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).

• ClinicalTrials.gov Identifier: NCT01218126
• Recruitment Status: Completed
• First Posted: October 11, 2010
• Results First Posted: January 4, 2018
• Last Update Posted: February 6, 2018
• Sponsor: GlaxoSmithKline
• Information provided by (Responsible Party): GlaxoSmithKline

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Pulmonary Disease, Chronic Obstructive	Drug: losmapimod; Drug: placebo	Phase 2

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 604 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: 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
• Actual Study Start Date: November 4, 2010
• Actual Primary Completion Date: December 21, 2011
• Actual Study Completion Date: December 21, 2011

Arms and Interventions

Arm	Intervention/treatment
Experimental: losmapimod 2.5 mg; losmapimod 2.5 mg	Drug: losmapimod; comparison of different dosages of drug 2.5 mg, 7.5 mg or 15 mg
Placebo Comparator: placebo	Drug: placebo; placebo comparison with active
Experimental: losmapimod 7.5 mg; losmapimod 7.5 mg	Drug: losmapimod; comparison of different dosages of drug 2.5 mg, 7.5 mg or 15 mg
Experimental: losmapimod 15 mg; losmapimod 15 mg	Drug: losmapimod; comparison of different dosages of drug 2.5 mg, 7.5 mg or 15 mg

Outcome Measures

Primary Outcome Measures :

1. Change From Baseline in Six Minute Walk Distance (6MWD) at Week 4, 12 and 24 [ Time Frame: 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 :

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

Eligibility Criteria

• Ages Eligible for Study: 40 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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

Contacts and Locations

Locations

United States, Alabama

GSK Investigational Site

Birmingham, Alabama, United States, 35294

United States, California

GSK Investigational Site

Torrance, California, United States, 90505

United States, Minnesota

GSK Investigational Site

Rochester, Minnesota, United States, 55905

United States, Missouri

GSK Investigational Site

Saint Charles, Missouri, United States, 63301

United States, South Carolina

GSK Investigational Site

Charleston, South Carolina, United States, 29406-7108

GSK Investigational Site

Greenville, South Carolina, United States, 29615

GSK Investigational Site

Spartanburg, South Carolina, United States, 29303

United States, Virginia

GSK Investigational Site

Richmond, Virginia, United States, 23225

Argentina

GSK Investigational Site

Mar del Plata, Buenos Aires, Argentina, 7600

GSK Investigational Site

Rosario, Santa Fe, Argentina, S2000DSR

GSK Investigational Site

Buenos Aires, Argentina, C1120AAC

GSK Investigational Site

Ciudad Autónoma de Buenos Aires, Argentina, C1426ABP

GSK Investigational Site

Mendoza, Argentina, 5500

GSK Investigational Site

Mendoza, Argentina, M5500CCG

GSK Investigational Site

Tucuman, Argentina, 4000

Czechia

GSK Investigational Site

Ostrava - Poruba, Czechia, 70868

GSK Investigational Site

Praha 8, Czechia, 182 00

GSK Investigational Site

Tabor, Czechia, 390 19

GSK Investigational Site

Zlin, Czechia, 762 75

Estonia

GSK Investigational Site

Tallinn, Estonia, 10138

GSK Investigational Site

Tallinn, Estonia, 13619

GSK Investigational Site

Tartu, Estonia, 51014

Germany

GSK Investigational Site

Potsdam, Brandenburg, Germany, 14467

GSK Investigational Site

Frankfurt, Hessen, Germany, 60389

GSK Investigational Site

Frankfurt, Hessen, Germany, 60596

GSK Investigational Site

Gelnhausen, Hessen, Germany, 63571

GSK Investigational Site

Ruesselsheim, Hessen, Germany, 65428

GSK Investigational Site

Mainz, Rheinland-Pfalz, Germany, 55131

GSK Investigational Site

Grosshansdorf, Schleswig-Holstein, Germany, 22927

GSK Investigational Site

Berlin, Germany, 10117

GSK Investigational Site

Berlin, Germany, 13581

GSK Investigational Site

Hamburg, Germany, 20354

Korea, Republic of

GSK Investigational Site

Seoul, Korea, Republic of, 100-032

GSK Investigational Site

Seoul, Korea, Republic of, 130-702

GSK Investigational Site

Seoul, Korea, Republic of, 130-848

GSK Investigational Site

Seoul, Korea, Republic of, 134-701

GSK Investigational Site

Seoul, Korea, Republic of

Norway

GSK Investigational Site

Bergen, Norway, N-5021

GSK Investigational Site

Follebu, Norway, 2656

GSK Investigational Site

Harstad, Norway, 9480

GSK Investigational Site

Levanger, Norway, 7600

GSK Investigational Site

Stavanger, Norway, 4011

GSK Investigational Site

Trondheim, Norway, 7030

Ukraine

GSK Investigational Site

Donetsk, Ukraine, 83003

GSK Investigational Site

Donetsk, Ukraine, 83099

GSK Investigational Site

Kiev, Ukraine, 03680

GSK Investigational Site

Kyiv, Ukraine, 03115

GSK Investigational Site

Kyiv, Ukraine, 03680

Sponsors and Collaborators

GlaxoSmithKline

Investigators

• Study Director: GSK Clinical Trials; GlaxoSmithKline

More Information

Additional Information:

Researchers can use this site to request access to anonymised patient level data and/or supporting documents from clinical studies to conduct further research. 

Study Data/Documents: Clinical Study Report 

Identifier: 113006
For additional information about this study please refer to the GSK Clinical Study Register

Statistical Analysis Plan 

Identifier: 113006
For additional information about this study please refer to the GSK Clinical Study Register

Dataset Specification 

Identifier: 113006
For additional information about this study please refer to the GSK Clinical Study Register

Individual Participant Data Set 

Identifier: 113006
For additional information about this study please refer to the GSK Clinical Study Register

Informed Consent Form 

Identifier: 113006
For additional information about this study please refer to the GSK Clinical Study Register

Annotated Case Report Form 

Identifier: 113006
For additional information about this study please refer to the GSK Clinical Study Register

Study Protocol 

Identifier: 113006
For additional information about this study please refer to the GSK Clinical Study Register

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Largajolli A, Beerahee M, Yang S. Bayesian approach to investigate a two-state mixed model of COPD exacerbations. J Pharmacokinet Pharmacodyn. 2019 Aug;46(4):371-384. doi: 10.1007/s10928-019-09643-6. Epub 2019 Jun 13. Erratum in: J Pharmacokinet Pharmacodyn. 2019 Dec;46(6):627.

Watz H, Barnacle H, Hartley BF, Chan R. Efficacy and safety of the p38 MAPK inhibitor losmapimod for patients with chronic obstructive pulmonary disease: a randomised, double-blind, placebo-controlled trial. Lancet Respir Med. 2014 Jan;2(1):63-72. doi: 10.1016/S2213-2600(13)70200-5. Epub 2013 Dec 5.

• Responsible Party: GlaxoSmithKline
• ClinicalTrials.gov Identifier: NCT01218126
• Other Study ID Numbers: 113006
• First Posted: October 11, 2010
• Results First Posted: January 4, 2018
• Last Update Posted: February 6, 2018
• Last Verified: January 2018

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: Patient-level data for this study will be made available through www.clinicalstudydatarequest.com following the timelines and process described on this site.

Additional relevant MeSH terms:

Lung Diseases; Lung Diseases, Obstructive; Pulmonary Disease, Chronic Obstructive; Respiratory Tract Diseases