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).

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

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.

Study Overview

• Status: Completed
• Conditions: Pulmonary Disease, Chronic Obstructive
• Intervention / Treatment: Drug: losmapimod; Drug: placebo

• Study Type: Interventional
• Enrollment (Actual): 604
• Phase: Phase 2

Contacts and Locations

Study Locations

• Argentina
  • Buenos Aires, Argentina, C1120AAC
    • GSK Investigational Site
  • Ciudad Autónoma de Buenos Aires, Argentina, C1426ABP
    • GSK Investigational Site
  • Mendoza, Argentina, M5500CCG
    • GSK Investigational Site
  • Mendoza, Argentina, 5500
    • GSK Investigational Site
  • Tucuman, Argentina, 4000
    • GSK Investigational Site
  • Buenos Aires
    • Mar del Plata, Buenos Aires, Argentina, 7600
      • GSK Investigational Site
  • Santa Fe
    • Rosario, Santa Fe, Argentina, S2000DSR
      • GSK Investigational Site
• Czechia
  • 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
    • GSK Investigational Site
• Estonia
  • Tallinn, Estonia, 13619
    • GSK Investigational Site
  • Tallinn, Estonia, 10138
    • GSK Investigational Site
  • Tartu, Estonia, 51014
    • GSK Investigational Site
• Germany
  • Berlin, Germany, 10117
    • GSK Investigational Site
  • Berlin, Germany, 13581
    • GSK Investigational Site
  • Hamburg, Germany, 20354
    • GSK Investigational Site
  • Brandenburg
    • Potsdam, Brandenburg, Germany, 14467
      • GSK Investigational Site
  • Hessen
    • Frankfurt, Hessen, Germany, 60596
      • GSK Investigational Site
    • Frankfurt, Hessen, Germany, 60389
      • GSK Investigational Site
    • Gelnhausen, Hessen, Germany, 63571
      • GSK Investigational Site
    • Ruesselsheim, Hessen, Germany, 65428
      • GSK Investigational Site
  • Rheinland-Pfalz
    • Mainz, Rheinland-Pfalz, Germany, 55131
      • GSK Investigational Site
  • Schleswig-Holstein
    • Grosshansdorf, Schleswig-Holstein, Germany, 22927
      • GSK Investigational Site
• Korea, Republic of
  • Seoul, Korea, Republic of
    • GSK Investigational Site
  • Seoul, Korea, Republic of, 130-702
    • GSK Investigational Site
  • Seoul, Korea, Republic of, 100-032
    • GSK Investigational Site
  • Seoul, Korea, Republic of, 130-848
    • GSK Investigational Site
  • Seoul, Korea, Republic of, 134-701
    • GSK Investigational Site
• Norway
  • 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
    • GSK Investigational Site
• Ukraine
  • Donetsk, Ukraine, 83003
    • GSK Investigational Site
  • Donetsk, Ukraine, 83099
    • GSK Investigational Site
  • Kiev, Ukraine, 03680
    • GSK Investigational Site
  • Kyiv, Ukraine, 03680
    • GSK Investigational Site
  • Kyiv, Ukraine, 03115
    • GSK Investigational Site
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35294
      • GSK Investigational Site
  • California
    • Torrance, California, United States, 90505
      • GSK Investigational Site
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • GSK Investigational Site
  • Missouri
    • Saint Charles, Missouri, United States, 63301
      • GSK Investigational Site
  • South Carolina
    • 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
      • GSK Investigational Site
  • Virginia
    • Richmond, Virginia, United States, 23225
      • GSK Investigational Site

Participation Criteria

Eligibility Criteria

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

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

4

Arms and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: GlaxoSmithKline

Publications and helpful links

General Publications

• 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.

Helpful Links

• 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 record dates

Study Major Dates

• Study Start (Actual): November 4, 2010
• Primary Completion (Actual): December 21, 2011
• Study Completion (Actual): December 21, 2011

Study Registration Dates

• First Submitted: October 7, 2010
• First Submitted That Met QC Criteria: October 7, 2010
• First Posted (Estimate): October 11, 2010

Study Record Updates

• Last Update Posted (Actual): February 6, 2018
• Last Update Submitted That Met QC Criteria: January 10, 2018
• Last Verified: January 1, 2018

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Lung Diseases; Lung Diseases, Obstructive; Pulmonary Disease, Chronic Obstructive
• Other Study ID Numbers: 113006

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD 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.

Study Data/Documents

1. Clinical Study Report
   Information identifier: 113006
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register
2. Statistical Analysis Plan
   Information identifier: 113006
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register
3. Dataset Specification
   Information identifier: 113006
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register
4. Individual Participant Data Set
   Information identifier: 113006
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register
5. Informed Consent Form
   Information identifier: 113006
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register
6. Annotated Case Report Form
   Information identifier: 113006
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register
7. Study Protocol
   Information identifier: 113006
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register