GOLD Stage I Chronic Obstructive Pulmonary Disease (COPD)

Study Overview
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Brief Summary
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Recently integrated in clinical practice, the Global Initiative for Chronic Obstructive Lung Disease (GOLD) classification states that a mild (stage I) chronic obstructive pulmonary disease (COPD) is present, in a smoker, when the postbronchodilator forced expired volume in 1 second (FEV1) to forced vital capacity (FVC) ratio is < 0.7. A major change that was introduced by the GOLD classification system was that COPD could be diagnosed despite an FEV1 that is within normal predicted values (above 80% predicted). Because it suggests diagnosing and detecting COPD earlier than done until very recently in medical practice, the GOLD standards bring in a new reality to clinicians. In fact, this novel COPD classification comes with new research challenges because the functional impacts and systemic consequences related to COPD are mostly documented in patients with moderate to severe stages with little information specifically in GOLD stage I COPD. This information is important if the investigators are to convince physicians that GOLD stage I COPD needs to be diagnosed and eventually treated. The investigators aimed to characterize GOLD stage I COPD patients according to activity-related dyspnea. More specifically, our objectives were to compare: i) baseline pulmonary function ii) exercise capacity iii) quadriceps muscle function iv) levels of physical activity in daily life between symptomatic (Sx) GOLD stage I COPD patients, asymptomatic (ASx) GOLD stage I COPD patients and healthy control subjects (CTRL). The investigators reasoned that exercise tolerance and physical activity levels would be decreased in Sx GOLD stage I COPD patients as it would be similar between ASx GOLD stage I COPD patients and CTRL.

Detailed Description
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The study will be conducted among three subgroups: symptomatic GOLD stage I patients with COPD, asymptomatic patients GOLD stage I COPD and healthy control subjects with normal lung function. Subjects will be paired for age, sex and smoking history. The project will require three visits. In the initial visit, assessment of the pulmonary function with respiratory symptoms quantification will allow to classify subjects in the proper subgroup. The Medical Research Council (MRC) dyspnea scale will serve as the reference outcome to determine whether COPD patients are symptomatic or not. Patients with an MRC dyspnea score < 2 will be considered asymptomatic. A second questionnaire (ATS-DLD-78) will serve to document cough, expectorations, wheezing and smoking history in every subjects. Body composition will be measured by bioimpedance and by waist circumference after a blood sample taken in the morning, in a fasting state. A six-minute walk test (6MWT) will be performed by all subjects. After a one-hour resting period, a maximal incremental shuttle walking test will be realized in the same visit to quantify maximal exercise capacity. Measures of force and endurance of the quadriceps will be taken by magnetic stimulation of the femoral nerve before the maximal walking test. Finally, subjects will receive a portable device to monitor physical activity for a period of 7 days. In the 2nd and 3rd visits, subjects will realize an endurance walking test at 85 % of their predetermined maximal capacity. Before each endurance test, a bronchodilator or a placebo will be administered following a randomized double-blind design. Measures of force and endurance of the quadriceps will be taken by magnetic stimulation of the femoral nerve before and 10-min after endurance exercise tests. A needle biopsy of the vastus lateralis will be performed at the end of the third visit.

Official Title
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GOLD Stage I COPD: Is it Really a Disease ? Exercise Tolerance, Muscle Function and Response to Bronchodilation in GOLD Stage I COPD Patients

Conditions
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Mild Chronic Obstructive Pulmonary Disease, Respiratory Symptoms, Physical Activity

Intervention / Treatment
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* Drug: Combination ipratropium/salbutamol or placebo (nebulization)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Smoking history (≥ 10 pack/year) Exclusion Criteria: Anticoagulation or coagulation defect Hypoxemia or exercise-induced desaturation (SpO2 < 85%) Antibiotic or oral corticosteroid therapy (end of treatment < 1 month prior to study) Anti-inflammatory treatment, exacerbation (< 3 months) Myopathy Neuromuscular or locomotor diseases Recent cancer Unstable cardiac condition Asthma

