Effects of Liraglutide in Chronic Obstructive Pulmonary Disease

Study Overview
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Brief Summary
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The study is a 44 weeks, prospective, randomized, placebo-controlled, double-blinded, parallel group two-center trial. Forty patients are recruited among the outpatients of the chronic obstructive pulmonary disease (COPD) clinic, Hospital of South West Jutland and Lillebælt Hospital according to the inclusion and exclusion criteria. The patients are randomized to receive liraglutide 3 mg per day (initial dose 0.6 mg, increasing by 0.6 mg weekly until 3 mg is reached) or placebo. At baseline, after four weeks (assessment of the acute effect of liraglutide), 20 weeks, and 40 weeks (assessment of the combined effect of liraglutide and weight loss) and at week 44 (assessment of the weight-loss after discontinuation of liraglutide) the patients are assessed by physical examination, carbon monoxide (CO) diffusion test, pulmonary function test, biomarkers of inflammation (CRP, interleucine-6 (IL-6), monocyte chemitactic protein-1 (MCP-1)), Fluorodeoxyglucose (FDG)/PET-CT scan of the lungs, 6-minute walking test, respiratory polygraphy and validated questionnaires including basic dyspnea index, transition dyspnea index, COPD Assessment Test (CAT)-score, short-form-36 (SF-36) and Epworth Sleepiness Score.

Detailed Description
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COPD is a common disease characterized by pulmonary inflammation, reduced pulmonary capacity, reduced physical activity and quality of life. Obesity is likewise a common disease characterized by inflammation, reduced physical activity and quality of life. Targeting both obesity and inflammation may turn out beneficial for patients with COPD and obesity, and this study explore the possibility to reverse a vicious cycle of COPD, lack of physical activity and obesity. The primary objective of the study is to evaluate the effect of Liraglutide 3mg in patients with COPD on patient reported outcomes as measured by the Transition Dyspnea Index. The hypothesis is that Liraglutide 3mg exerts beneficial effects on measures of pulmonary function and quality of life in overweight patients with COPD by reducing body weight and reducing inflammatory activity.

Official Title
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Effects of GLP-1 Receptor Agonist Treatment on Pulmonary Function and Quality of Life in Obese Patients With Chronic Obstructive Pulmonary Disease.

Conditions
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Pulmonary Disease, Chronic Obstructive

Intervention / Treatment
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* Drug: Liraglutide
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Informed consent obtained before any trial-related activities COPD as defined by FEV1/FVC<70% after maximal broncho-dilatation and in accordance with the Gold guidelines 2017 (25) Previous smoking of ≥ 20 pack-years Overweight defined as BMI > 27 kg/m2 Age 30 - 75 years Women of childbearing potential must use a safe anti-contraceptive method Exclusion Criteria: Chronic treatment with systemic steroids (inhalation steroids allowed) Current smokers Diabetes mellitus type 1 and type 2 as defined by current or previous treatment with antidiabetic medications of any kind or HbA1c ≥ 48mmol/mol Severe hepatic disease (Alanine transferase > 3 x UNL) Severe impaired renal function (eGFR < 30ml/min) Congestive heart disease New York Heart Association (NYHA) class 3-4 History of acute or chronic pancreatitis History of cholecystitis or cholecystolithiasis Pregnant or breastfeeding women Known bronchial asthma or interstitial lung disease Family history of multiple endocrine neoplasia type 2 (MEN2) or medullary thyroid carcinoma Large goiter or plasma-calcitonin > 50ng/ml

Ages Eligible for Study
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Minimum Age: 30 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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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: A prospective, randomized, placebo-controlled, double-blinded, parallel group and two-center trial.
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Liraglutide<br>Liraglutide injection 3.0 mg daily | Drug: Liraglutide<br>* Initially 0.6 mg daily, increasing weekly with 0.6 mg, until 3.0 mg is reached.<br>* Other names: NN2211;|
| Placebo Comparator: Placebo<br>Placebo, matching injection pen | Drug: Placebo<br>* Matching injection<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Transition Dyspnea Index (TDI) | The primary objective is to evaluate the effect of Liraglutide 3mg on Transition Dyspnea Index (TDI) after 40 weeks of treatment in subjects with COPD and overweight (BMI>27 kg/m2). A positive value indicates less dyspnea during specified activities | 40 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 6 minutes walking test | Walking distance during a 6-minutes walking test | 44 weeks | 
| Diffusion capacity of the lung for carbon monoxide (DLCO) | Pulmonary Diffusion Capacity measured by Carbon Monoxide (CO) diffusion capacity test | 44 weeks | 
| FEV1/FVC | Forced expiratory volume in first second (FEV1)/forced vital capacity (FVC) | 44 weeks | 
| Total lung capacity (TLC) | Total lung capacity | 44 weeks | 
| Residual volume (RV) | Residual volume | 44 weeks | 
| CAT-score | Chronic Obstructive Pulmonary Disease assessment test, a measure of COPD impact on every day life, total score ranges 0-25, a higher score indicates more symptoms | 44 weeks | 
| SF-36 | Short Form (36) Health Survey, which is a Quality of life questionnaire score, subscale scores are calculated according to the SF-36 manual | 44 weeks | 
| CRP | Inflammation marker, C-reactive protein, higher value indicates more inflammation | 44 weeks | 
| IL-6 | Inflammation marker, Interleukine 6, higher values indicates more inflammation | 44 weeks | 
| MCP-1 | Inflammation marker, Monocyte Chemoattractant Protein-1, higher value indicates more inflammation | 44 weeks | 
| Maximal standard uptake value (SUV max) | Maximal standard uptake value as measure by FDG-PET/CT scan of the lungs, a higher value indicates more inflammation | Twice over 44 weeks | 
| Mean standard uptake value (SUV mean) | Mean standard uptake value as measured by FDG-PET/CT scan of the lungs, a higher value indicates more inflammation | Twice over 44 weeks | 
| Total lesion glycolysis (TLG) | Total lesion glycolysis as measured by FDG-PET/CT, a higher value indicates more inflammation | Twice over 44 weeks | 
| Body weight | Changes in body weight | 44 weeks | 
| Number of COPD exacerbations | Mild-moderate exacerbations: Treatment with antibiotics or/and oral prednisolone and Moderate-severe exacerbations: Hospitalization due to pulmonary symptoms. | 44 weeks | 
| Changes in use of bronchodilator drugs and anti-inflammatory drugs | Defined by an increase in beta2agonists of more than 20 % per week and a change of more than 20 % of dose of anti-inflammatory drugs respectively. | 44 weeks | 
| Apnea/hypopnea index (AHI) | Apnea/hypopnea index, higher value indicates more apnea/hypopnea episodes | Twice during 44 weeks | 
| Oxygen desaturation index (ODI) | Oxygen desaturation index, higher values indicate more episodes of desaturation | Twice during 44 weeks | 
| Epworth score | Epworth sleepiness scale questionnaire, total score is calculated, 0-9: Normal, 10-15: mild to moderate sleep apnea, 16 or more indicate severe sleep apnea | Twice during 44 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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GLP-1 receptor agonist, Chronic obstructive pulmonary disease, FDG/PET-CT, inflammation, weightloss, quality of life