Multicentre Randomized Double Blind, Crossover, Placebo Controlled Clinical Trial to Evaluate the Effect of Liraglutide on Lung Function in Patients With Type 2 Diabetes Mellitus (LIRALUNG Study)
Phase: PHASE3
Conditions: Type 2 Diabetes
Sponsor: Lecube, Albert, M.D.

EudraCT number: 2014-005125-12 
UTN: U1111-1164-2060 
Version: LIRALUNG 4.0, Date: 04/April/2015 
 
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Study Title 
MULTICENTRE RANDOMIZED DOUBLE BLIND, CROSSOVER, 
PLACEBO-CONTROLLED CLINICAL TRIAL TO EVALUATE THE 
EFFECT OF LIRALUTIDE ON LUNG FUNCTION IN PATIENTS WITH 
TYPE 2 DIABETES MELLITUS (LIRALUNG STUDY). 
 
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EudraCT number: 2014-005125-12 
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Version: LIRALUNG 4.0 
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Date: 4/April/2015 
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Primary Investigator and sponsor: 
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Name 
Dr. Albert Lecube, Ph.D., M.D. 
Mailing Address 
Endocrinology and Nutrition Department 
Institut de Recerca Biomèdica de Lleida 
Hospital Universitari Arnau de Vilanova de Lleida  
Av. Rovira Roure, 80  
25198-Lleida 
Phone Number 
+34 973705183 
Alternate Phone Number 
+34 639143153 
Fax Number 
+34 973705189 
E-mail address 
alecube@gmail.com 
 
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EudraCT number: 2014-005125-12 
UTN: U1111-1164-2060 
Version: LIRALUNG 4.0, Date: 04/April/2015 
 
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TABLE OF CONTENTS 
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1. Project overwiew/Summary ……………………………………………………. 3 
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2. Introduction ……………………………………………………………………….. 4 
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3. Study Hypothesis ………………………………………………………………… 6 
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4. Primary Objective and Secondary Objectives ………………………………. 6 
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5. Research Design ………………………………………………………………….. 7 
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6. Inclusion/Exclusion Criteria …………………………………….…………........10 
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7. Primary and Secondary Measures ………………………………………….… 11 
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8 Sample Size Calculation …………………………..………………………….…. 12 
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9. Statistical Analysis ……..………………………………………………………... 13 
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10. Data Management ………………………………………………………………. 13 
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11. Timelines …………………………………………………………………..……… 14 
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12. Trial Supplies ……………………………………………………………………. 15 
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13. Randomisation procedure and breaking of blinded codes ……………... 16 
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14. Assessment of Safety ……….…………………………………………..…….. 17 
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15. Publication Strategy ………………………………………………………….... 19 
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16. Main References ……………………………………………………………...… 19 
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17. List of centers and investigators …………………….…………………….… 21 
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EudraCT number: 2014-005125-12 
UTN: U1111-1164-2060 
Version: LIRALUNG 4.0, Date: 04/April/2015 
 
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1. PROJECT OVERVIEW/SUMMARY 
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1.1. Background an hypothesis: Type 2 diabetes (T2DM) is related to reduced pulmonary function. As 
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experimental studies with glucagon-like peptide 1 (GLP-1) have shown an increase in pulmonary 
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surfactant secretion, and the GLP-1 receptor has been found in significant amounts in the lung, it could 
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be hypothesized that the treatment with liraglutide (a GL-1 agonist) will improve this reduced pulmonary 
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function  
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1.2. Aim and specific objectives: The general aim of this project is to evaluate the effect of short (5-
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weeks) incretin-based therapy (liraglutide 1.8 mg once daily) compared to placebo on pulmonary function 
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in type 2 diabetic patients. Our hypothesis is that liraglutide may ameliorate lung function independently of 
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weight reduction. 
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The specific objectives are the following: 
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a.- To identify changes in the parameters related to respiratory function of 5-week liraglutide 1.8 
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mg once daily treatment compared to placebo in type 2 diabetic patients. For this purpose 
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pulmonary volumes, expiratory flows, diffusion lung capacity for carbon monoxide, and exercise 
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tolerance will be assessed. 
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b.- To study the effect on respiratory parameters during sleep of 5-week liraglutide 1.8 mg once 
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daily treatment compared to placebo in type 2 diabetic patients. For this purpose a previously 
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validated non-attended respiratory polygraphy will be performed, and the apnea-hypopnea index 
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(AHI) and the cumulative percentage of time spent with oxygen saturations below 90% (CT90) 
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will be evaluated. 
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c.- To determine whether the mechanism involved in the expected beneficial effect of liraglutide 
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treatment on lung function could be attributed to their action on surfactant production. For this 
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purpose changes from basal in serum levels of surfactant A protein, the major surfactant-
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associated protein, will be evaluated. 
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d.- To establish the effect of 5-week liraglutide 1.8 mg once daily treatment compared to placebo 
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in type 2 diabetic patients on lung inflammation. For this purpose inflammation markers in 
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exhaled breath concentrate (nitric oxide, pH, and concentration of nitrites, nitrates and 
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isoprostane) will be measured.  
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EudraCT number: 2014-005125-12 
UTN: U1111-1164-2060 
Version: LIRALUNG 4.0, Date: 04/April/2015 
 
