bupropion and Airflow Obstruction, Chronic studies

Bupropion: A propiophenone-derived antidepressant and antismoking agent that inhibits the uptake of DOPAMINE.
bupropion : An aromatic ketone that is propiophenone carrying a tert-butylamino group at position 2 and a chloro substituent at position 3 on the phenyl ring.

Research Excerpts

Excerpt	Relevance	Reference
"Bupropion SR treatment is an efficacious aid to smoking cessation in patients with COPD."	9.11	Efficacy of bupropion and nortriptyline for smoking cessation among people at risk for or with chronic obstructive pulmonary disease. ( Huibers, MJ; Knipschild, PG; van Schayck, CP; Wagena, EJ; Wouters, EF, 2005)
"The advent of bupropion hydrochloride sustained release (Zyban) has heralded a major change in the options available for smoking cessation pharmacotherapy."	8.82	Review of bupropion for smoking cessation. ( Richmond, R; Zwar, N, 2003)
" The aim of this study was to assess the cost-effectiveness of varenicline compared with other existing strategies for smoking cessation within a 10-year time horizon in an adult population cohort from Central American and Caribbean countries using the health care payer's perspective."	7.78	Cost-effectiveness analysis of varenicline versus existing smoking cessation strategies in Central America and the Caribbean using the BENESCO model. ( Cuesta, G; Lovato, P; Lutz, MA, 2012)
"A total of 255 participants, aged 30-70 years, received smoking cessation counselling and were assigned bupropion, nortriptyline or placebo randomly for 12 weeks."	5.14	The cost-effectiveness of antidepressants for smoking cessation in chronic obstructive pulmonary disease (COPD) patients. ( Kaper, J; Severens, JL; Van Schayck, CP; Wagena, EJ; Wouters, EF, 2009)
"Bupropion SR treatment is an efficacious aid to smoking cessation in patients with COPD."	5.11	Efficacy of bupropion and nortriptyline for smoking cessation among people at risk for or with chronic obstructive pulmonary disease. ( Huibers, MJ; Knipschild, PG; van Schayck, CP; Wagena, EJ; Wouters, EF, 2005)
"The mainstay in smoking cessation is counselling in combination with varenicline, nicotine replacement therapy (NRT) or bupropion SR."	4.89	Smoking cessation and COPD. ( Tønnesen, P, 2013)
"The advent of bupropion hydrochloride sustained release (Zyban) has heralded a major change in the options available for smoking cessation pharmacotherapy."	4.82	Review of bupropion for smoking cessation. ( Richmond, R; Zwar, N, 2003)
"Bupropion and varenicline can substantially improve the chances of smoking cessation in patients with COPD, but are unsubsidized and relatively costly."	3.88	Socioeconomic inequality in the use of prescription medications for smoking cessation among patients with COPD: a nationwide study. ( Clark, AJ; Johnsen, SP; Lange, P; Thomsen, RW; Tøttenborg, SS, 2018)
"Varenicline and bupropion are effective smoking cessation treatments, but there are concerns about their safety in smokers with COPD."	3.85	Cardiovascular and neuropsychiatric risks of varenicline and bupropion in smokers with chronic obstructive pulmonary disease. ( Kotz, D; Sheikh, A; Simpson, CR; van Schayck, OCP; Viechtbauer, W; West, R, 2017)
" The aim of this study was to assess the cost-effectiveness of varenicline compared with other existing strategies for smoking cessation within a 10-year time horizon in an adult population cohort from Central American and Caribbean countries using the health care payer's perspective."	3.78	Cost-effectiveness analysis of varenicline versus existing smoking cessation strategies in Central America and the Caribbean using the BENESCO model. ( Cuesta, G; Lovato, P; Lutz, MA, 2012)
" The aim of this study was to compare the direct medical costs of smoking cessation therapies with varenicline, bupropion, nicotine replacement therapy, and unaided cessation in Nicaragua over 5 time horizons: 2, 5, 10, and 20 years, and lifetime."	3.78	Cost analysis of varenicline versus bupropion, nicotine replacement therapy, and unaided cessation in Nicaragua. ( Cuesta, G; Lovato, P; Lutz, MA, 2012)
"COPD is the fifth leading cause of death in the world and smoking leads to COPD in more than 80% of cases."	2.53	Evaluating the effectiveness of smoking cessation in the management of COPD. ( Ojo, O; Temitayo Orisasami, I, 2016)
"Smoking cessation is the most important treatment for smokers with chronic obstructive pulmonary disease (COPD), but little is known about the effectiveness of different smoking cessation interventions for this particular group of smokers."	2.53	Smoking cessation for people with chronic obstructive pulmonary disease. ( Kotz, D; van der Meer, RM; van Eerd, EA; van Schayck, OC, 2016)
"It is the major risk factor for chronic obstructive pulmonary disease in the developed world."	2.50	Smoking cessation. ( Daughton, DM; Rennard, SI, 2014)
"Pharmacotherapy to aid cessation in COPD smokers have proven to be highly cost effective."	2.49	Smoking cessation treatment for COPD smokers: the role of pharmacological interventions. ( Fagerström, KO; Jiménez-Ruiz, CA, 2013)
"Patients with COPD show higher nicotine dependence and seem to have greater difficulty in quitting smoking."	2.47	[Smoking in COPD]. ( Bernabé Barrios, MJ; Rodríguez Hermosa, JL; Santamaría Rodríguez, B; Zamarro García, C, 2011)
"Chronic obstructive pulmonary disease (COPD) is rapidly becoming a global public health crisis with smoking being recognized as its most important causative factor."	2.45	Smoking and chronic obstructive pulmonary disease (COPD). Parallel epidemics of the 21 century. ( Laniado-Laborín, R, 2009)
"Optimization of NRT is of importance in COPD patients because they may be more nicotine dependent and have more difficulties to quit than smokers without COPD."	2.45	Therapeutic strategies to optimize the efficacy of nicotine replacement therapies. ( Berlin, I, 2009)
"Smoking cessation is the most effective way to reduce the risk of developing chronic obstructive pulmonary disease (COPD) or to reduce its progression."	2.42	Benefits and risks of pharmacological smoking cessation therapies in chronic obstructive pulmonary disease. ( van Schayck, CP; Wagena, EJ; Wouters, EF; Zeegers, MP, 2003)
"Theophylline has weak antiinflammatory effects."	2.42	[New drug therapy of chronic obstructive pulmonary disease]. ( Kino, H, 2003)
" There is a dose-response relationship between the number and duration of sessions and quit rate."	2.42	Essential communication skills in individual smoking cessation. ( Tønnesen, P, 2004)
"A significant proportion of COPD patients (∼40%) continue smoking despite knowing that they have the disease."	1.91	Smoking cessation and vaccination. ( Laucho-Contreras, ME; Montes de Oca, M, 2023)
"For the COPD population (1598), there were no differences in the incidence of NPAEs between comparison groups in both the psychiatric cohort (aOR 0."	1.62	Neuropsychiatric safety of varenicline in the general and COPD population with and without psychiatric disorders: a retrospective cohort study in a real-world setting. ( Boezen, HM; Bos, JH; Hak, E; Schuiling-Veninga, CCM; van Boven, JFM; Wang, Y; Wilffert, B, 2021)
"Patients admitted for chronic obstructive pulmonary disease (COPD) commonly continue to smoke."	1.43	Utilization and effectiveness of pharmacotherapy for tobacco use following admission for exacerbation of COPD. ( Au, DH; Collins, MP; Feemster, LC; Melzer, AC, 2016)
"The model estimated that 17,756 COPD patients would stop smoking if public funding was available, compared with 1,303 without reimbursement."	1.42	Budgetary impact analysis on funding smoking-cessation drugs in patients with COPD in Spain. ( Altet-Gomez, N; Barrueco, M; de Higes-Martinez, E; Granda-Orive, JI; Jiménez-Ruiz, CA; Lorza-Blasco, JJ; Oyagüez, I; Rejas, J; Riesco-Miranda, JA; Signes-Costa, J; Solano-Reina, S, 2015)
"In turn COPD is a major independent risk factor for lung cancer."	1.38	Role of CHRNA5-A3 genetic Locus variants and developing drug for chronic obstructive pulmonary disease. ( Cesario, A; Granone, P; Lococo, F; Petracca-Ciavarella, L; Russo, P, 2012)
"Chronic obstructive pulmonary disease (COPD) is mainly caused by smoking, and smoking cessation is the single most important intervention to prevent disease progression."	1.35	High rate of smoking abstinence in COPD patients: Smoking cessation by hospitalization. ( Larsson, K; Nathell, L; Sundblad, BM, 2008)
"Rehabilitation of COPD-patients is an important part of the therapeutic management."	1.33	[COPD-rehabilitation]. ( Lichtenschopf, A; Zwick, H, 2005)
"Smoking causes chronic obstructive pulmonary disease (COPD) in 15 to 20% of smokers."	1.33	[Success of smoking cessation in patients with chronic obstructive pulmonary disease]. ( Aytemur Solak, Z; Başoğlu, OK; Erdinç, E, 2006)

Research

Studies (39)

Authors

Clinical Trials (4)

Trial Overview

Trial Outcomes

Change From Baseline in FEV1 AUC(0-12h) Normalized by Time at Week 6

Timeframe	Studies, this research(%)	All Research%
pre-1990	0 (0.00)	18.7374
1990's	0 (0.00)	18.2507
2000's	17 (43.59)	29.6817
2010's	19 (48.72)	24.3611
2020's	3 (7.69)	2.80

Authors	Studies
Montes de Oca, M	1
Laucho-Contreras, ME	1
Antoniu, SA	1
Buculei, I	1
Mihaltan, F	1
Crisan Dabija, R	1
Trofor, AC	1
Wang, Y	1
Bos, JH	1
Schuiling-Veninga, CCM	1
Boezen, HM	1
van Boven, JFM	1
Wilffert, B	1
Hak, E	1
Kotz, D	2
Viechtbauer, W	1
Simpson, CR	1
van Schayck, OCP	1
West, R	1
Sheikh, A	1
Jiménez Ruiz, CA	2
Buljubasich, D	1
Riesco Miranda, JA	3
Acuña Izcaray, A	1
de Granda Orive, JI	2
Chatkin, JM	1
Zabert, G	1
Guerreros Benavides, A	1
Paez Espinel, N	1
Noé, V	1
Sánchez-Angarita, E	1
Núñez-Sánchez, I	1
Sansores, RH	1
Casas, A	1
Palomar Lever, A	1
Alfageme Michavila, I	1
Kress, CM	1
Obi, NU	1
Prochazka, AV	1
Tøttenborg, SS	1
Clark, AJ	1
Thomsen, RW	1
Johnsen, SP	1
Lange, P	1
Tønnesen, P	2
Jiménez-Ruiz, CA	3
Altet Gómez, N	1
Lorza Blasco, JJ	1
Signes-Costa Miñana, J	1
Solano Reina, S	1
Ramos Pinedo, A	1
Martinez Muñiz, MA	1
Barrueco Ferrero, M	1
Fagerström, KO	1
Rennard, SI	1
Daughton, DM	1
Poulsen, PB	1
Spillemose, H	1
Nielsen, G	1
Hergel, LL	1
Wedell-Wedellsborg, D	1
Strand, M	1
Ringbæk, T	1
Solano-Reina, S	1
Signes-Costa, J	1
de Higes-Martinez, E	1
Granda-Orive, JI	1
Lorza-Blasco, JJ	1
Riesco-Miranda, JA	1
Altet-Gomez, N	1
Barrueco, M	1
Oyagüez, I	1
Rejas, J	1
Melzer, AC	1
Feemster, LC	1
Collins, MP	1
Au, DH	1
Temitayo Orisasami, I	1
Ojo, O	1
van Eerd, EA	1
van der Meer, RM	1
van Schayck, OC	1
Sundblad, BM	1
Larsson, K	1
Nathell, L	1
Paone, G	1
Serpilli, M	1
Girardi, E	1
Conti, V	1
Principe, R	1
Puglisi, G	1
De Marchis, L	1
Schmid, G	1
Bredesen, H	1
Lous, J	1
Laniado-Laborín, R	1
Berlin, I	1
Van Schayck, CP	3
Kaper, J	1
Wagena, EJ	3
Wouters, EF	3
Severens, JL	1
Christenhusz, LC	1
Prenger, R	1
Pieterse, ME	1
Seydel, ER	1
van der Palen, J	3
Lutz, MA	2
Lovato, P	2
Cuesta, G	2
Lococo, F	1
Cesario, A	1
Petracca-Ciavarella, L	1
Granone, P	1
Russo, P	1
Zamarro García, C	1
Bernabé Barrios, MJ	1
Santamaría Rodríguez, B	1
Rodríguez Hermosa, JL	1
Zeegers, MP	1
Richmond, R	1
Zwar, N	1
Kino, H	1
Monninkhof, E	1
van der Valk, P	1
Mulder, H	1
Pieterse, M	2
van Herwaarden, C	1
Zielhuis, G	1
Górecka, D	1
Bednarek, M	1
Nowiński, A	1
Puścińska, E	1
Goljan-Geremek, A	1
Zieliński, J	1
Zwick, H	1
Lichtenschopf, A	1
Knipschild, PG	1
Huibers, MJ	1
Aytemur Solak, Z	1
Başoğlu, OK	1
Erdinç, E	1
Christenhusz, L	1
Seydel, E	1
Hering, T	1

