carbamates and Airflow Obstruction, Chronic studies

Research Excerpts

Excerpt	Relevance	Reference
"Subjects with stable chronic obstructive pulmonary disease were randomized 2:1 to receive BAT/FF 300/100 or placebo once daily for 6 weeks."	2.94	A randomized, controlled, repeat-dose study of batefenterol/fluticasone furoate compared with placebo in the treatment of COPD. ( Baidoo, C; Castro-Santamaria, R; Crawford, C; Crim, C; Emmett, A; Gotfried, M; Spangenthal, S; Watkins, M, 2020)
"Treatment-emergent adverse events (AEs) were comparable across all treatment groups (n [%] patients; revefenacin 88 μg, 272 [74."	2.90	Revefenacin, a once-daily, lung-selective, long-acting muscarinic antagonist for nebulized therapy: Safety and tolerability results of a 52-week phase 3 trial in moderate to very severe chronic obstructive pulmonary disease. ( Barnes, CN; Crater, G; Dean, L; Donohue, JF; Haumann, B; Kerwin, E; Moran, EJ; Pendyala, S; Sethi, S, 2019)
" There were four major adverse cardiac events (MACEs) in Study 0126 (one, two, and one in the placebo, revefenacin 88 μg, and revefenacin 175 μg groups, respectively), no MACEs in Study 0127 and 26 MACEs in Study 0128 (9, 10 and 7 in the revefenacin 88 μg, revefenacin 175 μg and tiotropium groups, respectively)."	2.90	Cardiovascular safety of revefenacin, a once-daily, lung-selective, long-acting muscarinic antagonist for nebulized therapy of chronic obstructive pulmonary disease: Evaluation in phase 3 clinical trials. ( Barnes, CN; Bourdet, D; Crater, G; Donohue, JF; Feldman, G; Pendyala, S; Sethi, S, 2019)
" No effects were observed on glucose, potassium, heart rate, blood pressure and no dose-response effect was seen on corrected QT elongation."	2.78	A new class of bronchodilator improves lung function in COPD: a trial with GSK961081. ( Baggen, S; Chan, R; Locantore, N; Ludwig-Sengpiel, A; Riley, JH; Wielders, PL, 2013)
" Systemic pharmacodynamics (potassium, heart rate, glucose and QTc), adverse events and systemic pharmacokinetics were also assessed."	2.78	Bronchodilation and safety of supratherapeutic doses of salbutamol or ipratropium bromide added to single dose GSK961081 in patients with moderate to severe COPD. ( Ambery, C; Norris, V, 2013)
" No clinically relevant systemic pharmacodynamic effects were observed."	2.78	Pharmacodynamics of GSK961081, a bi-functional molecule, in patients with COPD. ( Ambery, C; Bateman, ED; Kornmann, O; Norris, V, 2013)
"Chronic obstructive pulmonary disease (COPD) is the 4th leading cause of death in the United States."	2.66	Emerging Treatments for COPD: Evidence to Date on Revefenacin. ( Khan, A; Lal, C, 2020)
" Revefenacin is the first once-daily dosed nebulized long-acting muscarinic antagonist indicated for the maintenance treatment of patients with COPD."	2.61	Revefenacin for the treatment of chronic obstructive pulmonary disease. ( Li, F; Yang, J, 2019)
" The objectives of this analysis were to evaluate the pharmacokinetics of revefenacin and its major metabolite (THRX-195518) in patients with chronic obstructive pulmonary disease, and identify significant covariates affecting revefenacin disposition using a population pharmacokinetic approach based on plasma concentration-time data obtained after single- and repeated-dose once-daily administration in three phase II and two phase III studies."	1.62	Population Pharmacokinetics of Revefenacin in Patients with Chronic Obstructive Pulmonary Disease. ( Borin, MT; Bourdet, DL; Lo, A, 2021)
" In a phase 2b trial, batefenterol produced statistical and clinically significant differences compared to placebo and numerically greater improvements in the primary end point of trough FEV1 compared to salmeterol after 4 weeks of dosing in patients with moderate to severe chronic obstructive pulmonary disease (COPD)."	1.42	Discovery of (R)-1-(3-((2-chloro-4-(((2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)-5-methoxyphenyl)amino)-3-oxopropyl)piperidin-4-yl [1,1'-biphenyl]-2-ylcarbamate (TD-5959, GSK961081, batefenterol): first-in-class dual pharmac ( Chen, Y; Hegde, SS; Hughes, AD; Jasper, JR; Jaw-Tsai, S; Lee, TW; Mammen, M; McNamara, A; Pulido-Rios, MT; Steinfeld, T, 2015)
"Chronic obstructive pulmonary disease (COPD) was diagnosed by the Global Obstructive Lung Disease (GOLD) criteria, and erythrocyte acetylcholinesterase (AChE) was measured by the Ellman method."	1.35	Chronic exposures to cholinesterase-inhibiting pesticides adversely affect respiratory health of agricultural workers in India. ( Chakraborty, S; Lahiri, T; Mukherjee, S; Ray, MR; Roychoudhury, S; Siddique, S, 2009)

