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Safety and Efficacy Study of Losmapimod (GW856553) in Frequently Exacerbating Participants With Chronic Obstructive Pulmonary Disease (COPD)

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ClinicalTrials.gov Identifier: NCT02299375
Recruitment Status : Completed
First Posted : November 24, 2014
Results First Posted : July 13, 2018
Last Update Posted : August 6, 2018
Sponsor:
Information provided by (Responsible Party):
GlaxoSmithKline

Brief Summary:

This is a randomised, double-blind, parallel-group, multi-centre study evaluating 15 milligram (mg) twice daily/ Bi-daily (BID) of losmapimod versus placebo, in addition to standard of care (SoC).

The primary objective of this study is to explore the therapeutic potential of losmapimod as a treatment to reduce the rate of exacerbations in the subset of participants with moderate-to-severe COPD who are at high risk of exacerbation, having experienced two or more moderate/severe exacerbations in the preceding 12 months, and who have <=2% of blood eosinophils at screening. As secondary objectives safety, effects on lung function, quality of life, pharmacokinetic (PK), biomarkers of both disease and inflammation shall be evaluated.

The duration of the treatment period is variable but will be at least 26 weeks and up to a maximum of 52 weeks, with the end of study date being established once the final participant has been randomized. The purpose of the variable dosing regimen is to enable participants to remain in the study for a longer duration, as it is anticipated that this will increase the likelihood of observing exacerbation events without increasing the overall study duration. It will also enable safety data on dosing periods beyond 6 months to be generated.

Approximately 200 participants in a 1:1 ratio between losmapimod and placebo will be randomized to the study. Sample size re-estimation will be performed during the course of the study to potentially increase the sample size up to a maximum of 600 participants.


Condition or disease Intervention/treatment Phase
Pulmonary Disease, Chronic Obstructive Drug: Losmapimod tablets Drug: Placebo tablets Drug: Salbutamol MDI Phase 2

Layout table for study information
Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 184 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Official Title: A Study to Evaluate the Efficacy and Safety of 15mg BID Losmapimod (GW856553) Compared to Placebo in Frequently Exacerbating Subjects With Chronic Obstructive Pulmonary Disease (COPD)
Actual Study Start Date : December 9, 2014
Actual Primary Completion Date : June 30, 2016
Actual Study Completion Date : June 30, 2016

Resource links provided by the National Library of Medicine

MedlinePlus related topics: COPD Lung Diseases
Drug Information available for: Albuterol

Arm Intervention/treatment
Experimental: Losmapimod 15 mg
Subjects with COPD will receive losmapimod 15 mg tablets orally, twice daily, approximately 12 hours apart and within 30 minutes after meals with a full glass of water for the duration of the treatment period in addition to standard of care, stratified according to whether a center collects sputum or not and current use of inhaled corticosteroid (ICS). Salbutamol metered dose inhaler (MDI) will be provided as a rescue medication.
Drug: Losmapimod tablets
Losmapimod tablets will be provided as 15 mg strength in a formulation containing lactose. Administered orally, twice daily approximately 12 hours apart and with food and water for the duration of the treatment period. Participants will be instructed to take their medication with a full glass of water twice-daily within 30 minutes after meals for the duration of their treatment period.

Drug: Salbutamol MDI
Salbutamol MDI will be provided as a rescue medication.

Experimental: Placebo
Subjects with COPD will receive placebo orally, twice daily, approximately 12 hours apart and within 30 minutes after meals with a full glass of water for the duration of the treatment period in addition to standard of care, stratified according to whether a center collects sputum or not and current use of ICS. Salbutamol MDI will be provided as a rescue medication.
Drug: Placebo tablets
Placebo tablets will be provided in a formulation containing lactose and visually matching the losmapimod tablets. Administered orally, twice daily approximately 12 hours apart and with food and water for the duration of the treatment period. Participants will be instructed to take their medication with a full glass of water twice-daily within 30 minutes after meals for the duration of their treatment period

Drug: Salbutamol MDI
Salbutamol MDI will be provided as a rescue medication.




