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).

Phase 2

Completed

Conditions: Pulmonary Disease, Chronic Obstructive

Interventions: Drug: placebo
Drug: losmapimod

Registration Number: NCT01218126

Lead Sponsor: GlaxoSmithKline

Brief Summary: 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.

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 604

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
placebo	placebo	-
losmapimod 7.5 mg	losmapimod	losmapimod 7.5 mg
losmapimod 2.5 mg	losmapimod	losmapimod 2.5 mg
losmapimod 15 mg	losmapimod	losmapimod 15 mg

Primary Outcome Measures

Name	Time	Method
Change From Baseline in Six Minute Walk Distance (6MWD) at Week 4, 12 and 24	Baseline (Week 0) and Week 4, 12, 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).

Secondary Outcome Measures

Name	Time	Method
Change From Baseline in Forced Vital Capacity (FVC) at Week 4, 8, 12, 16, 20 and 24	Baseline(Week 0) and 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).
Least Square Mean Ratio to Baseline of Plasma Fibrinogen Over 24 Weeks	Baseline (Week 0) and Week 4, 8, 12, 24	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.
Change From Baseline in Forced Expiratory Volume in 1 Sec (FEV1) at Week 4, 8, 12, 16, 20 and 24	Baseline(Week 0) and 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).
Least Square Mean Ratio to Baseline of High Sensitivity C-reactive Protein (HsCRP) Over 24 Weeks	Baseline (Week 0) and Week 4, 8, 12, 24	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.
Total Number of Exacerbations Over 24 Weeks	Up to 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.
Change From Baseline in St Georges Respiratory Questionnaire for COPD (SGRQ-C) at Week 12 and 24	Baseline (Week 0) and Week 12, 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).
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	Baseline(Week 0) and Week 12, 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).