Randomised, Double-Blind, Placebo-Controlled, Parallel-Group, Multi-centre, Dose Ranging Study to Evaluate the Efficacy and Safety of Losmapimod Tablets Administered Twice Daily Compared With Placebo for 24 Weeks in Adult Subjects With Chronic Obstructive Pulmonary Disease (COPD).

Study Overview
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Brief Summary
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Randomised, double-blind, parallel-group, multi-centre study evaluating three doses of losmapimod (2.5mg, 7.5 mg and 15 mg) twice daily (BID) versus placebo on exercise tolerance. Eligible subjects will be randomised to treatment after a one-week run-in period. The duration of the treatment period is 24 weeks. An estimated 1000 subjects will be screened to reach the target enrolment of approximately 600 randomised subjects.

Official Title
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A Randomised, Double-Blind, Placebo-Controlled, Parallel-Group, Multi-centre, Dose Ranging Study to Evaluate the Efficacy and Safety of Losmapimod (GW856553) Tablets Administered Twice Daily Compared With Placebo for 24 Weeks in Adult Subjects With Chronic Obstructive Pulmonary Disease

Conditions
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Pulmonary Disease, Chronic Obstructive

Intervention / Treatment
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* Drug: losmapimod
* Drug: placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: clinical history of COPD in accordance with the definition by the American Thoracic Society/European Respiratory Society FEV1/FVC ratio of ≤0.70 FEV1 ≤ 80% of predicted normal 6MWD < 350m male or female outpatients aged ≥40 years of age current or prior history of ≥10 pack-years of cigarette smoking aspartate transaminase (AST) or alanine transaminase (ALT) <2x Upper Limit Normal (ULN) alkaline phosphatase (alk phos), and bilirubin <1.5xULN (isolated bilirubin >1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin <35%) QTc <450 msec* on baseline ECG. For subjects with baseline complete bundle branch block, the QTc must be <480msec* on baseline ECG. Exclusion Criteria: current diagnosis of asthma pregnant or lactating α1-antitrypsin deficiency lung resection chest X-ray (or CT scan) that reveals evidence of clinically significant abnormalities not believed to be due to the presence of COPD exacerbation of COPD within previous 12 weeks treatment with roflumilast within previous 2 weeks and throughout the treatment period lower respiratory tract infection that required the use of antibiotics within previous 12 weeks long-term oxygen therapy (LTOT) or nocturnal oxygen therapy required for greater than 12 hours a day participation in the acute phase of a Pulmonary Rehabilitation Program within 12 weeks or planned during the study carcinoma that has not been in complete remission for at least 5 years current or chronic history of liver disease positive Hepatitis B surface antigen or positive Hepatitis C antibody Body Mass Index (BMI) > 35 known or suspected history of alcohol or drug abuse within the last 2 years