Primary Outcome Measures :
  1. Annual Rate of Moderate and Severe Exacerbations of COPD [ Time Frame: From the start of the study treatment up to 53 Weeks ]
    An exacerbation of COPD, is defined as the worsening of 2 or more major symptoms (dyspnea, sputum volume, sputum purulence) or the worsening of any 1 major symptom together with any 1 of the minor symptoms (sore throat, cold, fever without other cause, increased cough and wheeze), for at least 2 consecutive days. Moderate-severe exacerbations were defined as use of antibiotics and/or oral steroids and/or hospitalization. Summary only included exacerbations for which a date of resolution or death was provided. Analysis was performed by using Bayesian inference assuming non-informative priors. The mean exacerbation rate was adjusted for treatment group, smoking status, ICS use and region. The adjusted posterior median was summarized per treatment group. The number of exacerbation events per participant was assumed to follow a negative binomial distribution. Modified Intent-to-Treat (mITT) Population comprised of all randomized par. who received at least one dose of study treatment.


Secondary Outcome Measures :
  1. Time to First Occurrence of Moderate or Severe COPD Exacerbation [ Time Frame: From the start of the study treatment up to 53 Weeks ]
    The time to first moderate-severe COPD exacerbation in par. treated with losmapimod compared to placebo treated par. was evaluated. The time to the first on-treatment moderate-severe exacerbation was calculated as exacerbation onset date of first on-treatment exacerbation minus exposure start date plus 1. No statistical analysis was conducted. Data was summarized statistically only.

  2. Number of Participants Having Any Adverse Events (AEs), Serious Adverse Events (SAEs) [ Time Frame: From the start of the study treatment up to 53 Weeks ]
    An AE is any untoward medical occurrence in a patient or clinical investigation subject, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. Any untoward event resulting in death, life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, congenital anomaly/birth defect, any other situation according to medical or scientific judgment or all events of possible drug-induced liver injury with hyperbilirubinaemia were categorized as SAE. AEs were considered as on-treatment If AE onset date is on or after treatment start date & on or before treatment stop date. par. having any AE or SAE were included in analysis.

  3. Change From Baseline in Spirometry Parameters in Pre and Post Forced Expiratory Volume in 1 Second (FEV1); Pre and Post Forced Vital Capacity (FVC); Pre and Post Forced Expiratory Volume in 6 Seconds (FEV6). [ Time Frame: Baseline and up to Week 52 ]
    Pre and post FEV1, FVC and FEV6 were performed at Screening, Day 1 pre-dose and Weeks 2, 4, 8, 12, 18, 26, 39 and 52. Par. were asked to withheld all bronchodilator therapy included ipratropiumn bromide and salbutamol/albuterol for at least 4 hours prior to prebronchodilator spirometric test. Post-bronchodilator spirometric assessment was performed after inhalation of 400/360 micograms (µg) of salbutamol/albuterol in 10-15 minutes. Day 1 (pre-dose) values were considered as Baseline values. Change from Baseline was calculated as value at the indicated time point minus Baseline value. The maximum value of the 3 replicate assessments were used. Analysis performed using a mixed-effects repeated measures model. The adjusted mean values were summarized per treatment group. Par. were included in the analysis if they had at least one post-baseline measurement. Only those participants available at the specified time points were analyzed (represented by n=X, X in the category titles).

  4. Change From Baseline in Spirometry Parameters in Pre and Post FEV1/FVC, Percent Predicted (PP) FEV1, PP FEV6 and PP FVC [ Time Frame: Baseline and up to Week 52 ]
    Pre and post FEV1/FVC, PP FEV1, PP FEV6 and PP FVC were assessed at Screening, Day 1 pre-dose and Weeks 2, 4, 8, 12, 18, 26, 39 and 52. Par. were asked to withheld all bronchodilator therapy included ipratropiumn bromide and salbutamol/albuterol for at least 4 hours prior to the prebronchodilator spirometric test. Post-bronchodilator spirometric assessment was performed after inhalation of 400/360 µg of salbutamol/albuterol in 10-15 minutes. Day 1 (pre-dose) values were considered as Baseline values. Change from Baseline was calculated as value at indicated time point minus Baseline value. The maximum value of the 3 replicate assessments were used. Analysis performed using a mixed-effects repeated measures model. The adjusted mean values were summarized per treatment group. Par. were included in the analysis if they had at least one post-baseline measurement. Only those participants available at the specified time points were analyzed (represented by n=X, X in the category titles).