Research

Studies (23)

Authors

Clinical Trials (11)

Trial Overview

Trial Outcomes

Change From Baseline in 0 to 4 Hours Post-dose Weighted Mean Heart Rate at Day 42, Derived From Electrocardiograms (ECGs)

Timeframe	Studies, this research(%)	All Research%
pre-1990	0 (0.00)	18.7374
1990's	0 (0.00)	18.2507
2000's	2 (8.70)	29.6817
2010's	13 (56.52)	24.3611
2020's	8 (34.78)	2.80

Authors	Studies
Donohue, JF	4
Kerwin, E	3
Sethi, S	4
Haumann, B	4
Pendyala, S	3
Dean, L	2
Barnes, CN	5
Moran, EJ	4
Crater, G	3
Lal, C	1
Khan, A	1
Clark, CM	1
Jacobs, DM	1
Wilkinson, J	1
Tutalo, R	1
Antoniu, SA	1
Rajnoveanu, R	1
Ulmeanu, R	1
Mihaltan, F	1
Grigore, M	1
Crim, C	1
Gotfried, M	1
Spangenthal, S	1
Watkins, M	1
Emmett, A	1
Crawford, C	1
Baidoo, C	1
Castro-Santamaria, R	1
Crater, GD	1
Lo, A	1
Borin, MT	1
Bourdet, DL	2
Hvisdas, C	1
Quinn, D	1
Yates, W	1
Potgieter, P	1
Nicholls, A	1
Singh, D	1
Heo, YA	1
Li, F	1
Yang, J	1
Feldman, G	1
Bourdet, D	1
Wielders, PL	1
Ludwig-Sengpiel, A	2
Locantore, N	1
Baggen, S	1
Chan, R	2
Riley, JH	2
Norris, V	2
Ambery, C	2
Bateman, ED	1
Kornmann, O	1
Cazzola, M	1
Lopez-Campos, JL	1
Puente-Maestu, L	1
Hughes, AD	1
Chen, Y	1
Hegde, SS	1
Jasper, JR	1
Jaw-Tsai, S	1
Lee, TW	1
McNamara, A	1
Pulido-Rios, MT	1
Steinfeld, T	1
Mammen, M	1
Ambery, CL	1
Wielders, P	1
Chakraborty, S	1
Mukherjee, S	1
Roychoudhury, S	1
Siddique, S	1
Lahiri, T	1
Ray, MR	1
Lainé, DI	1
Xie, H	1
Buffet, N	1
Foley, JJ	1
Buckley, P	1
Webb, EF	1
Widdowson, KL	1
Palovich, MR	1
Belmonte, KE	1

Trial	Phase	Enrollment	Study Type	Start Date	Status
201546, A Repeat-dose Study of Batefenterol/FF (GSK961081/GW685698) Compared With Placebo in the Treatment of COPD[NCT02573870]	Phase 2	63 participants (Actual)	Interventional	2015-12-01	Completed
A Phase 3, 12-week, Randomized, Double-blind Placebo-controlled Parallel Group Study of Nebulized TD-4208 in Subjects With Chronic Obstructive Pulmonary Disease[NCT02512510]	Phase 3	611 participants (Actual)	Interventional	2015-09-30	Completed
A Phase 3, 12-week, Randomized, Double-blind Placebo-controlled Parallel Group Study of Nebulized TD-4208 in Subjects With Chronic Obstructive Pulmonary Disease[NCT02459080]	Phase 3	619 participants (Actual)	Interventional	2015-09-30	Completed
A Phase 2, Randomized, Double-Blind, Crossover Study to Examine the Pharmacodynamics, Safety and Tolerability, and Pharmacokinetics of Single Doses of TD-4208 in Subjects Diagnosed With Chronic Obstructive Pulmonary Disease[NCT03064113]	Phase 2	32 participants (Actual)	Interventional	2011-05-31	Completed
A Phase 2 Study of the Pharmacodynamics, Safety and Tolerability, and Pharmacokinetics of Multiple Doses of TD-4208 for 7 Days in Subjects Diagnosed With Chronic Obstructive Pulmonary Disease[NCT01704404]	Phase 2	62 participants (Actual)	Interventional	2012-12-31	Completed
A Phase 2B, 28-Day, Randomized, Double-Blind Placebo-Controlled Parallel Group Study of Nebulized TD-4208 in Subjects With Chronic Obstructive Pulmonary Disease[NCT02040792]	Phase 2	355 participants (Actual)	Interventional	2014-05-31	Completed
Revefenacin in Acute Respiratory Insufficiency in COPD (RARICO)[NCT04315558]	Phase 2	21 participants (Anticipated)	Interventional	2020-11-01	Recruiting
A Phase 3, 52-week, Randomized, Active-Controlled Parallel Group Study to Evaluate the Safety and Tolerability of Nebulized TD-4208 in Subjects With Chronic Obstructive Pulmonary Disease[NCT02518139]	Phase 3	1,060 participants (Actual)	Interventional	2015-09-30	Completed
A 4-week Dose-Ranging, Dose-Interval, Efficacy, Safety and Tolerability Study of GSK961081 in Subjects With Chronic Obstructive Pulmonary Disease (COPD)[NCT01319019]	Phase 2	437 participants (Actual)	Interventional	2010-12-31	Completed
A Randomized, Double-blind, Crossover Study to Investigate the Bronchodilatation Post-inhalation of GSK961081 Alone and With the Addition of Cumulative Doses of Short Acting Bronchodilators (Salbutamol and Ipratropium Bromide) in Patients With COPD[NCT00674817]	Phase 2	45 participants (Actual)	Interventional	2008-04-01	Completed
A Study to Assess the Pharmacokinetics of Single Escalating Doses of Inhaled GSK961081 DPI (a Dual Pharmacophore) in Healthy Subjects (Part 1) and a Randomised, Double-blind, Double Dummy, Crossover (Incomplete Block) Study to Assess the Safety, Tolerabil[NCT00478738]	Phase 2	82 participants (Actual)	Interventional	2007-06-30	Completed
[information is prepared from clinicaltrials.gov, extracted Sep-2024]