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1.3. Study design: This is a double-blind, randomized, crossover, placebo-controlled study, with two 
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parallel groups (liraglutide once daily sc vs. placebo sc/once daily) of 18-weeks. 
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1.4. Study periods: (1) selection, (2) active treatment (7 weeks, 5 of them at 1.8 mg once daily), (3) 
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wash-out (4 weeks), and (4) alternative treatment (7 weeks).  
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1.5. Sample size: We have estimated that a number of 60 patients at the end of the study will be 
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sufficient to test our hypothesis. However, taking into account a drop-out ratio of 20%, the final number of 
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patients that will be included in the study will be 76 (see details in point 9) 
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1.6. Population to be examined: Type 2 diabetic patients, treated with metformin (± sulfonylurea) at a 
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stable dose for at least the previous 3 months, with haemoglobin A1c between 7.0 and 10.0%, BMI ≥ 30 
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Kg/m2, and no known lung disease.  
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1.7. Participating institutions: 5 reference Spanish hospitals.  
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2. INTRODUCTION 
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2.1. Why this work is important? 
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There is growing evidence to suggest an association between type 2 diabetes and impaired pulmonary 
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function. In this regard, several cross-sectional studies have appeared showing decreased indices of 
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forced expiration, lung volume and diffusion capacity as the main lung dysfunctions detected in type 2 
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diabetic populations (Barrett-Connor et al. Diabetes Care 1996; Davis et al. Diabetes Res Clin Pract 
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2000; Yeh et al. Diabetes Care 2008). In fact, diabetes is frequently co-morbid with chronic obstructive 
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pulmonary disease (Mannino et al. Eur Respir J 2008), and data from the Atherosclerosis Risk in 
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Communities Study showed a faster pulmonary function decline in type 2 diabetic patients than in other 
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participants (Yeh et al. Diabetes Care 2008). This is important because the reduction of FEV1 has been 
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demonstrated an independent cause of mortality in diabetic patients (Davis et al. Diabetes Care 2004).  
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Interestingly, lung function measures start to decrease several years before the diagnosis of diabetes 
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(Davis et al. Diabetes Care 2004). In this regard we have found that insulin resistance is an independent 
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determinant of pulmonary function in non-diabetic morbidly obese women (Lecube et al. Diabetes Metab 
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Res Rev 2010). In addition, our results suggest that the metabolic pathways related to insulin resistance 
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are crucial in initiating lung abnormalities in type 2 diabetic patients.  
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UTN: U1111-1164-2060 
Version: LIRALUNG 4.0, Date: 04/April/2015 
 
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The reasons for the association between respiratory disease and diabetes are unclear. However, the 
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relationship between type 2 diabetes and muscle strength, the impairment in lung elastic properties, and 
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the presence of a low-grade chronic inflammation state are involved. In supporting these findings, 
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thickening of the alveolar epithelia and pulmonary capillary basal lamina, fibrosis, centrilobular 
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emphysema, and pulmonary microangiopathy have been detected in autopsies of diabetic patients 
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(Nicolaie et al. Rom J Intern Med 2003). In addition, defects in the bronchiolar surfactant layer, which is 
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involved in maintaining airway stability and diameter, may also be considered a contributing factor to the 
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impairment of airway calibre regulation in diabetic patients. When the alveolocapillary barrier is damaged, 
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surfactant proteins leak into the bloodstream. A recent population-based random sample study has 
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described how increased circulating levels of surfactant protein A, the major surfactant-associated 
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protein, were associated with altered glucose tolerance and insulin resistance (Fernández-Real et al. 
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Diabetes Care 2008). Therefore, surfactant defects in diabetic individuals may also lead to an increase in 
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airway resistance and to a reduction in ventilatory patterns as observed in our studies. In addition, as 
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experimental studies have shown that glucagon-like peptide 1 plays a role in the stimulation of surfactant 
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production (Benito et al. Endocrinology 1998; Vara et al. Am J Respir Crit Care Med 2001; Ahrén et al. 
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Horm Metab Res 2004), its underlying deficit in type 2 diabetes could also enhance the airway resistance 
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observed in these patients. However, the beneficial effects on pulmonary function using incretin-based 
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therapies remain to be elucidated. 
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2.2. What work has already been done? 
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Our group has recently shown that type 2 diabetes is an independent risk factor for severe nocturnal 
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hypoxaemia in obese patients (Lecube et al. PloS One 2009). In addition, we have provided, for the first 
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time, evidence that both insulin resistance and type 2 diabetes are risk factors for respiratory function 
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impairment in morbidly obese women (Lecube et al. Diabetologia 2010; Lecube et al. Diabetes Metab 
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Res Rev 2010). The two main abnormalities detected were an obstructive ventilatory pattern and an 
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increase in residual volume. As a 10% decrease in forced expiratory volume in 1 s (FEV1) has been 
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associated with a 12% increase in all-cause mortality in diabetic paients (Davis et al. Diabetes Care 
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2004), our results have serious implications for patients suffering from obesity and diabetes. Notably, we 
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have also found a relationship between the degree of blood glucose control (fasting glucose and HbA1c) 
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and the impairment of pulmonary function tests. In addition, fasting glucose and HbA1c contributed 
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independently to lung volumes in multiple linear regression analysis. This finding strongly suggests that 
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metabolic pathways related to hyperglycaemia are the main factor accounting for this impairment and 
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points to the lung as a new target of long-term diabetic complications. Finally, we have recently provided 
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first evidence that circulating levels of soluble TNF-α receptors type 1 (sTNF-R1) are related to reduced 
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lung volumes and airflow limitation in morbidly obese patients, being the main abnormalities a significant 
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negative correlation between sTNF-R1 and both FEV1 and forced vital capacity (FVC), as well as with the 
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EudraCT number: 2014-005125-12 
UTN: U1111-1164-2060 
Version: LIRALUNG 4.0, Date: 04/April/2015 
 
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maximum midexpiratory flow (Lecube et al. Cytokine 2011). This finding strongly suggests that 
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inflammatory pathways related to obesity are involved in this impairment and provide a mechanistic 
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support to previous studies showing an inverse relationship between FEV1 and anthropometric 
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parameters. 
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3. STUDY HYPOTHESIS 
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Our hypothesis is that treatment with an incretin mimetic such as liraglutide may ameliorate lung function 
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parameters in type 2 diabetics patients, independently of weight reduction. This hypothesis is based on 
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the following factors: 
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a.- There is growing evidence to suggest an association between type 2 diabetes and impaired 
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pulmonary function. 
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b.- In patients with type 2 diabetes, the incretin effect is severely reduced or absent, contributing 
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to the reduced lung function parameters observed in type 2 diabetic patients. 
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c.- GLP-1 stimulates surfactant production in “in vitro” studies and, in consequence, the increase 
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in surfactant production induced by liraglutide could be the main factor involved in the respiratory 
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improvement. 
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4. PRIMARY OBJECTIVE AND SECONDARY OBJECTIVES 
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The main objectives of the project are the following: 
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4.1. Primary objective: To assess the effect of 5-week liraglutide 1.8 mg once daily treatment compared 
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to placebo in type 2 diabetic patients on measurements of respiratory function. 
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4.2. Secondary objectives: To evaluate the effect of 5-week liraglutide 1.8 mg once daily treatment 
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compared to placebo in type 2 diabetic patients on: 
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the effect on respiratory parameters during sleep, 
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changes from basal in serum levels of surfactant A protein, and 
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inflammation markers in the exhaled air.  
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EudraCT number: 2014-005125-12 
UTN: U1111-1164-2060 
Version: LIRALUNG 4.0, Date: 04/April/2015 
 