  5. Number of Participants With Electrocardiogram (ECG) Findings [ Time Frame: Up to 53 Weeks ]
    12-lead ECGs were obtained in triplicate at Screening then singly at Baseline (day 1, pre-dose) and post dose at Weeks 2, 4, 8, 12, 26, 39, 52 and at follow up (Week 53) using an ECG machine that automatically calculates the heart rate (HR) and measures PR, QRS, QT, and QT duration corrected for heart rate by Fridericia's formula (QTcF) or QT duration corrected for heart rate by Bazett's formula (QTcB) intervals. Change in ECG findings were categorized as normal and abnormal. Abnormal ECG values could be clinically significant (CS) or not clinically significant (NCS), as determined by the investigator. Only those par. available at the specified time points were analyzed (represented by n=X, X in the category titles).

  6. Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) at the Indicated Time Points [ Time Frame: Baseline and up to Week 53 ]
    SBP and DBP were taken at Screening, Baseline (day 1, pre-dose) and post dose at Weeks 2, 4, 8, 12, 26, 39, 52 and at follow up (Week 53). Measurements were taken in a semi-recumbent position after 5 minutes rest. Change from Baseline was calculated as the post-Baseline value minus the Baseline value. The Baseline value of an assessment is defined as the value at day 1, pre-dose. Par. were included in the analysis if they had at least one post-baseline measurement. Only those par. available at the specified time points were analyzed (represented by n=X, X in the category titles).

  7. Change From Baseline in Heart Rate (HR) Values at the Indicated Time Points [ Time Frame: Baseline and up to Week 53 ]
    HR was assessed at Screening, Baseline (day 1, pre-dose) and post dose at Weeks 2, 4, 8, 12, 26, 39, 52 and at follow up (Week 53). Measurements were taken in a semi-recumbent position after 5 minutes rest. Change from Baseline was calculated as the post-Baseline value minus the Baseline value. The Baseline value of an assessment is defined as the value at day 1, pre-dose. Par. were included in the analysis if they had at least one post-baseline measurement. Only those par. available at the specified time points were analyzed (represented by n=X, X in the category titles).

  8. Plasma Losmapimod Area Under the Plasma Concentration Time Curve (AUC) From Time Zero to the End of Dosing Interval (AUC[0-tau]) [ Time Frame: Pre-dose at Weeks 2 and 12; pre-dose and at 2 hours post-dose at Week 26 ]
    Pharmacokinetics (PK) of losmapimod was evaluated in participants with COPD using PK samples collected at pre-dose at Week 2 and Week 12. At Week 26, a sample was collected at pre-dose and a second sample was collected at 2 hours post-dose. Par. of mITT population that provided at least one observed concentration data in this study were considered for PK analysis. Drug plasma concentration-time data were modelled by nonlinear mixed effects modelling. AUC[0-tau] (tau=12 hours) was estimated from the model.

  9. Plasma Losmapimod Maximum Concentration (Cmax) and Lowest Concentration (Ctrough) at Steady State [ Time Frame: Pre-dose at Weeks 2 and 12; pre-dose and at 2 hours post-dose at Week 26 ]
    Pharmacokinetics of losmapimod was evaluated in participants with COPD using PK samples collected at pre-dose at Week 2 and Week 12. At Week 26, a sample was collected at pre-dose and a second sample was collected at 2 hours post-dose. Par. of mITT population that provided at least one observed concentration data in this study were considered for PK analysis (represented by n=X, X in the category titles). Drug plasma concentration-time data were modelled by nonlinear mixed effects modelling to develop a Population PK model. Cmax and Ctrough were estimated from the PK model.