ECG measurements were taken in supine position after obtaining vital signs. Weighted mean was derived by calculating the area under the curve (AUC), and then dividing by the relevant time interval. Baseline was the pre-dose measurement on Day 1. Change from Baseline in 0 to 4 hours post-dose weighted mean heart rate was measured on Days 1, 28 and 42 and was analyzed using a mixed models repeated measures (MMRM) model. Intent-To-Treat (ITT) Population: all randomized participants who received at least one dose of study medication. (NCT02573870)
Timeframe: Baseline and Day 42

Change From Baseline in Trough FEV1 on Day 85

Percentage of Albuterol Rescue-free 24-hour Periods

St. George's Respiratory Questionnaire (SGRQ) Proportion of Responders on Day 85

Intervention	Beats per minute (bpm) (Least Squares Mean)
Placebo	0.688
BAT/FF 300/100 µg	-1.557

Intervention	mL (Least Squares Mean)
TD-4208-1	115.58
TD-4208-2	102.90
Placebo	-44.92

Intervention	Percentage of 24hr periods (Least Squares Mean)
TD-4208-1	44.79
TD-4208-2	43.26
Placebo	37.23

A Responder is defined as someone who experienced a decrease in SGRQ score of 4 or more units (NCT02512510)
Timeframe: Day 85

Summary of Change From Baseline to Peak FEV1 After First Dose

Summary of Rescue Medication Use: Puffs Per Day

Summary of Trough FEV1 Overall Treatment Effect From Day 15 to Day 85

Change From Baseline in Trough FEV1 on Day 85

Percentage of Albuterol Rescue-free 24-hour Periods

St. George's Respiratory Questionnaire (SGRQ) Proportion of Responders on Day 85

Intervention	Participants (Count of Participants)
TD-4208-1	67
TD-4208-2	67
Placebo	54

Intervention	mL (Least Squares Mean)
TD-4208-1	218.65
TD-4208-2	216.84
Placebo	88.22

Intervention	Puffs per Day (Least Squares Mean)
TD-4208-1	2.00
TD-4208-2	2.38
Placebo	2.54

Intervention	mL (Mean)
TD-4208-1	83.9
TD-4208-2	87.1
Placebo	-39.9

Intervention	mL (Least Squares Mean)
TD-4208-1	59.81
TD-4208-2	126.85
Placebo	-19.41

Intervention	Percentage of 24 hr periods (Least Squares Mean)
TD-4208-1	48.35
TD-4208-2	43.57
Placebo	45.21

A Responder is defined as someone who experienced a decrease in SGRQ score of 4 or more units (NCT02459080)
Timeframe: Baseline to Day 85

Summary of Change From Baseline to Peak FEV1 After First Dose

Summary of Rescue Medication Use: Puffs Per Day

Summary of Trough FEV1 Overall Treatment Effect From Day 15 to Day 85

Area Under the Forced Vital Capacity (FVC) vs. Time Curve

Peak Forced Expiratory Volume in One Second (FEV1) Relative to Baseline

Area Under the FEV1 vs. Peak FEV1, Time-matched Difference From Placebo

Area Under the FEV1 vs. Time Curve, Time-matched Difference From Placebo

Forced Expiratory Flow From 25% to 75% of Vital Capacity (FEF25-75), as Related to FEV1

Forced Vital Capacity (FVC)

Peak Expiratory Flow Rate (PEFR) From 25% to 75% of Vital Capacity (FEF25-75), as Related to FEV1

Change From Baseline to Day 7 in Trough FEV1 (Forced Expiratory Volume in 1 Second)

Cmax

Intervention	Participants (Count of Participants)
TD-4208-1	70
TD-4208-2	68
Placebo	46