Trial	Phase	Enrollment	Study Type	Start Date	Status
A 6-week, Multicenter, Randomized, Double-blind, Placebo and Active-controlled, Parallel Group, Dose-ranging Study to Evaluate the Efficacy and Safety of 4 Doses of CHF 5259 pMDI (HFA Glycopyrronium Bromide Via Pressurized Metered Dose Inhaler) in Subject[NCT03084796]	Phase 2	733 participants (Actual)	Interventional	2017-07-28	Completed
An 8-week, Multicenter, Randomized, Double-blind, Placebo and Active-controlled, Parallel Group, Dose-ranging Study to Evaluate the Efficacy and Safety of 3 Doses of CHF 718 pMDI (HFA Beclomethasone Dipropionate Via Pressured Metered Dose Inhaler) in Asth[NCT03084718]	Phase 2	610 participants (Actual)	Interventional	2017-07-28	Completed
"A Randomized Open-label, Superiority, Multicenter, Two-arm Intervention Study of the Effect of High-intensity vs. 'Low-intensity' Smoking Cessation Intervention in Active Smokers With COPD"[NCT04088942]	Phase 4	0 participants (Actual)	Interventional	2023-07-01	Withdrawn (stopped due to No funding)
A Randomized, Double-blind, Placebo and Active-controlled, Incomplete Block Cross-over, Dose Ranging Study to Evaluate the Efficacy and Safety of 4 Doses of CHF 1531 pMDI (Formoterol Fumarate) in Asthmatic Subjects[NCT03086460]	Phase 2	67 participants (Actual)	Interventional	2017-09-08	Completed
[information is prepared from clinicaltrials.gov, extracted Sep-2024]

"Change from baseline in FEV1 AUC(0-12h), normalized by time, at the end of treatment (Week 6).~Spirometry, used to measure FEV1, was performed according to internationally accepted standards. The AUC for FEV1 at Week 6 of treatment was calculated by using the linear trapezoidal rule, based on the changes in FEV1 from the baseline values, and divided by the observation time (12 hours).~Definitions:~AUC=Area under the curve; Baseline=Baseline value was the average of the pre-dose measurements (at 45 mins and 15 mins pre-dose), at Visit 2 (Week 0); FEV1=Forced expiratory volume in the 1st second; FEV1 AUC(0-12h)=Mean FEV1 after inhalation, measured at prespecified times for up to 12-h observation period (0-12 h), normalized by time;" (NCT03084796)
Timeframe: Baseline, Week 6

Change From Baseline in FEV1 AUC(0-12h) Normalized by Time on Day 1

Intervention	Litres (Least Squares Mean)
Treatment A	0.070
Treatment B	0.118
Treatment C	0.153
Treatment D	0.147
Treatment E	0.002
Treatment F	0.213

"Change from baseline in FEV1 AUC(0-12h), normalized by time, on Day 1.~Spirometry, used to measure FEV1, was performed according to internationally accepted standards. The AUC for FEV1 on Day 1 of treatment was calculated by using the linear trapezoidal rule, based on the changes in FEV1 from the baseline values, and divided by the observation time (12 hours).~Definitions:~AUC=Area under the curve; Baseline=Baseline value was the average of the pre-dose measurements (at 45 mins and 15 mins pre-dose), at Visit 2 (Week 0); Day 1=Day of the first dose of randomized study drug at Visit 2 (Week 0); FEV1=Forced expiratory volume in the 1st second; FEV1 AUC(0-12h)=Mean FEV1 after inhalation, measured at prespecified times for up to 12-h observation period (0-12 h), normalized by time;" (NCT03084796)
Timeframe: Baseline, Day 1

Number of Patients Achieving Onset of Action - Change From Baseline in Post-dose FEV1 ≥100 mL on Day 1

Intervention	Litres (Least Squares Mean)
Treatment A	0.067
Treatment B	0.086
Treatment C	0.135
Treatment D	0.149
Treatment E	0.009
Treatment F	0.192

Number of patients achieving onset of action was defined as a change from baseline in post-dose FEV1 ≥100 mL on Day 1. These are the patients who contributed to the results, reported as median and 95% CI for 'time to onset of action' presented in Outcome Measure 8, above. (NCT03084796)
Timeframe: Day 1

Time to Onset of Action (Change From Baseline in Post-dose FEV1 ≥ 100 mL) on Day 1

Intervention	Participants (Count of Participants)
Treatment A	90
Treatment B	103
Treatment C	103
Treatment D	110
Treatment E	74
Treatment F	113

Time to onset of action is defined as the time (in minutes) from receiving the study drug on Day 1, until the FEV1 change from baseline is ≥100 mL. (NCT03084796)
Timeframe: Day 1

Change From Baseline in 24-Hour Holter Electrocardiogram (ECG) Parameters - Fridericia-corrected QT Interval (QTcF)

Intervention	minutes (Mean)
Treatment A	45.1
Treatment B	32.6
Treatment C	29.5
Treatment D	27.3
Treatment E	240.1
Treatment F	28.1

"Change from baseline in 24-Hour Holter electrocardiogram (ECG) parameters - Fridericia-corrected QT interval (QTcF).~Subjects had a 24-h Holter recording before and 24 h after the 1st dose of study drug (Visit 2) and for 24 h before the last dose of study drug (Visit 4). The time-matched values recorded during the 24 h before the 1st dose of study drug on Visit 2 and served as the baseline for the Holter-extracted ECG parameters. The time-averaged baseline score is the average of the Day -1 scores at +5 min, +55 min, and at +2.5 h." (NCT03084796)
Timeframe: Baseline, Day 1, Week 6

Change From Baseline in 24-Hour Holter Electrocardiogram (ECG) Parameters - Heart Rate (HR)

Intervention	msec (Mean)
	QTcF, Day 1, 5 min post dose	QTcF, Day 1, 55 min post dose	QTcF, Day 1, 2.5 h post dose	QTcF, Day before Week 6, 5 min post dose	QTcF, Day before Week 6, 55 min post dose	QTcF, Day before Week 6, 2.5 h post dose
Treatment A	3.62	8.37	7.15	1.61	2.38	4.13
Treatment B	5.37	5.41	8.65	1.14	0.09	0.85
Treatment C	6.81	6.72	7.20	-0.60	1.41	-0.97
Treatment D	6.25	9.90	5.45	1.67	4.15	1.73
Treatment E	3.59	6.04	4.81	-3.56	1.02	0.14
Treatment F	5.56	5.43	6.77	1.41	3.19	2.50

"Change from baseline in 24-Hour Holter electrocardiogram (ECG) parameters - Heart rate (HR)~Subjects had a 24-h Holter recording before and 24 h after the 1st dose of study drug (Visit 2) and for 24 h before the last dose of study drug (Visit 4). The time-matched values recorded during the 24 h before the 1st dose of study drug on Visit 2 and served as the baseline for the Holter-extracted ECG parameters. The time-averaged baseline score is the average of the Day -1 scores at +5m, +55m, and at +2.5 h." (NCT03084796)
Timeframe: Baseline, Day 1, Week 6

Change From Baseline in 24-Hour Holter Electrocardiogram (ECG) Parameters - PR Interval

Intervention	bpm (Mean)
	HR, Day 1, 5 min post dose	HR, Day 1, 55 min post dose	HR, Day 1, 2.5 h post dose	HR, Day before Week 6, 5 min post dose	HR, Day before Week 6, 55 min post dose	HR, Day before Week 6, 2.5 h post dose
Treatment A	-8.85	-7.19	-7.57	-1.72	-1.52	-2.30
Treatment B	-6.62	-8.29	-6.75	-1.06	0.41	-0.01
Treatment C	-7.78	-8.28	-9.20	-1.61	-1.10	-1.13
Treatment D	-7.64	-9.59	-7.46	-1.85	-1.40	-0.73
Treatment E	-4.84	-7.44	-6.12	3.92	1.12	2.49
Treatment F	-5.54	-7.19	-8.96	1.70	1.22	-1.47

"Change from baseline in 24-Hour Holter electrocardiogram (ECG) parameters - PR Interval~Subjects had a 24-h Holter recording before and 24 h after the 1st dose of study drug (Visit 2) and for 24 h before the last dose of study drug (Visit 4). The time-matched values were recorded during the 24 h before the 1st dose of study drug on Visit 2 and served as the baseline for the Holter-extracted ECG parameters. The time-averaged baseline score is the average of the Day -1 scores at +5 min, +55 min, and at +2.5 h." (NCT03084796)
Timeframe: Baseline, Day 1, Week 6

Change From Baseline in 24-Hour Holter Electrocardiogram (ECG) Parameters - QRS Interval

Intervention	msec (Mean)
	PR Interval, Day 1, 5 min post dose	PR Interval, Day 1, 55 min post dose	PR Interval, Day 1, 2.5 h post dose	PR Interval, Day before Week 6, 5 min post dose	PR Interval, Day before Week 6, 55 min post dose	PR Interval, Day before Week 6, 2.5 h post dose
Treatment A	7.24	7.20	8.48	0.44	0.88	2.50
Treatment B	6.53	6.89	9.38	1.36	2.37	3.01
Treatment C	6.08	8.21	7.58	-0.11	1.91	0.16
Treatment D	6.71	6.77	6.16	3.88	0.82	0.84
Treatment E	3.06	4.38	5.84	-1.36	-1.13	-1.22
Treatment F	4.90	4.77	4.25	0.82	-1.66	-1.94

"Change from baseline in 24-Hour Holter electrocardiogram (ECG) parameters - QRS Interval~Subjects had a 24-h Holter recording before and 24 h after the 1st dose of study drug (Visit 2) and for 24 h before the last dose of study drug (Visit 4). The time-matched values were recorded during the 24 h before the 1st dose of study drug on Visit 2 and served as the baseline for the Holter-extracted ECG parameters. The time-averaged baseline score is the average of the Day -1 scores at +5 min, +55 min, and at +2.5 h." (NCT03084796)
Timeframe: Baseline, Day 1, Week 6

Change From Baseline in Average EXACT-Respiratory Symptom (E-RS) Total Score During Inter-Visit Periods and the Entire Treatment Period

Intervention	msec (Mean)
	QRS Interval, Day 1, 5 min post dose	QRS Interval, Day 1, 55 min post dose	QRS Interval, Day 1, 2.5 h post dose	QRS Interval, Day before Week 6, 5 min post dose	QRS Interval, Day before Week 6, 55 min post dose	QRS Interval, Day before Week 6, 2.5 h post dose
Treatment A	1.18	0.97	1.38	0.61	1.12	1.49
Treatment B	0.05	1.19	2.40	-1.76	-0.09	0.74
Treatment C	1.50	1.21	1.80	0.43	0.85	0.30
Treatment D	1.99	1.56	1.50	2.00	2.38	2.18
Treatment E	0.45	0.14	0.64	0.45	0.77	1.14
Treatment F	1.50	1.70	0.86	0.69	0.42	1.35

"Change from baseline in average EXACT-Respiratory Symptom (E-RS) total score during inter-visit periods and the entire treatment period~E-RS in COPD uses 11 respiratory symptom items from the 14-item EXAcerbations of COPD tool (EXACT). E-RS total score quantifies respiratory symptom severity on a scale ranging from 0 to 40. Higher E-RS total scores indicate more severe symptoms and a declining total score indicates health improvement. E-RS questionnaire was completed by the patient each evening (e-diary).~Definitions:~For details on baseline, inter-visit periods, and the entire treatment period, please refer to outcome measure #15." (NCT03084796)
Timeframe: Baseline, Inter-visit period 1, Inter-visit period 2, Entire treatment period

Change From Baseline in Average Use of Rescue Medication During Inter-Visit Periods and the Entire Treatment Period

Intervention	score on a scale (Least Squares Mean)
	Inter-visit period 1	Inter-visit period 2	Entire treatment period
Treatment A	-1.681	-2.030	-1.855
Treatment B	-1.539	-1.840	-1.689
Treatment C	-1.941	-2.147	-2.044
Treatment D	-1.663	-2.077	-1.870
Treatment E	-0.714	-0.681	-0.698
Treatment F	-1.280	-1.505	-1.393

"Evaluate the change from baseline in average use of rescue medication (number of puffs/day) during the inter-visit periods and the entire treatment period.~Results are shown as number of puffs/day; a decrease (implies improvement) from baseline in average use of rescue medication.~Definitions:~Baseline=Data recorded during the run-in period (a 2-week period prior to randomization to study treatment and study drug intake); Inter-visit period 1=Starts at randomization to treatment (Visit 2, Week 0) and runs to the day before the subject returns to the clinic (Visit 3 (Week 3); Inter-visit period 2=Starts when the subject returns to the clinic (Visit 3, Week 3) and runs to the end of the randomized treatment period (Visit 4, Week 6); Entire Treatment period=From day of randomization to drug intake to the end of the randomized treatment period (Visit 4, Week 6); Randomization=Randomization to study drug treatment (Visit 2, Week 0);" (NCT03084796)
Timeframe: Baseline, Inter-visit period 1, Inter-visit period 2, Entire treatment period

Change From Baseline in FEV1 AUC(0-4h) Normalized by Time on Day 1 and at Week 6

Intervention	Number of puffs/day (Least Squares Mean)
	Inter-visit period 1	Inter-visit period 2	Entire treatment period
Treatment A	-0.72	-0.59	-0.66
Treatment B	-0.58	-0.50	-0.54
Treatment C	-0.53	-0.51	-0.52
Treatment D	-0.71	-0.69	-0.70
Treatment E	-0.30	-0.17	-0.23
Treatment F	-0.52	-0.40	-0.46

"Change from baseline in FEV1 AUC(0-4h), normalized by time on Day 1 of treatment (Week 0).~Spirometry, used to measure FEV1, was performed according to internationally accepted standards. The AUC for FEV1 on Day 1 and at Week 6 of treatment was calculated by using the linear trapezoidal rule, based on the changes in FEV1 from the baseline values, and divided by the observation time (4 hours).~Definitions:~AUC=Area under the curve; Baseline=Baseline value was the average of the pre-dose measurements (at 45 mins and 15 mins pre-dose), at Visit 2 (Week 0); Day 1=Day of the first dose of randomized study drug at Visit 2 (Week 0); FEV1=Forced expiratory volume in the 1st second; FEV1 AUC(0-4h)=Mean FEV1 after inhalation, measured at prespecified times for up to 4-h observation period (0-4h), normalized by time;" (NCT03084796)
Timeframe: Baseline, Day 1, Week 6

