Safety and Efficacy Study of Losmapimod (GW856553) in Frequently Exacerbating Participants With Chronic Obstructive Pulmonary Disease (COPD)
Condition: Pulmonary Disease, Chronic Obstructive
MeSH terms: Lung Diseases; Lung Diseases, Obstructive; Pulmonary Disease, Chronic Obstructive
Intervention: Losmapimod tablets; Placebo tablets; Salbutamol MDI
Intervention description: 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.; 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; Salbutamol MDI will be provided as a rescue medication.
Intervention MeSH terms: Albuterol
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Enrollment: 184.0
Sex: All
Minimum age: 40 Years
Healthy volunteers: No
Keywords: Phase II clinical study; losmapimod; exacerbations; COPD; eosinophil sub-group

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.
    

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 <=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.