Intervention	mL (Least Squares Mean)
TD-4208-1	218.14
TD-4208-2	224.46
Placebo	91.79

Intervention	Puffs per Day (Least Squares Mean)
TD-4208-1	2.26
TD-4208-2	2.27
Placebo	2.72

Intervention	mL (Mean)
TD-4208-1	73.0
TD-4208-2	124.8
Placebo	-30.8

Intervention	hr*mL (Least Squares Mean)
Placebo	74168.1
TD-4208 700 μg	80057.0
TD-4208 350 μg	78143.6
Ipratropium 500 μg	76822.7

Intervention	mL (Least Squares Mean)
Placebo	1708.0
TD-4208 700 μg	1877.3
TD-4208 350 μg	1881.8
Ipratropium 500 μg	1883.6

Intervention	hr*mL (Least Squares Mean)
	AUC 0-12 hrs	AUC 0-24 hrs
Ipratropium 500 μg	287.7	271.7
Placebo	262.1	261.2
TD-4208 350 μg	288.5	281.3
TD-4208 700 μg	291.2	286.6

Intervention	mL (Least Squares Mean)
	FEV1 at 12hr	FEV1 at 24 hr
Ipratropium 500 μg	1534.5	1509.6
Placebo	1519.2	1533.8
TD-4208 350 μg	1631.7	1636.6
TD-4208 700 μg	1642.6	1670.4

Intervention	L/sec (Least Squares Mean)
	FEF 25-75% at 12 hr	FEF 25-75% at 24 hr
Ipratropium 500 μg	0.6	0.6
Placebo	0.6	0.6
TD-4208 350 μg	0.7	0.6
TD-4208 700 μg	0.7	0.6

Intervention	mL (Mean)
	Predose	15 min	30 min	45 min	1 hour	2 hours	3 hours	4 hours	6 hours	8 hours	10 hours	11 hours	12 hours	14 hours	22 hours	23 hours	24 hours	25 hours
Ipratropium 500 μg	2959.4	3339.7	3399.4	3394.1	3379.4	3441.6	3474.1	3368.8	3295.3	3305.2	3180.3	3162.3	3131.3	3123.8	3010.0	3006.3	3031.6	3219.4
Placebo	2941.9	2873.4	2944.7	2927.2	2968.1	3062.5	3122.2	3177.8	3192.6	3197.2	2958.7	3156.2	3092.8	3114.4	3033.8	2999.7	3018.1	3172.8
TD-4208 350 μg	2986.7	3119.3	3262.2	3328.8	3361.9	3408.8	3420.3	3340.9	3220.6	3301.6	3339.4	3295.5	3265.1	3319.1	3147.2	3232.2	3243.1	3295.2
TD-4208 700 μg	2949.1	3166.9	3263.8	3324.7	3269.4	3363.1	3430.4	3386.3	3442.8	3259.4	3335.3	3296.2	3229.4	3333.1	3314.5	3349.4	3345.6	3392.5

Intervention	L/sec (Least Squares Mean)
	Peak FEF 25-75% 24hr	Peak FEF 25-75% 12hr
Ipratropium 500 μg	0.9	0.9
Placebo	0.8	0.8
TD-4208 350 μg	0.9	0.9
TD-4208 700 μg	0.9	0.9

Intervention	FEV1 (mL) (Mean)
Dose 1 TD-4208	91.2
Dose 2 TD-4208	92.8
Dose 3 TD-4208	113.1
Dose 4 TD-4208	151.9
Dose 5 TD-4208	132.2
Dose 6 TD-4208	119.4
Placebo	37.8

"Day 1: 15 minutes pre-dose, post-dose at 15 and 30 minutes, 1, 2, 3, 4, and 6 hours.~Day 7: 15 minutes pre-dose, post-dose at 15 and 30 minutes, 1, 2, 3, 4, 6, 8, 12 and 24 hours." (NCT01704404)
Timeframe: From baseline to day 7

Plasma Half-life

Intervention	ng/mL (Mean)
Dose 1 TD-4208	.0125
Dose 2 TD-4208	.0224
Dose 3 TD-4208	.0526
Dose 4 TD-4208	.114
Dose 5 TD-4208	.243
Dose 6 TD-4208	.577

Tmax

Intervention	hours (Mean)
Dose 5 TD-4208	25.1
Dose 6 TD-4208	23.0

Change From Baseline in Trough FEV1 (Forced Expiratory Volume in One Second)

Adverse Events: Frequency and Severity

Intervention	hours (Mean)
Dose 1 TD-4208	.233
Dose 2 TD-4208	.233
Dose 3 TD-4208	0.233
Dose 4 TD-4208	0.233
Dose 5 TD-4208	0.233
Dose 6 TD-4208	0.233

Intervention	mL (Least Squares Mean)
Placebo	-32.4
44 mcg	19.4
88 mcg	155.0
175 mcg	134.2
350 mcg	138.2