Change From Baseline in FEV1 Peak(0-4h) at Day 1 and Week 6

Intervention	Litres (Least Squares Mean)
	Day 1	Week 6
Treatment A	0.101	0.116
Treatment B	0.115	0.157
Treatment C	0.173	0.198
Treatment D	0.190	0.204
Treatment E	0.030	0.024
Treatment F	0.194	0.253

"Change from baseline in FEV1 peak(0-4h) (L) on Day 1 and at Week 6.~Peak FEV1 is defined as the maximum FEV1 observed in the first 4 hours after dose of study medication.~Definitions:~Baseline=Baseline value was the average of the pre-dose measurements (at 45 mins and 15 mins pre-dose), at Visit 2 (Week 0); Day 1=Day of the first dose of randomized study drug at Visit 2 (Week 0); FEV1=Forced expiratory volume in the 1st second; Peak(0-4h)=Maximum FEV1 between 0 and 4 h." (NCT03084796)
Timeframe: Baseline, Day 1, Week 6

Change From Baseline in FVC AUC(0-12h), Normalized by Time on Day 1 and at Week 6

Intervention	Litres (Least Squares Mean)
	Day 1	Week 6
Treatment A	0.197	0.212
Treatment B	0.211	0.255
Treatment C	0.260	0.305
Treatment D	0.288	0.301
Treatment E	0.136	0.143
Treatment F	0.299	0.356

"Change from baseline in FVC AUC(0-12h), normalized by time, on Day 1 and at the end of treatment (Week 6).~Spirometry, used to measure FVC, was performed according to internationally accepted standards. The AUC for FVC was calculated by using the linear trapezoidal rule, based on the changes in FVC from the baseline values, and divided by the observation time (4 hours).~Definitions:~AUC=Area under the curve; Baseline=Baseline value was the average of the pre-dose measurements (at 45 mins and 15 mins pre-dose), at Visit 2 (Week 0); Day 1=Day of the first dose of randomized study drug at Visit 2 (Week 0); FVC=Forced Vital Capacity; FVC AUC(0-12h)=Mean FVC after inhalation, measured at prespecified times for up to 12-h observation period (0-12 h), normalized by time;" (NCT03084796)
Timeframe: Baseline, Day 1, Week 6

Change From Baseline in FVC AUC(0-4h) Normalized by Time on Day 1 and at Week 6

Intervention	Litres (Least Squares Mean)
	Day 1	Week 6
Treatment A	0.086	0.084
Treatment B	0.133	0.145
Treatment C	0.195	0.190
Treatment D	0.220	0.184
Treatment E	0.011	-0.029
Treatment F	0.305	0.298

"Change from baseline in FVC AUC(0-4h), normalized by time, on Day 1 and at the end of treatment (Week 6).~Spirometry, used to measure FVC, was performed according to internationally accepted standards. The AUC for FVC was calculated by using the linear trapezoidal rule, based on the changes in FVC from the baseline values, and divided by the observation time (4 hours).~Definitions:~AUC=Area under the curve; Baseline=Baseline value was the average of the pre-dose measurements (at 45 mins and 15 mins pre-dose), at Visit 2 (Week 0); Day 1=Day of the first dose of randomized study drug at Visit 2 (Week 0); FVC=Forced Vital Capacity; FVC AUC(0-4)=Mean FVC after inhalation, measured at prespecified times for up to 4-h observation period (0-4 h), normalized by time;" (NCT03084796)
Timeframe: Baseline, Day 1, Week 6

Change From Baseline in FVC Peak(0-4h) on Day 1 and at Week 6

Intervention	Litres (Least Squares Mean)
	Day 1	Week 6
Treatment A	0.133	0.149
Treatment B	0.192	0.203
Treatment C	0.244	0.248
Treatment D	0.273	0.253
Treatment E	0.036	0.000
Treatment F	0.311	0.353

"Change from baseline in FVC peak(0-4h) (L) on Day 1 and at the end of treatment at Week 6. Peak FEV1 is defined as the maximum FEV1 observed in the first 4 hours after dose of study medication.~Definitions:~Baseline=Baseline value was the average of the pre-dose measurements (at 45 mins and 15 mins pre-dose), at Visit 2 (Week 0); Day 1=Day of the first dose of randomized study drug at Visit 2 (Week 0); FVC=Forced Vital Capacity; Peak(0-4h)=Maximum FEV1 between 0 and 4 h." (NCT03084796)
Timeframe: Baseline, Day 1, Week 6

Change From Baseline in Percentage of Rescue Medication-Free Days During Inter-Visit Periods and the Entire Treatment Period

Intervention	Litres (Least Squares Mean)
	Day 1	Week 6
Treatment A	0.293	0.322
Treatment B	0.372	0.379
Treatment C	0.414	0.431
Treatment D	0.455	0.427
Treatment E	0.213	0.182
Treatment F	0.491	0.530

"Evaluate the number of rescue medication-free days compared with baseline. Results are shown as percentage (%) of rescue medication-free days; an increased value indicates improvement from baseline.~Definitions:~Baseline=Data recorded during the run-in period (a 2-week period prior to randomization to study treatment and study drug intake); Inter-visit period 1=Starts at randomization to treatment (Visit 2, Week 0) and runs to the day before the subject returns to the clinic (Visit 3, Week 3); Inter-visit period 2=Starts when the subject returns to the clinic (Visit 3, Week 3) and runs to the end of the randomized treatment period (Visit 4, Week 6); Entire Treatment period=From day of randomization to drug intake to the end of the randomized treatment period (Visit 4, Week 6); Randomization=Randomization to study drug treatment (Visit 2, Week 0)." (NCT03084796)
Timeframe: Baseline, Inter-visit period 1, Inter-visit period 2, Entire treatment period

Change From Baseline in Pre-dose Morning FEV1 at Week 3 and Week 6

Intervention	% of of rescue medication-free days (Least Squares Mean)
	Inter-visit period 1	Inter-visit period 2	Entire treatment period
Treatment A	16.78	13.83	15.30
Treatment B	15.67	15.51	15.59
Treatment C	15.55	14.03	14.79
Treatment D	18.19	18.15	18.17
Treatment E	8.90	7.07	7.98
Treatment F	13.51	11.27	12.39

"Change from baseline in FEV1 at treatment visit 3 (Week 3) and treatment visit 4 (Week 6) of treatment. Spirometry, used to measure FEV1, was performed according to internationally accepted standards.~Definitions:~Baseline=Baseline value was the average of the pre-dose measurements (at 45 mins and 15 mins pre-dose), at Visit 2 (Week 0); FEV1=Forced expiratory volume in the 1st second;" (NCT03084796)
Timeframe: Baseline, Week 3, Week 6

Change From Baseline in Pre-Dose Morning Inspiratory Capacity (IC) at Week 3 and Week 6

Intervention	Litres (Least Squares Mean)
	Week 3	Week 6
Treatment A	0.059	0.020
Treatment B	0.080	0.088
Treatment C	0.122	0.107
Treatment D	0.111	0.130
Treatment E	0.000	-0.012
Treatment F	0.122	0.112

"Change from baseline in IC at treatment Visit 3 (Week 3) and treatment Visit 4 (Week 6). Spirometry was used to measure IC and was performed according to internationally accepted standards.~Definitions:~Baseline: value of the measurement recorded at 45 mins pre-dose at Visit 2 (Week 0); IC=Inspiratory capacity;" (NCT03084796)
Timeframe: Baseline, Week 3, Week 6

Transition Dyspnea Index (TDI) Focal Score at Week 3 and Week 6

Intervention	Litres (Least Squares Mean)
	Week 3	Week 6
Treatment A	0.156	0.045
Treatment B	0.137	0.090
Treatment C	0.106	0.136
Treatment D	0.140	0.105
Treatment E	0.047	0.025
Treatment F	0.090	0.099

"Transitional Dyspnea Index (TDI) focal score at treatment visit 3 (Week 3) and treatment visit 4 (Week 6).~TDI is a validated, interviewer-administered questionnaire that measures changes in dyspnea severity from the baseline established by the BDI questionnaire. TDI consists of the same 24 items and 3 domains as the BDI, with the same 2-week recall period. Each category is rated by 7 grades ranging from -3 (major deterioration) to +3 (major improvement), with a total score ranging from -9 to +9, with higher scores indicating better outcomes. The minimal clinically important differences (MCID) is considered a change of ≥1 unit. The same investigator or designee interviewed the subject for the BDI and TDI during the study period. A TDI focal score of ≥1 is considered as clinically important.~Definitions:~Baseline=The BDI focal score value at Visit 2 (Week 0); BDI=Baseline Dyspnea Index; MCID=Minimal Clinically Important Differences; TDI=Transition Dyspnea Index;" (NCT03084796)
Timeframe: Baseline, Week 3, Week 6

Transition Dyspnea Index (TDI) Response (Focal Score ≥1) at Week 3 and Week 6

Intervention	score on a scale (Least Squares Mean)
	Week 3	Week 6
Treatment A	1.29	1.65
Treatment B	1.55	2.02
Treatment C	1.54	2.05
Treatment D	1.94	2.55
Treatment E	1.14	1.03
Treatment F	1.66	2.11

"Number of subjects achieving TDI focal score ≥1, at treatment visit 3 (Week 3) and at treatment visit 4 (Week 6).~TDI is a validated, interviewer-administered questionnaire that measures changes in dyspnea severity from the baseline established by the BDI questionnaire. TDI consists of the same 24 items and 3 domains as the BDI, with the same 2-week recall period. Each category is rated by 7 grades ranging from -3 (major deterioration) to +3 (major improvement); total score ranging from -9 to +9, with higher scores indicating better outcomes. The minimal clinically important differences (MCID) is considered a change of ≥1 unit. The same investigator or designee interviewed the subject for the BDI and TDI during the study period. A TDI focal score of ≥1 is considered as clinically important.~Definitions:~Baseline=The BDI focal score value at Visit 2 (Week 0); BDI=Baseline Dyspnea Index; MCID=Minimal Clinically Important Differences; TDI=Transition Dyspnea Index;" (NCT03084796)
Timeframe: Baseline, Week 3, Week 6

Vital Signs -- Systolic Blood Pressure (SBP), Diastolic Blood Pressure (DBP)

Intervention	Participants (Count of Participants)
	Week 3 Focal Score ≥ 1	Week 6 Focal Score ≥ 1
Treatment A	70	74
Treatment B	78	83
Treatment C	75	82
Treatment D	84	91
Treatment E	67	55
Treatment F	74	80

"Vital signs -- Systolic blood pressure (SBP), Diastolic blood pressure (DBP) were measured at prespecified times, using a 12-Lead single ECGs were recorded at all study visits (pre-dose at V1 (Week -2) and V3 (Week 3), as well as at pre-dose and 1.5 hours post-dose at Visit 2 (Week 0) and Visit 4 (Week 6).~Results are shown by treatment group, as change from baseline (in mmHg) for representative timepoints.~Definitions:~Baseline=Values recorded pre-dose (Visit 2, Week 0); Day 1=Day of the first dose of randomized study drug (Visit 2, Week 0);" (NCT03084796)
Timeframe: Baseline, Day 1, Week 6

24-hour Holter ECG - Prolonged QTcF - Change From Baseline

Intervention	mmHg (Mean)
	SBP, Day 1, 30 min post dose	DBP, Day 1, 30 min post dose	SBP, Day 1, 1,5 h post dose	DBP, Day 1, 1,5 h post dose	SBP, Day 1, 11 h post dose	DBP, Day 1, 11 h post dose	SBP, Week 6, pre-dose	DBP, Week 6, pre-dose	SBP, Week 6, 30 min post dose	DBP, Week 6, 30 min post dose	SBP, Week 6, 1,5 h post dose	DBP, Week 6, 1,5 h post dose	SBP, Week 6, 11 h post dose	DBP, Week 6, 11 h post dose
Treatment A	-1.4	-0.7	0.3	-0.7	1.1	-0.9	0.4	0.4	-1.6	-0.7	-1.3	-1.0	0.2	-0.9
Treatment B	-0.4	-0.6	-1.1	-1.8	2.0	0.3	0.8	0.5	-0.9	-0.9	-0.6	-2.7	1.5	-2.0
Treatment C	-2.0	-2.1	-0.6	-1.7	-0.0	-1.6	0.4	-0.3	-0.5	-1.5	-0.5	-2.0	0.5	-2.3
Treatment D	-1.9	-1.4	-1.8	-1.6	1.7	-1.4	-1.0	-1.0	-2.5	-2.0	-2.3	-2.3	2.2	-1.4
Treatment E	-0.9	-0.8	0.2	-1.7	1.9	-1.0	1.6	0.0	0.5	-0.8	0.1	-1.1	3.2	-1.0
Treatment F	-1.2	0.1	-1.5	-1.5	0.9	-1.2	1.3	-0.2	0.1	-1.2	0.5	-0.6	2.0	-0.7

"24-hour Holter ECG - Prolonged QTcF - Change from baseline.~Subjects had a 24-h Holter recording before and 24 h after the 1st dose of study drug (Visit 2) and for 24 h before the last dose of study drug (Visit 4). The time-matched values recorded during the 24 h before the 1st dose of study drug on Visit 2 and served as the baseline for the Holter-extracted ECG parameters. The time-averaged baseline score is the average of the Day -1 scores at +5 min, +55 min, and at +2.5 h.~Results are presented as the number of subjects who had a change from baseline in QTcF of: > 30 msec, > 60 msec, and no prolongation (by > 30 msec or > 60 msec)." (NCT03084796)
Timeframe: Baseline, Day 1, Week 6