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5. RESEARCH DESIGN 
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5.1 Setting 
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The clinical trial will be performed in 5 reference Spanish hospitals and will involve close collaboration 
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between recognized endocrinologists and pneumologists.  
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These are the centres that will participate in this clinical trial and their main investigators, all from the 
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Endocrinology and Nutrition Department: 
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. Hospital Universitari Arnau de Vilanova, Lleida, Spain (Dr. Albert Lecube, Ph.D. ,M.D.) 
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. Hospital Universitari Germans Trias i Pujol, Badalona, Spain (Dr. Didac Mauricio, Ph.D., M.D.) 
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. Hospital Universitari Vall d’Hebron, Barcelona, Spain (Dr. Rafael Simó, Ph.D., M.D.) 
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. Clínica Universitaria de Pamplona, Pamplona, Spain (Dr. Javier Salvador, Ph.D., M.D.) 
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. Hospital Universitario Virgen de la Victoria de Málaga, Málaga, Spain (Dr. Francisco Tinahones,   
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  Ph.D., M.D.) 
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.Back up centre: Hospital Universitario Virgen del Rocio de Sevilla, Sevilla, Spain (Dr. Pedro  
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  Pablo García Luna, Ph.D., M.D.) 
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5.2 Ethic considerations 
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The trial has been registered in the European Clinical Trial Database (EudraCT number: 2010-023518-
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29). Once accepted, the last version of the protocol will be newly submitted to the Investigational Ethics 
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Committees of all the participating clinical centres. Investigators believe that no major ethical implications 
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have to be considered in this clinical trial. However, patients diagnosed of severe sleep disorder breathing 
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will be evaluated with the Pneumology Department in each center. Patients in whom treatment with 
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continuous positive airway pressure should be considered mandatory will be withdrawn from the clinical 
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trial. In addition, the trial will follow the Helsinki Declaration as well as the Good Clinical Practice 
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Guidelines. 
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5.3 Study design 
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5.3.1. Study type: This is a phase IV double-blind, randomized, crossover, placebo-controlled study, with 
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two parallel groups (1.8 mg of liraglutide once daily sc vs placebo once daily sc) for 14 weeks. 
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5.3.2. The consent process: The consent process will begin when a potential research patient is initially 
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contacted. Prior to any study-related activity, including screening procedures, potential candidates to be 
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recruited will receive extensive, both oral and written, information about the study, including the risk 
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EudraCT number: 2014-005125-12 
UTN: U1111-1164-2060 
Version: LIRALUNG 4.0, Date: 04/April/2015 
 
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associated with the study procedures and study-drug. In addition to signing the consent, the patient will 
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enter the date of the signature on the consent document, to permit verification that consent was actually 
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obtained before the patient began participation in the study. A copy of the consent document will be 
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provided to the patient and the original signed consent document will be retained in the study records. 
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5.3.3. Screening phase (population to be examinated): The study will include type 2 diabetic patients, 
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treated with metformin (± sulfonylurea) at a stable dose for at least the previous 3 months, with HbA1c 
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between 7.0 and 10.0%, BMI ≥ 30 Kg/m2, and no known lung disease. The patients included in the study 
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will be recruited from the Endocrinology Departments of all the participating centers and will be followed-
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up by the endocrinologists and pneumologists in the investigating teams. The main exclusion criteria 
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include type 1 diabetes mellitus, treatment with insulin, dipeptidyl peptidase-4 inhibitors and/or 
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pioglitazone, history of smoking habit, chronic respiratory disease, asthma, cardiovascular disease, 
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hearth failure, stroke, and/or chest wall disease.  
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5.3.4. Inclusion phase: After informed consent, the recruited patients will be transferred to Pneumology 
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Departments where the following examinations will be performed: expiratory flows, pulmonary volumes, 6-
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minute walking test, non-attended respiratory polygraphy with oxygen saturation monitoring, inflammatory 
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markers in exhaled air, and serum surfactant A protein measurement. After these evaluations patients will 
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be randomly allocated in a 1:1 ratio to one of the two treatment groups.  
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5.3.5. Treatment groups:  
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Group A: (i) 7-week subcutaneous liraglutide treatment once daily, (ii) a 4-week wash-out period, 
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and (iii) 7-week subcutaneous placebo once daily. 
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Group B: (i) 7-week subcutaneous placebo once daily, (ii) a 4-week wash-out period, and (iii) 7-
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week subcutaneous liraglutide treatment once daily.  
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5.3.6. Titration schedule: in order to minimize the loss of weight associated with incretin therapies and to 
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achieve the optimal dose of liraglutide, active treatment will start at 0.6 mg once daily during the first 
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week, 1.2 mg once daily during the second week, and 5 weeks at 1.8 mg once daily.  Whether a dose of 
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liraglutide is not well tolered, it will be reduced to the minimum tolerated dose. Placebo arm will perform 
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the same scalation that active treated patients. 
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5.3.7. Treatment formulation: both liraglutide and placebo will be administered subcutaneous using a 3 
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mL pre-filled pen injector. Regarding liraglutide, one ml of solution will contain 6 mg of the product, so one 
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pre-filled pen injector will contain 18 mg of liraglutide in 3 mL. 
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5.3.8. Sample size: we have estimated that a number of 76 screened patients at the end of the study will 
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be enable to demonstrate our hypothesis (see below sample size calculation).  
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5.3.9. Baseline treatment: all type 2 diabetic patients who gave their written informed consent will 
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continue with metformine (± sulfonylurea) at the same doses.  
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5.3.10. Chronogram: see next page 
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5.3.11. Visit schedule: see next page 
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  0.6 to                         1.8 mg 
 1.2 mg            
                liraglutide 
placebo 
Visit 4 
Visit 5 
Visit 3  
Visit 0 
Visit -1 
Week 11 
Week 13 
0.6 to                             1.8 mg 
   1.2 mg        
                liraglutide 
placebo 
Week 0 
Week 2 
Week 7 
Week 18 
Visit 1 
Visit 2   