To assess the safety and tolerability of TD-4208 by assessing the frequency and severity of Treatment Emergent Adverse Events (TEAE) (NCT02518139)
Timeframe: Baseline to Day 365

Area Under Plasma Concentration Time Curve (AUC) of GSK961081 to the Last Quantifiable Concentration

Intervention	Participants (Count of Participants)
	Adverse Event (AE)	Moderate or Severe AE	Serious AE
TD-4208-1	272	226	58
TD-4208-2	242	174	43
Tiotropium	275	210	58

AUC(0-t) is the area under plasma concentration time curve of GSK961081 to the last quantifiable concentration. This parameter was determined using the linear trapezoidal rule for increasing concentrations and the logarithmic trapezoidal rule for decreasing concentrations. A large proportion of AUC(0-t) and Cmax values were reported as not countable (NC) at the GSK961081 400 micrograms (ug) dose level, therefore only limited summaries were calculated. Logarithmic transformed values are presented. AUC(0-t) imputed with 1/2 lowest observed AUC(0-t), where lowest AUC(0-t) was 56.46 hour picograms per milliliter (h*pg/mL). (NCT00674817)
Timeframe: Up to 82 days

Maximum Change From Baseline (Pre-dose on Day 1) in QTc (F) in Supine Position From 0 to 27 Hours After Dosing

Intervention	h*pg/mL (Geometric Mean)
GSK961081 400 mg Plus SAL	NA
GSK961081 1200 mg Plus SAL	233.93
GSK961081 400 mg Plus IPR	NA
GSK961081 1200 mg Plus IPR	216.22
GSK961081 400 mg Plus Placebo	NA
GSK961081 1200 mg Plus Placebo	229.51

Analysis of Q T (F) interval during ECG (taken in supine position) was performed using Fridericia's method. Change from baseline is the value at indicated time point minus the value at Baseline. Adjusted means are considered as LS mean values while presenting the data . (NCT00674817)
Timeframe: From dosing until 27 hours (0-27h)

Maximum Change From Baseline (Pre-dose on Day 1) in QTc (F) in Supine Position From 0 to 4 Hours After Dosing

Intervention	msec (Mean)
GSK961081 400 mg Plus SAL	19.70
GSK961081 1200 mg Plus SAL	19.53
GSK961081 400 mg Plus IPR	17.41
GSK961081 1200 mg Plus IPR	17.45
GSK961081 400 mg Plus Placebo	15.14
GSK961081 1200 mg Plus Placebo	18.60

Analysis of QT (F) interval during ECG (taken in supine position) was performed using Fridericia's method. Change from baseline is the value at indicated time point minus the value at Baseline. Adjusted means are considered as least square (LS) mean values while presenting the data. (NCT00674817)
Timeframe: From dosing until 4 hours (0-4h)

Maximum Plasma Concentration (Cmax) of GSK961081 Over Period Determined Directly From the Concentration-time Data

Intervention	msec (Mean)
GSK961081 400 mg Plus SAL	14.34
GSK961081 1200 mg Plus SAL	14.98
GSK961081 400 mg Plus IPR	12.31
GSK961081 1200 mg Plus IPR	11.99
GSK961081 400 mg Plus Placebo	10.60
GSK961081 1200 mg Plus Placebo	13.22

Cmax is the Maximum observed concentration of GSK961081 determined directly from the concentration-time data. A large proportion of Cmax values were reported as not countable (NC ) at the GSK961081 400 micrograms (ug) dose level, therefore only limited summaries were calculated. Logarithmic transformed values are presented. Cmax was imputed with 1/2 lowest limit of quantification (LLQ), where LLQ was 25 picograms per milliliter (pg/mL). (NCT00674817)
Timeframe: Up to 82 days

Time to Last Quantifiable Plasma Concentration (Tlast) of GSK961081 Over Period Determined Directly From the Concentration-time Data

Intervention	pg/mL (Geometric Mean)
GSK961081 400 mg Plus SAL	66.93
GSK961081 1200 mg Plus SAL	169.05
GSK961081 400 mg Plus IPR	70.77
GSK961081 1200 mg Plus IPR	153.59
GSK961081 400 mg Plus Placebo	70.52
GSK961081 1200 mg Plus Placebo	176.92

Tlast is the time to last quantifiable plasma concentration of GSK961081 over period determined directly from the concentration-time data (NCT00674817)
Timeframe: Up to 82 days

Time to Maximum Plasma Concentration (Tmax) of GSK961081 Over Period Determined Directly From the Concentration-time Data

Intervention	hours (Median)
GSK961081 400 mg Plus SAL	0.960
GSK961081 1200 mg Plus SAL	2.000
GSK961081 400 mg Plus IPR	1.930
GSK961081 1200 mg Plus IPR	3.920
GSK961081 400 mg Plus Placebo	1.920
GSK961081 1200 mg Plus Placebo	2.050

Tmax is the time to maximum plasma concentration of GSK961081 over period determined directly from the concentration-time data (NCT00674817)
Timeframe: Up to 82 days