24-hour Holter ECG - Prolonged QTcF - Female Subjects

Intervention	Participants (Count of Participants)
	QTcF, Any post dose time point72488794	QTcF, Any post dose time point72488795	QTcF, Any post dose time point72488796	QTcF, Any post dose time point72488797	QTcF, Any post dose time point72488798	QTcF, Any post dose time point72488793	QTcF, Day 1, 5 min post dose72488793	QTcF, Day 1, 5 min post dose72488795	QTcF, Day 1, 5 min post dose72488796	QTcF, Day 1, 5 min post dose72488797	QTcF, Day 1, 5 min post dose72488798	QTcF, Day 1, 5 min post dose72488794	QTcF, Day 1, 55 min post dose72488793	QTcF, Day 1, 55 min post dose72488794	QTcF, Day 1, 55 min post dose72488796	QTcF, Day 1, 55 min post dose72488797	QTcF, Day 1, 55 min post dose72488798	QTcF, Day 1, 55 min post dose72488795	QTcF, Day 1, 2.5 h post dose72488793	QTcF, Day 1, 2.5 h post dose72488795	QTcF, Day 1, 2.5 h post dose72488796	QTcF, Day 1, 2.5 h post dose72488797	QTcF, Day 1, 2.5 h post dose72488798	QTcF, Day 1, 2.5 h post dose72488794	QTcF, Day before Week 6, 5 min post dose72488793	QTcF, Day before Week 6, 5 min post dose72488794	QTcF, Day before Week 6, 5 min post dose72488795	QTcF, Day before Week 6, 5 min post dose72488796	QTcF, Day before Week 6, 5 min post dose72488797	QTcF, Day before Week 6, 5 min post dose72488798	QTcF, Day before Week 6, 55 min post dose72488793	QTcF, Day before Week 6, 55 min post dose72488794	QTcF, Day before Week 6, 55 min post dose72488796	QTcF, Day before Week 6, 55 min post dose72488797	QTcF, Day before Week 6, 55 min post dose72488798	QTcF, Day before Week 6, 55 min post dose72488795	QTcF, Day before Week 6, 2.5 h post dose72488794	QTcF, Day before Week 6, 2.5 h post dose72488796	QTcF, Day before Week 6, 2.5 h post dose72488797	QTcF, Day before Week 6, 2.5 h post dose72488798	QTcF, Day before Week 6, 2.5 h post dose72488793	QTcF, Day before Week 6, 2.5 h post dose72488795
	Change from baseline: > 60 msec	No change from baseline (> 30 msec or > 60 msec)	Change from baseline: > 30 msec
Treatment A	19
Treatment B	20
Treatment C	21
Treatment D	20
Treatment E	16
Treatment F	18
Treatment A	0
Treatment B	1
Treatment C	0
Treatment D	2
Treatment E	2
Treatment F	1
Treatment A	102
Treatment B	102
Treatment C	100
Treatment D	101
Treatment E	103
Treatment F	104
Treatment A	2
Treatment B	4
Treatment C	9
Treatment E	3
Treatment F	4
Treatment D	0
Treatment E	0
Treatment A	119
Treatment B	119
Treatment C	112
Treatment D	121
Treatment E	118
Treatment F	119
Treatment A	8
Treatment C	5
Treatment D	6
Treatment E	4
Treatment F	5
Treatment A	113
Treatment C	116
Treatment D	116
Treatment E	116
Treatment F	118
Treatment A	5
Treatment B	12
Treatment C	6
Treatment D	5
Treatment E	6
Treatment F	8
Treatment B	0
Treatment D	1
Treatment E	1
Treatment F	0
Treatment A	116
Treatment B	111
Treatment C	115
Treatment D	117
Treatment E	114
Treatment F	115
Treatment B	3
Treatment D	3
Treatment F	3
Treatment C	121
Treatment D	120
Treatment E	121
Treatment F	120
Treatment C	7
Treatment D	7
Treatment B	123
Treatment C	114
Treatment A	6
Treatment B	6
Treatment C	3
Treatment F	7
Treatment A	115
Treatment B	117
Treatment C	118
Treatment F	116

"24-hour Holter ECG - Prolonged QTcF - Female subjects.~Subjects had a 24-h Holter recording before and 24 h after the 1st dose of study drug (Visit 2) and for 24 h before the last dose of study drug (Visit 4). The time-matched values recorded during the 24 h before the 1st dose of study drug on Visit 2 and served as the baseline for the Holter-extracted ECG parameters. The time-averaged baseline score is the average of the Day -1 scores at +5 min, +55 min, and at +2.5 h." (NCT03084796)
Timeframe: Baseline, Day 1, Week 6

24-hour Holter ECG - Prolonged QTcF - Male Subjects

Intervention	Participants (Count of Participants)
	QTcF, Day -1, 5 min72488795	QTcF, Day -1, 5 min72488798	QTcF, Day -1, 5 min72488793	QTcF, Day -1, 5 min72488794	QTcF, Day -1, 5 min72488796	QTcF, Day -1, 5 min72488797	QTcF, Day -1, 55 min72488795	QTcF, Day -1, 55 min72488797	QTcF, Day -1, 55 min72488798	QTcF, Day -1, 55 min72488793	QTcF, Day -1, 55 min72488794	QTcF, Day -1, 55 min72488796	QTcF, Day -1, 2.5 h72488794	QTcF, Day -1, 2.5 h72488797	QTcF, Day -1, 2.5 h72488795	QTcF, Day -1, 2.5 h72488793	QTcF, Day -1, 2.5 h72488796	QTcF, Day -1, 2.5 h72488798	QTcF, Any post dose time point72488794	QTcF, Any post dose time point72488795	QTcF, Any post dose time point72488797	QTcF, Any post dose time point72488798	QTcF, Any post dose time point72488793	QTcF, Any post dose time point72488796	QTcF, Day 1, 5 min post dose72488798	QTcF, Day 1, 5 min post dose72488795	QTcF, Day 1, 5 min post dose72488793	QTcF, Day 1, 5 min post dose72488794	QTcF, Day 1, 5 min post dose72488796	QTcF, Day 1, 5 min post dose72488797	QTcF, Day 1, 55 min post dose72488793	QTcF, Day 1, 55 min post dose72488798	QTcF, Day 1, 55 min post dose72488797	QTcF, Day 1, 55 min post dose72488794	QTcF, Day 1, 55 min post dose72488795	QTcF, Day 1, 55 min post dose72488796	QTcF, Day 1, 2.5 h post dose72488795	QTcF, Day 1, 2.5 h post dose72488793	QTcF, Day 1, 2.5 h post dose72488794	QTcF, Day 1, 2.5 h post dose72488796	QTcF, Day 1, 2.5 h post dose72488797	QTcF, Day 1, 2.5 h post dose72488798	QTcF, Day before Week 6, 5 min post dose72488798	QTcF, Day before Week 6, 5 min post dose72488793	QTcF, Day before Week 6, 5 min post dose72488794	QTcF, Day before Week 6, 5 min post dose72488795	QTcF, Day before Week 6, 5 min post dose72488796	QTcF, Day before Week 6, 5 min post dose72488797	QTcF, Day before Week 6, 55 min post dose72488798	QTcF, Day before Week 6, 55 min post dose72488793	QTcF, Day before Week 6, 55 min post dose72488794	QTcF, Day before Week 6, 55 min post dose72488795	QTcF, Day before Week 6, 55 min post dose72488796	QTcF, Day before Week 6, 55 min post dose72488797	QTcF, Day before Week 6, 2.5 h post dose72488798	QTcF, Day before Week 6, 2.5 h post dose72488793	QTcF, Day before Week 6, 2.5 h post dose72488794	QTcF, Day before Week 6, 2.5 h post dose72488795	QTcF, Day before Week 6, 2.5 h post dose72488796	QTcF, Day before Week 6, 2.5 h post dose72488797
	Actual value > 470 msec	Actual value > 500 msec	No prolongation (> 470 msec or > 500 msec)
Treatment B	64
Treatment C	67
Treatment E	0
Treatment A	3
Treatment F	1
Treatment A	55
Treatment F	0
Treatment F	57
Treatment A	2
Treatment B	3
Treatment A	56
Treatment B	65
Treatment C	0
Treatment F	56
Treatment A	1
Treatment A	57
Treatment B	2
Treatment A	0
Treatment B	0
Treatment D	0
Treatment A	58
Treatment B	66
Treatment D	65
Treatment E	52
Treatment B	1
Treatment D	1
Treatment B	67
Treatment D	64

"24-hour Holter ECG - Prolonged QTcF - Male subjects.~Subjects had a 24-h Holter recording before and 24 h after the 1st dose of study drug (Visit 2) and for 24 h before the last dose of study drug (Visit 4). The time-matched values recorded during the 24 h before the 1st dose of study drug on Visit 2 and served as the baseline for the Holter-extracted ECG parameters. The time-averaged baseline score is the average of the Day -1 scores at +5 min, +55 min, and at +2.5 h." (NCT03084796)
Timeframe: Baseline, Day 1, Week 6

12-lead ECG Parameters - Heart Rate - Change From Baseline

Intervention	Participants (Count of Participants)
	QTcF, Day -1, 5 min72488794	QTcF, Day -1, 5 min72488798	QTcF, Day -1, 5 min72488797	QTcF, Day -1, 5 min72488793	QTcF, Day -1, 5 min72488795	QTcF, Day -1, 5 min72488796	QTcF, Day -1, 55 min72488793	QTcF, Day -1, 55 min72488794	QTcF, Day -1, 55 min72488795	QTcF, Day -1, 55 min72488798	QTcF, Day -1, 55 min72488797	QTcF, Day -1, 55 min72488796	QTcF, Day -1, 2.5 h72488794	QTcF, Day -1, 2.5 h72488797	QTcF, Day -1, 2.5 h72488798	QTcF, Day -1, 2.5 h72488793	QTcF, Day -1, 2.5 h72488795	QTcF, Day -1, 2.5 h72488796	QTcF, Any post dose time point72488793	QTcF, Any post dose time point72488794	QTcF, Any post dose time point72488797	QTcF, Any post dose time point72488798	QTcF, Any post dose time point72488795	QTcF, Any post dose time point72488796	QTcF, Day 1, 5 min post dose72488794	QTcF, Day 1, 5 min post dose72488797	QTcF, Day 1, 5 min post dose72488798	QTcF, Day 1, 5 min post dose72488793	QTcF, Day 1, 5 min post dose72488795	QTcF, Day 1, 5 min post dose72488796	QTcF, Day 1, 55 min post dose72488795	QTcF, Day 1, 55 min post dose72488797	QTcF, Day 1, 55 min post dose72488798	QTcF, Day 1, 55 min post dose72488793	QTcF, Day 1, 55 min post dose72488794	QTcF, Day 1, 55 min post dose72488796	QTcF, Day 1, 2.5 h post dose72488794	QTcF, Day 1, 2.5 h post dose72488798	QTcF, Day 1, 2.5 h post dose72488797	QTcF, Day 1, 2.5 h post dose72488793	QTcF, Day 1, 2.5 h post dose72488795	QTcF, Day 1, 2.5 h post dose72488796	QTcF, Day before Week 6, 5 min post dose72488794	QTcF, Day before Week 6, 5 min post dose72488797	QTcF, Day before Week 6, 5 min post dose72488798	QTcF, Day before Week 6, 5 min post dose72488793	QTcF, Day before Week 6, 5 min post dose72488795	QTcF, Day before Week 6, 5 min post dose72488796	QTcF, Day before Week 6, 55 min post dose72488793	QTcF, Day before Week 6, 55 min post dose72488798	QTcF, Day before Week 6, 55 min post dose72488794	QTcF, Day before Week 6, 55 min post dose72488795	QTcF, Day before Week 6, 55 min post dose72488796	QTcF, Day before Week 6, 55 min post dose72488797	QTcF, Day before Week 6, 2.5 h post dose72488793	QTcF, Day before Week 6, 2.5 h post dose72488794	QTcF, Day before Week 6, 2.5 h post dose72488797	QTcF, Day before Week 6, 2.5 h post dose72488798	QTcF, Day before Week 6, 2.5 h post dose72488795	QTcF, Day before Week 6, 2.5 h post dose72488796
	Actual value > 450 msec	Actual value > 480 msec	Actual value > 500 msec	No prolongation (> 450 msec or > 480 msec or > 500
Treatment F	1
Treatment B	55
Treatment C	54
Treatment F	65
Treatment C	1
Treatment A	62
Treatment C	53
Treatment E	68
Treatment F	63
Treatment B	1
Treatment E	1
Treatment B	54
Treatment E	66
Treatment F	66
Treatment B	4
Treatment C	6
Treatment D	4
Treatment E	2
Treatment F	5
Treatment E	0
Treatment F	3
Treatment B	0
Treatment F	0
Treatment B	51
Treatment C	47
Treatment D	54
Treatment E	67
Treatment F	58
Treatment B	2
Treatment C	0
Treatment C	51
Treatment F	61
Treatment C	3
Treatment A	1
Treatment B	53
Treatment C	50
Treatment A	3
Treatment B	3
Treatment F	4
Treatment A	59
Treatment B	52
Treatment F	62
Treatment D	3
Treatment F	2
Treatment A	0
Treatment A	60
Treatment D	55
Treatment A	2
Treatment C	2
Treatment D	2
Treatment D	0
Treatment A	61
Treatment C	52
Treatment D	56
Treatment E	69
Treatment D	1
Treatment D	57

"12-lead electrocardiogram (12-lead ECG) parameter - heart rate (HR) was measured at baseline (Day 1) and Week 8.~Change from baseline.~Definitions:~Baseline=Baseline values were defined at visit 2 (Week 0) pre-dose;~bpm=Beats per minute;" (NCT03084718)
Timeframe: Baseline, Week 8

24-hr Creatinine - Change From Baseline.

