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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/show/NCT03345407




Registration number
NCT03345407
Ethics application status
Date submitted
14/11/2017
Date registered
17/11/2017
Date last updated
10/02/2020

Titles & IDs
Public title
Dose Finding Study of Nemiralisib (GSK2269557) in Subjects With an Acute Moderate or Severe Exacerbation of Chronic Obstructive Pulmonary Disease (COPD)
Scientific 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)
Secondary ID [1] 0 0
2017-001074-42
Secondary ID [2] 0 0
200879
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Pulmonary Disease, Chronic Obstructive 0 0
Condition category
Condition code
Respiratory 0 0 0 0
Chronic obstructive pulmonary disease

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - Placebo ELLIPTA
Treatment: Drugs - Nemiralisib ELLIPTA 50 µg
Treatment: Drugs - Nemiralisib ELLIPTA 100 µg
Treatment: Drugs - Nemiralisib ELLIPTA 250 µg
Treatment: Drugs - Nemiralisib ELLIPTA 500 µg
Treatment: Drugs - Nemiralisib ELLIPTA 750 µg
Treatment: Drugs - Albuterol (Salbutamol) MDI or nebules
Treatment: Drugs - Standard of care therapy

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.

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.

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.

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.

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.

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.


Treatment: Drugs: Placebo ELLIPTA
Placebo will be administered via oral inhalation route once daily in the morning.

Treatment: Drugs: 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.

Treatment: Drugs: 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.

Treatment: Drugs: 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.

Treatment: Drugs: 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.

Treatment: Drugs: 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.

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

Treatment: Drugs: 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.

Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Change From Baseline in Clinic Visit Trough Forced Expiratory Volume in One Second (FEV1) at Day 84 Measured Post Bronchodilator - FEV1 is maximal amount of air exhaled forcefully from lungs in 1 second. Post-bronchodilator FEV1 was conducted approximately 10-30 minutes after participant was administered 4 inhalations of albuterol (salbutamol) via MDI using spacer/valved-holding chamber or via one nebulized treatment. Post-bronchodilator Baseline FEV1 is latest FEV1 measured prior to first dose of study treatment and post-bronchodilator. Change from Baseline in clinic visit trough FEV1 at Day 84 measured post-bronchodilator is FEV1 measured prior to dosing and post-bronchodilator on Day 84 minus post-bronchodilator Baseline FEV1. Bayesian repeated measure model adjusted for Baseline by visit interaction, treatment by visit interaction, smoking status at Baseline, region, severity of index exacerbation, number of moderate/severe exacerbations in previous 12 months and gender was used. Posterior adjusted median change from Baseline and 95% highest posterior density (HPD) credible interval (CrI) was presented.
Timepoint [1] 0 0
Baseline and Day 84
Secondary outcome [1] 0 0
Rate of Moderate and Severe Exacerbations Over 12-week Treatment Period - Moderate COPD exacerbations are defined as worsening symptoms of COPD treated with short-acting bronchodilators (SABDs) plus antibiotics and/or oral/systemic corticosteroids. Severe COPD 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. Rate of exacerbations was analyzed using Bayesian Poisson model adjusting for length of on-treatment follow-up, smoking status at Baseline, region, severity of index exacerbation, number of moderate/severe exacerbations in the previous 12 months and gender. Posterior median exacerbation rate and 95% HPD CrI has been presented.
Timepoint [1] 0 0
Up to Week 12
Secondary outcome [2] 0 0
Number of Participants With Time to Next Moderate/Severe Exacerbation Following Index Exacerbation - Number of participants with time to next (on-treatment) moderate/severe exacerbation following index exacerbation during the 12-Week Treatment Period was defined as time from the date of randomization until the date of onset of the first moderate/severe exacerbation whilst on study treatment. Participants who did not have an exacerbation whilst on study treatment were censored at the date of their last dose of study treatment. Time to next exacerbation was analyzed using a Bayesian Cox proportional hazards model adjusting for treatment group, smoking status at Baseline, region, severity of index exacerbation, number of moderate/severe exacerbations in the previous 12 months and gender.
Timepoint [2] 0 0
Up to Week 12
Secondary outcome [3] 0 0
Change From Baseline in Clinic Visit Trough FEV1 Measured Pre and Post-bronchodilator - Pulmonary function was measured by FEV1, defined as maximal amount of air exhaled forcefully from the lungs in 1 second. Post-bronchodilator FEV1 was conducted approximately 10-30 minutes after participant was administered with 4 inhalations of albuterol via MDI using a spacer/valved-holding chamber or via 1 nebulized treatment. Pre-bronchodilator and post-bronchodilator Baseline FEV1 is latest FEV1 measured prior to first dose of study treatment and pre-bronchodilator and post-bronchodilator, respectively. Change from Baseline in clinic visit trough FEV1 at Days 14, 28, 56 and 84 measured pre-bronchodilator is defined as FEV1 measured prior to dosing and pre-bronchodilator on Days 14, 28, 56 and 84 minus pre-bronchodilator Baseline FEV1.
Timepoint [3] 0 0
Baseline and Days 14, 28, 56 (pre and post bronchodilaor), 84 (pre-bronchodilator) and at hospital discharge (maximum 24 Weeks)
Secondary outcome [4] 0 0
Change From Hospital Discharge in Clinic Visit Trough FEV1 Measured Pre and Post-bronchodilator - Pulmonary function was measured by FEV1, defined as maximal amount of air exhaled forcefully from the lungs in 1 second. Post-bronchodilator FEV1 was conducted approximately 10 to 30 minutes after participant was administered with 4 inhalations of albuterol via MDI using a spacer/valved-holding chamber or via 1 nebulized treatment. Pre-bronchodilator and post-bronchodilator Baseline FEV1 is defined as latest FEV1 measured prior to first dose of study treatment and pre-bronchodilator and post-bronchodilator, respectively. Change from hospital discharge in clinic visit trough FEV1 at Days 14, 28, 56 and 84 measured pre- and post-bronchodilator is defined as FEV1 measured prior to dosing and pre- and post-bronchodilator on Days 14, 28, 56 and 84 minus pre and post-bronchodilator Baseline FEV1.