Weighted Mean Change From Baseline (Pre-dose on Day 1) in Heart Rate in Supine Position From 0 to 4 Hours

Intervention	Hours (Median)
GSK961081 400 mg Plus SAL	0.920
GSK961081 1200 mg Plus SAL	0.930
GSK961081 400 mg Plus IPR	0.925
GSK961081 1200 mg Plus IPR	0.920
GSK961081 400 mg Plus Placebo	0.920
GSK961081 1200 mg Plus Placebo	0.920

Heart rate was recorded in supine position. Change from baseline is the value at indicated time point minus the value at Baseline. Weighted means are considered as LS mean values while presenting the data. (NCT00674817)
Timeframe: From dosing until 4 hours (0-4h)

Weighted Mean Change From Baseline (Pre-dose on Day 1) in QTc(B) in Supine Position From 0 to 4 Hours

Intervention	Beats per minute (Least Squares Mean)
GSK961081 400 mg Plus SAL	0.52
GSK961081 1200 mg Plus SAL	1.77
GSK961081 400 mg Plus IPR	-2.93
GSK961081 1200 mg Plus IPR	-1.27
GSK961081 400 mg Plus Placebo	-3.57
GSK961081 1200 mg Plus Placebo	-2.21

Analysis of QT (B) interval during ECG (taken in supine position) was performed using Bazett's method. Change from baseline is the value at indicated time point minus the value at Baseline. Weighted means are considered as LS mean values while presenting the data. (NCT00674817)
Timeframe: From dosing until 4 hours (0-4h)

Weighted Mean Change From Baseline (Pre-dose on Day 1) in QTc(F) in Supine Position From 0 to 4 Hours

Intervention	msec (Least Squares Mean)
GSK961081 400 mg Plus SAL	5.27
GSK961081 1200 mg Plus SAL	9.08
GSK961081 400 mg Plus IPR	0.08
GSK961081 1200 mg Plus IPR	4.44
GSK961081 400 mg Plus Placebo	0.07
GSK961081 1200 mg Plus Placebo	6.12

Analysis of QT(F) interval during ECG (taken in supine position) was performed using Fridericia's method. Change from baseline is the value at indicated time point minus the value at Baseline. Weighted means are considered as LS mean values while presenting the data. (NCT00674817)
Timeframe: From dosing until 4 hours (0-4h)

Change From Baseline (Pre-dose on Day 1) in Systolic and Diastolic Blood Pressure up to 27 Hours

Intervention	msec (Least Squares Mean)
GSK961081 400 mg Plus SAL	5.42
GSK961081 1200 mg Plus SAL	7.53
GSK961081 400 mg Plus IPR	4.59
GSK961081 1200 mg Plus IPR	6.23
GSK961081 400 mg Plus Placebo	4.17
GSK961081 1200 mg Plus Placebo	8.18

Change from Baseline in systolic blood pressure (SBP) and diastolic blood pressure (DBP) was analyzed. Change from baseline is the difference in the blood pressure at the indicated time point minus the Baseline value. (NCT00674817)
Timeframe: Up to 27 hours post Day 1 dosing

Maximal Change in Forced Expiratory Volume in One Second (FEV1) From Baseline (Pre-dose on Day 1) in Combination With Short Acting Bronchodialator (Salbutamol or Ipratropium Bromide) at 1h,12h and 24h.

Intervention	Millimeters of mercury (mm of Hg) (Mean)
	SBP, 1 hour(h)	SBP, 2h	SBP, 4h	SBP, 9h	SBP, 12h	SBP, 13h	SBP, 24h	SBP, 25h	SBP, 27h	DBP, 1h	DBP, 2h	DBP, 4h	DBP, 9h	DBP, 12h	DBP, 13h	DBP, 24h	DBP, 25h	DBP, 27h
GSK961081 1200 mg Plus IPR	-1.73	2.33	2.68	2.71	0.32	2.27	2.56	2.44	-0.32	-2.66	0.48	0.12	-0.34	-0.90	-0.39	2.32	1.49	-1.12
GSK961081 1200 mg Plus Placebo	-0.33	1.31	2.38	2.95	-0.51	2.21	1.68	1.49	-1.24	-2.21	-1.05	1.54	-0.79	-0.51	-0.34	-0.58	2.22	-1.55
GSK961081 1200 mg Plus SAL	3.10	1.22	4.20	3.08	2.08	3.46	4.65	4.05	2.43	-1.41	-2.27	1.23	0.03	-1.25	-1.97	3.13	0.75	-0.03
GSK961081 400 mg Plus IPR	0.61	3.49	3.27	1.07	-0.46	1.05	1.41	2.32	-3.24	1.25	0.07	1.24	-1.73	-2.68	-0.56	0.37	1.24	-2.51
GSK961081 400 mg Plus Placebo	-0.13	1.03	0.63	0.00	-1.95	3.45	-1.50	-0.10	-3.25	0.55	-1.48	1.38	0.28	-3.05	0.85	-0.23	0.78	-3.35
GSK961081 400 mg Plus SAL	-1.33	-3.41	-2.36	-0.87	-3.49	-5.62	-3.31	-3.38	-5.59	-1.59	-4.15	-0.26	-1.59	-3.18	-4.19	-0.95	-2.26	-3.28

