Dose Finding Study of Nemiralisib (GSK2269557) in Subjects With an Acute Moderate or Severe Exacerbation of Chronic Obstructive Pulmonary Disease (COPD)
Dose Finding Study of Nemiralisib (GSK2269557) in Subjects With an Acute Moderate or Severe Exacerbation of Chronic Obstructive Pulmonary Disease (COPD)
Nemiralisib is being developed as an anti-inflammatory drug for the treatment of inflammatory
 airways disease. This study is designed to assess the dose response, efficacy, safety, and
 pharmacokinetics of nemiralisib across a range of doses [up to 750 micrograms (µg)] compared
 with placebo. The study consists of a Screening Period, a 12-Week Treatment Period and a
 12-Week Post-Treatment Follow-Up Period. Approximately 1,250 subjects with an acute moderate
 or severe exacerbation of COPD requiring standard of care (SoC) therapy will be randomized in
 this double-blind study. Subjects will be randomized to receive different doses of
 nemiralisib or placebo via ELLIPTA® inhaler. The total duration of study participation is
 approximately 6 months (170 days). ELLIPTA is the registered trademark of GlaxoSmithKline
 (GSK) group of companies.
Inclusion Criteria:

 -  40 to 80 years of age, inclusive, at Screening (Visit 1).

 -  An established clinical history of COPD in accordance with the definition by the
 American Thoracic Society/European Respiratory Society [ global initiative for chronic
 obstructive lung disease (GOLD), 2017] as follows: "Chronic obstructive pulmonary
 disease is a common, preventable and treatable disease that is characterized by
 persistent respiratory symptoms and airflow limitation that is due to airway and/or
 alveolar abnormalities usually caused by significant exposure to noxious particles or
 gases."

 -  Current or former cigarette smoker with a history of cigarette smoking of >=10
 pack-years. Former smokers are defined as those who have stopped smoking for at least
 6 months prior to Screening (Visit 1). Number of pack years = (number of cigarettes
 per day / 20) x number of years smoked).

 -  Acute exacerbation of COPD requiring an escalation in therapy to include oral/systemic
 corticosteroid(s) (prednisone 40 mg/day or equivalent) for 5 days and antibiotic(s)
 for 7 days; the dose and/or duration of prednisone (40 mg/day or equivalent) and/or
 the antibiotic can be modified according to the Investigator's/medically qualified
 designee's judgment or according to local country/institution practice. Acute
 exacerbation to be confirmed by an experienced physician and to represent a recent
 worsening of at least two major and one minor symptoms, one major and two minor
 symptoms, or all 3 major symptoms. Major symptoms include subjective increase in
 dyspnea, increase in sputum volume or change in sputum color. Minor symptoms include
 increased cough, increased wheeze, sore throat, colds or fever (oral temperature >37.5
 degree Celsius) without other cause.

 -  Body weight >=45 kilogram (kg) and body mass index (BMI) within the range 16 - 35 kg
 per meter square (kg/m^2) (inclusive)

 -  Male and female subjects are eligible to participate in the study. A female subject is
 eligible to participate if she is not pregnant, not breastfeeding, and at least one of
 the following conditions applies: Not a woman of childbearing potential (WOCBP) or a
 WOCBP who agrees to follow the contraceptive guidance during the 12-Week Double-Blind
 Treatment Period and for at least 5 half-lives (10 days) after the last of
 double-blind study treatment.

 -  Capable of giving signed informed consent.

 Exclusion Criteria:

 -  Current diagnosis of asthma, according to the Global Initiative for Asthma (GINA,
 2017). Subjects with a prior history of asthma are eligible if they have a current
 diagnosis of COPD.

 -  Potential of hydrogen (pH) < 7.30 or the need for invasive mechanical ventilation.

 -  Moderate/severe exacerbation of COPD for which SoC was started >48 hours since
 diagnosis.

 -  A chest X-ray [or computed tomography (CT) scan] that reveals evidence of clinically
 significant abnormalities not believed to be due to the presence of COPD. A chest
 X-ray (or CT scan) must be taken at Screening (Visit 1). For sites in Germany: if a
 chest X-ray (or CT scan) within 1 year of Screening (Visit 1) is not available,
 approval to conduct a diagnostic chest X-ray (CT scan) will need to be obtained from
 the Federal Office for Radiation Protection (BfS).

 -  Clinically significant pneumonia, identified by chest X-ray (CT scan) at Screening.

 -  A diagnosis of alpha 1-antitrypsin deficiency as the underlying cause of COPD, active
 tuberculosis, lung cancer, clinically overt bronchiectasis (Note: focal bronchiectasis
 is not exclusionary), sarcoidosis, pulmonary fibrosis (Note: focal fibrotic pulmonary
 lesions are not exclusionary), primary pulmonary hypertension, interstitial lung
 diseases,or any other respiratory condition that might, in the opinion of the
 investigator, compromise the safety of the subject or affect the interpretation of the
 results.

 -  A history or current evidence of clinically significant and unstable disease such as
 cardiovascular (e.g., subjects requiring implanted cardioverter defibrillator [ICD],
 pacemaker requiring a rate set >60 beats per minute (bpm), uncontrolled hypertension,
 New Your Heart Association Class IV [NYHA, 1994], known left ventricular ejection
 fraction <30 percent) neurological, psychiatric, renal, hepatic, immunological,
 endocrine (including uncontrolled diabetes or thyroid disease), peptic ulcer disease,
 or hematological abnormalities. Significant is defined as any disease that, in the
 opinion of the investigator, would put the safety of the subject at risk through
 participation, or which would affect the efficacy or safety analysis if the
 disease/condition exacerbated during the study. (Note: subjects with adequately
 treated and well controlled concurrent medical conditions (e.g. hypertension or
 noninsulin-dependent diabetes mellitus [NIDDM]) are permitted to be entered into the
 study).

