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

Pulmonary Disease, Chronic Obstructive Clinical Trial

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)

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT03345407
• Other study ID #: 200879
• Secondary ID: 2017-001074-42
• Status: Terminated
• Phase: Phase 2
• Start date: November 28, 2017
• Est. completion date: January 10, 2019

Study information

• Verified date: July 2021
• Source: GlaxoSmithKline
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 943
• Est. completion date: January 10, 2019
• Est. primary completion date: January 10, 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 40 Years to 80 Years

Eligibility

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.

Related Conditions & MeSH terms

• Lung Diseases
• Lung Diseases, Obstructive
• Pulmonary Disease, Chronic Obstructive

Intervention

Drug:
• Placebo ELLIPTA
Placebo will be administered via oral inhalation route once daily in the morning.
• 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.
• 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.
• 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.
• 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.
• 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.
• Albuterol (Salbutamol) MDI or nebules
Albuterol (Salbutamol) MDI or nebules will be provided to all subjects as a rescue medication.
• 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.

Locations

Country	Name	City	State
Argentina	GSK Investigational Site	Buenos Aires
Argentina	GSK Investigational Site	Buenos Aires
Argentina	GSK Investigational Site	Ciudad Autonoma de Buenos Aires
Argentina	GSK Investigational Site	Ciudad Autonoma de Buenos Aires	Buenos Aires
Argentina	GSK Investigational Site	Ciudad Autónoma de Buenos Aires
Argentina	GSK Investigational Site	Florida	Buenos Aires
Argentina	GSK Investigational Site	Mar del Plata	Buenos Aires
Argentina	GSK Investigational Site	Mendoza
Argentina	GSK Investigational Site	Mendoza
Argentina	GSK Investigational Site	Rosario	Santa Fe
Argentina	GSK Investigational Site	San Rafael	Mendoza
Argentina	GSK Investigational Site	Santo Tome	Santa Fe
Argentina	GSK Investigational Site	Tucuman
Australia	GSK Investigational Site	Clayton	Victoria
Australia	GSK Investigational Site	Gosford	New South Wales
Australia	GSK Investigational Site	Murdoch	Western Australia
Australia	GSK Investigational Site	Westmead	New South Wales
Australia	GSK Investigational Site	Woodville South	South Australia
Australia	GSK Investigational Site	Woolloongabba	Queensland
Canada	GSK Investigational Site	Edmonton	Alberta
Canada	GSK Investigational Site	Montreal	Quebec
Canada	GSK Investigational Site	Quebec City	Quebec
Canada	GSK Investigational Site	Sherwood Park	Alberta
Canada	GSK Investigational Site	St-Charles-Borromée	Quebec
Canada	GSK Investigational Site	Windsor	Ontario
Canada	GSK Investigational Site	Winnipeg	Manitoba
France	GSK Investigational Site	Brest cedex
France	GSK Investigational Site	Lyon
France	GSK Investigational Site	Montpellier cedex 5
France	GSK Investigational Site	Rennes Cedex 9
France	GSK Investigational Site	Vandoeuvre-lès-Nancy cedex
Germany	GSK Investigational Site	Aschaffenburg	Bayern
Germany	GSK Investigational Site	Bamberg	Bayern
Germany	GSK Investigational Site	Berlin
Germany	GSK Investigational Site	Darmstadt	Hessen
Germany	GSK Investigational Site	Frankfurt	Hessen
Germany	GSK Investigational Site	Frankfurt	Hessen
Germany	GSK Investigational Site	Geesthacht	Schleswig-Holstein
Germany	GSK Investigational Site	Hannover	Niedersachsen
Germany	GSK Investigational Site	Koblenz	Rheinland-Pfalz
Germany	GSK Investigational Site	Leipzig	Sachsen
Germany	GSK Investigational Site	Luebeck	Schleswig-Holstein
Germany	GSK Investigational Site	Potsdam	Brandenburg
Germany	GSK Investigational Site	Rheine	Nordrhein-Westfalen
Germany	GSK Investigational Site	Rosenheim	Bayern
Germany	GSK Investigational Site	Schleswig	Schleswig-Holstein
Germany	GSK Investigational Site	Warendorf	Nordrhein-Westfalen
Italy	GSK Investigational Site	Catania	Sicilia
Italy	GSK Investigational Site	Messina	Sicilia
Italy	GSK Investigational Site	Milano	Lombardia
Italy	GSK Investigational Site	Negrar	Veneto
Italy	GSK Investigational Site	Pavia	Lombardia
Italy	GSK Investigational Site	Reggio Emilia	Emilia-Romagna
Italy	GSK Investigational Site	Roma	Lazio
Italy	GSK Investigational Site	Roma	Lazio
Italy	GSK Investigational Site	Tradate (VA)	Lombardia
Korea, Republic of	GSK Investigational Site	Daejon
Korea, Republic of	GSK Investigational Site	Incheon
Korea, Republic of	GSK Investigational Site	Jeonju-si, Jeollabuk-do
Korea, Republic of	GSK Investigational Site	Seongnam-si, Gyeonggi-do
Korea, Republic of	GSK Investigational Site	Seoul
Korea, Republic of	GSK Investigational Site	Seoul
Korea, Republic of	GSK Investigational Site	Seoul
Korea, Republic of	GSK Investigational Site	Seoul
