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Dose Finding Study of Nemiralisib (GSK2269557) in Subjects With an Acute Moderate or Severe Exacerbation of Chronic Obstructive Pulmonary Disease (COPD)

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ClinicalTrials.gov Identifier: NCT03345407
Recruitment Status : Completed
First Posted : November 17, 2017
Last Update Posted : April 16, 2019
Sponsor:
Information provided by (Responsible Party):
GlaxoSmithKline

Brief 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.

Condition or disease Intervention/treatment Phase
Pulmonary Disease, Chronic Obstructive Drug: Placebo ELLIPTA Drug: Nemiralisib ELLIPTA 50 µg Drug: Nemiralisib ELLIPTA 100 µg Drug: Nemiralisib ELLIPTA 250 µg Drug: Nemiralisib ELLIPTA 500 µg Drug: Nemiralisib ELLIPTA 750 µg Drug: Albuterol (Salbutamol) MDI or nebules Drug: Standard of care therapy Phase 2

Layout table for study information
Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 948 participants
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.
Primary Purpose: Treatment
Official Title: A Phase IIb, Randomized (Stratified), Double-Blind (Sponsor Open), Parallel-Group, Placebo-Controlled, Dose-Finding Study of Nemiralisib (GSK2269557) Added to Standard of Care (SoC) Versus SoC Alone in Participants Diagnosed With an Acute Moderate or Severe Exacerbation of Chronic Obstructive Pulmonary Disease (COPD)
Actual Study Start Date : November 28, 2017
Actual Primary Completion Date : January 10, 2019
Actual Study Completion Date : January 10, 2019

Resource links provided by the National Library of Medicine

MedlinePlus related topics: COPD Lung Diseases

Arm Intervention/treatment
Placebo Comparator: placebo once daily
Eligible subjects will receive placebo ELLIPTA dry powder (blended with lactose) for oral inhalation once daily in the morning for 12 weeks. Albuterol (Salbutamol) MDI or nebules will also be provided to all subjects for use as rescue medication as needed.
Drug: Placebo ELLIPTA
Placebo will be administered via oral inhalation route once daily in the morning.

Drug: Albuterol (Salbutamol) MDI or nebules
Albuterol (Salbutamol) MDI or nebules will be provided to all subjects as a rescue medication.

Drug: Standard of care therapy
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.

Experimental: Nemiralisib 50 µg once daily
Eligible subjects will receive nemiralisib ELLIPTA 50 µg dry powder (blended with lactose and magnesium stearate) for oral inhalation once daily in the morning for 12 weeks. Albuterol (Salbutamol) MDI or nebules will also be provided to all subjects for use as rescue medication as needed.
Drug: Nemiralisib ELLIPTA 50 µg
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.

Drug: Albuterol (Salbutamol) MDI or nebules
Albuterol (Salbutamol) MDI or nebules will be provided to all subjects as a rescue medication.

Drug: Standard of care therapy
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.

Experimental: Nemiralisib 100 µg once daily
Eligible subjects will receive nemiralisib ELLIPTA 100 µg dry powder (blended with lactose and magnesium stearate) for oral inhalation once daily in the morning for 12 weeks. Albuterol (Salbutamol) MDI or nebules will also be provided to all subjects for use as rescue medication as needed.
Drug: Nemiralisib ELLIPTA 100 µg
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.

Drug: Albuterol (Salbutamol) MDI or nebules
Albuterol (Salbutamol) MDI or nebules will be provided to all subjects as a rescue medication.

Drug: Standard of care therapy
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.

Experimental: Nemiralisib 250 µg once daily
Eligible subjects will receive nemiralisib ELLIPTA 250 µg dry powder (blended with lactose and magnesium stearate) for oral inhalation once daily in the morning for 12 weeks. Albuterol (Salbutamol) MDI or nebules will also be provided to all subjects for use as rescue medication as needed.
Drug: Nemiralisib ELLIPTA 250 µg
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.