  10. Change From Baseline in Frequency of Short Acting Beta-agonist or Anti-cholinergic Use [ Time Frame: Baseline and up to Week 52 ]
    Use of short acting bronchodilators (short-acting beta2-agonists or short-acting anti-cholinergic) was allowed and was recorded in daily patient diary. It included inhaled short-acting beta2-agonists (e.g. Ipratropium bromide, salbutamol, Ipratropium/salbutamol (albuterol) combination product) and short-acting anti-cholinergics (e.g., ipratropium bromide3). Use of these medications was allowed throughout the study except 4 hours prior to and during each clinic visit. Only those par. available at the specified time points were analyzed (represented by n=X, X in the category titles).

  11. Change From Baseline in St Georges Respiratory Questionnaire (SGRQ) Total, SGRQ Symptoms Score, SGRQ Activity Score and SGRQ Impact Score Over Time [ Time Frame: Baseline and up to Week 52 ]
    SGRQ-C is a health related quality of life questionnaire consisting of 14 questions. SGRQ-C total score was calculated as 100 multiplied by summed weights from all positive items divided by sum of weights for all items in questionnaire. Components (Activity, Symptoms, Impacts) were calculated as 100 multiplied by summed weights from all positive items in that component divided by sum of weights for all items in that component. Score range for SGRQ-C total is 0-100. Maximum weights for Activity, Symptoms and Impacts component is 982.9, 566.2 and 1652.8 respectively. SGRQ-C was transformed to SGRQ for reporting. Higher scores indicate greater disease impact. Score at Day 1, pre-dose (Week 0) was considered as Baseline. Change from Baseline was calculated as score at indicated time point minus Baseline value. Only those par. with analyzable data at the given time points (represented by n=X, X in category titles) were included in analysis.

  12. Number of Participants With Abnormal Liver Events During the Treatment Period [ Time Frame: Up to Week 53 ]
    Various liver chemistry parameters were monitored periodically to ensure the safety and tolerability of Losmapimod as compared to placebo. Study treatments were discontinued for par. if alanine aminotransferase (ALT) absolute >= 5xupper limit of normal (ULN) or; ALT >= 3xULN persists for >=4 Weeks or; ALT>=3x ULN and bilirubin >=2xULN or; ALT>=3x ULN and International normalized ratio (INR) >=1.5 or; ALT>=3x ULN and cannot be monitored weekly for 4 Weeks or; ALT>=3x ULN symptomatic.

  13. Change From Baseline in Hemoglobin, Total Protein, Albumin and Mean Corpuscle Hemoglobin Concentration (MCHC) at the Indicated Time Points [ Time Frame: Baseline and up to Week 53 ]
    Blood samples were collected at Baseline (Day 1, pre-dose) and at Weeks 2, 4, 8, 12, 18, 26, 39, 52 (or at early withdrawal) and follow up (Week 53) to evaluate hemoglobin, total protein, albumin and MCHC. Values obtained at Day 1, pre-dose (Week 0) were considered as Baseline values. Change from Baseline was calculated as laboratory test value obtained at indicated time point minus Baseline value. If post-dose value was missing for a particular assessment visit, then no derivation were performed and the change from Baseline were set to missing for that visit. Only those par. available at the specified time points were analyzed (represented by n=X, X in the category titles).

  14. Change From Baseline in Hematocrit at the Indicated Time Points [ Time Frame: Baseline and up to Week 53 ]
    Blood samples were collected at Baseline (Day 1, pre-dose) and at Weeks 2, 4, 8, 12, 18, 26, 39, 52 (or at early withdrawal) and follow up (Week 53) to evaluate hematocrit. Values obtained at Day 1, pre-dose (Week 0) were considered as Baseline values. Change from Baseline was calculated as laboratory test value obtained at indicated time point minus Baseline value. If post-dose value was missing for a particular assessment visit, then no derivation were performed and the change from Baseline were set to missing for that visit. Only those par. available at the specified time points were analyzed (represented by n=X, X in the category titles).