Korea, Republic of	GSK Investigational Site	Seoul
Korea, Republic of	GSK Investigational Site	Seoul
Mexico	GSK Investigational Site	Guadalajara	Jalisco
Mexico	GSK Investigational Site	Monterrey	Nuevo León
Mexico	GSK Investigational Site	Zapopan	Jalisco
Netherlands	GSK Investigational Site	Alkmaar
Netherlands	GSK Investigational Site	Breda
Netherlands	GSK Investigational Site	Eindhoven
Netherlands	GSK Investigational Site	Groningen
Netherlands	GSK Investigational Site	Harderwijk
Netherlands	GSK Investigational Site	Hoorn
Netherlands	GSK Investigational Site	Rotterdam
Netherlands	GSK Investigational Site	Utrecht
Netherlands	GSK Investigational Site	Zwolle
Poland	GSK Investigational Site	Bialystok
Poland	GSK Investigational Site	Elblag
Poland	GSK Investigational Site	Krakow
Poland	GSK Investigational Site	Lubin
Poland	GSK Investigational Site	Olawa
Poland	GSK Investigational Site	Ruda Slaska
Poland	GSK Investigational Site	Slupsk
Poland	GSK Investigational Site	Sosnowiec
Poland	GSK Investigational Site	Tarnow
Romania	GSK Investigational Site	Bucarest
Romania	GSK Investigational Site	Bucharest
Romania	GSK Investigational Site	Bucharest
Romania	GSK Investigational Site	Cluj Napoca
Romania	GSK Investigational Site	Comuna Alexandru Cel Bun
Romania	GSK Investigational Site	Iasi
Romania	GSK Investigational Site	Oradea
Romania	GSK Investigational Site	Ramnicu Valcea
Romania	GSK Investigational Site	Suceava
Romania	GSK Investigational Site	Timisoara
Russian Federation	GSK Investigational Site	Barnaul
Russian Federation	GSK Investigational Site	Belgorod
Russian Federation	GSK Investigational Site	Blagoveshchensk
Russian Federation	GSK Investigational Site	Chelyabinsk
Russian Federation	GSK Investigational Site	Chelyabinsk
Russian Federation	GSK Investigational Site	Ivanovo
Russian Federation	GSK Investigational Site	Kemerovo
Russian Federation	GSK Investigational Site	Nizhniy Novgorod
Russian Federation	GSK Investigational Site	Novgorod
Russian Federation	GSK Investigational Site	Novosibirsk
Russian Federation	GSK Investigational Site	Perm
Russian Federation	GSK Investigational Site	Ryazan
Russian Federation	GSK Investigational Site	Saratov
Russian Federation	GSK Investigational Site	Tomsk
Russian Federation	GSK Investigational Site	Ulyanovsk
Russian Federation	GSK Investigational Site	Voronezh
Spain	GSK Investigational Site	Barcelona
Spain	GSK Investigational Site	Basurto/Bilbao
Spain	GSK Investigational Site	Cáceres
Spain	GSK Investigational Site	Cartagena (Murcia)
Spain	GSK Investigational Site	Elda (Alicante)
Spain	GSK Investigational Site	Gerona
Spain	GSK Investigational Site	Laredo	Cantabria
Spain	GSK Investigational Site	Logroño
Spain	GSK Investigational Site	Madrid
Spain	GSK Investigational Site	Madrid
Spain	GSK Investigational Site	Madrid
Spain	GSK Investigational Site	Mérida (Badajoz)
Spain	GSK Investigational Site	Orihuela (Alicante)
Spain	GSK Investigational Site	Palma de Mallorca
Spain	GSK Investigational Site	Pama de Mallorca
Spain	GSK Investigational Site	Ponferrada (León)
Spain	GSK Investigational Site	Pozuelo De Alarcón/Madrid
Sweden	GSK Investigational Site	Göteborg
Sweden	GSK Investigational Site	Lund
United Kingdom	GSK Investigational Site	Blackburn
United Kingdom	GSK Investigational Site	Bradford
United Kingdom	GSK Investigational Site	Chesterfield	Derbyshire
United Kingdom	GSK Investigational Site	Edgbaston
United Kingdom	GSK Investigational Site	Edinburgh
United Kingdom	GSK Investigational Site	Liverpool
United Kingdom	GSK Investigational Site	Sheffield
United Kingdom	GSK Investigational Site	Stockton-on-Tees
United Kingdom	GSK Investigational Site	Wishaw	Lanarkshire
United States	GSK Investigational Site	Abingdon	Virginia
United States	GSK Investigational Site	Adairsville	Georgia
United States	GSK Investigational Site	Charleston	South Carolina
United States	GSK Investigational Site	Chesterfield	Missouri
United States	GSK Investigational Site	Cincinnati	Ohio
United States	GSK Investigational Site	Colorado Springs	Colorado
United States	GSK Investigational Site	Columbia	Maryland
United States	GSK Investigational Site	Dayton	Ohio
United States	GSK Investigational Site	Daytona Beach	Florida
United States	GSK Investigational Site	Erie	Pennsylvania
United States	GSK Investigational Site	Gastonia	North Carolina
United States	GSK Investigational Site	Mobile	Alabama
United States	GSK Investigational Site	Morgantown	West Virginia
United States	GSK Investigational Site	Omaha	Nebraska
United States	GSK Investigational Site	Rapid City	South Dakota
United States	GSK Investigational Site	Richmond	Virginia
United States	GSK Investigational Site	Richmond	Virginia
United States	GSK Investigational Site	Saint Charles	Missouri
United States	GSK Investigational Site	Saint Petersburg	Florida
United States	GSK Investigational Site	Spartanburg	South Carolina
United States	GSK Investigational Site	Woodstock	Georgia