Intervention	bpm (Mean)
Treatment A (CHF 718 pMDI 100 µg TDD)	0.6
Treatment B (CHF 718 pMDI 400 µg TDD)	0.2
Treatment C (CHF 718 pMDI 800 µg TDD)	0.4
Treatment D (Placebo)	1.2
Treatment E (QVAR^®, 320 µg TDD)	-0.4

"24-hr Creatinine - Change From Baseline.~For the evaluation of the 24-hr creatinine excretion, 24-hour urine sample were collected. Creatinine was measured using liquid chromatography-tandem mass spectrometry (LC-MS/MS).~Definitions:~Baseline=Baseline values were defined at visit 2 (Week 0) pre-dose;" (NCT03084718)
Timeframe: Baseline, Week 8

24-hr Urine Free Cortisol - Change From Baseline

Intervention	umol/mol (Median)
Treatment A (CHF 718 pMDI 100 µg TDD)	0.00
Treatment B (CHF 718 pMDI 400 µg TDD)	0.00
Treatment C (CHF 718 pMDI 800 µg TDD)	0.00
Treatment D (Placebo)	0.00
Treatment E (QVAR^®, 320 µg TDD)	0.00

"24-hr Urinary Free Cortisol - Change From Baseline.~For the evaluation of the 24-hr Urine-Free cortisol excretion, 24-hour urine samples were collected. Urine-free cortisol was measured using liquid chromatography-tandem mass spectrometry (LC-MS/MS).~Definitions:~Baseline=Baseline values were defined at visit 2 (Week 0) pre-dose;" (NCT03084718)
Timeframe: Baseline, Week 8

Pre-dose Morning FEV1 at Week 4 - Change From Baseline

Intervention	nmol/day (Median)
Treatment A (CHF 718 pMDI 100 µg TDD)	-3.60
Treatment B (CHF 718 pMDI 400 µg TDD)	-5.35
Treatment C (CHF 718 pMDI 800 µg TDD)	-4.10
Treatment D (Placebo)	1.40
Treatment E (QVAR^®, 320 µg TDD)	-3.50

"Change from baseline in pre-dose morning FEV1 at Week 4.~Spirometry, used to measure FEV1, was performed according to internationally accepted standards.~Definitions:~Baseline=Baseline values for pre-dose FEV1 were the average of measurements taken at V2 (Week 0) at 45 minutes and 15 minutes pre-dose; FEV1=Forced expiratory volume in the 1st second;" (NCT03084718)
Timeframe: Baseline, Week 4

Pre-dose Morning FEV1 at Week 8 - Change From Baseline

Intervention	Litres (Least Squares Mean)
Treatment A (CHF 718 pMDI 100 µg TDD)	0.021
Treatment B (CHF 718 pMDI 400 µg TDD)	0.120
Treatment C (CHF 718 pMDI 800 µg TDD)	0.073
Treatment D (Placebo)	0.003
Treatment E (QVAR^®, 320 µg TDD)	0.077

"Change from baseline in pre-dose morning FEV1 (average of pre-dose FEV1 measurements) at Week 8.~Spirometry, used to measure FEV1, was performed according to internationally accepted standards.~Definitions:~Baseline=Baseline values for pre-dose FEV1 were the average of measurements taken at V2 (Week 0) at 45 minutes and 15 minutes pre-dose; FEV1=Forced expiratory volume in the 1st second;" (NCT03084718)
Timeframe: Baseline, Week 8

12-lead ECG Parameters - PR, QRS, QTcF - Change From Baseline.

Intervention	Litres (Least Squares Mean)
Treatment A (CHF 718 pMDI 100 µg TDD)	0.021
Treatment B (CHF 718 pMDI 400 µg TDD)	0.090
Treatment C (CHF 718 pMDI 800 µg TDD)	0.070
Treatment D (Placebo)	-0.023
Treatment E (QVAR^®, 320 µg TDD)	0.078

"12-lead electrocardiogram (12-lead ECG) parameters - PR, QRS, QTcF intervals - were measured at baseline (Day 1) and Week 8.~Changes from baseline.~Definitions:~Baseline=Baseline values were defined at visit 2 (Week 0); QTcF=Fridericia-corrected QT interval; msec=Millisecond;" (NCT03084718)
Timeframe: Baseline, Week 8

12-lead ECG Parameters - Prolonged QTcF - Change From Baseline

Intervention	msec (Mean)
	PR	QRS	QTcF
Treatment A (CHF 718 pMDI 100 µg TDD)	-2.6	0.1	1.6
Treatment B (CHF 718 pMDI 400 µg TDD)	1.5	-1.3	0.7
Treatment C (CHF 718 pMDI 800 µg TDD)	-1.9	0.9	0.7
Treatment D (Placebo)	-1.3	-0.5	4.6
Treatment E (QVAR^®, 320 µg TDD)	1.0	-0.3	1.2

"Number of participants with prolonged QTcF. Change from baseline.~Baseline=Baseline values were defined at visit 2 (Week 0) pre-dose; QTcF=Fridericia-corrected QT interval;" (NCT03084718)
Timeframe: Baseline, Week 8

Asthma Control Questionnaire-7© (ACQ-7) Score at Week 4 and Week 8 - Change From Baseline

Intervention	Participants (Count of Participants)
	QTcF > 30 msec	QTcF > 60 msec
Treatment A (CHF 718 pMDI 100 µg TDD)	6	1
Treatment B (CHF 718 pMDI 400 µg TDD)	4	1
Treatment C (CHF 718 pMDI 800 µg TDD)	4	0
Treatment D (Placebo)	9	2
Treatment E (QVAR^®, 320 µg TDD)	3	1

"The ACQ consists of 7 items: 6 simple self-administered questions referring to asthma control and rescue treatment usage with 1 week recall, and a 7th item consisting of the percent (%) predicted FEV1 completed by clinic staff. Scoring uses a 7-point scale: 0 = totally controlled and 6 = severely uncontrolled. The ACQ score was calculated as the average of all 7 items.~Definitions:~ACQ-7 score=Asthma Control Questionnaire-7©; Information regarding the American Thoracic Society ACQ questionnaire is also available at: https://member.thoracic.org/members/assemblies/assemblies/srn/questionaires/acq.php; Baseline ACQ-7 score = ACQ score recorded at V2 (Week 0) Day 1, before randomization; FEV1=Forced expiratory volume in the 1st second;" (NCT03084718)
Timeframe: Baseline, Week 4, Week 8

Average Use of Rescue Medication - Change From Baseline

Intervention	score on a scale (Least Squares Mean)
	Week 4	Week 8
Treatment A (CHF 718 pMDI 100 µg TDD)	-0.43	-0.53
Treatment B (CHF 718 pMDI 400 µg TDD)	-0.53	-0.58
Treatment C (CHF 718 pMDI 800 µg TDD)	-0.49	-0.66
Treatment D (Placebo)	-0.27	-0.43
Treatment E (QVAR^®, 320 µg TDD)	-0.47	-0.64

"Change from baseline in average use of rescue medication, during Inter-visit period 1, Inter-visit period 2, Entire treatment period.~Definitions:~Baseline=For the efficacy variable -- average use of rescue medication -- derived from the electronic diary (eDiary), baseline values were the averages recorded during the run-in period;~Inter-visit period 1=Starts from the pm assessment of the Start of the Randomized Treatment Period to the am assessment at Visit 3 (Week 4);~Inter-visit Period 2=Starts from the pm assessment of the day the subject returns to the clinic (Visit 3) to the am assessment of the date of Visit 4 (Week 8);~Entire treatment period=Average of 8 weeks;~am=morning pm=evening" (NCT03084718)
Timeframe: Baseline (average of the 2-week run-in period); Inter-visit period 1 (average of the first 4 weeks); Inter-visit period 2 (average of the last 4 weeks); Entire treatment period (average of 8 weeks)

Overall Daily Asthma Symptoms Scores - Change From Baseline

Intervention	puffs/day (Least Squares Mean)
	Inter-visit period 1	Inter-visit period 2	Entire treatment period
Treatment A (CHF 718 pMDI 100 µg TDD)	-0.11	-0.12	-0.11
Treatment B (CHF 718 pMDI 400 µg TDD)	-0.27	-0.35	-0.31
Treatment C (CHF 718 pMDI 800 µg TDD)	-0.14	-0.25	-0.20
Treatment D (Placebo)	0.07	0.01	0.04
Treatment E (QVAR^®, 320 µg TDD)	-0.13	-0.18	-0.15

"Overall daily asthma symptoms scores - Change From Baseline (am and pm).~Subjects had to record asthma symptom score (overall symptoms, cough, wheeze, chest tightness and breathlessness) in the am (night-time asthma symptom score) and in the pm (daytime asthma symptom score). These data were collected in the subject's diary. Daily asthma symptoms score were performed separately for am score and pm score and also as a total, where the total equals the sum of the am and pm scores. Degree of asthma symptoms by score: 0=None, 1=Mild, 2=Moderate, and 3=Severe.~Baseline=Averages values during the run-in period;~Inter-visit period 1=Starts from the pm assessment of the Start of the Randomized Treatment Period to the am assessment at Visit 3 (Week 4);~Inter-visit Period 2=Starts from the pm assessment of the day the subject returns to the clinic (Visit 3) to the am assessment of the date of Visit 4 (Week 8);~Entire treatment period=Average of 8 weeks;~am=morning pm=evening" (NCT03084718)
Timeframe: Baseline (average of the 2-week run-in period); Inter-visit period 1 (average of the first 4 weeks); Inter-visit period 2 (average of the last 4 weeks); Entire treatment period (average of 8 weeks)

Percentage (%) of Asthma Control Days - Change From Baseline

Intervention	score on a scale (Least Squares Mean)
	Inter-visit period 1	Inter-visit period 2	Entire treatment period
Treatment A (CHF 718 pMDI 100 µg TDD)	-0.1	-0.1	-0.1
Treatment B (CHF 718 pMDI 400 µg TDD)	-0.1	-0.1	-0.1
Treatment C (CHF 718 pMDI 800 µg TDD)	-0.1	-0.1	-0.1
Treatment D (Placebo)	0.0	-0.0	0.0
Treatment E (QVAR^®, 320 µg TDD)	-0.1	-0.1	-0.1

"Change from baseline in percentage (%) of asthma control days, during Inter-visit period 1, Inter-visit period 2, Entire treatment period.~This outcome measure was calculated according to the following definition: Days with a total daily morning + evening asthma score = 0 AND No rescue medication use.~Definitions:~Baseline=For the efficacy variable -- asthma control days -- derived from the eDiary, baseline values were the averages/percentages recorded during the run-in period;~Inter-visit period 1=Starts from the pm assessment of the Start of the Randomized Treatment Period to the am assessment at Visit 3 (Week 4);~Inter-visit Period 2=Starts from the pm assessment of the day the subject returns to the clinic (Visit 3) to the am assessment of the date of Visit 4 (Week 8);~Entire treatment period=Average of 8 weeks;~am=morning pm=evening" (NCT03084718)
Timeframe: Baseline (average of the 2-week run-in period); Inter-visit period 1 (average of the first 4 weeks); Inter-visit period 2 (average of the last 4 weeks); Entire treatment period (average of 8 weeks)

Percentage (%) of Asthma Symptoms-free Days - Change From Baseline

Intervention	% of asthma control days (Least Squares Mean)
	Inter-visit period 1	Inter-visit period 2	Entire treatment period
Treatment A (CHF 718 pMDI 100 µg TDD)	7.3	14.3	10.8
Treatment B (CHF 718 pMDI 400 µg TDD)	10.6	16.3	13.4
Treatment C (CHF 718 pMDI 800 µg TDD)	10.4	17.5	13.9
Treatment D (Placebo)	5.0	10.5	7.7
Treatment E (QVAR^®, 320 µg TDD)	12.8	20.63	16.7

"Change from baseline in Percentage (%) of asthma symptoms-free days.~Asthma symptoms-free days is the number of days with a total asthma score=0 (daily morning plus evening asthma score).~Subjects recorded asthma symptom score as described in the Outcome measure #7.~Definitions:~Baseline=For the efficacy variables -- daytime and night-time asthma symptom scores -- derived from the eDiary, baseline values were the averages/percentages recorded during the run-in period;~Inter-visit period 1=Starts from the pm assessment of the Start of the Randomized Treatment Period to the am assessment at Visit 3 (Week 4);~Inter-visit Period 2=Starts from the pm assessment of the day the subject returns to the clinic (Visit 3) to the am assessment of the date of Visit 4 (Week 8);~Entire treatment period=Average of 8 weeks;~am=morning pm=evening" (NCT03084718)
Timeframe: Baseline (average of the 2-week run-in period); Inter-visit period 1 (average of the first 4 weeks); Inter-visit period 2 (average of the last 4 weeks); Entire treatment period (average of 8 weeks)

Percentage (%) of Rescue Medication-free Days - Change From Baseline

Intervention	% of of asthma symptom-free days (Least Squares Mean)
	Inter-visit period 1	Inter-visit period 2	Entire treatment period
Treatment A (CHF 718 pMDI 100 µg TDD)	8.6	16.4	12.5
Treatment B (CHF 718 pMDI 400 µg TDD)	10.5	17.0	13.8
Treatment C (CHF 718 pMDI 800 µg TDD)	10.1	17.2	13.6
Treatment D (Placebo)	5.7	11.7	8.7
Treatment E (QVAR^®, 320 µg TDD)	12.8	21.2	17.0

"Change from baseline in percentage (%) of rescue medication-free days. An increased value indicates improvement from baseline.~Definitions:~Baseline=For the efficacy variable -- percentage (%) of rescue medication-free days -- derived from the electronic diary (eDiary), baseline values were the averages/percentages recorded during the run-in period.~Inter-visit period 1=Starts from the pm assessment of the Start of the Randomized Treatment Period to the am assessment at Visit 3 (Week 4);~Inter-visit Period 2=Starts from the pm assessment of the day the subject returns to the clinic (Visit 3) to the am assessment of the date of Visit 4 (Week 8);~Entire treatment period=Average of 8 weeks;~am=morning pm=evening" (NCT03084718)
Timeframe: Baseline (average of the 2-week run-in period); Inter-visit period 1 (average of the first 4 weeks); Inter-visit period 2 (average of the last 4 weeks); Entire treatment period (average of 8 weeks)