  15. Change From Baseline in Absolute White Blood Cell (WBC) Count, Total Neutrophil, Total Lymphocyte, Basophil, Eosinophil, Monocyte and Platelet Count at the Indicated Time Point [ Time Frame: Baseline and up to Week 53 ]
    Blood samples were collected at Baseline (Day 1, pre-dose) and at Weeks 2, 4, 8, 12, 18, 26, 39, 52 (or at early withdrawal) and follow up (Week 53) to evaluate absolute WBC count, total neutrophil, total lymphocyte, basophil, absolute eosinophil, percentage eosinophil, monocyte and platelet count. Values obtained at Day 1, pre-dose (Week 0) were considered as Baseline values. Change from Baseline was calculated as laboratory test value obtained at the indicated time point minus Baseline value. If post-dose value was missing for a particular assessment visit, then no derivation were performed and the change from Baseline were set to missing for that visit. Only those par. available at the specified time points were analyzed (represented by n=X, X in the category titles).

  16. Change From Baseline in Eosinophil Percentage at the Indicated Time Points [ Time Frame: Baseline and up to Week 53 ]
    Blood samples were collected at Baseline (Day 1, pre-dose) and at Weeks 2, 4, 8, 12, 18, 26, 39, 52 (or at early withdrawal) and follow up (Week 53) to evaluate eosinophil percentage. Values obtained at Day 1, pre-dose (Week 0) were considered as Baseline values. Change from Baseline was calculated as laboratory test value obtained at the indicated time point minus Baseline value. If post-dose value was missing for a particular assessment visit, then no derivation were performed and the change from Baseline were set to missing for that visit. Only those par. available at the specified time points were analyzed (represented by n=X, X in the category titles).

  17. Change From Baseline in Total Bilirubin, Direct Bilirubin, Uric Acid and Creatinine at the Indicated Time Point [ Time Frame: Baseline and up to Week 53 ]
    Blood samples were collected at Baseline (Day 1, pre-dose) and at Weeks 2, 4, 8, 12, 18, 26, 39, 52 (or at early withdrawal) and follow up (Week 53) to evaluate total bilirubin, direct bilirubin, urice acid and creatinine. Values obtained at Day 1, pre-dose (Week 0) were considered as Baseline values. Change from Baseline was calculated as laboratory test value obtained at the indicated time point minus Baseline value. If post-dose value was missing for a particular assessment visit, then no derivation were performed and the change from Baseline were set to missing for that visit. Only those par. available at the specified time points were analyzed (represented by n=X, X in the category titles).

  18. Change From Baseline in Alanine Aminotransferase, Aspartate Aminotransferase, Alkaline Phosphatase and Gamma Glutamyl Transferase at the Indicated Time Points [ Time Frame: Baseline and up to Week 53 ]
    Blood samples were collected at Baseline (Day 1, pre-dose) and at Weeks 2, 4, 8, 12, 18, 26, 39, 52 (or at early withdrawal) and follow up (Week 53) to evaluate alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase and gamma glutamyl transferase at the indicated time point. Values obtained at Day 1, pre-dose (Week 0) were considered as Baseline values. Change from Baseline was calculated as laboratory test value obtained at the indicated time point minus Baseline value. If post-dose value was missing for a particular assessment visit, then no derivation were performed and the change from Baseline were set to missing for that visit. Only those par. available at the specified time points were analyzed (represented by n=X, X in the category titles).

  19. Change From Baseline in Chloride, Calcium, Glucose, Potassium, Sodium and Blood Urea Nitrogen at the Indicated Time Points [ Time Frame: Baseline and up to Week 53 ]
    Blood samples were collected at Baseline (Day 1, pre-dose) and at Weeks 2, 4, 8, 12, 18, 26, 39, 52 (or at early withdrawal) and follow up (Week 53) to evaluate calcium, chloride, glucose, potassium, sodium and blood urea nitrogenat the indicated time point. Values obtained at Day 1, pre-dose (Week 0) were considered as Baseline values. Change from Baseline was calculated as laboratory test value obtained at the indicated time point minus Baseline value. If post-dose value was missing for a particular assessment visit, then no derivation were performed and the change from Baseline were set to missing for that visit. Only those par. available at the specified time points were analyzed (represented by n=X, X in the category titles).