Ages Eligible for Study
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Minimum Age: 40 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Healthy control subjects<br>Subjects with a significant smoking history (more than 10 pack-years) and a normal lung function. | |
| Asymptomatic GOLD stage I COPD patients<br>GOLD stage I COPD (post-bronchodilator forced expiratory volume in 1 second [FEV1] > 80% predicted and FEV1/ forced vital capacity [FVC] < 0.7 and a smoking history > 10 pack-years) were recruited. A Medical Research Council (MRC) dyspnea score ≥ 2 was used to define the presence of symptoms (dyspnea). Concretely, this group did not present any respiratory symptoms, with a MRC dyspnea score of 1/5. | Drug: Combination ipratropium/salbutamol or placebo (nebulization)<br>* The COPD patients were randomly assigned a combination of ipratropium/salbutamol or a placebo in a double-blind crossover design. The bronchodilation produced by the medication was given in order to evaluate if bronchodilation was effective in increasing exercise tolerance during an endurance shuttle walking test in patients with GOLD stage I COPD.<br>* Other names: Combivent or placebo (nebulization);|
| Symptomatic GOLD stage I COPD patients<br>GOLD stage I COPD (post-bronchodilator forced expiratory volume in 1 second [FEV1] > 80% predicted and FEV1/ forced vital capacity [FVC] < 0.7 and a smoking history > 10 pack-years) were recruited. A Medical Research Council (MRC) dyspnea score ≥ 2 was used to define the presence of symptoms (dyspnea) in this group. | Drug: Combination ipratropium/salbutamol or placebo (nebulization)<br>* The COPD patients were randomly assigned a combination of ipratropium/salbutamol or a placebo in a double-blind crossover design. The bronchodilation produced by the medication was given in order to evaluate if bronchodilation was effective in increasing exercise tolerance during an endurance shuttle walking test in patients with GOLD stage I COPD.<br>* Other names: Combivent or placebo (nebulization);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximal oxygen consumption | Exercise capacity was directly assessed following an incremental progressive shuttle test. The exercise capacity was defined as the maximal oxygen consumption (VO2 peak, ml/kg/min) by direct measurements of gas exchanges. | Baseline | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Quadriceps muscle force | Quadriceps muscle strength was measured with magnetic stimulation of the femoral nerve. Mid-thigh cross-sectional area (MTCSA) was obtained following a computed-tomography scan. Quadriceps muscle biopsy was performed to measure muscle metabolism. | Baseline | 
| Levels of physical activity in daily life | A portable armband was worn by the participants on a 7-days basis to monitor physical activities in daily life. | Baseline | 
| Oxydative stress | Oxydative stress will be quantified in the blood and in the muscle samples obtained during the muscular biopsy. | Baseline | 
| Pulmonary function | Pulmonary function will be measured by spirometry and plethysmography in the initial visit. In the subsequent visits, pulmonary function will be measured by spirometry before and 60-min after the nebulization of either placebo or bronchodilator. A computed-tomography scan of the lungs was also assessed | At baseline and before and 60-min after the nebulization of either placebo or bronchodilator | 
| Time to exhaustion during a constant intensity exercise test | Time to exhaustion was also defined as exercise tolerance and was assessed during a endurance shuttle walking test 90-min following the nebulization of whether Combivent or Placebo in a double-blind crossover design. It was defined as the time in seconds for which a subject could maintain an intensity of 85% of the maximal oxygen consumption during walking or running. | Before and 90-min after bronchodilation or placebo | 
| Systemic inflammation | Systemic inflammation will be studied from blood samples obtained in every participants. | Baseline | 
| Quadriceps muscle endurance | Quadriceps muscle endurance was defined as the time to exhaustion following a constant quadriceps force corresponding to 50 % of the maximal voluntary contraction. | Baseline | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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chronic obstructive pulmonary disease, lung function, symptoms, activity-related dyspnea, quadriceps muscle function, exercise capacity, physical activity in daily life, muscle biopsy, systemic inflammation, GOLD stage I, pulmonary function