Timepoint [4] 0 0
Baseline and pre- and post-bronchodilator on Days 14, 28, 56 and 84
Secondary outcome [5] 0 0
Percentage of Participants Achieving the Exacerbations of Chronic Pulmonary Disease Tool (EXACT) Definition of Recovery From the Index Exacerbation - EXACT patient-reported outcome (EXACT-PRO), 14-item instrument to capture occurrence, frequency, severity, and duration of exacerbations using an electronic diary (eDiary). Total score ranges from 0-100, higher score indicates more severe condition. Participants were required to complete EXACT-PRO every evening; however, on the day of randomization it was to be completed in the morning. Response was decrease in rolling average EXACT Total Score >=9 points from maximum observed value, sustained for >=7 days, with first of 7 days defined as recovery day. Analysis was performed using Bayesian Cox proportional hazards model adjusting for treatment group, smoking status at Baseline, region, severity of index exacerbation, number of moderate/severe exacerbations in previous 12 months and gender.
Timepoint [5] 0 0
Days 14, 28, 56 and 84
Secondary outcome [6] 0 0
Number of Participants With Time to Recovery From Index Exacerbation Using EXACT- PRO Tool - Time to EXACT-defined recovery from index exacerbation is defined as time from the date of randomization until date of the first EXACT-defined recovery day during the 12-Week Treatment Period. EXACT-defined recovery from the index exacerbation is defined as a decrease in the Rolling Average EXACT total Score >=9 points from the Maximum Observed Value, sustained for >=7 days, with the first of the 7 days defined as the recovery day. Analysis was performed using a Bayesian Cox proportional hazards model adjusting for treatment group, smoking status at Baseline, region, severity of index exacerbation, number of moderate/severe exacerbations in the previous 12 months and gender. Number of participants reporting events is presented.
Timepoint [6] 0 0
From randomization to Week 12
Secondary outcome [7] 0 0
Mean Severity of Subsequent Health Care Resource Use (HCRU) Exacerbations Defined by EXACT - Severity of subsequent HCRU-defined exacerbations defined by EXACT was defined as the highest EXACT Total Score (not using the 3-day Rolling Average) during the period from date of onset of the subsequent HCRU-exacerbation until date of EXACT-defined recovery of subsequent exacerbation. EXACT-PRO, 14-item instrument to capture occurrence, frequency, severity, and duration of exacerbations using an eDiary. Total score ranges from 0-100, higher score indicates more severe condition. For participants with more than one subsequent exacerbation, severity was calculated for each subsequent exacerbation.
Timepoint [7] 0 0
Up to Week 12
Secondary outcome [8] 0 0
Percentage of Responders Using the COPD Assessment Test (CAT) on Treatment Days 28, 56, and 84, and Following EXACT Defined Recovery From the Index Exacerbation - The CAT is a short, self-completed, 8-item questionnaire, each item was rated on a 6-point scale ranging from 0 (no impairment) to 5 (maximum impairment). The total CAT score is calculated by summing the scores of all items and ranges from 0 to 40, higher scores indicating severe condition. The percentage of responders using the CAT is defined as number of participants with a decrease from Baseline in CAT Total Score >=2 on or before Days 28, 56 and 84 divided by total number of participants in the MITT population. Percentage of responders using CAT was derived only for participants with a Baseline CAT Total Score >=2. Analysis was performed using a separate Bayesian logistic regression for each time point adjusting for treatment group, smoking status at baseline, region, severity of index exacerbation, number of moderate/severe exacerbations in the previous 12 months and gender.
Timepoint [8] 0 0
Days 28, 56 and 84
Secondary outcome [9] 0 0