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Screening 
Basal 
Week 2 
Week 7 
Week 11 
Week 13 
Week 18 
Visit number 
-1 
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Informed Consent                   
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- 
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- 
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Inclusion/exclusion criteria                
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X 
X 
X 
X 
X 
X 
Randomization                                     
- 
X 
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Physical examination 
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X 
X 
X 
X 
X 
X 
Liraglutide/placebo dispensed           
- 
X 
X 
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X 
X 
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Drug accountability            
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X 
X 
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X 
Concomitant Medication                    
- 
X 
X 
X 
X 
X 
X 
Expiratory flows                                
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X 
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X 
X 
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X 
Pulmonary volumes                         
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X 
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X 
X 
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X 
6-minute walking test                 
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X 
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X 
X 
- 
X 
Respiratory polygraphy 
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X 
- 
X 
X 
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Nocturnal Oxygen Saturation 
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X 
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X 
X 
- 
X 
Serum Surfactant A Protein                
- 
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X 
X 
X 
X 
X 
Inflamm. markers in exhaled air         
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X 
X 
X 
X 
X 
Laboratory                                            
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X 
X 
X 
X 
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Urine pregnacy test (if applicable) 
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Active collection of adverse events 
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X 
 
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6. INCLUSION/EXCLUSION CRITERIA 
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6.1. Inclusion criteria: 
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- Type 2 diabetic patients (≥ 18 years of age) with more than 5 years of evolution of the disease, 
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- treatment with metformin (± sulfonylurea) at a stable dose for at least the previous 3 months, 
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- HbA1c ≥ 7.0 and ≤ 10.0%, 
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- body mass index ≥ 30 Kg/m2, 
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- no known lung disease, 
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- baseline reduction in FEV1 equal or higher than 10% in the percentage predicted value, 
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- provision of an informed consent form signed and personally dated by the patient. 
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6.2. Exclusion criteria: 
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- type 1 diabetes, 
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- treatment with insulin, dipeptidyl peptidase-4 inhibitors, and/or pioglitazone, 
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- history of smoking habit, 
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- chronic pulmonary obstructive disease, 
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- sleep-breathing disorders that require CPAP (continuous positive airway pressure) therapy, 
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- asthma, 
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- previous bariatric surgery, 
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- cardiovascular disease, heart failure, and/or stroke, 
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- chest wall diseases, 
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- serum creatinine > 1.7 mg/dl, 
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- abnormal liver function test (ALT/AST levels greater than twice the upper limit of normal), 
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- history of acute or chronic pancreatitis, 
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- history or family history of medullary carcinoma or the thyroid or MEN 2, 
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- female of child-bearing potential who is pregnant, breast-feeding or intends to become pregnant 
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- females of childbearing potential who are not using adequate contraceptive methods (as 
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required by local law or practice). 
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6.3. Concomitant therapies: the next concomitant therapies will be included in the exclusion criteria 
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because of their effects on pulmonary function or glucose metabolism. Patients enrolled in the study who 
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initiate any of these concomitant treatments will be also excluded from the study: 
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- insulin 
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- antidiabetic agents others than metformin or sulfonylureas 
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- inhaled bronchodilator drugs or teophilin 
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- CPAP (continuous positive airway pressure) therapy  
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- oral corticosteroids. 
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7. PRIMARY AND SECONDARY MEASURES 
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All these measurements will be performed throught a forced spirometry (DATOSPIR touch, Sibel S.A.) 
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and a non-attended ambulatory respiratory polygraphy (“Sleep&Go”, Sibel S.A.) devices. Blood 
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specimens will be recollected, processed and stored in each centre, and evaluations will be evaluated in 
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a central laboratory. 
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7.1. Primary efficacy measure: Forced expiratory volume in 1 s (FEV1). We have selected this variable 
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because in our previous studies the main abnormality detected in type 2 diabetic patients was a decrease 
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in FEV 1 (Lecube et al. Diabetologia 2010; Lecube et al. Diabetes Metab Res Rev 2010). In this regard, it 
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shoud be emphasized that a 10% decrease in FEV1 has been associated with a 12% increase in all 
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cause mortality in diabetic patients (Davis et al. Diabetes Care 2004). 
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7.2. Secondary efficacy measures: 
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- Other parameters drown from a forced spirometry: 
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- Forced vital capacity (FVC) 
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- Maximum mid-expiratory flow (FEF25–75) 
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- FEV1 to FVC ratio 
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- Parameters from static pulmonary volume measurements: 
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- Residual volume (RV) 
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- Total lung capacity (TLC) 
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- Residual functional capacity (RFC) 
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- Transfer factor of the lungs for carbon monoxide (TLCO) 
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- Data from the six-minute walking test 
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- Parameters from a previously validated non-attended respiratory polygraphy  
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- apnea-hypopnea index (AHI)  
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- cumulative percentage of time spent with oxygen saturations below 90% (CT90) 
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- Changes from basal in serum levels of surfactant A protein, 
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- Data from the study of inflammation markers in the exhaled breath concentrate: nitric oxide, pH, 
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and concentration of nitrites, nitrates and isoprostane 
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7.3. Other variables to be evaluated: 
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- Anthropometric data: weight, height, waist circumference, and neck circumference 
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- Daytime sleepiness through the Epworth Sleepiness Test 
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- Fasting blood glucose, HbA1c, fructosamine, fasting insulin, and insulin resistance measured by 
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HOMA-IR. 
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8. SAMPLE SIZE CALCULATION 
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The inclusion of 50 patients will achieve a 80% of statistical power (β=0.2) to detect a significant increase, 
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due to the treatment, in the FEV1 levels of at least 20%, assuming a baseline expected values of FEV1 
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for untreated patients of 88.4±19.7 [as previously reported by Lecube et al (Diabetologia 2010)] and using 
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and ANOVA test to specifically assess the effect in a cross-over design, setting the threshold for statistical 
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significance at 5% (α=0.05, one sided). For this computation, the within mean square error of the ANOVA 
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test for repeated measurements was calculated as √(2 x (19.7 2) = 27.86. Sample size will be increased in 
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10 patients according to an expected drop-out rate of 20%. Hence, a total of 60 patients will be included 
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in the cross-over randomized trial. In addition, in order to avoid unexpected changes in the final sample 
396 
size, we will recruit only patients with a baseline decrease in FEV1 equal or higher than 10% in the 
397 
percentage predicted value.  
398 
However, data regarding factors to be analysed in the present project (for example, levels of 
399 
serum surfactant A protein and parameters measured in the exhaled air) are lacking and, therefore, to 
400 
give ourselves a safety margin we have increased the sample size. Hence, we hope that the number of 
401 
76 patients will be sufficient to demonstrate our hypothesis.  
402 
 