 -  Having undergone lung volume reduction surgery or lung resection for any other reason
 e.g. lung carcinoma

 -  Liver diseases including ALT>2x upper limit of normal (ULN); Total bilirubin >1.5xULN
 (Isolated bilirubin >1.5xULN is acceptable if bilirubin is fractionated and direct
 bilirubin <35 percent); current or chronic history of liver disease or known hepatic
 or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic
 gallstones); Presence of hepatitis B surface antigen (HBsAg) at Screening or within 3
 months prior to first dose of study treatment; Positive hepatitis C antibody test
 result at Screening or within 3 months prior to first dose of study treatment.

 -  Positive hepatitis C ribonucleic acid (RNA) test result at Screening or within 3
 months prior to first dose of study treatment.

 -  Carcinoma that has not been in complete remission for at least 5 years. Carcinoma in
 situ of the cervix, squamous cell carcinoma and basal cell carcinoma of the skin are
 not excluded if the subject has been considered cured within 5 years since diagnosis.

 -  History of allergy or hypersensitivity to any of the study medications [e.g.
 beta-agonists, Phosphoinositide 3-Kinase Delta (PI3Kd) inhibitors] or components of
 the inhalation powder (e.g., lactose). In addition, subjects with a history of severe
 milk protein allergy that, in the opinion of the investigator, contraindicates the
 subject's participation are excluded.

 -  Strong inhibitors of cytochrome P450 3A4 (CYP3A4) including antiretrovirals including
 protease inhibitors; Oral antifungal treatments such as ketoconazole and itraconazole.
 It is recommended that posaconazole is used as the oral antifungal treatment of
 choice. Short courses of up to 14 days are allowed for fluconazole and voriconazole,
 but chronic administrations are not permitted; Antibiotics such as telithromycin and
 troleandomycin (macrolide). It is recommended that azithromycin is used as the
 macrolide antibiotic of choice. Short courses up to 14 days are allowed for mibefradil
 (calcium channel blocker), erythromycin and clarithromycin (including intravenous
 clarithromycin) but chronic administrations are not permitted; Anti-epileptic
 treatments; and anti-tuberculosis therapy. These medications must all have been
 stopped at least 14 days prior to first dose of study treatment. Use of sensitive
 narrow therapeutic index CYP3A4 substrates including alfentanil, cyclosporine,
 dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus and
 tacrolimus; Intravenous theophylline will be allowed but only under strict therapeutic
 drug monitoring for signs of theophylline toxicity as a result of co-administration
 with nemiralisib; Subjects may be recruited into the study already under treatment
 with theophylline or started on theophylline following the start of treatment and
 before the end of 14 days post last dose.

 -  Chronic treatment with long-term oxygen therapy (LTOT) or nocturnal oxygen therapy
 required for >15 hours a day. Oxygen prn use (<=15 hours per day) is not exclusionary.
 Oxygen use during an exacerbation is permitted.

 -  Chronic treatment with anti-Tumor Necrosis Factor (anti-TNF), anti-Interleukin-1
 (anti-IL1), or any other immunosuppressive therapy within 60 days prior to the first
 dose of double-blind study treatment.

 -  Clinically significant sleep apnea that requires the use of continuous positive airway
 pressure (CPAP) device or non-invasive positive pressure ventilation (NIPPV) for > 48
 hours.

 -  Any other investigational treatment within the following time periods prior to the
 first dose of double-blind study treatment in the current study: 30 days, 5 half-lives
 or twice the duration of the biological effect of the investigational product,
 whichever is longer. Note: subjects who participated in a previously completed study
 and/or were withdrawn from an ongoing study that included/includes nemiralisib are
 excluded from participating in this study.

 -  Exposure to more than 4 investigational medicinal products within 12 months prior to
 the first dose of double-blind study treatment in the current study.

 -  A clinical abnormality or laboratory parameter(s) which is/are not specifically listed
 in the exclusion criteria, outside of the reference range for the population being
 studied may be included if the Investigator [in consultation with the GlaxoSmithKline
 (GSK) Medical Monitor if required] documents that the finding is unlikely to introduce
 additional risk factors and will not interfere with the study procedures.

 -  Abnormal, clinically significant ECG finding (e.g. myocardial Infarction or
 demonstrating a clinically significant arrhythmia requiring treatment) at Screening
 (Visit 1) or upon repeat prior to randomization.

 -  QT interval corrected for heart rate according to Fridericia's formula (QTcF) >480
 milliseconds (msec) for subjects with or without Bundle Branch Block, based on single
 QTcF value.

 -  A positive test for human immunodeficiency virus (HIV) antibody at Screening.

 -  Known or suspected history of alcohol or drug abuse within the last 2 years.

 -  History of regular alcohol consumption defined as an average weekly intake of >28
 units for males or >21 units for females within 6 months of Screening (Visit 1). One
 unit is equivalent to 8 grams of alcohol: a half-pint [approximately 240 milliliter
 (mL)] of beer, 1 glass (125 mL) of wine or 1 (25 mL) measure of spirits.

 -  Subjects 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.

 -  Subjects 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.

 -  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.