Change From Baseline in CAT Total Score - The CAT is a short, self-completed, 8-item questionnaire, each item was rated on a 6-point scale ranging from 0 (no impairment) to 5 (maximum impairment). The total CAT score was calculated by summing the scores of all items and ranges from 0 to 40, higher scores indicating more severe condition. Baseline (Day 1) is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits. Change from Baseline in CAT Total Score is defined as CAT Total Score on Days 28, 56 and 84 minus Baseline CAT Total Score. Analysis was performed using Bayesian repeated measures model adjusting for Baseline by visit interaction, treatment by visit interaction, smoking status at Baseline, region, severity of index exacerbation, number of moderate/severe exacerbations in the previous 12 months and gender. Posterior adjusted median change from Baseline and 95% HPD CrI has been presented.
Timepoint [9] 0 0
Baseline and at Days 28, 56 and 84
Secondary outcome [10] 0 0
Percentage of Responders on the St. George's Respiratory Questionnaire (SGRQ) Total Score as Measured by the SGRQ for COPD Participants (SGRQ-C) at Days 28, 56, and 84 - SGRQ-C is a 40-item questionnaire designed specifically to focus on COPD participants and was scored equivalent to the SGRQ Total Score, ranging from 0 to 100, where higher scores reflect worse health-related quality of life. The percentage of responders on the SGRQ Total Score was derived for participants with a Baseline SGRQ Total Score >=4. Percentage of responders on the SGRQ Total Score is defined as number of participants with a decrease from Baseline in SGRQ Total Score >=4 on or before Days 28, 56 and 84 divided by total number of participants in the MITT population. Analysis was performed using a separate Bayesian logistic regression for each time point adjusting for treatment group, smoking status at baseline, region, severity of index exacerbation, number of moderate/severe exacerbations in the previous 12 months and gender.
Timepoint [10] 0 0
Days 28, 56 and 84
Secondary outcome [11] 0 0
Change From Baseline in SGRQ Total Score at Days 28, 56 and 84 - SGRQ-C is a 40-item questionnaire designed specifically to focus on COPD participants and was scored equivalent to SGRQ Total Score, ranging from 0 to 100, where higher scores reflect worse health-related quality of life. Scores on a scale were calculated as 100 multiplied by summed weights from positive items in questionnaire divided by sum of weights of all items in questionnaire. Baseline (Day 1) is defined as latest pre-dose assessment with a non-missing value, including those from unscheduled visits. Change from Baseline in SGRQ Total Score is defined as SGRQ Total Score on Days 28, 56 and 84 minus Baseline SGRQ Total Score. Analysis was performed using Bayesian repeated measures model adjusting for Baseline by visit interaction, treatment by visit interaction, smoking status at Baseline, region, severity of index exacerbation, number of moderate/severe exacerbations in previous 12 months and gender. Posterior adjusted median change from Baseline and 95% HPD CrI was presented
Timepoint [11] 0 0
Baseline and Days 28, 56 and 84
Secondary outcome [12] 0 0
Mean Number of Occasions of Rescue Medication Use Per Day - Albuterol (Salbutamol) MDI or nebules was used as a rescue medication. Rescue medication use was recorded as the number of occasions of rescue medication use each day. The mean number of occasions of rescue medication use per day is defined as sum of the number of occasions of rescue medication use each day within the time-period divided by the total number of days with non-missing values within the time-period. Over the 12-Week treatment period is defined as Day 1 to Day of last dose.
Timepoint [12] 0 0
Weeks 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12 of treatment and over the Week 12 treatment period
Secondary outcome [13] 0 0
Percentage of Rescue-free Days - Albuterol (Salbutamol) MDI or nebules was used as a rescue medication. Percentage of Rescue-Free Days is defined as sum of the number of days where the number of occasions of rescue medication use is zero within the time-period divided by total number of days with non-missing values within the time-period multiplied by 100 where the time-period is defined as follows: Week 1: Day 1-7; Week 2: Day 8 - 14; Week 3: Day 15-21; Week 4: Day 22-28; Week 5: Day 29-35; Week 6: Day 36-42; Week 7: Day 43-49; Week 8: Day 50-56; Week 9: Day 57-63; Week 10: Day 64-70; Week 11: Day 71-77; Week 12: Day 78 to Day of last dose; Over the 12-Week: Day 1 to Day of last dose.
Timepoint [13] 0 0