403 

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404 
9. STATISTICAL ANALYSIS  
405 
 
406 
First, a homogeneity analysis will be undergone to compare patients in both groups (A and B) with 
407 
regards to basal clinical and anthropometric variables. Mean (and standard deviation) and frequency (and 
408 
percentage) will be used to describe quantitative and qualitative variables respectively, using Mann-
409 
Whitney test for categorical variables to assess the differences between groups. Second, the effect of the 
410 
treatment will be evaluated using an ANOVA test with repeated measures, also adjusting for the potential 
411 
carry-over effect and those potential confounders detected in the homogeneity analysis, using for this 
412 
purposed mixed linear models. Third, similar analysis will be performed to assess the effect of the 
413 
treatment on the secondary outcomes. All analysis will be obtained using R statistical package and 
414 
threshold for statistical significance will be set at 0.05. 
415 
 
416 
10. DATA MANAGEMENT 
417 
 
418 
Data management is always the responsibility of the primary investigator. Data management will be 
419 
delegated under an agreement of transfer of responsabilities to an external Contract Research 
420 
Organisation (CRO). Appropiate measures, including encryption of data files containing person 
421 
identifiable data, will be used to ensure confidentiality of patients data, when they are transmitted over 
422 
open networks.  
423 
 
424 
An electronic Case Report Form (eCRF) that accurately represents the protocol of the clinical trial will be 
425 
designed and developed by the CRO to collect the specific data. 
426 
 
427 
The primary investigators of each center will fulfill the sponsor responsibilities detailed in the Spanish 
428 
legislation as well as in the Good Clinical Practices of the ICH. To prevent patient confidentiality each 
429 
patient will be identified with a unique code, this will be the only identifiable information that will be 
430 
recorded in the eCRF. No patient initials will be recorded.  
431 
 
432 
Monitors designated by the CRO will be responsible for contacting and visiting the investigators for the 
433 
purpose of inspecting the facilities and, upon request, inspecting the various records of the clinical study 
434 
(eg, case report forms and other pertinent data) to provide that patient confidentially is respected. The 
435 
monitor will also be responsible for verifying the eCRF at regular intervals throughout the study to verify 
436 
adherence to the protocol: completeness, accuracy, and consistency of the data; and adherence to local 
437 
regulations on the conduct of clinical research. 
438 
 
439 
 
440 

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11. TIMELINES 
441 
 
442 
Overall study duration: 24 months 
443 
Treatment duration: 14 weeks 
444 
Enrollment period: 18 months 
445 
Anticipated date of first patient visit: January 18, 2016 (or as soon as contract will be signed) 
446 
Anticipated date that first patient enters treatment: January 25, 2016 
447 
Anticipated date that last patient enters trial: September 26, 2016 
448 
Anticipated date that last patient enters treatment: October 3, 2016 
449 
Anticipated date of the final last patient visit: January 16, 2017 
450 
Anticipated date of first manuscript submitted: May 1, 2017 
451 

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12. TRIAL SUPPLIES 
452 
 
453 
Trial supplies comprise trial products and auxiliary supplies: 
454 
 
455 
12.1 Trial products: Trial products comprise investigational trial products. The following trial products for 
456 
s.c. injection will be provided by Novo Nordisk: 
457 
 
. liraglutide 6 mg/mL, 3 mL pre-filled pen-injector 
458 
 
. liraglutide placebo 6 mg/mL, 3 mL pre-filled pen-injector. 
459 
 
460 
Patients will be instructed when randonised and ready to start the trial in administration of s.c. injection of 
461 
trial product in order to ensure patient’s willingness and ability to self-inject. 
462 
 
463 
Liraglutide, both active drug and placebo will be visually identical. 
464 
 
465 
Novo Nordisk will supply trial product and DFU to the primary investigator located at Hospital Univesitari 
466 
Arnau de Vilanova de Lleida (Spain). Therefore, primary investigator will ensure to supply with sufficient 
467 
trial products to the four other sites. 
468 
 
469 
12.2. Auxiliary supplies: Novo Nordisk will supply directions for use devices,  whereas needles for pre-
470 
filled pen systems will be provided by the primary sponsor. 
471 
 
472 
12.3 Labelling: Labelling of the investigational medicinal products will be in accordance with local law 
473 
and trial requirements. 
474 
 
475 
12.4. Storage: The investigator from each centre must ensure the availability of proper storage 
476 
conditions, and record and evaluate the temperature. The investigator from each centre must inform 
477 
Primary Investigator immediately if any trial product has been stored outside defined conditions (eg, 
478 
outside temperature range).  
479 
 
480 
Trial products stored outside the temperature range for more than fifteen minutes are not to be used and 
481 
must be stored separately within allowed temperature range until after evaluation of condition. Evaluation 
482 
will be performed by Novo Nordisk. Trial products that have been stored improperly must not be 
483 
dispensed to any patient before it has been re-evaluated and approved for further use. 
484 
 
485 
Returned trial products (unused, partly used or used including empty packaging material) must be stored 
486 
separately fron non-allocated trial products. 
487 
 
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The temperature during storage should be monitored by a calibrated, stationary and continuously 
489 
recording system. A temperature log must be kept to document storage within the right temperature 
490 
interval and storage facilities should be checked frequently. 
491 
 
492 
Storage conditions: Not in use, liraglutide both active drug and placebo must be store in a refrigerator 
493 
between 2ºC and 8ªC, and must not be exposed to excessive heat or direct sunlight 
494 
 
495 
In-use conditions: Liraglutide both active drug and placebo must be stored below 30ºC or in a 
496 
refrigerator (2ºC-8ºC), protected from light, not freezed, and used within 1 month. 
497 
 
498 
12.5. Drug accountability and destruction: The trial products will be dispensed to each patient as 
499 
required according to treatment group. A total DUN list provided by Novo Nordisk to the primary 
500 
investigator will be used to link randomisation codes to treatments. A blinded randomisation list will be 
501 
created by our own statisticians. Different parts of the code list will be allocated to the other four 
502 
participant trial sites, and when a patient will be randomised, a randomisation code will be assigned from 
503 
this list. The correct DUN must be dispensed to the patient. 
504 
 
505 
The investigator from each centre is responsible for ensuring that: 
506 
. trial product is not dispensed to any person not included in the trial, 
507 
. drug accountability, 
508 
. patients are instructed to return all used, partly used and unused trial product including empty    
509 
  packaging material at each dispensing visit and at End of Treatment visit, 
510 
. all returned trial products is kept and storage separately from non-allocated trial products. 
511 
 