Drug: Albuterol (Salbutamol) MDI or nebules
Albuterol (Salbutamol) MDI or nebules will be provided to all subjects as a rescue medication.

Drug: Standard of care therapy
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.

Experimental: Nemiralisib 500 µg once daily
Eligible subjects will receive nemiralisib ELLIPTA 500 µg dry powder (blended with lactose and magnesium stearate) for oral inhalation once daily in the morning for 12 weeks. Albuterol (Salbutamol) MDI or nebules will also be provided to all subjects for use as rescue medication as needed.
Drug: Nemiralisib ELLIPTA 500 µg
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.

Drug: Albuterol (Salbutamol) MDI or nebules
Albuterol (Salbutamol) MDI or nebules will be provided to all subjects as a rescue medication.

Drug: Standard of care therapy
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.

Experimental: Nemiralisib 750 µg once daily
Eligible subjects will receive nemiralisib ELLIPTA 750 µg dry powder (blended with lactose and magnesium stearate) for oral inhalation once daily in the morning for 12 weeks. Albuterol (Salbutamol) MDI or nebules will also be provided to all subjects for use as rescue medication as needed.
Drug: Nemiralisib ELLIPTA 750 µg
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.

Drug: Albuterol (Salbutamol) MDI or nebules
Albuterol (Salbutamol) MDI or nebules will be provided to all subjects as a rescue medication.

Drug: Standard of care therapy
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.




Primary Outcome Measures :
  1. Change from Baseline in Clinic Visit trough forced expiratory volume in one second (FEV1) measured post-bronchodilator [ Time Frame: Baseline and Week 12 ]
    Pulmonary function will be measured by FEV1, defined as the maximal amount of air that can be forcefully exhaled from the lungs in one second. Post-bronchodilator FEV1 will be conducted approximately 10 to 30 minutes after the subject administers 4 inhalations of albuterol (salbutamol) via metered dose inhaler (MDI, i.e., total of 400 µg) using a spacer/valved-holding chamber or via one nebulized treatment. Baseline is defined as the post-bronchodilator FEV1 measured prior to the first dose of double-blind study treatment and post-bronchodilator on Day 1.


Secondary Outcome Measures :
  1. Rate of moderate and severe exacerbations [ Time Frame: Up to Week 12 ]
    Moderate exacerbations are defined as worsening symptoms of COPD treated with short-acting bronchodilators (SABDs) plus antibiotics and/or oral/systemic corticosteroids. Severe exacerbations are defined as worsening symptoms of COPD that require hospitalization or visit to the emergency room. Severe exacerbation may also be associated with acute respiratory failure.

  2. Time to next moderate or severe exacerbation following the index exacerbation [ Time Frame: Up to Week 12 ]
    Moderate exacerbations are defined as worsening symptoms of COPD treated with SABDs plus antibiotics and/or oral/systemic corticosteroids. Severe exacerbations are defined as worsening symptoms of COPD that require hospitalization or visit to the emergency room. Severe exacerbation may also be associated with acute respiratory failure.

  3. Change from Baseline in Clinic Visit trough FEV1 measured pre- and post-bronchodilator [ Time Frame: Baseline and up to Week 12 ]
    Clinic visit trough FEV1 will be measured pre and post-bronchodilator administration. Pre-bronchodilator FEV1 will be conducted approximately 24 hours following the previous morning's dose of study drug. Post-bronchodilator FEV1 will be conducted approximately 10 to 30 minutes after the subject administers 4 inhalations of albuterol (salbutamol) via MDI, (i.e., total of 400 µg) using a spacer/valved-holding chamber or via one nebulized treatment. Baseline is defined as the post-bronchodilator FEV1 measured prior to the first dose of double-blind study treatment and post-bronchodilator on Day 1.