Pre-dose Morning FVC at Week 4 and 8 - Change From Baseline

Intervention	% of rescue medication-free days (Least Squares Mean)
	Inter-visit period 1	Inter-visit period 2	Entire treatment period
Treatment A (CHF 718 pMDI 100 µg TDD)	5.9	8.9	7.4
Treatment B (CHF 718 pMDI 400 µg TDD)	9.0	13.1	11.1
Treatment C (CHF 718 pMDI 800 µg TDD)	6.1	10.0	8.1
Treatment D (Placebo)	1.5	4.1	2.8
Treatment E (QVAR^®, 320 µg TDD)	7.7	11.2	9.5

"Change from baseline in pre-dose morning FVC at Week 4 and 8.~Spirometry, used to measure FVC, was performed according to internationally accepted standards.~Definitions:~Baseline=Baseline values for pre-dose FVC were the average of measurements taken at V2 (Week 0) at 45 minutes and 15 minutes pre-dose; FVC=Forced vital capacity;" (NCT03084718)
Timeframe: Baseline, Week 4, Week 8

Pre-dose Peak Expiratory Flow (PEF) (L/Min) (Morning and Evening) - Change From Baseline

Intervention	Litres (Least Squares Mean)
	Week 4	Week 8
Treatment A (CHF 718 pMDI 100 µg TDD)	0.036	0.014
Treatment B (CHF 718 pMDI 400 µg TDD)	0.099	0.089
Treatment C (CHF 718 pMDI 800 µg TDD)	0.066	0.036
Treatment D (Placebo)	0.023	-0.016
Treatment E (QVAR^®, 320 µg TDD)	0.056	0.063

"Change from baseline in pre-dose Peak Expiratory Flow (PEF) (Liters/min), morning and evening measurements.~Definitions:~Baseline=For the efficacy variable -- morning and evening PEF -- derived from the eDiary, the baseline values were the averages/percentages recorded during the run-in period; PEF=evening peak expiratory flow;~Inter-visit period 1=Starts from the pm assessment of the Start of the Randomized Treatment Period to the am assessment at Visit 3 (Week 4);~Inter-visit Period 2=Starts from the pm assessment of the day the subject returns to the clinic (Visit 3) to the am assessment of the date of Visit 4 (Week 8);~Entire treatment period=Average of 8 weeks;~am=morning pm=evening" (NCT03084718)
Timeframe: Baseline (average of the 2-week run-in period); Inter-visit period 1 (average of the first 4 weeks); Inter-visit period 2 (average of the last 4 weeks); Entire treatment period (average of 8 weeks)

Vital Signs (Systolic and Diastolic Blood Pressure) - Change From Baseline

Intervention	Liters/min (Least Squares Mean)
	Inter-visit period 1	Inter-visit period 2	Entire treatment period
Treatment A (CHF 718 pMDI 100 µg TDD)	-2	-4	-3
Treatment B (CHF 718 pMDI 400 µg TDD)	-3	3	0.3
Treatment C (CHF 718 pMDI 800 µg TDD)	-4	-5	-4
Treatment D (Placebo)	-6	-4	-4.9
Treatment E (QVAR^®, 320 µg TDD)	0	2	1

"Vital signs (systolic and diastolic blood pressure) at baseline, week 4, and week 8.~Change from baseline.~Definitions:~Baseline=Baseline values were defined at visit 2 (Week 0) pre-dose; DBP=Diastolic blood pressure; SBP=Systolic blood pressure;" (NCT03084718)
Timeframe: Baseline, Week 4, Week 8

FEV1 Area Under the Curve Between 0 and 12 h [AUC(0-12h)], Normalized by Time -- Change From Baseline to Post Dose Day 14

Intervention	mmHg (Mean)
	SBP, Week 4	SBP, Week 8	DBP, Week 4	DBP, Week 8
Treatment A (CHF 718 pMDI 100 µg TDD)	-0.4	1.0	-0.1	0.8
Treatment B (CHF 718 pMDI 400 µg TDD)	1.0	2.5	0.2	1.0
Treatment C (CHF 718 pMDI 800 µg TDD)	0.5	0.8	-0.8	0.3
Treatment D (Placebo)	0.6	0.2	0.1	-0.5
Treatment E (QVAR^®, 320 µg TDD)	0.0	-0.9	0.8	1.2

"Spirometry used to measure FEV1, was performed according to internationally accepted standards. Results show the change from baseline in FEV1 AUC(0-12h), normalized by time on Day 14; it was calculated by using the linear trapezoidal rule, based on the changes in FEV1 from the baseline values.~Patients receiving the same treatment during two periods are considered twice in the ANCOVA model (once for each period attended).~Definitions:~AUC=Area under the curve; AUC(0-12h)=AUC between 0 and 12 h; Baseline=Baseline value was the average of the pre-dose measurements (at 45 mins and 15 mins pre-dose) on Day 1 of the treatment period; FEV1=Forced expiratory volume in the 1st second;" (NCT03086460)
Timeframe: Baseline, Day 14 post-dose

FEV1 AUC(0-12h), Normalized by Time -- Change From Baseline to Post Dose Day 1

Intervention	Litres (Least Squares Mean)
Treatment A	0.174
Treatment B	0.221
Treatment C	0.197
Treatment D	0.231
Treatment E	0.064
Treatment F	0.208

"Spirometry used to measure FEV1, was performed according to internationally accepted standards.~Patients receiving the same treatment during two periods are considered twice in the ANCOVA model (once for each period attended).~Baseline=Baseline value was the average of the pre-dose measurements (at 45 mins and 15 mins pre-dose) on Day 1 of the treatment period;" (NCT03086460)
Timeframe: Baseline, Day 1 post-dose

Patients Achieving Onset of Action -- Change From Baseline in Post-dose FEV1 ≥12% and ≥200 mL to Post Dose Day 1

Intervention	Litres (Least Squares Mean)
Treatment A	0.181
Treatment B	0.221
Treatment C	0.260
Treatment D	0.282
Treatment E	0.067
Treatment F	0.239

"Patients achieving onset of action, defined as a change from baseline in post-dose FEV1 ≥12% and ≥200 mL, on Day 1. These are the subjects who contributed to the results, reported as median and 95% CI for 'Time to onset of action' presented in the Outcome Measure 13, above.~For patients receiving the same treatment twice, the analysis includes only data from the first instance of each treatment.~Definitions:~Onset of action=Change from baseline in post-dose FEV1 ≥12% and ≥200 mL; Baseline=Baseline value was the average of the pre-dose measurements (at 45 mins and 15 mins pre-dose);" (NCT03086460)
Timeframe: Baseline, Day 1 post-dose

Pre-dose Morning FEV1 (L) -- Change From Baseline to Post Dose Day 14

Intervention	Participants (Count of Participants)
Treatment A	23
Treatment B	22
Treatment C	30
Treatment D	29
Treatment E	11
Treatment F	31

"Spirometry, used to measure FEV1, was performed according to internationally accepted standards.~Patients receiving the same treatment during two periods are considered twice in the ANCOVA model (once for each period attended).~Baseline=Baseline value was the average of the pre-dose measurements (at 45 mins and 15 mins pre-dose) on Day 1 of the treatment period;" (NCT03086460)
Timeframe: Baseline, Day 14 post-dose

Pre-dose Morning FVC -- Change From Baseline to Post Dose Day 14

Intervention	Litres (Least Squares Mean)
Treatment A	0.071
Treatment B	0.102
Treatment C	0.073
Treatment D	0.149
Treatment E	0.037
Treatment F	0.126

"Spirometry, used to measure FVC, was performed according to internationally accepted standards.~Patients receiving the same treatment during two periods are considered twice in the ANCOVA model (once for each period attended).~Baseline=Baseline value was the average of the pre-dose measurements (at 45 mins and 15 mins pre-dose) on Day 1 of the treatment period;" (NCT03086460)
Timeframe: Baseline, Day 14 post-dose

Sensitivity Analysis 1: FEV1 AUC(0-12h), Normalized by Time -- Change From Baseline to Post Dose Day 14

Intervention	Litres (Least Squares Mean)
Treatment A	0.048
Treatment B	0.044
Treatment C	0.048
Treatment D	0.114
Treatment E	0.053
Treatment F	0.114

"The primary analysis was repeated, considering patients as randomized and including only the first instance of each treatment.~Patients receiving the same treatment in more than one period were included in the analysis with only data from the first instance of each treatment." (NCT03086460)
Timeframe: Baseline, Day 14 post-dose

Sensitivity Analysis 2: FEV1 AUC(0-12h), Normalized by Time -- Change From Baseline to Post Dose Day 14

Intervention	Litres (Least Squares Mean)
Treatment A	0.169
Treatment B	0.224
Treatment C	0.196
Treatment D	0.232
Treatment E	0.058
Treatment F	0.206

"The primary analysis was repeated, considering only patients and treatment periods for which treatment was assigned on or after the randomization error occurred.~The number of patients shown represents those with at least one post-baseline assessment available." (NCT03086460)
Timeframe: Baseline, Day 14 post-dose

Sensitivity Analysis 3: FEV1 AUC(0-12h), Normalized by Time -- Change From Baseline to Post Dose Day 14

"Patients receiving the same treatment during two treatment periods are considered twice in the ANCOVA model (once for each period attended).~Patients considered in this analysis are those with at least one available post-baseline assessment." (NCT03086460)
Timeframe: Baseline, Day 14 post-dose

Time to Onset of Action -- Change From Baseline in Post-dose FEV1 ≥12% and ≥200 mL to Post Dose Day 1

"Spirometry, used to measure FEV1, was performed according to internationally accepted standards.~For patients receiving the same treatment twice, the analysis includes only data from the first instance of each treatment.~Definitions:~Time to onset of action=The time (in minutes) from receiving the study drug on Day 1, until the FEV1 change from baseline is ≥200 mL; Baseline=Baseline value was the average of the pre-dose measurements (at 45 mins and 15 mins pre-dose) on Day 1 of the treatment period;" (NCT03086460)
Timeframe: Baseline, Day 1 post-dose

12-lead ECG Parameter -- Heart Rate (HR) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14

"Results are shown by treatment group, as change from baseline (in bpm).~For patients receiving the same treatment in 2 periods, the average of the 2 available data points was considered in the calculation.~For safety variables, the baseline for each period was defined as pre-dose measurements on Day 1 of each treatment period." (NCT03086460)
Timeframe: Baseline, Day 1, Day 14 post-dose

12-lead Electrocardiogram (ECG) Parameter (PR Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14

"12-lead electrocardiogram (ECG) parameters were monitored during the study. Results are shown by treatment group, as change from baseline (in msec).~For patients receiving the same treatment in 2 periods, the average of the 2 available data points was considered in the calculation.~For safety variables, the baseline for each period was defined as pre-dose measurements on Day 1 of each treatment period." (NCT03086460)
Timeframe: Baseline, Day 1, Day 14 post-dose

12-lead Electrocardiogram (ECG) Parameter (QRS Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14

12-lead Electrocardiogram (ECG) Parameter (QTcF Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14

FEV1 AUC(0-4h), Normalized by Time -- Change From Baseline to Post Dose Day 1 and Day 14

FEV1 Peak(0-4h), Normalized by Time -- Change From Baseline to Post Dose Day 1 and Day 14

FVC AUC(0-12h), Normalized by Time -- Change From Baseline to Post Dose Day 1 and Day 14

FVC AUC(0-4h), Normalized by Time -- Change From Baseline to Post Dose Day 1 and Day 14

FVC Peak(0-4h), Normalized by Time -- Change From Baseline to Post Dose Day 1 and Day 14

Heart Rate (HR) AUC(0-4h) and Peak(0-4h), Normalized by Time -- Change From Pre-dose to Post Dose Day 14

"Heart rate (HR) AUC(0-4h) and HR peak(0-4h), normalized by time (in bpm).~Results are shown as change from pre-dose on Day 14 (in bpm).~For patients receiving the same treatment in 2 periods, the average of the 2 available data points was considered in the calculation.~Definitions:~HR=Heart rate; HR AUC(0-4h)=Area under the curve between 0 and 4 h for heart rate; HR peak(0-4h)=The maximum observed value over 4 h after dosing;" (NCT03086460)
Timeframe: Baseline, Day 14 post-dose

Heart Rate (HR) AUC(0-4h), Normalized by Time -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14

"Heart rate HR AUC(0-4h) normalized by time. Results are shown by treatment group, as change from baseline (in bpm).~The HR AUC(0-4h) normalized by time is calculated based on the actual times, using the linear trapezoidal rule.~For patients receiving the same treatment in 2 periods, the average of the 2 available data points was considered in the calculation.~For safety variables, the baseline for each period was defined as pre-dose measurements on Day 1 of each treatment period." (NCT03086460)
Timeframe: Baseline, Day 1, Day 14 post-dose

Heart Rate (HR) Peak(0-4h), Normalized by Time -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14

"Heart rate (HR) peak(0-4h) normalized by time.~Results are shown by treatment group, as change from baseline (in bpm).~For patients receiving the same treatment in 2 periods, the average of the 2 available data points was considered in the calculation.~For safety variables, the baseline for each period was defined as pre-dose measurements on Day 1 of each treatment period.~Definitions:~HR=Heart rate; HR peak(0-4h)=The maximum observed value over 4 hours following dosing;" (NCT03086460)
Timeframe: Baseline, Day 1, Day 14 post-dose

Serum Glucose -- Change From Baseline to Post-dose Day 1 and Day 14

"Serum glucose level was monitored during the study. Results are shown by treatment group, as change from baseline (in mmol/L).~For patients receiving the same treatment in 2 periods, the average of the 2 available data points was considered in the calculation.~For safety variables, the baseline for each period was defined as pre-dose measurements on Day 1 of each treatment period." (NCT03086460)
Timeframe: Baseline, Day 1, Day 14 post-dose