512 
Destruction of trial products will be done according to local law after accountability is finalised at site and 
513 
reconciled by monitor. Destruction of trial products must be documented. 
514 
 
515 
 
516 
13. RANDOMISATION PROCEDURE AND BREAKING OF BLINDED CODES 
517 
 
518 
The trial is a double-blind trial. A randomization session will be carried out for all patients by using the 
519 
blinded randomization list. At the randomization visit patients meeting all inclusion/exclusion criteria will 
520 
be randomized to one of two parallel treatments groups: 
521 
Group A: (i) 7-week subcutaneous liraglutide treatment once daily, (ii) a 4-week wash-out period, 
522 
and (iii) 7-week subcutaneous placebo once daily. 
523 
Group B: (i) 7-week subcutaneous placebo once daily, (ii) a 4-week wash-out period, and (iii) 7-
524 
week subcutaneous liraglutide treatment once daily.  
525 

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526 
13.1 Breaking of blinded codes: If the site needs to break the treatment code, the sponsor should, if 
527 
possible, be contacted before the code is broken.  
528 
 
529 
The code for a particular patient may be broken in a medical emergency if knowing the actual treatment 
530 
would influence the treatment of the patient. The reason for code break should be documented in the 
531 
medical record. Whenever a code is broken the person breaking the code must print the Code Break 
532 
Confirmation Notification, and sign and date the document. 
533 
 
534 
If the code has been broken, the patient should be discontinued from the trial product but be asked to 
535 
continue in the trial.  
536 
 
537 
 
538 
14. ASSESSMENT OF SAFETY 
539 
 
540 
14.1. Definitions 
541 
An Adverse Event (AE) is any untoward medical occurrence in a patient or clinical investigation 
542 
participants administered a medicinal product, which does not necessarily have to have a causal 
543 
relationship with this treatment (the study medication).  
544 
An Adverse Reaction (AR) is all untoward and unintended responses to a medicinal product related 
545 
to any dose. The phrase "responses to a medicinal product" means that a causal relationship between 
546 
a study medication and an AE is at least a reasonable possibility, i.e., the relationship cannot be ruled 
547 
out. 
548 
A Serious Adverse Event (SAE) is an experience that at any dose results in any of the following: (1) 
549 
Deah; (2) Life-threatening experience; (3) Inpatient hospitalization or prolongation of existing 
550 
hospitalization; (4) A persistent or significant disability/incapacity; or (5) A congenital anomaly/birth 
551 
defect. Important medical events that may not result in death, be life-threatening, or require 
552 
hospitalization may be considered an SAE when, based upon appropriate medical judgement, they 
553 
may jeopardise the patient or require medical or surgical intervention to prevent one of the outcomes 
554 
listed in this definition. Suspicion of transmission of infectious agents must be always be considered 
555 
an SAE. Note: the term “life-threatening” in the previous definition of SAE refers to an event in which 
556 
the patient was at risk of death at the time of the event; it does not refer to an event which 
557 
hypothetically might have caused death if it was more severe. 
558 
A Serious Adverse Reaction (SAR) is an adverse event (expected or unexpected) that is both 
559 
serious and, in the opinion of the reporting investigator, believed with reasonable probability to be due 
560 
to one of the study treatments, based on the information provided. 
561 
A Suspected Unexpected Serious Adverse Reaction (SUSAR) is: 
562 

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A serious adverse reaction, the nature or severity of which is not consistent with the applicable product 
563 
information (e.g. Investigator’s Brochure for an unapproved investigational product or summary of 
564 
product characteristics for an approved product). 
565 
 
566 
14.2 Causality: The relationship of each adverse event to the trial medication must be determined by a 
567 
medically qualified individual according to the following definitions: 
568 
Related: The adverse event follows a reasonable temporal sequence from trial medication administration. 
569 
It cannot reasonably be attributed to any other cause. 
570 
Not Related: The adverse event is probably produced by the participant’s clinical state or by other modes 
571 
of therapy administered to the participant.  
572 
 
573 
14.3. Procedures for recording adverse events: All AEs occurring during the study observed by the 
574 
investigator or reported by the participant, whether or not attributed to study medication, will be recorded 
575 
on the CRF. The following information will be recorded: study name, patient identification (e.g., patient 
576 
number, sex, and age), trial drug, description of the event and diagnosis when possible, date of onset and 
577 
end date, severity, assessment of relatedness to study medication, other suspect drug or device, action 
578 
taken, and reporter. Follow-up information should be provided as necessary. AEs considered related to 
579 
the study medication as judged by a medically qualified investigator or the sponsor will be followed until 
580 
resolution or the event is considered stable.  All related AEs that result in a participant’s withdrawal from 
581 
the study or are present at the end of the study, should be followed up until a satisfactory resolution 
582 
occurs. 
583 
 
584 
It will be left to the investigator’s clinical judgment whether or not an AE is of sufficient severity to require 
585 
the participant’s removal from treatment.  If either of these occurs, the participant must undergo an end of 
586 
study assessment and be given appropriate care under medical supervision until symptoms cease or the 
587 
condition becomes stable. The relationship of AEs to the study medication will be assessed by a 
588 
medically qualified investigator. Any pregnancy occurring during the clinical study and the outcome of the 
589 
pregnancy, should be recorded and followed up for congenital abnormality or birth defect. 
590 
 
591 
14.4. Reporting procedures for serious adverse events: All SAEs must be reported to the Sponsor or 
592 
designated organization within one working day of discovery or notification of the event. The Sponsor or 
593 
designated organization will perform an initial check of the report, request any additional information. All 
594 
SAE information must be recorded on an SAE forms and faxed to the Sponsor or designated 
595 
organization. Additional information received for a case (follow-up or corrections to the original case) 
596 
need to be detailed on a new SAE form and faxed to the Sponsor or designated organization.  
597 
As a minimum, the investigator should copy Novo Nordisk when expediting SARs or SUSARs, 
598 
and should report all SARs related to Novo Nordisk product to the local Novo Nordisk affiliate safety 
599 

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department. The submission to Novo Nordisk must be within day 15 from the investigator’s first 
600 
knowledge about a valid case. 
601 
 
602 
14.5. Pregnancies: Female patients must be instructed to notify the investigator immediately if they 
603 
become pregnant during the trial. The invstigator must report any pregnancy in patients who received 
604 
Novo Nordisk provided trial product. 
605 
 
