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

NCT02299375 | Completed Phase 2 Results

• 1 other identifier: 201496
• Study Type: interventional
• Target: 184
• Locations: 8 countries
• Sites: 36

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.

Conditions

Pulmonary Disease, Chronic Obstructive

Keywords

Phase II clinical study; losmapimod; exacerbations; COPD; eosinophil sub-group

Outcome Measures

Primary Outcomes (1)

• Annual Rate of Moderate and Severe Exacerbations of COPD

  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.

  From the start of the study treatment up to 53 Weeks

Secondary Outcomes (22)

• Time to First Occurrence of Moderate or Severe COPD Exacerbation

  From the start of the study treatment up to 53 Weeks

• Number of Participants Having Any Adverse Events (AEs), Serious Adverse Events (SAEs)

  From the start of the study treatment up to 53 Weeks

• 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).

  Baseline and up to Week 52

• Change From Baseline in Spirometry Parameters in Pre and Post FEV1/FVC, Percent Predicted (PP) FEV1, PP FEV6 and PP FVC

  Baseline and up to Week 52

• Number of Participants With Electrocardiogram (ECG) Findings

  Up to 53 Weeks

Study Arms (2)

Losmapimod 15 mg

EXPERIMENTAL

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; Drug: Salbutamol MDI

Placebo

EXPERIMENTAL

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; Drug: Salbutamol MDI

Interventions

Losmapimod tablets DRUG

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.

Losmapimod 15 mg

Placebo tablets DRUG

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

Placebo

Salbutamol MDI DRUG

Salbutamol MDI will be provided as a rescue medication.

Losmapimod 15 mg; Placebo

Eligibility Criteria

• Age: 40 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.
• 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.

You may not qualify if:

• Eosinophils: \>2.0% blood eosinophils at Screening (Visit 1)
• 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.

Sponsors & Collaborators

• GlaxoSmithKline: lead

Study Sites (36)

GSK Investigational Site

Buenos Aires, C1426ABP, Argentina

Location

GSK Investigational Site

Mendoza, 5500, Argentina

Location

GSK Investigational Site

Mendoza, M5500CCG, Argentina

Location

GSK Investigational Site

San Miguel de Tucumán, 4000, Argentina

Location

GSK Investigational Site

São Paulo, 04266-010, Brazil

Location

GSK Investigational Site

Dimitrovgrad, 6400, Bulgaria

Location

GSK Investigational Site

Sofia, 1233, Bulgaria

Location

GSK Investigational Site

Sofia, 1336, Bulgaria

Location

GSK Investigational Site

Svoge, 2260, Bulgaria

Location

GSK Investigational Site

Talca, Maule Region, 3465584, Chile

Location

GSK Investigational Site

Santiago, Región Metro de Santiago, 8910131, Chile

Location

GSK Investigational Site

Santiago, 8380453, Chile

Location

GSK Investigational Site

Potsdam, Brandenburg, 14467, Germany

Location

GSK Investigational Site

Frankfurt am Main, Hesse, 60389, Germany

Location

GSK Investigational Site

Hanover, Lower Saxony, 30173, Germany

Location

GSK Investigational Site

Cologne, North Rhine-Westphalia, 51069, Germany

Location

GSK Investigational Site

Düren, North Rhine-Westphalia, 52349, Germany

Location

GSK Investigational Site

Koblenz, Rhineland-Palatinate, 56068, Germany

Location

GSK Investigational Site

Berlin, 10119, Germany

Location

GSK Investigational Site

Berlin, 13581, Germany

Location

GSK Investigational Site

Hamburg, 20354, Germany

Location

GSK Investigational Site

Hamburg, 22763, Germany

Location

GSK Investigational Site

Humenné, 066 01, Slovakia

Location

GSK Investigational Site

Poprad, 058 01, Slovakia

Location

GSK Investigational Site

Spišská Nová Ves, 052 01, Slovakia

Location

GSK Investigational Site

Šaľa, 927 01, Slovakia

Location

GSK Investigational Site

Vráble, 952 01, Slovakia

Location

GSK Investigational Site

Incheon, 403-720, South Korea

Location

GSK Investigational Site

Seoul, 130-709, South Korea

Location

GSK Investigational Site

(Barakaldo) Vizcaya, 48903, Spain

Location

GSK Investigational Site

Alicante, 03004, Spain

Location

GSK Investigational Site

Barcelona, 08006, Spain

Location

GSK Investigational Site

Barcelona, 08036, Spain

Location

GSK Investigational Site

L'Hospitalet de Llobregat. Barcelona, 08907, Spain

Location

GSK Investigational Site

Pozuelo de Alarcón/Madrid, 28223, Spain

Location

GSK Investigational Site

Valencia, 46014, Spain

Location

Related Links

• IPD for this study will be made available via the Clinical Study Data Request site.

MeSH Terms

Conditions

Pulmonary Disease, Chronic Obstructive

Interventions

6-(5-((cyclopropylamino)carbonyl)-3-fluoro-2-methylphenyl)-N-(2,2-dimethylprpyl)-3-pyridinecarboxamide

Condition Hierarchy (Ancestors)

Lung Diseases, Obstructive; Lung Diseases; Respiratory Tract Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Results Point of Contact

• Title: GSK Response Center
• Organization: GlaxoSmithKline

866-435-7343

Study Officials

• GSK Clinical Trials

  GlaxoSmithKline

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 3, 2014
• First Posted: November 24, 2014
• Study Start: December 9, 2014
• Primary Completion: June 30, 2016
• Study Completion: June 30, 2016
• Last Updated: August 6, 2018
• Results First Posted: July 13, 2018

Record last verified: 2018-08

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, 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.

Locations

CL (3); ES (7); KR (2); SL (5); BU (4); DE (10); AR (4); BR (1)