Serum Potassium -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14

"Serum potassium level was monitored during the study. Results are shown by treatment group, as change from baseline (in mmol/L).~For patients receiving the same treatment in 2 periods, the average of the 2 available data points was considered in the calculation.~For safety variables, the baseline for each period was defined as pre-dose measurements on Day 1 of each treatment period." (NCT03086460)
Timeframe: Baseline, Day 1, Day 14 post-dose

Vital Signs (Systolic Blood Pressure [SBP] and Diastolic Blood Pressure [DBP]) -- Change From Baseline for Post-dose on Day 1 and on Day 14

"Vital signs -- Systolic blood pressure (SBP) and Diastolic blood pressure (DBP) were measured at pre-specified times (at baseline - pre dose and on Day 14 of each treatment period or on the day of early study termination).~Results are shown by treatment group, as change from baseline (in mmHg).~For patients receiving the same treatment in 2 periods, the average of the 2 available data points was considered in the calculation.~Definitions:~For safety variables, the baseline for each treatment period was defined as pre-dose measurements on Day 1 of each treatment period; Day 14=The day of the last dosing of a treatment period. Day 14 of the second, third, and fourth treatment periods (day of last dosing); treatments were separated by a 2-week wash-out interval;" (NCT03086460)
Timeframe: Baseline, Day 1 and Day 14 post-dose

Intervention	Litres (Least Squares Mean)
Treatment A	0.129
Treatment B	0.180
Treatment C	0.159
Treatment D	0.179
Treatment E	-0.006
Treatment F	0.170

Intervention	Litres (Least Squares Mean)
Treatment A	0.144
Treatment B	0.194
Treatment C	0.170
Treatment D	0.198
Treatment E	0.037
Treatment F	0.184

Intervention	minutes (Median)
Treatment A	358.8
Treatment B	60.3
Treatment C	33.6
Treatment D	44.3
Treatment E	NA
Treatment F	45.5

Intervention	bpm (Mean)
	Day 1, 30 min post-dose	Day 1, 1h post-dose	Day 1, 4h post-dose	Day 1, 8h post-dose	Day 1, 12h post-dose	Day 14, pre-dose	Day 14, 30 min post-dose	Day 14, 1h post-dose	Day 14, 4h post-dose	Day 14, 8h post-dose	Day 14, 12h post-dose
Treatment A	0.3	-1.3	2.1	5.0	5.1	2.5	2.9	1.9	2.8	5.5	7.4
Treatment B	1.2	0.3	1.5	2.4	5.5	0.1	-0.8	-1.2	2.3	3.5	7.5
Treatment C	1.7	2.7	3.3	5.0	5.5	3.1	1.6	1.6	6.7	4.9	6.7
Treatment D	2.5	1.5	5.3	3.9	7.6	2.0	4.3	3.2	3.4	3.8	5.4
Treatment E	-2.4	-1.8	0.2	0.5	2.4	0.7	-1.5	-1.2	1.8	1.6	0.5
Treatment F	-0.3	-1.2	3.2	2.1	5.2	0.4	1.3	0.4	2.3	2.6	5.1

Intervention	Litres (Least Squares Mean)
	Day 1	Day 14
Treatment A	0.220	0.214
Treatment B	0.250	0.251
Treatment C	0.270	0.231
Treatment D	0.317	0.278
Treatment E	0.047	0.061
Treatment F	0.288	0.259

Intervention	bpm (Mean)
	HR AUC(0-4h)	HR peak(0-4h)
Treatment A	-0.4	3.5
Treatment B	0.5	5.1
Treatment C	0.4	5.1
Treatment D	1.3	5.3
Treatment E	-0.2	4.3
Treatment F	0.9	4.8

Intervention	mmol/L (Mean)
	Day 1; 1.5h post-dose	Day 1; 3h post-dose	Day 1; 5h post-dose	Day 1; 7h post-dose	Day 1; 11h post-dose	Day 14; pre-dose	Day 14; 1.5h post-dose	Day 14; 3h post-dose	Day 14; 5h post-dose	Day 14; 7h post-dose	Day 14; 11h post-dose
Treatment A	0.49	0.45	0.83	0.81	0.98	-0.34	0.09	0.09	0.04	-0.04	0.39
Treatment B	0.34	0.54	1.12	0.42	1.08	0.00	0.26	0.77	0.90	0.60	1.30
Treatment C	0.57	1.10	1.11	1.24	1.89	0.49	0.97	1.31	1.12	0.73	1.50
Treatment D	1.19	1.79	1.58	1.37	1.42	0.49	1.21	1.51	1.16	1.09	1.47
Treatment E	0.47	0.26	0.51	0.84	1.40	0.37	0.35	0.25	0.32	0.25	1.03
Treatment F	-0.06	0.39	0.44	0.61	0.90	-0.03	-0.03	0.16	0.53	0.18	0.68

Intervention	mmHg (Mean)
	SBP, Day 1, 30 min post-dose	SBP, Day 1, 1 h post-dose	SBP, Day 1, 4 h post-dose	SBP, Day 1, 8 h post-dose	SBP, Day 1, 12 h post-dose	SBP, Day 14, pre-dose	SBP, Day 14, 30 min post-dose	SBP, Day 14, 1 h post-dose	SBP, Day 14, 4 h post-dose	SBP, Day 14, 8 h post-dose	SBP, Day 14, 12 h post-dose	DBP, Day 1, 30 min post-dose	DBP, Day 1, 1 h post-dose	DBP, Day 1, 4 h post-dose	DBP, Day 1, 8 h post-dose	DBP, Day 1, 12 h post-dose	DBP, Day 14, pre-dose	DBP, Day 14, 30 min post-dose	DBP, Day 14, 1 h post-dose	DBP, Day 14, 4 h post-dose	DBP, Day 14, 8 h post-dose	DBP, Day 14, 12 h post-dose
Treatment A	-1.2	-0.1	1.7	0.8	1.8	1.0	0.3	0.1	0.9	0.7	1.2	-2.1	0.0	-0.6	-1.5	-0.5	-1.2	-0.2	-0.3	-1.0	-1.1	0.0
Treatment B	0.2	0.5	0.4	0.2	2.1	-1.8	-3.1	-1.8	0.1	1.3	1.0	-1.5	-1.9	-1.4	-0.9	-0.1	0.1	-2.1	-2.4	-1.5	-1.0	-0.7
Treatment C	-0.8	-0.6	-0.9	1.1	3.0	0.0	-0.7	-1.8	-1.4	1.1	1.5	-1.2	-0.4	-0.4	-0.4	0.4	1.1	-0.8	-0.5	-1.7	0.3	0.7
Treatment D	-1.2	-0.6	0.9	0.7	1.4	-0.4	-0.7	-1.9	1.0	0.6	4.4	-2.0	-1.6	-1.0	-1.9	-1.0	-0.1	-2.9	-2.4	-2.5	-2.6	-0.6
Treatment E	-0.5	-0.8	0.2	0.5	-0.1	-2.5	-3.6	-1.7	-0.5	-3.3	-0.3	-0.3	-2.5	-1.6	-1.7	-0.3	-0.6	-1.5	-1.8	0.4	-1.7	1.4
Treatment F	-0.8	-0.8	0.5	2.5	3.4	-0.3	-2.5	-1.1	-0.8	0.6	2.5	-1.2	-1.7	-1.0	0.4	0.0	-0.7	-2.0	-1.6	-2.3	-1.3	-0.1

Article	Year
Pharmacological strategies for smoking cessation in patients with chronic obstructive pulmonary disease: a pragmatic review. Expert opinion on pharmacotherapy, 2021, Volume: 22, Issue:7 Topics: Benzazepines; Bupropion; Humans; Nicotine; Pulmonary Disease, Chronic Obstructive; Quinoxalines; Smo	2021
Smoking cessation and COPD. European respiratory review : an official journal of the European Respiratory Society, 2013, Mar-01, Volume: 22, Issue:127 Topics: Benzazepines; Bupropion; Counseling; Humans; Nicotine; Nicotinic Agonists; Prevalence; Pulmonary Dis	2013
Smoking cessation and COPD. European respiratory review : an official journal of the European Respiratory Society, 2013, Mar-01, Volume: 22, Issue:127 Topics: Benzazepines; Bupropion; Counseling; Humans; Nicotine; Nicotinic Agonists; Prevalence; Pulmonary Dis	2013
Smoking cessation and COPD. European respiratory review : an official journal of the European Respiratory Society, 2013, Mar-01, Volume: 22, Issue:127 Topics: Benzazepines; Bupropion; Counseling; Humans; Nicotine; Nicotinic Agonists; Prevalence; Pulmonary Dis	2013
Smoking cessation and COPD. European respiratory review : an official journal of the European Respiratory Society, 2013, Mar-01, Volume: 22, Issue:127 Topics: Benzazepines; Bupropion; Counseling; Humans; Nicotine; Nicotinic Agonists; Prevalence; Pulmonary Dis	2013
Smoking cessation and COPD. European respiratory review : an official journal of the European Respiratory Society, 2013, Mar-01, Volume: 22, Issue:127 Topics: Benzazepines; Bupropion; Counseling; Humans; Nicotine; Nicotinic Agonists; Prevalence; Pulmonary Dis	2013
Smoking cessation and COPD. European respiratory review : an official journal of the European Respiratory Society, 2013, Mar-01, Volume: 22, Issue:127 Topics: Benzazepines; Bupropion; Counseling; Humans; Nicotine; Nicotinic Agonists; Prevalence; Pulmonary Dis	2013
Smoking cessation and COPD. European respiratory review : an official journal of the European Respiratory Society, 2013, Mar-01, Volume: 22, Issue:127 Topics: Benzazepines; Bupropion; Counseling; Humans; Nicotine; Nicotinic Agonists; Prevalence; Pulmonary Dis	2013
Smoking cessation and COPD. European respiratory review : an official journal of the European Respiratory Society, 2013, Mar-01, Volume: 22, Issue:127 Topics: Benzazepines; Bupropion; Counseling; Humans; Nicotine; Nicotinic Agonists; Prevalence; Pulmonary Dis	2013
Smoking cessation and COPD. European respiratory review : an official journal of the European Respiratory Society, 2013, Mar-01, Volume: 22, Issue:127 Topics: Benzazepines; Bupropion; Counseling; Humans; Nicotine; Nicotinic Agonists; Prevalence; Pulmonary Dis	2013
Smoking cessation and COPD. European respiratory review : an official journal of the European Respiratory Society, 2013, Mar-01, Volume: 22, Issue:127 Topics: Benzazepines; Bupropion; Counseling; Humans; Nicotine; Nicotinic Agonists; Prevalence; Pulmonary Dis	2013
Smoking cessation and COPD. European respiratory review : an official journal of the European Respiratory Society, 2013, Mar-01, Volume: 22, Issue:127 Topics: Benzazepines; Bupropion; Counseling; Humans; Nicotine; Nicotinic Agonists; Prevalence; Pulmonary Dis	2013
Smoking cessation and COPD. European respiratory review : an official journal of the European Respiratory Society, 2013, Mar-01, Volume: 22, Issue:127 Topics: Benzazepines; Bupropion; Counseling; Humans; Nicotine; Nicotinic Agonists; Prevalence; Pulmonary Dis	2013
Smoking cessation and COPD. European respiratory review : an official journal of the European Respiratory Society, 2013, Mar-01, Volume: 22, Issue:127 Topics: Benzazepines; Bupropion; Counseling; Humans; Nicotine; Nicotinic Agonists; Prevalence; Pulmonary Dis	2013
Smoking cessation and COPD. European respiratory review : an official journal of the European Respiratory Society, 2013, Mar-01, Volume: 22, Issue:127 Topics: Benzazepines; Bupropion; Counseling; Humans; Nicotine; Nicotinic Agonists; Prevalence; Pulmonary Dis	2013
Smoking cessation and COPD. European respiratory review : an official journal of the European Respiratory Society, 2013, Mar-01, Volume: 22, Issue:127 Topics: Benzazepines; Bupropion; Counseling; Humans; Nicotine; Nicotinic Agonists; Prevalence; Pulmonary Dis	2013
Smoking cessation and COPD. European respiratory review : an official journal of the European Respiratory Society, 2013, Mar-01, Volume: 22, Issue:127 Topics: Benzazepines; Bupropion; Counseling; Humans; Nicotine; Nicotinic Agonists; Prevalence; Pulmonary Dis	2013
Smoking cessation treatment for COPD smokers: the role of pharmacological interventions. Monaldi archives for chest disease = Archivio Monaldi per le malattie del torace, 2013, Volume: 79, Issue:1 Topics: Benzazepines; Bupropion; Humans; Nicotine; Pulmonary Disease, Chronic Obstructive; Quinoxalines; Smo	2013
Smoking cessation. Clinics in chest medicine, 2014, Volume: 35, Issue:1 Topics: Benzazepines; Bupropion; Dopamine Uptake Inhibitors; Humans; Nicotine; Nicotinic Agonists; Pulmonary	2014
Evaluating the effectiveness of smoking cessation in the management of COPD. British journal of nursing (Mark Allen Publishing), 2016, Jul-28, Volume: 25, Issue:14 Topics: Antidepressive Agents, Second-Generation; Bupropion; Counseling; Humans; Nicotinic Agonists; Nurse's	2016
Smoking cessation for people with chronic obstructive pulmonary disease. The Cochrane database of systematic reviews, 2016, Aug-20, Issue:8 Topics: Adult; Behavior Therapy; Bupropion; Combined Modality Therapy; Female; Humans; Male; Nicotine; Nicot	2016
Smoking cessation for people with chronic obstructive pulmonary disease. The Cochrane database of systematic reviews, 2016, Aug-20, Issue:8 Topics: Adult; Behavior Therapy; Bupropion; Combined Modality Therapy; Female; Humans; Male; Nicotine; Nicot	2016
Smoking cessation for people with chronic obstructive pulmonary disease. The Cochrane database of systematic reviews, 2016, Aug-20, Issue:8 Topics: Adult; Behavior Therapy; Bupropion; Combined Modality Therapy; Female; Humans; Male; Nicotine; Nicot	2016
Smoking cessation for people with chronic obstructive pulmonary disease. The Cochrane database of systematic reviews, 2016, Aug-20, Issue:8 Topics: Adult; Behavior Therapy; Bupropion; Combined Modality Therapy; Female; Humans; Male; Nicotine; Nicot	2016
Smoking cessation for people with chronic obstructive pulmonary disease. The Cochrane database of systematic reviews, 2016, Aug-20, Issue:8 Topics: Adult; Behavior Therapy; Bupropion; Combined Modality Therapy; Female; Humans; Male; Nicotine; Nicot	2016
Smoking cessation for people with chronic obstructive pulmonary disease. The Cochrane database of systematic reviews, 2016, Aug-20, Issue:8 Topics: Adult; Behavior Therapy; Bupropion; Combined Modality Therapy; Female; Humans; Male; Nicotine; Nicot	2016
Smoking cessation for people with chronic obstructive pulmonary disease. The Cochrane database of systematic reviews, 2016, Aug-20, Issue:8 Topics: Adult; Behavior Therapy; Bupropion; Combined Modality Therapy; Female; Humans; Male; Nicotine; Nicot	2016
Smoking cessation for people with chronic obstructive pulmonary disease. The Cochrane database of systematic reviews, 2016, Aug-20, Issue:8 Topics: Adult; Behavior Therapy; Bupropion; Combined Modality Therapy; Female; Humans; Male; Nicotine; Nicot	2016
Smoking cessation for people with chronic obstructive pulmonary disease. The Cochrane database of systematic reviews, 2016, Aug-20, Issue:8 Topics: Adult; Behavior Therapy; Bupropion; Combined Modality Therapy; Female; Humans; Male; Nicotine; Nicot	2016
Smoking cessation for people with chronic obstructive pulmonary disease. The Cochrane database of systematic reviews, 2016, Aug-20, Issue:8 Topics: Adult; Behavior Therapy; Bupropion; Combined Modality Therapy; Female; Humans; Male; Nicotine; Nicot	2016
Smoking cessation for people with chronic obstructive pulmonary disease. The Cochrane database of systematic reviews, 2016, Aug-20, Issue:8 Topics: Adult; Behavior Therapy; Bupropion; Combined Modality Therapy; Female; Humans; Male; Nicotine; Nicot	2016
Smoking cessation for people with chronic obstructive pulmonary disease. The Cochrane database of systematic reviews, 2016, Aug-20, Issue:8 Topics: Adult; Behavior Therapy; Bupropion; Combined Modality Therapy; Female; Humans; Male; Nicotine; Nicot	2016
Smoking cessation for people with chronic obstructive pulmonary disease. The Cochrane database of systematic reviews, 2016, Aug-20, Issue:8 Topics: Adult; Behavior Therapy; Bupropion; Combined Modality Therapy; Female; Humans; Male; Nicotine; Nicot	2016
Smoking cessation for people with chronic obstructive pulmonary disease. The Cochrane database of systematic reviews, 2016, Aug-20, Issue:8 Topics: Adult; Behavior Therapy; Bupropion; Combined Modality Therapy; Female; Humans; Male; Nicotine; Nicot	2016
Smoking cessation for people with chronic obstructive pulmonary disease. The Cochrane database of systematic reviews, 2016, Aug-20, Issue:8 Topics: Adult; Behavior Therapy; Bupropion; Combined Modality Therapy; Female; Humans; Male; Nicotine; Nicot	2016
Smoking cessation for people with chronic obstructive pulmonary disease. The Cochrane database of systematic reviews, 2016, Aug-20, Issue:8 Topics: Adult; Behavior Therapy; Bupropion; Combined Modality Therapy; Female; Humans; Male; Nicotine; Nicot	2016
Smoking and chronic obstructive pulmonary disease (COPD). Parallel epidemics of the 21 century. International journal of environmental research and public health, 2009, Volume: 6, Issue:1 Topics: Benzazepines; Bupropion; Combined Modality Therapy; Dopamine Uptake Inhibitors; Humans; Nicotine; Ni	2009
Therapeutic strategies to optimize the efficacy of nicotine replacement therapies. COPD, 2009, Volume: 6, Issue:4 Topics: Administration, Cutaneous; Administration, Oral; Antidepressive Agents, Second-Generation; Antidepre	2009
[Smoking in COPD]. Archivos de bronconeumologia, 2011, Volume: 47 Suppl 8 Topics: Benzazepines; Bupropion; Clonidine; Comorbidity; Disease Progression; Europe; Humans; Motivation; Ni	2011
Benefits and risks of pharmacological smoking cessation therapies in chronic obstructive pulmonary disease. Drug safety, 2003, Volume: 26, Issue:6 Topics: Administration, Buccal; Administration, Intranasal; Antidepressive Agents, Second-Generation; Behavi	2003
Review of bupropion for smoking cessation. Drug and alcohol review, 2003, Volume: 22, Issue:2 Topics: Antidepressive Agents, Second-Generation; Bupropion; Cardiovascular Diseases; Delayed-Action Prepara	2003
[New drug therapy of chronic obstructive pulmonary disease]. Nihon rinsho. Japanese journal of clinical medicine, 2003, Volume: 61, Issue:12 Topics: Administration, Inhalation; Adrenal Cortex Hormones; Adrenergic beta-Agonists; Antidepressive Agents	2003
Essential communication skills in individual smoking cessation. Chronic respiratory disease, 2004, Volume: 1, Issue:4 Topics: Antidepressive Agents, Second-Generation; Bupropion; Communication; Humans; Interpersonal Relations;	2004