606 
The investigator must follow the pregnancy until the pregnancy outcome and the newborn infant(s) until 
607 
the age of 1 month. The investigator must report all information on pregnancy, including AEs in the 
608 
patient, the foetus, and newborn infant. All this information must be forwarded to Novo Nordisk. 
609 
 
610 
When an abnormality is reported in the foetus or newborn infant, information is needed from the male 
611 
partner. Informed consent must be obtained prior to this. 
612 
 
613 
14.6 Indemnity insurance: A written assurance indemnity or clinical trial insurance to protect the 
614 
institutions from claims of non-negligent harm resulting from the clinical research and to coverage 
615 
patients for untoward events will be subscribed by the principal investigator. The amount of 
616 
compensations paid should be appropriate to the nature, severity, and persistence of the injury. This 
617 
insurance indemnity will be in accordance with Royal decree 223/2004, of 6th February 2004, establishing 
618 
the requisites regarding clinical trials. 
619 
 
620 
15. PUBLICATION STRATEGY 
621 
 
622 
The diffusion of the results will follow the procedures that we are currently using. Therefore, the results 
623 
will first be presented at national and international congresses and oral presentation will be prioritized. 
624 
Afterwards, we will submit the papers to top journals (first quartile journals or with impact factor > 5). If a 
625 
late break result is obtained this will be sent as a “Rapid Communication” to a relevant journal that allows 
626 
this type of publication or it will be sent to a prestigious on-line journal (i.e. PLoS One). Simultaneously, a 
627 
parallel diffusion through informative channels (newspapers, radio or TV interviews) will be conducted 
628 
Novo Nordisk will be informed of any intended publication related to the clinical trial results, and a 
629 
period of 4 weeks will be stablished in order to receive Novo Nordisk comments. 
630 
The Novo Nordisk involvement in this clinical trial will always be acknowledged in any diffusion 
631 
action related with its results.  
632 
 
633 
16. MAIN REFERENCES  
634 
 
635 
Ahrén B. GLP-1 and extra-islet effects. Horm Metab Res 2004; 36: 842-5. 
636 

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637 
Barrett-Connor E, Frette C. NIDDM, impaired glucose tolerance, and pulmonary function in older adults. 
638 
The Rancho Bernardo Study. Diabetes Care 1996; 19(12) : 1441-4. 
639 
 
640 
Benito E, Blazquez E, Bosch MA. Glucagon-Like Peptide-1-(7-36)amide increases pulmonary surfactant 
641 
secretion through a cyclic adenosine 3’,5’-monophosphate-dependent protein kinase mechanism in rat 
642 
type II pneumocytes. Endocrinology 1998; 139: 2363-8. 
643 
 
644 
Davis TM, Knuiman M, Kendall P, Vu H, Davis WA. Reduced pulmonary function and its associations in 
645 
type 2 diabetes: the Fremantle Diabetes Study. Diabetes Res Clin Pract 2000; 50(2): 153-9. 
646 
 
647 
Davis WA, Knuiman M, Kendall P, Grange V, Davis TME. Glycemic exposure is associated with reduced 
648 
pulmonary function in type 2 diabetes. The Fremantle Diabetes Study. Diabetes Care 2004; 27:752-7. 
649 
 
650 
Fernández-Real JM, Chico B, Shiratori M, Nara Y, Takahashi H, Ricart W. Circulating surfactant protein A 
651 
(SP-A), a marker of lung injury, is associated with insulin resistance. Diabetes Care 2008; 31: 958-63. 
652 
 
653 
Lecube A, Sampol G, Lloberes P et al (2009) Diabetes is an independent risk factor for severe nocturnal 
654 
hypoxemia in obese patients. A case-control study. PloS One 4:e4692 
655 
 
656 
Lecube A, Sampol G, Muñoz X, Hernández C, Mesa J, Simó R. Type 2 diabetes impairs pulmonary 
657 
function in morbidly obese women. A case-control study. Diabetologia 2010; 53: 1210-6. 
658 
 
659 
Lecube A, Sampol G, Muñoz X, Lloberes P, Hernández C, Simó R. Insulin resistance is related to 
660 
impaired lung function in morbidly obese women. A case-control study. Diabetes Metab Res Rev 2010; 
661 
26(8): 639-45. 
662 
 
663 
Mannino DM, Thorn D, Swensen A, Holguin F. Prevalence and outcomes of diabetes, hypertension and 
664 
cardiovascular disease in COPD. Eur Respir J 2008;32(4):962-9.  
665 
 
666 
Nicolaie T, Zavoianu C, Nuta P. Pulmonary involvement in diabetes mellitus. Rom J Intern Med 2003; 
667 
41(4) : 365-74. 
668 
 
669 
Vara E, Arias-Díaz J, García C, Balibrea JL, Blázquez E. Glucagon-like peptide-1(7-36) amide stimulates 
670 
surfactant secretion in human type 2 pneumocytes. Am J Respir Crit Care Med 2001; 163: 840-6. 
671 
 
672 

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Yeh HC, Punjabi NM, Wang NY, Pankow JS, Duncan BB, Cox CE, Selvin E, Brancati FL. Cross-sectional 
673 
and prospective study of lung function in adults with type 2 diabetes: the Atherosclerosis Risk in 
674 
Communities (ARIC) study. Diabetes Care 2008; 31(4): 741-6. 
675 
 
676 
Yeh HC, Punjabi NM, Wang NY et al. Cross-sectional and prospective study of lung function in adults 
677 
with type 2 diabetes: the Atherosclerosis Risk in Communities (ARIC) study. Diabetes Care 2008; 31:741-
678 
6. 
679 
 