  20. Change From Baseline in Red Blood Cell Count at the Indicated Time Points [ Time Frame: Baseline and up to Week 53 ]
    Blood samples were collected at Baseline (Day 1, pre-dose) and at Weeks 2, 4, 8, 12, 18, 26, 39, 52 (or at early withdrawal) and follow up (Week 53) to evaluate Red blood cell count. Values obtained at Day 1, pre-dose (Week 0) were considered as Baseline values. Change from Baseline was calculated as laboratory test value obtained at the indicated time point minus Baseline value. If post-dose value was missing for a particular assessment visit, then no derivation were performed and the change from Baseline were set to missing for that visit. Only those par. available at the specified time points were analyzed (represented by n=X, X in the category titles).

  21. Change From Baseline in Mean Corpuscle Hemoglobin at the Indicated Time Points [ Time Frame: Baseline and up to Week 53 ]
    Blood samples were collected at Baseline (Day 1, pre-dose) and at Weeks 2, 4, 8, 12, 18, 26, 39, 52 (or at early withdrawal) and follow up (Week 53) to evaluate mean corpuscle hemoglobin. Values obtained at Day 1, pre-dose (Week 0) were considered as Baseline values. Change from Baseline was calculated as laboratory test value obtained at the indicated time point minus Baseline value. If post-dose value was missing for a particular assessment visit, then no derivation were performed and the change from Baseline were set to missing for that visit. Only those par. available at the specified time points were analyzed (represented by n=X, X in the category titles).

  22. Change From Baseline in Mean Corpuscle Volume at the Indicated Time Points [ Time Frame: Baseline and up to Week 53 ]
    Blood samples were collected at Baseline (Day 1, pre-dose) and at Weeks 2, 4, 8, 12, 18, 26, 39, 52 (or at early withdrawal) and follow up (Week 53) to evaluate mean corpuscle volume. Values obtained at Day 1, pre-dose (Week 0) were considered as Baseline values. Change from Baseline was calculated as laboratory test value obtained at the indicated time point minus Baseline value. If post-dose value was missing for a particular assessment visit, then no derivation were performed and the change from Baseline were set to missing for that visit. Only those par. available at the specified time points were analyzed (represented by n=X, X in the category titles).



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Layout table for eligibility information
Ages Eligible for Study:   40 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • COPD diagnosis and severity: Participants with a clinical history of COPD (established by a physician) in accordance with the following definition by the American Thoracic Society/European Respiratory Society, for at least 6 months prior to enrolment. Participants must have evidence of airflow obstruction, defined as post-bronchodilator FEV1 equal to or less than 80% of predicted normal value calculated using "Third National Health and Nutrition Examination Survey" (NHANES III) reference equation at Visit 1 and a FEV1 / FVC ratio <=70% at Screening (Visit 1). Note: Post-bronchodilator spirometry will be performed approximately 10-15 minutes after the participants has self-administered 4 inhalations (i.e., total 400/360 [microgram] mcg) of salbutamol/albuterol via a Metered Dose Inhaler (MDI) (use of spacer will be optional). The study-provided central spirometry equipment will calculate the FEV1/FVC ratio and FEV1 percent predicted values.
  • Exacerbation History: A documented history (e.g., medical record verification) in the 12 months prior to Visit 1 of >=2 COPD exacerbations resulting in prescription for antibiotics and/or oral corticosteroids or hospitalisation or extended observation in a hospital emergency room or outpatient centre. Note: Prior use of antibiotics alone does not qualify as a moderate exacerbation unless the use was specifically for the treatment of worsening symptoms of COPD.
  • Existing COPD maintenance treatment: Participants must be receiving daily maintenance treatment for their COPD for at least 3 months prior to Screening. Notes: Participants receiving only "pro re nata" or as needed (PRN) COPD medications are not eligible for inclusion in the study. All participants will continue on their current Standard of Care (SoC) COPD medications throughout the entire duration of the study.
  • Tobacco use: Participants with a current or prior history of >=10 pack-years of cigarette smoking at Screening (Visit 1). Former smokers are defined as those who have stopped smoking for at least 6 months prior to Visit 1. One pack year =20 cigarettes smoked per day for 1 year or the equivalent. Number of pack years=(number of cigarettes per day/20) x number of years smoked.
  • Sex: Male or female participants aged >=40 years at Screening (Visit 1). A female participant is eligible to participate if she is of non-child bearing potential defined as pre-menopausal females with a documented tubal ligation or hysterectomy; or postmenopausal defined as 12 months of spontaneous amenorrhea [in questionable cases a blood sample with simultaneous follicle stimulating hormone (FSH) >40 milli-international unit/milliliter (MIU/mL) and estradiol <40 picogram/milliliter (pg/mL) (<140 [Picomoles per liter] pmol/L) is confirmatory] or if of child-bearing potential is using a highly effective method for avoidance of pregnancy from 30 days before the first dose, for the duration of dosing and until 2 weeks post last-dose.
  • Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form.
  • Corrected ECG QT interval (QTc)<450 milliseconds(msec) or QTc<480 msec for participants with bundle branch block. The QTc is the QT interval corrected for heart rate according to either Bazett's formula (QTcB), Fridericia's formula (QTcF), or another method, machine or manual over-read. For eligibility and withdrawal, ideally the same QT correction formula will be used for all participants. However, because this is not always possible, the same QT correction formula will be used for each individual participant to determine eligibility for and withdrawal from the study. The QTc will be based on single or averaged QTc values of triplicate ECGs obtained over a brief recording period.