Article	Year
The cost-effectiveness of antidepressants for smoking cessation in chronic obstructive pulmonary disease (COPD) patients. Addiction (Abingdon, England), 2009, Volume: 104, Issue:12 Topics: Adult; Aged; Antidepressive Agents; Bupropion; Confidence Intervals; Cost-Benefit Analysis; Cotinine	2009
Cost-effectiveness of an intensive smoking cessation intervention for COPD outpatients. Nicotine & tobacco research : official journal of the Society for Research on Nicotine and Tobacco, 2012, Volume: 14, Issue:6 Topics: Adult; Aged; Bupropion; Cost-Benefit Analysis; Cotinine; Decision Support Techniques; Delivery of He	2012
[Effect of treatment for nicotine dependence in patients with COPD]. Pneumonologia i alergologia polska, 2003, Volume: 71, Issue:9-10 Topics: Administration, Cutaneous; Adult; Aged; Attitude to Health; Bupropion; Delayed-Action Preparations;	2003
Efficacy of bupropion and nortriptyline for smoking cessation among people at risk for or with chronic obstructive pulmonary disease. Archives of internal medicine, 2005, Oct-24, Volume: 165, Issue:19 Topics: Antidepressive Agents, Second-Generation; Antidepressive Agents, Tricyclic; Bupropion; Depression; D	2005
Prospective determinants of smoking cessation in COPD patients within a high intensity or a brief counseling intervention. Patient education and counseling, 2007, Volume: 66, Issue:2 Topics: Adult; Aged; Bupropion; Combined Modality Therapy; Counseling; Female; Humans; Logistic Models; Male	2007

Article	Year
Smoking cessation and vaccination. European respiratory review : an official journal of the European Respiratory Society, 2023, Mar-31, Volume: 32, Issue:167 Topics: Bupropion; Electronic Nicotine Delivery Systems; Humans; Nicotinic Agonists; Pulmonary Disease, Chro	2023
Neuropsychiatric safety of varenicline in the general and COPD population with and without psychiatric disorders: a retrospective cohort study in a real-world setting. BMJ open, 2021, 05-25, Volume: 11, Issue:5 Topics: Benzazepines; Bupropion; Cohort Studies; Humans; Netherlands; Nicotinic Agonists; Pulmonary Disease,	2021
Cardiovascular and neuropsychiatric risks of varenicline and bupropion in smokers with chronic obstructive pulmonary disease. Thorax, 2017, Volume: 72, Issue:10 Topics: Adult; Bupropion; Cardiovascular Diseases; Dopamine Uptake Inhibitors; England; Female; Humans; Male	2017
Using PICO Methodology to Answer Questions About Smoking in COPD Patients. Archivos de bronconeumologia, 2017, Volume: 53, Issue:11 Topics: Biomarkers; Bupropion; Clinical Trials as Topic; Cost-Benefit Analysis; Counseling; Evidence-Based M	2017
In smokers with COPD, neither varenicline nor bupropion was linked to increased CV or neuropsychiatric risk vs NRT. Annals of internal medicine, 2017, 09-19, Volume: 167, Issue:6 Topics: Benzazepines; Bupropion; Humans; Nicotinic Agonists; Pulmonary Disease, Chronic Obstructive; Quinoxa	2017
Socioeconomic inequality in the use of prescription medications for smoking cessation among patients with COPD: a nationwide study. International journal of chronic obstructive pulmonary disease, 2018, Volume: 13 Topics: Adult; Age Factors; Aged; Bupropion; Denmark; Female; Humans; Male; Middle Aged; Pulmonary Disease,	2018
Treatment of smoking in smokers with chronic obstructive pulmonary disease. Sociedad Española de Neumología y Cirugía Torácica (SEPAR). Archivos de bronconeumologia, 2013, Volume: 49, Issue:8 Topics: Benzazepines; Bupropion; Clinical Trials as Topic; Cognitive Behavioral Therapy; Combined Modality T	2013
Real-life effectiveness of smoking-cessation treatments in general practice clinics in Denmark. The Escape Smoke project. Respiratory medicine, 2015, Volume: 109, Issue:2 Topics: Adolescent; Adult; Aged; Aged, 80 and over; Bupropion; Counseling; Denmark; Dopamine Uptake Inhibito	2015
Budgetary impact analysis on funding smoking-cessation drugs in patients with COPD in Spain. International journal of chronic obstructive pulmonary disease, 2015, Volume: 10 Topics: Adult; Aged; Aged, 80 and over; Bupropion; Cohort Studies; Female; Health Care Costs; Health Expendi	2015
Utilization and effectiveness of pharmacotherapy for tobacco use following admission for exacerbation of COPD. Journal of hospital medicine, 2016, Volume: 11, Issue:4 Topics: Adult; Aged; Aged, 80 and over; Bupropion; Cohort Studies; Disease Progression; Drug Therapy, Combin	2016
Do COPD treatment guidelines correctly address the treatment of smoking? Archivos de bronconeumologia, 2016, Volume: 52, Issue:12 Topics: Bupropion; Depression; Humans; Nicotinic Agonists; Practice Guidelines as Topic; Pulmonary Disease,	2016
High rate of smoking abstinence in COPD patients: Smoking cessation by hospitalization. Nicotine & tobacco research : official journal of the Society for Research on Nicotine and Tobacco, 2008, Volume: 10, Issue:5 Topics: Adult; Antidepressive Agents, Second-Generation; Bupropion; Female; Follow-Up Studies; Ganglionic St	2008
The combination of a smoking cessation programme with rehabilitation increases stop-smoking rate. Journal of rehabilitation medicine, 2008, Volume: 40, Issue:8 Topics: Adult; Bupropion; Dopamine Uptake Inhibitors; Follow-Up Studies; Humans; Middle Aged; Nicotine; Prog	2008
[Smoking cessation with special focus on primary health care]. Ugeskrift for laeger, 2009, Feb-23, Volume: 171, Issue:9 Topics: Antidepressive Agents, Second-Generation; Antidepressive Agents, Tricyclic; Bupropion; Cardiovascula	2009
Cost-effectiveness analysis of varenicline versus existing smoking cessation strategies in Central America and the Caribbean using the BENESCO model. Hospital practice (1995), 2012, Volume: 40, Issue:1 Topics: Benzazepines; Bupropion; Cardiovascular Diseases; Central America; Cost-Benefit Analysis; Dominican	2012
Cost analysis of varenicline versus bupropion, nicotine replacement therapy, and unaided cessation in Nicaragua. Hospital practice (1995), 2012, Volume: 40, Issue:1 Topics: Adolescent; Adult; Aged; Benzazepines; Bupropion; Coronary Disease; Costs and Cost Analysis; Dopamin	2012
Role of CHRNA5-A3 genetic Locus variants and developing drug for chronic obstructive pulmonary disease. Current medicinal chemistry, 2012, Volume: 19, Issue:34 Topics: Benzazepines; Bupropion; Chromosomes, Human, Pair 15; Genetic Loci; Genome-Wide Association Study; H	2012
The effect of a minimal contact smoking cessation programme in out-patients with chronic obstructive pulmonary disease: a pre-post-test study. Patient education and counseling, 2004, Volume: 52, Issue:3 Topics: Adult; Aged; Behavior Therapy; Bupropion; Cotinine; Counseling; Female; Follow-Up Studies; Health Kn	2004
[COPD-rehabilitation]. Wiener medizinische Wochenschrift (1946), 2005, Volume: 155, Issue:5-6 Topics: Acupuncture Therapy; Adrenergic alpha-Agonists; Antidepressive Agents, Second-Generation; Antidepres	2005
[Success of smoking cessation in patients with chronic obstructive pulmonary disease]. Tuberkuloz ve toraks, 2006, Volume: 54, Issue:1 Topics: Bupropion; Case-Control Studies; Female; Humans; Male; Middle Aged; Nicotine; Outcome Assessment, He	2006
[Giving up smoking is crucial for COPD patients]. MMW Fortschritte der Medizin, 2007, Feb-22, Volume: 149, Issue:8 Topics: Benzazepines; Bupropion; Family Practice; Humans; Patient Care Team; Patient Education as Topic; Phy	2007

bupropion and Airflow Obstruction, Chronic