680 
 
681 
17. LIST OF CENTERS AND INVESTIGATORS 
682 
 
683 
17.1 List of centers: 
684 
 
685 
Hospital Universitario Arnau de Vilanova 
686 
 
Endocrinology and Nutrition Department 
687 
 
Pneumology Department 
688 
 
 
Avda. Rovira Roure, 80 
689 
 
 
25198-Lleida 
690 
 
 
Tlf: 973 705 183 
691 
 
692 
Hospital Universitario Vall d’Hebrón 
693 
 
Endocrinology and Nutrition Department 
694 
 
Pneumology Department 
695 
 
 
Passeig Vall d’Hebrón 119-129 
696 
 
 
08035-Barcelona 
697 
 
 
Tlf: 932746238 
698 
 
699 
Hospital Universitario Germans Trias i Pujol 
700 
 
Endocrinology and Nutrition Department 
701 
 
Pneumology Department 
702 
 
 
Carretera del Canyet s/n 
703 
 
 
08916-Badalona 
704 
 
 
Tlf: 934978860 
705 
 
706 
Clínica Universitaria de Navarra 
707 
 
Endocrinology and Nutrition Department 
708 
 
Pneumology Department 
709 
 
 
Avenida Pío XIII, 36. 
710 
 
 
31008-Pamplona 
711 
 
 
Tlf: 948255400 (ext 4483), 948425600 (ext 6567) 
712 
 
713 
 
714 
Hospital Universitario Virgen de la Victoria de Málaga 
715 
 
Endocrinology and Nutrition Department 
716 
 
Pneumology Department 
717 
 
 
Campus de Teatinos s/n 
718 

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29010-Málaga 
719 
 
 
Tlf: 951034016 
720 
 
721 
17.2. Back-up center 
722 
 
 
723 
Hospital Universitario Virgen del Rocio de Sevilla 
724 
 
Endocrinology and Nutrition Department 
725 
 
Pneumology Department 
726 
 
 
Avda. Manuel Siurot s/n 
727 
41013-Sevilla  
728 
Tlf: 955 012 000 
729 
 
730 
 
731 
17.3. Main investigator from each center: 
732 
 
733 
Dr. Albert Lecube Torelló 
734 
 
Head of Endocrinology and Nutrition Department 
735 
 
Hospital Universitari Arnau de Vilanova, Lleida, Spain 
736 
 
alecube@gmail.com 
737 
 
738 
Dr. Rafael Simó Canonge 
739 
 
Head of the Diabetes and Metabolism Group 
740 
 
Vall d’Hebron Institut de Recerca  
741 
 
Hospital Universitari Vall d’Hebrón, Barcelona, Spain 
742 
 
rafael.simo@vhir.org 
743 
 
744 
Dr. Javier Salvador Rodríguez 
745 
 
Head of the Endocrinology and Nutrition Department 
746 
 
Clínica Universitaria de Navarra, Pamplona, Spain 
747 
 
jsalvador@unav.es 
748 
 
749 
Dr. Manuel Puig Domingo 
750 
 
Head of the Germans Trias i Pujol Research Fundation in Health Sciences (IGTP) 
751 
 
Hospital Universitari Germans Trias I Pujol, Badalona, Spain 
752 
 
mpuigd@gmail.com 
753 
 
754 
Dr. Francisco José Tinahones Madueño 
755 
 
Head of the Endocrinologya and Nutrition Department  
756 
 
Hospital Universitario Virgen de la Victoria, Málaga, Spain 
757 
 
fjtinahones@terra.es 
758 
 
759 
Dr. Pedro Pablo García Luna 
760 
 
Head of the Endocrinologya and Nutrition Department  
761 
 
Hospital Universitario Virgen del Rocio, Sevilla, Spain 
762 
 
pedrop.garcia.sspa@juntadeandalucia.es 
763 
 
764 
 
765 
17.4. Co-investigators: 
766 
 
767 
Dr. Ferran Barbé Illa 
768 

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Head of Pneumology Department 
769 
Hospital Universitario Arnau de Vilanova, Lleida 
770 
febarbe.lleida.ics@gencat.cat 
771 
 
772 
Dra. Cristina Hernández Pascual 
773 
Endocrinology and Nutrition Department 
774 
Hospital Universitari Vall d’Hebrón, Barcelona, Spain 
775 
cristina.hernandez@vhir.org 
776 
 
777 
Dr. Gabriel Sampol Rubio 
778 
Head ot the Multifunctional Sleep Unit. Pneumology Department. 
779 
Hospital Universitari Vall d’Hebrón, Barcelona, Spain 
780 
gsampol@vhebron.net 
781 
 
782 
Dr. Xavier Muñoz Gall 
783 
Head of the Functional Respiratory Unit. Pneumology Department 
784 
Hospital Universitari Vall d’Hebrón, Barcelona, Spain 
785 
xmunoz@vhebron.net 
786 
 
787 
Dra. Gema Frübeck Martínez 
788 
Head of the Metabolic Research Laboratory 
789 
Clínica Universitaria de Navarra, Pamplona, Spain 
790 
gfruhbeck@unav.es 
791 
 
792 
Dr Javier Gómez Ambrosi 
793 
Metabolic Research Laboratory 
794 
Clínica Universitaria de Navarra, Pamplona, Spain 
795 
jagomez@unav.es 
796 
 
797 
Dra Aránzazu Campo Ezquibela 
798 
Pneumology Department 
799 
Clínica Universitaria de Navarra, Pamplona, Spain 
800 
acampo@unav.es 
801 
 
802 
Dídac Mauricio Puente 
803 
Head of the Endocrinology and Nutrition Department 
804 
Hospital Universitario Germans Trias i Pujol, Badalona, Spain 
805 
didacmauricio@gmail.com 
806 
 
807 
Dr. Jorge Luis Reverter Calatayud 
808 
Endocrinology and Nutrition Department  
809 
Hospital Universitario Germans Trias i Pujol, Badalona, Spain 
810 
jreverter.germanstrias@gencat.cat 
811 
 
812 
Dra. Silvia Pellitero Rodríguez 
813 
Endocrinology and Nutrition Department 
814 
Hospital Universitario Germans Trias i Pujol, Badalona, Spain 
815 
spellitero.germanstrias@gencat.cat 
816 
 
817 
Dr. José Antonio Fiz Fernández 
818 
Pneumology Department 
819 

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Hospital Universitario Germans Trias i Pujol, Badalona, Spain 
820 
jafiz@msn.com 
821 
 
822 
Dr. Jorge Abad Capa 
823 
Pneumology Department 
824 
Hospital Universitario Germans Trias i Pujol, Badalona, Spain 
825 
jabadc.germanstrias@gencat.cat 
826 
 
827 
 
828 
17.5. Central laboratory 
829 
Dr. Federico Mallo 
830 
Laboratory for Endocrinology of the Centre for Biomedical Research 
831 
University of Vigo 
832 
As Lagras, Marcosende 
833 
36310-Vigo 
834 
Tlf: 986 812 393 
835 
fmallo@uvigo.es 
836 
 
837 
 
838