  4. Change from hospital discharge in clinic visit trough FEV1 [ Time Frame: Up to Week 12 ]
    Clinic visit trough FEV1 will be measured pre and post-bronchodilator administration for subjects hospitalized due to index exacerbation. FEV1 will be measured pre- and post-bronchodilator at Days 14, 28, 56, and 84 (in subjects hospitalized for index exacerbation only).

  5. Percentage of subjects achieving the exacerbations of chronic pulmonary disease tool (EXACT) definition of recovery from the index exacerbation [ Time Frame: Up to Week 12 ]
    The EXACT patient-reported outcome (EXACT-PRO) is a 14-item instrument designed to capture information on the occurrence, frequency, severity, and duration of exacerbations of disease in subjects with COPD. Subjects will need to complete the tool every evening using an electronic diary (eDiary). The total score for EXACT-PRO ranges from 0 to 100, where higher score indicates a more severe condition. At Visit 2, the EXACT-PRO will be completed as the first assessment before randomization and prior to completing the COPD assessment test (CAT) and St. George's Respiratory Questionnaire for COPD subjects (SGRQ-C), and thereafter it will be completed each evening (typically at bedtime). For subjects who are hospitalized, if the subject is too ill to complete PRO without assistance on a given day, a member of the study staff may verbally recite the questions verbatim to the subject and the staff member may enter the subject's verbal response in the eDiary.

  6. Time to recovery from index exacerbation using EXACT- PRO tool [ Time Frame: Up to Week 12 ]
    The EXACT-PRO is a 14-item instrument designed to capture information on the occurrence, frequency, severity, and duration of exacerbations of disease in subjects with COPD. Subjects will need to complete the tool every evening using an eDiary. The total score for EXACT-PRO ranges from 0 to 100, where higher score indicates a more severe condition. At Visit 2, the EXACT-PRO will be completed as the first assessment before randomization and prior to completing the CAT and SGRQ-C, and thereafter it will be completed each evening (typically at bedtime). For subjects who are hospitalized, if the subject is too ill to complete PRO without assistance on a given day, a member of the study staff may verbally recite the questions verbatim to the subject and the staff member may enter the subject's verbal response in the eDiary.

  7. Percentage of health care resource utilization (HCRU) defined exacerbations [ Time Frame: Up to Week 12 ]
    Severity of subsequent HCRU-defined exacerbation(s) defined by EXACT will be evaluated using EXACT-PRO instrument. The EXACT-PRO is a 14-item instrument designed to capture information on the occurrence, frequency, severity, and duration of exacerbations of disease in subjects with COPD. Subjects will need to complete the tool every evening using an eDiary. The total score for EXACT-PRO ranges from 0 to 100, where higher score indicates a more severe condition. At Visit 2, the EXACT-PRO will be completed as the first assessment before randomization and prior to completing the CAT and SGRQ-C, and thereafter it will be completed each evening (typically at bedtime). For subjects who are hospitalized, if the subject is too ill to complete PRO without assistance on a given day, a member of the study staff may verbally recite the questions verbatim to the subject and the staff member may enter the subject's verbal response in the eDiary.

  8. Percentage of responders using the CAT [ Time Frame: Up to Week 12 ]
    COPD-related health status will be assessed using the CAT, which will be completed using the eDiary. The CAT is a short, self-completed, 8-item questionnaire which is rated on a 6-point scale ranging from 0 (no impairment) to 5 (maximum impairment) with a scoring range of 0 to 40. For subjects who are hospitalized, if the subject is too ill to complete PRO without assistance on a given day, a member of the study staff may verbally recite the questions verbatim to the subject and the staff member may enter the subject's verbal response in the eDiary. CAT will be completed prior to completion of the St. George's Respiratory Questionnaire for COPD subjects (SGRQ-C) and prior to completing any other study procedures.