Weeks 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12 of treatment and over the Week 12 treatment period
Secondary outcome [14] 0 0
Plasma Concentration of Nemiralisib - Plasma samples were collected at indicated time points and analyzed for concentrations of Nemiralisb. Pharmacokinetic (PK) Population consists of all participants in the Safety population who had at least 1 non-missing PK assessment (Non-quantifiable [NQ] values will be considered as non-missing values). Participants were summarized according to the treatment that they actually received.
Timepoint [14] 0 0
Pre-dose, 0-1 hour, >1-6 hours post-dose on Days 14 and 28
Secondary outcome [15] 0 0
Number of Participants Reporting Non-serious Adverse Events (Non-SAEs), SAEs and AE of Special Interest (AESI) - 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 other important medical events. Safety Population consists of all randomized participants who received at least one dose of study treatment. Participants were summarized according to treatment that they actually received.
Timepoint [15] 0 0
Up to Week 24
Secondary outcome [16] 0 0
Number of Participants With Worst Case Post Baseline Diastolic Blood Pressure (DBP), Systolic Blood Pressure (SBP) and Pulse Rate - The DBP, SBP and pulse rate were measured with participants seated at least 5 minutes before the assessments. Participants are counted in the worst case category if their value changes to (low, within range or no change, or high). Participants whose value category was unchanged (e.g., High to High), or whose value became within range, are recorded in the "To w/in Range or No Change" category. Participants are counted twice if the participant has values that changed "To Low" and "To High", so the percentages may not add to 100%. Participants with missing baseline value are assumed to have within range value.
Timepoint [16] 0 0
Up to Week 16
Secondary outcome [17] 0 0
Number of Participants With Abnormal Electrocardiogram (ECG) Findings - A single 12-lead ECG with a 15-second rhythm strip was obtained using an ECG machine that automatically calculated the heart rate and measured PR, QRS, QT and corrected QT (QTc) intervals. Abnormal ECG findings are presented.
Timepoint [17] 0 0
Screening, Days 14, 84, 112 and at early withdrawal
Secondary outcome [18] 0 0
Number of Participants With Worst Case Post Baseline Clinical Chemistry Values - Blood samples were collected for the analysis of clinical chemistry parameters including: blood urea nitrogen (BUN), creatinine (Crt), glucose (Glu), potassium (Pot), sodium (Sod), calcium (Cal), aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), total and direct bilirubin, total protein and albumin (Alb). Participants are counted in the worst case category if their value changes to (low, within range or no change, or high). Participants whose value category was unchanged (e.g., High to High), or whose value became within range, are recorded in the "To w/in Range or No Change" category. Participants are counted twice if the participant has values that changed "To Low" and "To High", so the percentages may not add to 100%. Participants with missing baseline value are assumed to have within range value.
Timepoint [18] 0 0
Upto Week 16
Secondary outcome [19] 0 0
Number of Participants With Worst Case Post Baseline Hematology Values - Blood samples were collected for the analysis of hematology parameters including: platelets (Pla), red blood cells count, Hemoglobin (Hb), Hematocrit, mean corpuscular volume (MCV), mean corpuscular haemoglobin (MCH), percentage reticulocytes, neutrophils (Neu), lymphocytes (Lym), monocytes, eosinophils, leukocytes (Leu) and basophils. Participants are counted in the worst case category if their value changes to (low, within range or no change, or high). Participants whose value category was unchanged (e.g., High to High), or whose value became within range, are recorded in the "To w/in Range or No Change" category. Participants are counted twice if the participant has values that changed "To Low" and "To High", so the percentages may not add to 100%. Participants with missing baseline value are assumed to have within range value.
Timepoint [19] 0 0
Upto Week 16
Secondary outcome [20] 0 0
Number of Participants Reporting COPD Exacerbations - Participants reporting acute COPD exacerbations during the study period has been presented.
Timepoint [20] 0 0
Up to Week 16