FEV1 is a measure of lung function and is defined as the maximal amount of air that can be forcefully exhaled in one second as measured by spirometry. Adjusted mean has been presented as least square (LS) mean. (NCT00674817)
Timeframe: Baseline (pre-dose on Day 1), 1h, 12h, and 24h on Day 1

Maximal Change in Forced Vital Capacity (FVC) in One Second From Pre-dose in Combination With Short Acting Bronchodialator (Salbutamol or Ipratropium Bromide) at 1h, 12h and 24h.

Intervention	Liters (Least Squares Mean)
	1 hour	12 hour	24 hour
GSK961081 1200 mg Plus IPR	0.111	0.098	0.172
GSK961081 1200 mg Plus Placebo	0.094	0.043	0.049
GSK961081 1200 mg Plus SAL	0.113	0.134	0.175
GSK961081 400 mg Plus IPR	0.087	0.127	0.179
GSK961081 400 mg Plus Placebo	0.072	0.002	0.039
GSK961081 400 mg Plus SAL	0.111	0.141	0.161

FVC is defined as the amount of air that can be forcibly exhaled from the lungs after a maximum inspiration as measured by spirometry. Adjusted mean has been presented as least square (LS) mean. (NCT00674817)
Timeframe: Baseline (Pre-dose on Day 1), 1h, 12h, and 24h on Day 1

Maximum Change From Baseline (Pre-dose on Day 1) in Glucose Over 4 and 27 Hours and Weighted Mean Change From Baseline in Glucose Over 4 Hours

Intervention	Liters (Least Squares Mean)
	1 hour	12 hour	24 hour
GSK961081 1200 mg Plus IPR	0.207	0.223	0.214
GSK961081 1200 mg Plus Placebo	0.229	0.088	0.113
GSK961081 1200 mg Plus SAL	0.281	0.182	0.205
GSK961081 400 mg Plus IPR	0.167	0.188	0.279
GSK961081 400 mg Plus Placebo	0.234	0.068	0.179
GSK961081 400 mg Plus SAL	0.169	0.160	0.247

Maximum change (MC) from Baseline (BL) and weighted mean change (WMC) from baseline in glucose (GLU) were analyzed. Change from Baseline is the value at indicated time point minus the value at Baseline. Weighted means are considered as LS mean values while presenting the data. (NCT00674817)
Timeframe: 0-4h and 0-27h for maximum change and 0-4 h for weighted mean change

Maximum Change From Baseline (Pre-dose on Day 1) in QTc(B) in Supine Position From 0 to 4 Hours and 0 to 27 Hours

Intervention	Millimoles per Liter (Least Squares Mean)
	MC from BL, Glu, 0-4h	MC from BL, Glu, 0-27h	WMC from BL, Glu, 0-4h
GSK961081 1200 mg Plus IPR	0.53	1.87	-0.08
GSK961081 1200 mg Plus Placebo	0.22	1.30	0.19
GSK961081 1200 mg Plus SAL	0.53	2.13	0.02
GSK961081 400 mg Plus IPR	0.52	1.78	-0.12
GSK961081 400 mg Plus Placebo	0.13	1.83	-0.29
GSK961081 400 mg Plus SAL	0.66	2.71	0.02

Analysis of QT (B) interval during ECG (taken in supine position) was performed using Bazett's method. Change from baseline is the value at indicated time point minus the value at Baseline. Weighted means are considered as LS mean values while presenting the data . (NCT00674817)
Timeframe: From dosing until 4 hours (0-4h) and 27 hours (0-27h)

Maximum Change From Baseline (Pre-dose on Day 1) in Supine Heart Rate From 0 to 4 Hours and From 0 to 27 Hours.

Intervention	msec (Least Squares Mean)
	0-4 hours	0-27 hours
GSK961081 1200 mg Plus IPR	10.77	17.83
GSK961081 1200 mg Plus Placebo	11.65	19.91
GSK961081 1200 mg Plus SAL	19.51	25.88
GSK961081 400 mg Plus IPR	9.19	17.33
GSK961081 400 mg Plus Placebo	6.50	12.94
GSK961081 400 mg Plus SAL	16.70	24.17

Heart rate was measured in supine position. Change from baseline is the value at indicated time point minus the value at Baseline. Adjusted means are considered as LS mean values while presenting the data. (NCT00674817)
Timeframe: From dosing until 4 hours (0-4h) and until 27 hours (0-27 h)

Maximum Change From Baseline (Pre-dose on Day 1) in Supine Systolic Blood Pressure (SBP) Over 4 and 27 Hours and Weighted Mean Change From Baseline in Supine SBP Over 4 Hours

