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

Study Overview
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Brief Summary
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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.

Detailed Description
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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: Low-intensity group: encouraged to quit smoking via own doctor and varenicline is prescribed for 12 weeks. 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: A hotline is established which the high-intensity group can call. 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.

Official Title
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A Randomized Open-label, Superiority, Multicenter, Two-arm Intervention Study of the Effect of High-intensity vs. 'Low-intensity' Smoking Cessation Intervention in Active Smokers With COPD

Conditions
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Chronic Obstructive Pulmonary Disease, Smoking Cessation, Lung Diseases, Obstructive, Pulmonary Disease, Chronic Obstructive

Intervention / Treatment
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* Other: High-intensity smoking cessation intervention
* Drug: Low-intensity smoking cessation intervention


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 50 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: This study will be performed as a randomized, open label, superiority, 2-arm intervention study in active smokers with COPD. A total of 600 participants will be included with startup 1st January 2020 and is expected to be completed 3 years later, January 2023. Participants are randomized (random allocation) 1:1 to a low-intensity group and a high-intensity group. Stratified for age (>65 years vs. ≤65 years) and number of daily cigarettes (>10/day vs. ≤10/day). Blocked randomization through REDCap with blocks of varying sizes (4-8), which will not be disclosed. Participants, their data and laboratory specimens etc. will be assigned a coded identification number (ID) to maintain participant confidentiality. Participants will be randomized to either a low-intensity or a high-intensity smoking cessation intervention.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: High-intensity group<br>Will receive high-intensity intervention, which is a combination of pharmacological (varenicline) and behavioural support, described later. | Other: High-intensity smoking cessation intervention<br>* Varenicline for 12 weeks - Day 1-3: 0.5 mg daily. Dag 4-7: 0.5 mg two times daily. Thereafter 1 mg 2 times daily. Group-sessions in 6 months: Preparation phase: 5 sessions Day 1-14: 5 sessions Day 15-30: 5 sessions Day 31-60: 5 sessions Day 61-90: 5 sessions Day 90-180: 5 sessions c) Hotline and scheduled phone consultations: A hotline is established which the high-intensity group can call. Weekly calls to all patients in the project for 26 weeks. Call for 5-10 min. If the patient has not had relapse, there will be called week 34 and week 42. If the patient has had relapse, calls continue until relapse-free for 10 weeks, then week 34 and week 42. d) Buddy-arrangement: i. Patients 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 patients are matched with patients from pulmonary medical outpatient clinic who have ceased smoking.<br>|
| Active Comparator: Low-intensity group<br>Encouraged to quit smoking via own doctor and is prescribed varenicline. | Drug: Low-intensity smoking cessation intervention<br>* Varenicline prescribed for 12 weeks - Day 1-3: 0.5 mg daily. Dag 4-7: 0.5 mg two times daily. Thereafter 1 mg 2 times daily.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Anamnestic and biochemical* validated smoking cessation | *Cotinine is analyzed in a urine sample, as validated point-prevalence for the last 7 days | 12 months after inclusion | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of admissions for exacerbations of COPD or death |  | Within 12 months after inclusion | 
| Number of admissions for all causes or death |  | Within 12 months after inclusion | 
| Number of cardiovascular events | Defined as cardiovascular death, acute myocardial infarction or unstable angina pectoris | Within 12 months after inclusion | 
| Changes in CAT-score (COPD Assessment Test) | Range of CAT scores from 0-40. Higher scores denote a more severe impact of COPD on a patient's life. | 12 months after inclusion | 
| Changes in FEV1 from baseline |  | 12 months after inclusion | 
| Changes in BMI | BMI loss more than 1 unit | 12 months after inclusion | 
| Clinically relevant changes in HADS-score (Hospital Anxiety and Depression Scale) | Each item on the questionnaire is scored from 0-3. A person can score between 0 and 21 for either anxiety or depression. Higher scores indicate a more greater risk of either anxiety or depression. | 12 months after inclusion | 
| Occurrence of DNA from the following: M. catarrhalis, H. influenzae and P. aeruginosa | These end-points are only examined on the first 50 who stop smoking from the high-intensity group against the first 50 who do not stop smoking from the low-intensity group. | 12 months after inclusion | 
| Changes in the total lung microbiome | These end-points are only examined on the first 50 who stop smoking from the high-intensity group against the first 50 who do not stop smoking from the low-intensity group. | 12 months after inclusion | 
| Occurrence of smoking-related cancer | Lung cancer, urothelial cancer, pancreatic cancer, esophageal cancer, pharyngeal cancer, laryngeal cancer, tongue cancer, oral cancer, tonsil cancer | Within 12 months after inclusion | 
| Number of admissions requiring non-invasive ventilation (NIV) treatment or admissions to intensive care or death |  | Within 12 months after inclusion | 
| Changes in status from MRC-dyspnea score from < 3 to 3 ≥ (Medical Research Council dyspnea scale) | The scale ranges from 1-5, higher score indicate a greater extent to which patients' breathlessness affects their mobility. Patients who score 3, 4 or 5 on MRC-dyspnea scale may be offered rehabilitation according to international recommendations. | 12 months after inclusion | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Chronic Obstructive Pulmonary Disease, Randomized Controlled Trial, Smoking Cessation, Behavioural support, varenicline, exacerbations