  9. Change from Baseline in CAT total score [ Time Frame: Baseline and up to Week 12 ]
    COPD-related health status will be assessed using the CAT, which will be completed using the eDiary. The CAT is a short, self-completed, 8-item questionnaire which is rated on a 6-point scale ranging from 0 (no impairment) to 5 (maximum impairment) with a scoring range of 0 to 40. For subjects who are hospitalized, if the subject is too ill to complete PRO without assistance on a given day, a member of the study staff may verbally recite the questions verbatim to the subject and the staff member may enter the subject's verbal response in the eDiary. CAT will be completed prior to completion of the SGRQ--C and prior to completing any other study procedures.

  10. Percentage of St. George's Respiratory Questionnaire (SGRQ) responders [ Time Frame: Up to Week 12 ]
    Health-related quality of life will be assessed by SGRQ for COPD subjects (SGRQ-C). The SGRQ-C is a COPD-specific questionnaire derived from the original SGRQ and designed to measure the impact of COPD and its treatment on the subject's health-related quality of life. It consists of two parts; Part 1 produces the symptom score and Part 2 produces the activity and impact score. A Total score is also calculated which summarizes the impact of the disease on overall health status. Scores are expressed as a percentage of overall impairment where 100 represents worst possible health status and zero indicates best possible health status. For subjects who are hospitalized, if the subject is too ill to complete PRO without assistance on a given day, a member of the study staff may verbally recite the questions verbatim to the subject and the staff member may enter the subject's verbal response in the eDiary.

  11. Change from Baseline in SGRQ-C total score [ Time Frame: Baseline and up to Week 12 ]
    The SGRQ-C is a COPD-specific questionnaire designed to measure the impact of COPD and its treatment on the subject's health-related quality of life. It consists of two parts; Part 1 produces the symptom score and Part 2 produces the activity and impact score. A Total score is also calculated which summarizes the impact of the disease on overall health status. Scores are expressed as a percentage of overall impairment where 100 represents worst possible health status and zero indicates best possible health status. For subjects who are hospitalized, if the subject is too ill to complete PRO without assistance on a given day, a member of the study staff may verbally recite the questions verbatim to the subject and the staff member may enter the subject's verbal response in the eDiary.

  12. Percentage of subjects using rescue medication [ Time Frame: Up to Week 12 ]
    Albuterol (Salbutamol) MDI or nebules will be used as a rescue medication. Rescue medication use by subjects will be captured using the clip-on Propeller Sensor for MDI and via eDiary. The rescue medication use (occasions/day) averaged over each week of treatment and over the 84-day treatment period will be evaluated.

  13. Percentage of rescue-free days [ Time Frame: Up to Week 12 ]
    Albuterol (Salbutamol) MDI or nebules will be used as a rescue medication. Rescue medication use by subjects will be captured using the clip-on Propeller Sensor for MDI and via eDiary. The percentage of rescue-free days (24-hour periods) over each week of treatment and over the 84-day treatment period will be evaluated.

  14. Area under the concentration time curve (AUC) from time zero to 24 hours [AUC(0-24)] of nemiralisib [ Time Frame: Pre-dose, 0-1 hour and >1-6 hours post dose on Day 14 and Day 28 ]
    Blood samples will be collected at specific time points for pharmacokinetic analysis of nemiralisib.

  15. AUC from time zero to time 't' [AUC(0-t)] of nemiralisib [ Time Frame: Pre-dose, 0-1 hour and >1-6 hours post dose on Day 14 and Day 28 ]
    Blood samples will be collected at specific time points for pharmacokinetic analysis of nemiralisib.

  16. Maximum Observed Plasma Drug Concentration (Cmax) of nemiralisib [ Time Frame: Pre-dose, 0-1 hour and >1-6 hours post dose on Day 14 and Day 28 ]
    Blood samples will be collected at specific time points for pharmacokinetic analysis of nemiralisib.

  17. Time to reach Cmax (Tmax) of nemiralisib [ Time Frame: Pre-dose, 0-1 hour and >1-6 hours post dose on Day 14 and Day 28 ]
    Blood samples will be collected at specific time points for pharmacokinetic analysis of nemiralisib.

