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

• Register: ClinicalTrials.gov
• Last refreshed on: 12 December 2020
• Main ID: NCT02299375
• Date of registration: 03/11/2014
• Prospective Registration: Yes
• Primary sponsor: GlaxoSmithKline
• Public title: Safety and Efficacy Study of Losmapimod (GW856553) in Frequently Exacerbating Participants With Chronic Obstructive Pulmonary Disease (COPD)
• Scientific 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)
• Date of first enrolment: December 9, 2014
• Target sample size: 184
• Recruitment status: Completed
• URL: https://clinicaltrials.gov/show/NCT02299375
• Study type: Interventional
• Study design: Allocation: Randomized. Intervention model: Parallel Assignment. Primary purpose: Treatment. Masking: Double (Participant, Investigator).
• Phase: Phase 2

Countries of recruitment

Argentina, Brazil, Bulgaria, Chile, Germany, Korea, Republic of, Slovakia, Spain

Contacts

• Name: GSK Clinical Trials
• Affiliation: GlaxoSmithKline

Key inclusion & exclusion 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 e


Age minimum: 40 Years
Age maximum: N/A
Gender: All

Health Condition(s) or Problem(s) studied

Pulmonary Disease, Chronic Obstructive

Intervention(s)

Drug: Salbutamol MDI

Drug: Placebo tablets

Drug: Losmapimod tablets

Primary Outcome(s)

Annual Rate of Moderate and Severe Exacerbations of COPD [Time Frame: From the start of the study treatment up to 53 Weeks]

Secondary Outcome(s)

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]

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]

Change From Baseline in Red Blood Cell Count at the Indicated Time Points [Time Frame: Baseline and up to Week 53]

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]

Number of Participants With Electrocardiogram (ECG) Findings [Time Frame: Up to 53 Weeks]

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]

Change From Baseline in Mean Corpuscle Hemoglobin at the Indicated Time Points [Time Frame: Baseline and up to Week 53]

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]

Change From Baseline in Mean Corpuscle Volume at the Indicated Time Points [Time Frame: Baseline and up to Week 53]

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]

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]

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]

Change From Baseline in Eosinophil Percentage at the Indicated Time Points [Time Frame: Baseline and up to Week 53]

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]

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]

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]

Change From Baseline in Frequency of Short Acting Beta-agonist or Anti-cholinergic Use [Time Frame: Baseline and up to Week 52]

Change From Baseline in Heart Rate (HR) Values at the Indicated Time Points [Time Frame: Baseline and up to Week 53]

Change From Baseline in Hematocrit at the Indicated Time Points [Time Frame: Baseline and up to Week 53]

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]

Number of Participants With Abnormal Liver Events During the Treatment Period [Time Frame: Up to Week 53]

Time to First Occurrence of Moderate or Severe COPD Exacerbation [Time Frame: From the start of the study treatment up to 53 Weeks]

Secondary ID(s)

201496

Source(s) of Monetary Support

Please refer to primary and secondary sponsors

Results

• Results available: Yes
• Date Posted: 13/07/2018
• URL: https://clinicaltrials.gov/ct2/show/results/NCT02299375