Dose Finding Study of Nemiralisib (GSK2269557) in Subjects With an Acute Moderate or Severe Exacerbation of Chronic Obstructive Pulmonary Disease (COPD)
Condition: Pulmonary Disease, Chronic Obstructive
MeSH terms: Lung Diseases; Lung Diseases, Obstructive; Pulmonary Disease, Chronic Obstructive
Intervention: Placebo ELLIPTA; Nemiralisib ELLIPTA 50 µg; Nemiralisib ELLIPTA 100 µg; Nemiralisib ELLIPTA 250 µg; Nemiralisib ELLIPTA 500 µg; Nemiralisib ELLIPTA 750 µg; Albuterol (Salbutamol) MDI or nebules; Standard of care therapy
Intervention description: Placebo will be administered via oral inhalation route once daily in the morning.; Nemiralisib is a potent and highly selective inhaled PI3Kd inhibitor being developed as an anti-inflammatory for the treatment of inflammatory airways disease. Nemiralisib 50 µg will be administered as a dry powder inhaler via oral inhalation route. In addition, subjects will receive SOC therapy for the index acute moderate or severe exacerbation of COPD.; Nemiralisib is a potent and highly selective inhaled PI3Kd inhibitor being developed as an anti-inflammatory for the treatment of inflammatory airways disease. Nemiralisib 100 µg will be administered as a dry powder inhaler via oral inhalation route. In addition, subjects will receive SOC therapy for the index acute moderate or severe exacerbation of COPD.; Nemiralisib is a potent and highly selective inhaled PI3Kd inhibitor being developed as an anti-inflammatory for the treatment of inflammatory airways disease. Nemiralisib 250 µg will be administered as a dry powder inhaler via oral inhalation route. In addition, subjects will receive SOC therapy for the index acute moderate or severe exacerbation of COPD.; Nemiralisib is a potent and highly selective inhaled PI3Kd inhibitor being developed as an anti-inflammatory for the treatment of inflammatory airways disease. Nemiralisib 500 µg will be administered as a dry powder inhaler via oral inhalation route. In addition, subjects will receive SOC therapy for the index acute moderate or severe exacerbation of COPD.; Nemiralisib is a potent and highly selective inhaled PI3Kd inhibitor being developed as an anti-inflammatory for the treatment of inflammatory airways disease. Nemiralisib 750 µg will be administered as a dry powder inhaler via oral inhalation route. In addition, subjects will receive SOC therapy for the index acute moderate or severe exacerbation of COPD.; Albuterol (Salbutamol) MDI or nebules will be provided to all subjects as a rescue medication.; SoC therapy for the index exacerbation is defined as treatment with oral/systemic corticosteroid (prednisone 40 mg/day or equivalent) for 5 days and antibiotic for 7 days. Subjects will receive SoC as prescribed by the Investigator or medically qualified designee. The dose and/or duration of prednisone and/or the antibiotic can be modified according to the Investigator's/medically qualified designee's judgment or according to local country/institution practice.
Intervention MeSH terms: Albuterol; Nemiralisib
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: Subjects will be randomized to receive either nemiralisib (50-750 µg) or placebo in a parallel group.
Masking: Double (Participant, Investigator)
Masking description: This will be a double blind, sponsor- open study.
Enrollment: 943.0
Sex: All
Minimum age: 40 Years
Maximum age: 80 Years
Healthy volunteers: No
Keywords: Nemiralisib; Dose-Finding; GSK2269557; Acute Moderate or Severe Exacerbation of Chronic Obstructive Pulmonary Disease

Summary:

      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.
    

Eligibility criteria:

        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.