Eligibility
Key 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.
Minimum age
40 Years
Maximum age
80 Years
Gender
Both males and females
Can healthy volunteers participate?
No
Key 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.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s


The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 2
Type of endpoint(s)
Statistical methods / analysis

Recruitment
Recruitment status
Terminated
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW,QLD,SA,VIC,WA
Recruitment hospital [1] 0 0
GSK Investigational Site - Gosford
Recruitment hospital [2] 0 0
GSK Investigational Site - Westmead
Recruitment hospital [3] 0 0
GSK Investigational Site - Woolloongabba
Recruitment hospital [4] 0 0
GSK Investigational Site - Woodville South
Recruitment hospital [5] 0 0
GSK Investigational Site - Clayton
Recruitment hospital [6] 0 0
GSK Investigational Site - Murdoch
Recruitment postcode(s) [1] 0 0
2250 - Gosford
Recruitment postcode(s) [2] 0 0
2145 - Westmead
Recruitment postcode(s) [3] 0 0
4102 - Woolloongabba
Recruitment postcode(s) [4] 0 0
5011 - Woodville South
Recruitment postcode(s) [5] 0 0
3168 - Clayton
Recruitment postcode(s) [6] 0 0
6150 - Murdoch
Recruitment outside Australia
Country [1] 0 0
United States of America
State/province [1] 0 0
Alabama
Country [2] 0 0
United States of America
State/province [2] 0 0
Colorado
Country [3] 0 0
United States of America
State/province [3] 0 0
Florida
Country [4] 0 0
United States of America
State/province [4] 0 0
Georgia
Country [5] 0 0
United States of America
State/province [5] 0 0
Maryland
Country [6] 0 0
United States of America
State/province [6] 0 0
Missouri
Country [7] 0 0
United States of America
State/province [7] 0 0
Nebraska
Country [8] 0 0
United States of America
State/province [8] 0 0
North Carolina
Country [9] 0 0
United States of America
State/province [9] 0 0
Ohio
Country [10] 0 0
United States of America
State/province [10] 0 0
Pennsylvania
Country [11] 0 0
United States of America
State/province [11] 0 0
South Carolina
Country [12] 0 0
United States of America
State/province [12] 0 0
South Dakota
Country [13] 0 0
United States of America
State/province [13] 0 0
Virginia
Country [14] 0 0
United States of America
State/province [14] 0 0
West Virginia
Country [15] 0 0
Argentina
State/province [15] 0 0
Buenos Aires
Country [16] 0 0
Argentina
State/province [16] 0 0
Mendoza
Country [17] 0 0
Argentina
State/province [17] 0 0
Santa Fe
Country [18] 0 0
Argentina
State/province [18] 0 0
Ciudad Autonoma de Buenos Aires
Country [19] 0 0
Argentina
State/province [19] 0 0
Ciudad Autónoma de Buenos Aires
Country [20] 0 0
Argentina
State/province [20] 0 0
Tucuman
Country [21] 0 0
Canada
State/province [21] 0 0
Alberta
Country [22] 0 0
Canada
State/province [22] 0 0
Manitoba
Country [23] 0 0
Canada
State/province [23] 0 0
Ontario
Country [24] 0 0
Canada
State/province [24] 0 0
Quebec
Country [25] 0 0
France
State/province [25] 0 0
Brest cedex
Country [26] 0 0
France
State/province [26] 0 0
Lyon
Country [27] 0 0
France
State/province [27] 0 0
Montpellier cedex 5
Country [28] 0 0
France
State/province [28] 0 0
Rennes Cedex 9
Country [29] 0 0
France
State/province [29] 0 0
Vandoeuvre-lès-Nancy cedex
Country [30] 0 0
Germany
State/province [30] 0 0
Bayern
Country [31] 0 0
Germany
State/province [31] 0 0
Brandenburg
Country [32] 0 0
Germany
State/province [32] 0 0
Hessen
Country [33] 0 0
Germany
State/province [33] 0 0
Niedersachsen
Country [34] 0 0
Germany
State/province [34] 0 0
Nordrhein-Westfalen
Country [35] 0 0
Germany
State/province [35] 0 0
Rheinland-Pfalz
Country [36] 0 0
Germany
State/province [36] 0 0
Sachsen
Country [37] 0 0
Germany
State/province [37] 0 0
Schleswig-Holstein
Country [38] 0 0
Germany
State/province [38] 0 0
Berlin
Country [39] 0 0
Italy
State/province [39] 0 0
Emilia-Romagna
Country [40] 0 0
Italy
State/province [40] 0 0
Lazio
Country [41] 0 0
Italy
State/province [41] 0 0
Lombardia
Country [42] 0 0
Italy
State/province [42] 0 0
Sicilia
Country [43] 0 0
Italy
State/province [43] 0 0
Veneto
Country [44] 0 0
Korea, Republic of
State/province [44] 0 0
Daejon
Country [45] 0 0
Korea, Republic of
State/province [45] 0 0
Incheon
Country [46] 0 0
Korea, Republic of
State/province [46] 0 0
Jeonju-si, Jeollabuk-do
Country [47] 0 0
Korea, Republic of
State/province [47] 0 0
Seongnam-si, Gyeonggi-do
Country [48] 0 0
Korea, Republic of
State/province [48] 0 0
Seoul
Country [49] 0 0
Mexico
State/province [49] 0 0
Jalisco
Country [50] 0 0
Mexico
State/province [50] 0 0
Nuevo León
Country [51] 0 0
Netherlands
State/province [51] 0 0
Alkmaar
Country [52] 0 0
Netherlands
State/province [52] 0 0
Breda
Country [53] 0 0