  18. Plasma drug concentration at pre-dose (Ctrough) of nemiralisib [ Time Frame: Pre-dose, 0-1 hour and >1-6 hours post dose on Day 14 and Day 28 ]
    Blood samples will be collected at specific time points for pharmacokinetic analysis of nemiralisib.

  19. Percentage of subjects with adverse events (AEs), serious adverse events (SAEs) and AEs of special interest (AESIs) [ Time Frame: Up to Week 24 ]
    An AE is any untoward medical occurrence in a clinical investigation subject, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. SAE is defined as any untoward medical occurrence that, at any dose results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability, is a congenital anomaly/ birth effect and is associated with liver injury or impaired liver function. AESIs of post-inhalation cough will be monitored within 5 minutes immediately following dosing.

  20. Percentage of subjects with abnormal pulse rate levels [ Time Frame: Up to Week 16 ]
    Pulse rate will be measured in a seated position after at least 5 minutes of rest.

  21. Percentage of subjects with abnormal blood pressure levels [ Time Frame: Up to Week 16 ]
    Systolic blood pressure (SBP) and diastolic blood pressure (DBP) will be measured in a seated position after at least 5 minutes of rest.

  22. Percentage of subjects with abnormal electrocardiogram (ECG) finding [ Time Frame: Up to Week 16 ]
    A single 12-lead ECG with a 15-second rhythm strip will be obtained using an ECG machine and abnormal ECG findings will be evaluated.

  23. Percentage of subjects with abnormal clinical chemistry levels [ Time Frame: Up to Week 16 ]
    Clinical chemistry parameters including blood urea nitrogen (BUN), creatinine, glucose, potassium, sodium, calcium, aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase, total and direct bilirubin, total protein and albumin will be evaluated as a safety measure.

  24. Percentage of subjects with abnormal hematology levels [ Time Frame: Up to Week 16 ]
    Clinical hematology parameters including platelet count, red blood cell (RBC) count, hemoglobin and hematocrit levels will be evaluated as a safety measure.

  25. Percentage of subjects with COPD exacerbations [ Time Frame: Up to Week 16 ]
    Acute exacerbation of COPD requiring an escalation in therapy to include oral/systemic corticosteroid(s) [prednisone 40 milligrams per day (mg/day) or equivalent] for 5 days and antibiotic(s) for 7 days. Number of subjects with acute COPD exacerbations will be evaluated as a safety measure.



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Layout table for eligibility information
Ages Eligible for Study:   40 Years to 80 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03345407


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Sponsors and Collaborators
GlaxoSmithKline
Investigators
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Study Director: GSK Clinical Trials GlaxoSmithKline
Study Director: GSK Clinical Trials GlaxoSmithKline (for GlaxoSmithKline; Human Genome Sciences Inc., a GSK Company; Sirtris, a GSK Company; Stiefel, a GSK Company; ViiV Healthcare)

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Responsible Party: GlaxoSmithKline
ClinicalTrials.gov Identifier: NCT03345407     History of Changes
Other Study ID Numbers: 200879
2017-001074-42 ( EudraCT Number )
First Posted: November 17, 2017    Key Record Dates
Last Update Posted: April 16, 2019
Last Verified: April 2019

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by GlaxoSmithKline:
Nemiralisib
Dose-Finding
GSK2269557
Acute Moderate or Severe Exacerbation of Chronic Obstructive Pulmonary Disease
Additional relevant MeSH terms:
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Lung Diseases
Lung Diseases, Obstructive
Pulmonary Disease, Chronic Obstructive
Respiratory Tract Diseases
Albuterol
Bronchodilator Agents
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Anti-Asthmatic Agents
Respiratory System Agents
Tocolytic Agents
Reproductive Control Agents
Adrenergic beta-2 Receptor Agonists
Adrenergic beta-Agonists
Adrenergic Agonists
Adrenergic Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action