Sponsors (1)

Lead Sponsor	Collaborator
GlaxoSmithKline

Countries where clinical trial is conducted

United States,  Argentina,  Australia,  Canada,  France,  Germany,  Italy,  Korea, Republic of,  Mexico,  Netherlands,  Poland,  Romania,  Russian Federation,  Spain,  Sweden,  United Kingdom, 

References & Publications (1)

Fahy WA, Homayoun-Valiani F, Cahn A, Robertson J, Templeton A, Meeraus WH, Wilson R, Lowings M, Marotti M, West SL, Tabberer M, Hessel EM. Nemiralisib in Patients with an Acute Exacerbation of COPD: Placebo-Controlled, Dose-Ranging Study. Int J Chron Obstruct Pulmon Dis. 2021 Jun 3;16:1637-1646. doi: 10.2147/COPD.S309320. eCollection 2021. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Area Under the Concentration Time Curve (AUC) From Time Zero to 24 Hours [AUC(0-24)] of Nemiralisib	Plasma samples were collected at indicated time points and analyzed.	Pre-dose, 0-1 hour, >1-6 hours post-dose on Days 14 and 28
Other	AUC From Time Zero to Time 't' [AUC(0-t)] of Nemiralisib	Plasma samples were collected at indicated time points and analyzed.	Pre-dose, 0-1 hour, >1-6 hours post-dose on Days 14 and 28
Other	Maximum Observed Plasma Drug Concentration (Cmax) of Nemiralisib	Plasma samples were collected at indicated time points and analyzed.	Pre-dose, 0-1 hour, >1-6 hours post-dose on Days 14 and 28
Other	Time to Reach Cmax (Tmax) of Nemiralisib	Plasma samples were collected at indicated time points and analyzed.	Pre-dose, 0-1 hour, >1-6 hours post-dose on Days 14 and 28
Other	Plasma Drug Concentration at Pre-dose (Ctrough) of Nemiralisib	Plasma samples were collected at indicated time points and analyzed.	Pre-dose, 0-1 hour, >1-6 hours post-dose on Days 14 and 28
Primary	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.	Baseline and Day 84
Secondary	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.	Up to Week 12
Secondary	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.	Up to Week 12
Secondary	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.	Baseline and Days 14, 28, 56 (pre and post bronchodilaor), 84 (pre-bronchodilator) and at hospital discharge (maximum 24 Weeks)
Secondary	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.	Baseline and pre- and post-bronchodilator on Days 14, 28, 56 and 84
Secondary	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.	Days 14, 28, 56 and 84
Secondary	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.	From randomization to Week 12
Secondary	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.	Up to Week 12
Secondary	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.	Days 28, 56 and 84
Secondary	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.	Baseline and at Days 28, 56 and 84
Secondary	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.	Days 28, 56 and 84
Secondary	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	Baseline and Days 28, 56 and 84
Secondary	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.	Weeks 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12 of treatment and over the Week 12 treatment period
Secondary	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.	Weeks 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12 of treatment and over the Week 12 treatment period
Secondary	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.	Pre-dose, 0-1 hour, >1-6 hours post-dose on Days 14 and 28
Secondary	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.	Up to Week 24
Secondary	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.	Up to Week 16
Secondary	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.	Screening, Days 14, 84, 112 and at early withdrawal
Secondary	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.	Upto Week 16
Secondary	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.	Upto Week 16
Secondary	Number of Participants Reporting COPD Exacerbations	Participants reporting acute COPD exacerbations during the study period has been presented.	Up to Week 16