors in the estimates. Such an advanced,
 multipoint smoking cessation has never been tested in a solid design like a randomized
 controlled trial.

 Method:

 Design:

 Study A) A randomized open-label, superiority, multicenter, 2-arm intervention study, in
 which it is examined if a "high-intensity" intervention causes fewer people (diagnosed with
 COPD) to smoke after 12 months than in a "low-intensity" intervention in people diagnosed
 with COPD. The effect on survival for 12, 24 and 48 months, incidence of COPD exacerbations,
 number of admissions for all causes and cardiovascular admissions will also be analyzed at
 the same times.

 Study B) Depression/anxiety within the framework of the randomized study ("high-intensity"
 vs. "low-intensity" group). Measured by means of questionnaires and by recording the
 prescription of drugs for depression and anxiety.

 Study C) A microbiological study within the framework of the randomized study, which aims to
 investigate the respiratory microbiome and possibly changes in participants in the two
 randomized groups. Subgroup analyzes for participants who actively smoke vs. have ceased and
 exploratory analyzes to determine if the microbiome changes within 6 months after

 Data collection:

 The primary daily project management is handled by the project manager. In addition, a
 project group, consisting of health professionals from the departments involved, is trained
 to assist the project manager with recruitment, sampling and follow-up of participants.
 Recruitment in general practice is done by the project-trained nurse.

 Upon entering the program and all visits in the future (after 1, 3, 6, 12, 24 and 36 months),
 the participant is summoned to a conversation with staff, asking if the participant smokes
 (yes vs. no), and if yes, how much. In addition, a urine sample is taken for cotinine
 analysis for biochemical verification of smoking status and standard blood samples to examine
 health status at these visits (analyzed on Department of Clinical Biochemistry, KBA). In
 addition, questionnaires: COPD Assessment Test (CAT), Medical Research Council dyspnea scale
 (MRC), and Hospital Anxiety and Depression Scale (HADS) are completed with the participant.
 In the case of inclusion and follow-up visits after 3, 6, 12, 24 and 36 months, spirometry is
 also carried out at regular intervals. Height measurement is done by inclusion in the study
 along with weight measurement, which is only further measured after 6, 12, 24 and 36 months
 to monitor BMI.

 The Hamilton Depression scale (HAM-D) score is performed by inclusion, after 12, 24 and 36
 months and if the score becomes high (≥25), i.e. that there is a high risk of developing
 depression, the participant is referred for examination for depression via their own doctor.

 In addition, sputum samples are induced (with isotonic saline water) for microbiome analysis
 by inclusion of the study, and again after 12 months in the first 50 participants in the
 "high-intensity" group who quit smoking, and in the first 50 participants in the
 "low-intensity" group, who do not quit smoking.

 Intervention:

 600 active smokers with COPD will be included. Stratified for age (>65 years vs. 65 years)
 and number of daily cigarettes (>5/day vs. ≤5/day). There are randomized blocks of varying
 sizes (4-8). Block sizes will be concealed to investigators.

 Participants will be randomized to one of the following two treatment groups:

 1. "Low-intensity group": encouraged to quit smoking via own doctor and varenicline is
 prescribed for 12 weeks.

 2. "High-intensity group": a. Varenicline for 12 weeks b. Group-sessions - in all 30
 sessions divided into 6 months i. Preparation phase: 5 sessions ii. Day 1-14: 5 sessions
 iii. Day 15-30: 5 sessions iv. Day 31-60: 5 sessions v. Day 61-90: 5 sessions vi. Day
 90-180: 5 sessions

 Group sessions are controlled by:

 I. Pulmonary Nurse [Mapping of different smoking patterns and different reasons for smoking.
 When is smoking the greatest? When in the process, smoking starts to fall. Dangerous
 situations regarding smoking relapses. Initial focus on nicotine-craving and coping methods]
 II. Pulmonary doctor [Lung function, Lung age, Anatomy, Physiology, Pathophysiology of lung
 cancer and COPD]. Focus on why smoking cessation is good. Is there anything you want to
 experience in your life that smoking can prevent? Either by death or because illness would
 prevent it? III. Psychologist [Focus on behavior before smoking and how this behavior is
 slowed down at an early stage. Coping by smoking. Cognitive smoking cessation strategies.
 Handle digito-oral habit].

 IV. Physiotherapist [Training on how to improve general physical form. Forming individual
 training programs].

 V. Dietician (focus on keeping weight (both ways), nutrition). Suggestions for what to eat by
 smoking craving.

 c) Relationships and retention via these: i. Hotline and scheduled phone consultations:

 1. A hotline is established which the "high-intensity group" can call.

 2. Weekly calls to all participants in the project for 26 weeks. Call for 5-10 min. If the
 participant has not had relapse, there will be called week 34 and week 42. If the
 participant has had relapse, calls continue until relapse-free for 10 weeks, then week
 34 and week 42.

 d) "Buddy-arrangement": i. Participants who have completed the program and have become
 smoke-free, are matched with new ones in the program. A meeting frequency of approx.
 every 7-14 days. The first participants are matched with patients from respiratory
 medicine outpatient clinic who have ceased smoking.

 Patients with COPD fear acute exacerbations since this increases dyspnea, cough, sputum
 and is associated with significant morbidity and mortality. Smoking cessation is the
 best intervention for exacerbations and progression of COPD in active smokers with COPD.
 The potential benefit of this project is to prevent smoking-related exacerbations of
 COPD and thereby reduce logistics and costs of hospitalization and treatment of COPD. In
 addition, the participants can potentially benefit from fewer mental depressions,
 increased self-rated quality of life and longevity of COPD patients and can reduce the
 risk of developing lung cancer (the leading cause of death in COPD patients with >50%
 lung function (FEV1) preserved) and other smoking-related diseases. Possibly, the
 project may also cause "healthy" smokers to stop smoking. Based on this, the
 investigators believe that the experiment is scientifically sound and that the trial
 participants will not be exposed to irresponsible risks.
Inclusion Criteria:

 -  Competent and mature

 -  Have diagnosed COPD [spirometry verified and evaluated by pulmonary specialist]

 -  Current daily smoker [Minimum 1 cigarette daily]

 -  Have smoked minimum 20 pack years (1 pack year = 20 cigarettes daily in 1 year)

 -  Want to or try to stop smoking

 -  Do not mind taking varenicline or NRT during the trial

 -  Are willing to give blood and urine samples according to the protocol

 Exclusion Criteria:

 -  Previously included in the trial

 -  Hospitalized with COPD-exacerbation within the last 24 months

 -  Are associated with hospital outpatient clinic for COPD disease treatment

 -  Have FEV1<50%.

 -  Pregnancy/breastfeeding

 -  Life expectancy less than 1 year

 -  Severe linguistic problems or inability to give informed consent

 -  Severe mental illness that is not controlled with medication

 -  Active alcohol or substance abuse

 -  Active cancer disease* *The person can participate if he or she has had a cancer
 disease that is now referred to as curative/radically treated. Basal cell carcinoma of
 the skin does not count as an exclusion criterion.