Ages Eligible for Study
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Minimum Age: 40 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
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: losmapimod 2.5 mg<br>losmapimod 2.5 mg | Drug: losmapimod<br>* comparison of different dosages of drug 2.5 mg, 7.5 mg or 15 mg<br>|
| Placebo Comparator: placebo<br> | Drug: placebo<br>* placebo comparison with active<br>|
| Experimental: losmapimod 7.5 mg<br>losmapimod 7.5 mg | Drug: losmapimod<br>* comparison of different dosages of drug 2.5 mg, 7.5 mg or 15 mg<br>|
| Experimental: losmapimod 15 mg<br>losmapimod 15 mg | Drug: losmapimod<br>* comparison of different dosages of drug 2.5 mg, 7.5 mg or 15 mg<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Six Minute Walk Distance (6MWD) at Week 4, 12 and 24 | Exercise tolerance was assessed using the 6MWD. If a participant was recorded as having used supplemental oxygen or a walking aid (including sitting down then continuing walking) or a technical problem during a 6MWD then that walk was considered as invalid; otherwise the 6MWD was considered as valid. The baseline 6MWD value was defined as the longest distance walked, for a valid walk, at Visit 2. Variability between the distances walked during the first six-minute walk test (6MWD1) and the second six-minute walk test (6MWD2) being compared was defined as: Variability = [100 x (6MWD2 - 6MWD1)]/6MWD1. Change from Baseline was calculated as the endpoint value minus the Baseline value. Baseline visit was Visit 2 (Week 0). | Baseline (Week 0) and Week 4, 12, 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Forced Expiratory Volume in 1 Sec (FEV1) at Week 4, 8, 12, 16, 20 and 24 | Pulmonary function was measured by FEV1, defined as the maximal amount of air that can be forcefully exhaled in one second. Pre and post-bronchodilator spirometry was performed by the investigator. For post-bronchodilator measurements, spirometry was performed 10-15 minutes after inhalation of 400/360 microgram (mcg) of salbutamol/albuterol. Participants were asked to withhold all bronchodilator therapy (regularly used ipratropium bromide and salbutamol/albuterol used as required) for at least 4 hours prior to spirometric testing. The change from Baseline was calculated by subtracting the Baseline value from the individual post-randomization values.Baseline visit was Visit 2 (Week 0). | Baseline(Week 0) and Week 4, 8, 12, 16, 20 and 24 | 
| Change From Baseline in Forced Vital Capacity (FVC) at Week 4, 8, 12, 16, 20 and 24 | FVC is the total amount of air exhaled during the lung function test. and post-bronchodilator spirometry was performed by the investigator. For post-bronchodilator measurements, spirometry was performed 10-15 minutes after inhalation of 400/360 microgram (mcg) of salbutamol/albuterol. Participants were asked to withhold all bronchodilator therapy (regularly used ipratropium bromide and salbutamol/albuterol used as required) for at least 4 hours prior to spirometric testing. The change from Baseline was calculated by subtracting the Baseline value from the individual post-randomization values.. Baseline visit was Visit 2 (Week 0). | Baseline(Week 0) and Week 4, 8, 12, 16, 20 and 24 | 
| Change From Baseline in St Georges Respiratory Questionnaire for COPD (SGRQ-C) at Week 12 and 24 | The SGRQ-C questionnaire had 14 questions of COPD and participant had to rate each question. These 14 questions were separated to evaluate the three components of SGRQ-C. These three components were symptom component (question 1 to 7), activity component (question 9 and 12) and impact component (question 8, 10, 11, 13 and 14). The total score is 0 to 100 with a higher score indicating greater impairment of health status. Change from Baseline was calculated as the specified time point value minus the Baseline value. Baseline visit was Visit 2 (Week 0). | Baseline (Week 0) and Week 12, 24 | 
| Change From Baseline in Inspiratory Capacity (IC), Residual Volume(RV), Total Lung Capacity(TLC) , Thoracic Gas Volume (TGV) at Functional Residual Capacity ( FRC), Slow Vital Capacity (SVC) at Week 12 and 24 | A plethysmograph is an instrument for measuring changes in volume within an organ or whole body (usually resulting from fluctuations in the amount of blood or air it contains). Plethysmography was used to assess IC, RV, TGV at FRC, SLV, and TLC. Change from Baseline was calculated as the endpoint value minus the Baseline value. Baseline visit was Visit 2 (Week 0). | Baseline(Week 0) and Week 12, 24 | 
| Least Square Mean Ratio to Baseline of Plasma Fibrinogen Over 24 Weeks | Least square mean ratio to Baseline of plasma fibrinogen was assessed at Week 4, 8, 12, 24. Blood samples for biomarker analysis were taken at selected visits. | Baseline (Week 0) and Week 4, 8, 12, 24 | 
| Least Square Mean Ratio to Baseline of High Sensitivity C-reactive Protein (HsCRP) Over 24 Weeks | Least square mean ratio to Baseline of HsCRP was assessed at Week 4, 8, 12, 24. Blood samples for biomarker analysis were taken at selected visits. | Baseline (Week 0) and Week 4, 8, 12, 24 | 
| Total Number of Exacerbations Over 24 Weeks | An exacerbation of COPD is defined as a worsening of COPD symptoms requiring changes to normal treatment (other than increased use of relief salbutamol/albuterol) including antimicrobial therapy, short courses of oral steroids, other bronchodilator therapy and/or emergency treatment or hospitalization. | Up to 24 weeks |