Netherlands
State/province [53] 0 0
Eindhoven
Country [54] 0 0
Netherlands
State/province [54] 0 0
Groningen
Country [55] 0 0
Netherlands
State/province [55] 0 0
Harderwijk
Country [56] 0 0
Netherlands
State/province [56] 0 0
Hoorn
Country [57] 0 0
Netherlands
State/province [57] 0 0
Rotterdam
Country [58] 0 0
Netherlands
State/province [58] 0 0
Utrecht
Country [59] 0 0
Netherlands
State/province [59] 0 0
Zwolle
Country [60] 0 0
Poland
State/province [60] 0 0
Bialystok
Country [61] 0 0
Poland
State/province [61] 0 0
Elblag
Country [62] 0 0
Poland
State/province [62] 0 0
Krakow
Country [63] 0 0
Poland
State/province [63] 0 0
Lubin
Country [64] 0 0
Poland
State/province [64] 0 0
Olawa
Country [65] 0 0
Poland
State/province [65] 0 0
Ruda Slaska
Country [66] 0 0
Poland
State/province [66] 0 0
Slupsk
Country [67] 0 0
Poland
State/province [67] 0 0
Sosnowiec
Country [68] 0 0
Poland
State/province [68] 0 0
Tarnow
Country [69] 0 0
Romania
State/province [69] 0 0
Bucarest
Country [70] 0 0
Romania
State/province [70] 0 0
Bucharest
Country [71] 0 0
Romania
State/province [71] 0 0
Cluj Napoca
Country [72] 0 0
Romania
State/province [72] 0 0
Comuna Alexandru Cel Bun
Country [73] 0 0
Romania
State/province [73] 0 0
Iasi
Country [74] 0 0
Romania
State/province [74] 0 0
Oradea
Country [75] 0 0
Romania
State/province [75] 0 0
Ramnicu Valcea
Country [76] 0 0
Romania
State/province [76] 0 0
Suceava
Country [77] 0 0
Romania
State/province [77] 0 0
Timisoara
Country [78] 0 0
Russian Federation
State/province [78] 0 0
Barnaul
Country [79] 0 0
Russian Federation
State/province [79] 0 0
Belgorod
Country [80] 0 0
Russian Federation
State/province [80] 0 0
Blagoveshchensk
Country [81] 0 0
Russian Federation
State/province [81] 0 0
Chelyabinsk
Country [82] 0 0
Russian Federation
State/province [82] 0 0
Ivanovo
Country [83] 0 0
Russian Federation
State/province [83] 0 0
Kemerovo
Country [84] 0 0
Russian Federation
State/province [84] 0 0
Nizhniy Novgorod
Country [85] 0 0
Russian Federation
State/province [85] 0 0
Novgorod
Country [86] 0 0
Russian Federation
State/province [86] 0 0
Novosibirsk
Country [87] 0 0
Russian Federation
State/province [87] 0 0
Perm
Country [88] 0 0
Russian Federation
State/province [88] 0 0
Ryazan
Country [89] 0 0
Russian Federation
State/province [89] 0 0
Saratov
Country [90] 0 0
Russian Federation
State/province [90] 0 0
Tomsk
Country [91] 0 0
Russian Federation
State/province [91] 0 0
Ulyanovsk
Country [92] 0 0
Russian Federation
State/province [92] 0 0
Voronezh
Country [93] 0 0
Spain
State/province [93] 0 0
Cantabria
Country [94] 0 0
Spain
State/province [94] 0 0
Barcelona
Country [95] 0 0
Spain
State/province [95] 0 0
Basurto/Bilbao
Country [96] 0 0
Spain
State/province [96] 0 0
Cartagena (Murcia)
Country [97] 0 0
Spain
State/province [97] 0 0
Cáceres
Country [98] 0 0
Spain
State/province [98] 0 0
Elda (Alicante)
Country [99] 0 0
Spain
State/province [99] 0 0
Gerona
Country [100] 0 0
Spain
State/province [100] 0 0
Logroño
Country [101] 0 0
Spain
State/province [101] 0 0
Madrid
Country [102] 0 0
Spain
State/province [102] 0 0
Mérida (Badajoz)
Country [103] 0 0
Spain
State/province [103] 0 0
Orihuela (Alicante)
Country [104] 0 0
Spain
State/province [104] 0 0
Palma de Mallorca
Country [105] 0 0
Spain
State/province [105] 0 0
Pama de Mallorca
Country [106] 0 0
Spain
State/province [106] 0 0
Ponferrada (León)
Country [107] 0 0
Spain
State/province [107] 0 0
Pozuelo De Alarcón/Madrid
Country [108] 0 0
Sweden
State/province [108] 0 0
Göteborg
Country [109] 0 0
Sweden
State/province [109] 0 0
Lund
Country [110] 0 0
United Kingdom
State/province [110] 0 0
Derbyshire
Country [111] 0 0
United Kingdom
State/province [111] 0 0
Lanarkshire
Country [112] 0 0
United Kingdom
State/province [112] 0 0
Blackburn
Country [113] 0 0
United Kingdom
State/province [113] 0 0
Bradford
Country [114] 0 0
United Kingdom
State/province [114] 0 0
Edgbaston
Country [115] 0 0
United Kingdom
State/province [115] 0 0
Edinburgh
Country [116] 0 0
United Kingdom
State/province [116] 0 0
Liverpool
Country [117] 0 0
United Kingdom
State/province [117] 0 0
Sheffield
Country [118] 0 0
United Kingdom
State/province [118] 0 0
Stockton-on-Tees

Funding & Sponsors
Primary sponsor type
Commercial sector/Industry
Name
GlaxoSmithKline
Address
Country

Ethics approval
Ethics application status

Summary
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.
Trial website
https://clinicaltrials.gov/show/NCT03345407
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
GSK Clinical Trials
Address 0 0
GlaxoSmithKline
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries

Summary results
For IPD and results data, please see https://clinicaltrials.gov/show/NCT03345407