Exclusion Criteria:

  • Eosinophils: >2.0% blood eosinophils at Screening (Visit 1)
  • Concomitant medication: COPD Medication: Participants currently on chronic treatment with macrolides or Roflumilast; Long term oxygen therapy (LTOT) or nocturnal oxygen therapy required for greater than 12 hours a day. Oxygen PRN use (i.e. <=12 hours per day) is not exclusionary. Multidrug and toxin extrusion (MATE) transporter 1 (MATE1) inhibitors: cimetidine, pyrimethamine, trimethoprim (short course treatment with trimethoprim is allowed). Other medications: Chronic maintenance therapy with anti-Tumor Necrosis Factor (anti-TNF), anti-Interleukin-1 (anti-IL1), phosphodiesterase type 4 (PDE4) inhibitors, or any other immunosuppressive therapy (not including steroids) within 60 days prior to dosing. Any other investigational drug within 30 days or 5 half lives, whichever is longer prior to Screening Visit.
  • Other respiratory disorders: Participants with asthma (as primary diagnosis) lung cancer, bronchiectasis, active sarcoidosis, active lung fibrosis, cystic fibrosis, idiopathic pulmonary hypertension, active interstitial lung diseases or other active pulmonary diseases. Participants with alpha-1-antitrypsin deficiency as the underlying cause of COPD.
  • Participants with clinically significant sleep apnea who require use of continuous positive airway pressure (CPAP) device.
  • Participants who require a non-invasive positive pressure ventilation (NIPPV) device (Note: Use of non invasive ventilation (NIV) in hospital as part of the medical management of an acute exacerbation is permitted.)
  • Lung resection: Participants who have undergone previous lung reduction surgery (e.g. lobectomy, pneumonectomy, or lung volume reduction).
  • COPD stability: Less than 30 days prior to Visit 1 have elapsed from completion of a course of antibiotics or oral corticosteroids for a recent COPD exacerbation.
  • Evidence of pneumonia or a clinically significant abnormality not believed to be due to the presence of COPD on chest X-ray (posteroanterior with lateral) or computerised tomography (CT) scan (historic data up to 1 year may be used).
  • Pulmonary rehabilitation program: Participation in the acute phase of a pulmonary rehabilitation program within 4 weeks prior to Visit 1. Participants who are in the maintenance phase of a pulmonary rehabilitation program are not excluded.
  • Alanine aminotransferase (ALT) >2x Upper limits of normal (ULN) and bilirubin >1.5xULN (isolated bilirubin >1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin <35%).
  • Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones).
  • Malignancy: A current malignancy or previous history of cancer in remission for less than 12 months prior to Visit 1 (Participants that had localized carcinoma of the skin or cervix which was resected for cure will not be excluded).
  • Other diseases/abnormalities: History or current evidence of clinically significant or uncontrolled cardiovascular, pulmonary, metabolic, neurological, endocrine (including uncontrolled diabetes or thyroid disease), renal, hepatic, haematological (including agranulocytosis) or gastrointestinal conditions that are uncontrolled on permitted therapy and in the opinion of the investigator and/or GSK Medical Monitor, places the participant at an unacceptable risk as participant in this trial or which would affect the efficacy or safety analysis if the disease/condition exacerbated during the study
  • Viral infections: Presence of hepatitis B surface antigen (HBsAg), Hepatitis C antibody test result at screening or within 3 months prior to first dose of study treatment. Note: Participants with positive Hepatitis C antibody due to prior resolved disease can be enrolled, only if a confirmatory negative Hepatitis C Ribonucleic acid (RNA) polymerase chain reaction (PCR) test is obtained.
  • A positive test for human immunodeficiency virus (HIV) antibody
  • Tuberculosis (TB): Participant with active TB or who have previously tested positive for latent TB and not received treatment or prophylaxis following the positive test.
  • Vaccination: Participants who have received live attenuated vaccines in the 6 weeks prior to randomization. The use of live attenuated vaccines during the treatment period and in the 4 weeks post-discontinuation of investigational product is prohibited.
  • Drug/food allergy: Participants with a history of hypersensitivity to any of the study medications (e.g., lactose, magnesium stearate).
  • Lactating females
  • Pregnant females (as determined by positive urine human chorionic gonadotropin (hCG) test prior to dosing).
  • Drug/alcohol abuse: Participants with a known or suspected history of alcohol or drug abuse within the last 2 years.
  • Prior use of study medication/other investigational drugs: Participants who have received an investigational drug within 30 days of entry into this study or within 5 drug half-lives of the investigational drug, whichever is longer.
  • Affiliation with investigator site: Study investigators, sub-investigators, study coordinators, employees of a participating investigator or immediate family members of the aforementioned are excluded from participating in this study.
  • Inability to read: In the opinion of the investigator, any participant who is unable to read and/or would not be able to complete study related materials.
  • Non-compliance: Participants at risk of non-compliance, or unable to comply with the study procedures. Any infirmity, disability, or geographic location that would limit compliance for scheduled visits.
  • Questionable validity of consent: Participants with a history of psychiatric disease, intellectual deficiency, poor motivation or other conditions that will limit the validity of informed consent to participate in the study.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02299375


