Phase 2
Completed N=184
Safety and Efficacy Study of Losmapimod (GW856553) in Frequently Exacerbating Participants With Chronic Obstructive Pulmonary Disease (COPD)
Pulmonary Disease, Chronic Obstructive
Source: ClinicalTrials.gov NCT02299375 ↗
Enrolled (actual)
184
Serious AEs
14.7%
Results posted
Jul 2018
Primary outcomePrimary: Annual Rate of Moderate and Severe Exacerbations of COPD — 0.84; 0.88 Exacerbations per participant per year
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.
Outcome Measures
| Outcome | Result | p-value |
|---|---|---|
| PRIMARY Annual Rate of Moderate and Severe Exacerbations of COPD |
0.84; 0.88 | — |
| SECONDARY Time to First Occurrence of Moderate or Severe COPD Exacerbation |
168.01; 160.18 | — |
| SECONDARY Number of Participants Having Any Adverse Events (AEs), Serious Adverse Events (SAEs) |
34; 38; 8; 19 | — |
| SECONDARY 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). |
0.002; 0.028; -0.010; 0.025; -0.031; 0.028 | 0.371 |
| SECONDARY Change From Baseline in Spirometry Parameters in Pre and Post FEV1/FVC, Percent Predicted (PP) FEV1, PP FEV6 and PP FVC |
0.72; 1.31; -0.73; 1.72; -2.05; 0.47 | 0.661 |
| SECONDARY Number of Participants With Electrocardiogram (ECG) Findings |
49; 51; 39; 36; 9; 5 | — |
| SECONDARY Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) at the Indicated Time Points |
0.2; -2.9; -0.8; -0.4; -1.9; -0.3 | — |
| SECONDARY Change From Baseline in Heart Rate (HR) Values at the Indicated Time Points |
1.2; 1.5; 1.4; 0.6; 1.0; 1.6 | — |
| SECONDARY Plasma Losmapimod Area Under the Plasma Concentration Time Curve (AUC) From Time Zero to the End of Dosing Interval (AUC[0-tau]) |
668.5 | — |
| SECONDARY Plasma Losmapimod Maximum Concentration (Cmax) and Lowest Concentration (Ctrough) at Steady State |
49.7; 23.7 | — |
| SECONDARY Change From Baseline in Frequency of Short Acting Beta-agonist or Anti-cholinergic Use |
-0.0029; -0.0400; 0.1143; -0.1473; 0.0904; 0.0022 | — |
| SECONDARY Change From Baseline in St Georges Respiratory Questionnaire (SGRQ) Total, SGRQ Symptoms Score, SGRQ Activity Score and SGRQ Impact Score Over Time |
-0.75; -1.42; -2.20; -1.31; -0.37; -3.19 | 0.706 |
| SECONDARY Number of Participants With Abnormal Liver Events During the Treatment Period |
0; 0 | — |
| SECONDARY Change From Baseline in Hemoglobin, Total Protein, Albumin and Mean Corpuscle Hemoglobin Concentration (MCHC) at the Indicated Time Points |
-0.3; 0.0; -0.6; -1.0; -0.9; -2.5 | — |
| SECONDARY Change From Baseline in Hematocrit at the Indicated Time Points |
-0.001; -0.002; -0.002; -0.002; -0.001; -0.006 | — |
| SECONDARY 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 |
-0.04; 0.21; 0.03; 0.12; 0.04; 0.32 | — |
| SECONDARY Change From Baseline in Eosinophil Percentage at the Indicated Time Points |
0.09; 0.30; 0.03; 0.16; 0.14; 0.11 | — |
| SECONDARY Change From Baseline in Total Bilirubin, Direct Bilirubin, Uric Acid and Creatinine at the Indicated Time Point |
-0.5; 0.2; 0.2; -0.1; -0.4; -0.7 | — |
| SECONDARY Change From Baseline in Alanine Aminotransferase, Aspartate Aminotransferase, Alkaline Phosphatase and Gamma Glutamyl Transferase at the Indicated Time Points |
-0.3; 1.2; 1.8; 0.3; -0.3; -0.1 | — |
| SECONDARY Change From Baseline in Chloride, Calcium, Glucose, Potassium, Sodium and Blood Urea Nitrogen at the Indicated Time Points |
0.3; 0.5; -0.2; 1.1; 0.3; 0.7 | — |
| SECONDARY Change From Baseline in Red Blood Cell Count at the Indicated Time Points |
-0.01; -0.00; -0.03; -0.02; -0.03; -0.05 | — |
| SECONDARY Change From Baseline in Mean Corpuscle Hemoglobin at the Indicated Time Points |
0.02; 0.03; 0.09; -0.04; 0.02; -0.20 | — |
| SECONDARY Change From Baseline in Mean Corpuscle Volume at the Indicated Time Points |
0.0; -0.4; 0.1; 0.1; 0.2; -0.4 | — |
Eligibility 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 =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 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. 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 obtain
Data sourced from ClinicalTrials.gov (NCT02299375). Outcome figures and adverse-event rates are extracted automatically from the registry's posted results and are provided for clinician reference, not as a substitute for the primary publication. Informational only — not medical advice.