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Sponsors and Collaborators
GlaxoSmithKline
Investigators
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Study Director: GSK Clinical Trials GlaxoSmithKline

Additional Information:
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Responsible Party: GlaxoSmithKline
ClinicalTrials.gov Identifier: NCT02299375     History of Changes
Other Study ID Numbers: 201496
First Posted: November 24, 2014    Key Record Dates
Results First Posted: July 13, 2018
Last Update Posted: August 6, 2018
Last Verified: August 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: IPD for this study will be made available via the Clinical Study Data Request site.
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Informed Consent Form (ICF)
Clinical Study Report (CSR)
Time Frame: IPD is available via the Clinical Study Data Request site (click on the link provided below)
Access Criteria: Access is provided after a research proposal is submitted and has received approval from the Independent Review Panel and after a Data Sharing Agreement is in place. Access is provided for an initial period of 12 months but an extension can be granted, when justified, for up to another 12 months.
URL: https://clinicalstudydatarequest.com

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by GlaxoSmithKline:
Phase II clinical study
losmapimod
exacerbations
COPD
eosinophil sub-group
Additional relevant MeSH terms:
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Lung Diseases
Lung Diseases, Obstructive
Pulmonary Disease, Chronic Obstructive
Respiratory Tract Diseases
Albuterol
Bronchodilator Agents
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Anti-Asthmatic Agents
Respiratory System Agents
Tocolytic Agents
Reproductive Control Agents
Adrenergic beta-2 Receptor Agonists
Adrenergic beta-Agonists
Adrenergic Agonists
Adrenergic Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action