Intervention	Beats per minute (Least Squares Mean)
	0-4 h	0-27 h
GSK961081 1200 mg Plus IPR	3.17	10.28
GSK961081 1200 mg Plus Placebo	0.92	8.66
GSK961081 1200 mg Plus SAL	7.90	12.92
GSK961081 400 mg Plus IPR	2.18	9.49
GSK961081 400 mg Plus Placebo	0.92	9.21
GSK961081 400 mg Plus SAL	7.51	13.33

Systolic blood pressure (SBP) values were recorded in supine position. Change from baseline is the value at indicated time point minus the value at Baseline. Adjusted or maximum change/ (MC) and weighted mean change (WMC) are considered as LS mean change values while presenting the data. (NCT00674817)
Timeframe: 0-4h and 0-27h for maximum change and 0-4 h for weighted mean change

Mean Change From Baseline (Pre-dose on Day 1) in Heart Rate Over 27 Hours

Intervention	Millimeters of mercury (Least Squares Mean)
	MC from BL,SBP,0-4h	MC from BL,SBP,0-27h	WMC from BL SBP,0-4h
GSK961081 1200 mg Plus IPR	5.55	12.87	0.10
GSK961081 1200 mg Plus Placebo	7.74	14.10	0.82
GSK961081 1200 mg Plus SAL	8.06	15.93	0.92
GSK961081 400 mg Plus IPR	8.05	14.08	2.24
GSK961081 400 mg Plus Placebo	7.45	14.16	1.06
GSK961081 400 mg Plus SAL	5.61	10.89	-0.34

Heart rate was considered as a measure of vital sign. Change from baseline is the difference in the blood pressure at the indicated time point minus the Baseline value. (NCT00674817)
Timeframe: Up to 27 hours post Day 1 dosing

Minimum Change From Baseline (Pre-dose on Day 1) in Potassium Over 4 and 27 Hours and Weighted Mean Change From Baseline in Potassium Over 4 Hours

Intervention	Beats per minute (Mean)
	1h	1h 15 minutes	1h 35 minutes	1h 55 minutes	4h	9h	12h	12h 15 minutes	12h 35 minutes	12h 55 minutes	24h	24h 15 minutes	24h 35 minutes	24h 55 minutes	27h
GSK961081 1200 mg Plus IPR	-2.27	-0.15	-0.98	-0.39	-1.78	1.37	2.83	4.10	3.41	1.90	-1.85	-0.98	-1.02	-2.05	4.44
GSK961081 1200 mg Plus Placebo	-3.10	-1.74	-2.36	-2.21	-3.97	0.28	1.87	2.05	1.29	1.37	-4.55	-4.03	-4.63	-4.21	2.68
GSK961081 1200 mg Plus SAL	-1.37	-0.46	1.51	4.54	1.13	2.97	3.65	5.35	6.90	6.50	-1.08	-1.60	0.53	0.83	6.38
GSK961081 400 mg Plus IPR	-3.90	-2.80	-2.34	-3.46	-3.59	-1.66	1.46	1.83	1.51	1.07	-3.24	-0.83	-2.93	-2.46	1.17
GSK961081 400 mg Plus Placebo	-3.55	-4.03	-3.63	-3.63	-4.75	-0.70	2.68	1.80	2.28	0.98	-3.63	-2.95	-4.48	-4.13	2.05
GSK961081 400 mg Plus SAL	-2.56	-0.95	-0.03	3.21	-0.71	1.92	1.95	3.95	4.97	5.79	-2.36	-1.49	0.23	1.05	6.74

Maximum change (MC) from Baseline (BL) and weighted mean change (WMC) from baseline in potassium (K) were analyzed. Change from Baseline is the value at indicated time point minus the value at Baseline. Weighted means are considered as LS mean values while presenting the data. (NCT00674817)
Timeframe: 0-4h and 0-27h for maximum change and 0-4 h for weighted mean change

Minimum Change From Baseline (Pre-dose on Day 1) in Supine Diastolic Blood Pressure (DBP) Over 4 and 27 Hours and Weighted Mean Change From Baseline in Supine DBP Over 4 Hours

Intervention	Millimoles per Liter (Least Squares Mean)
	MC from BL, K, 0-4h	MC from BL, K, 0-27h	WMC from BL, K, 0-4h
GSK961081 1200 mg Plus IPR	-0.39	-0.46	-0.17
GSK961081 1200 mg Plus Placebo	-0.36	-0.45	-0.14
GSK961081 1200 mg Plus SAL	-0.44	-0.62	-0.22
GSK961081 400 mg Plus IPR	-0.25	-0.42	-0.06
GSK961081 400 mg Plus Placebo	-0.25	-0.37	-0.07
GSK961081 400 mg Plus SAL	-0.42	-0.53	-0.18

Diastolic blood pressure (DBP) values were recorded in supine position. Change from baseline is the value at indicated time point minus the value at Baseline. Adjusted or maximum change/(MC) and weighted mean change (WMC) are considered as LS mean change values while presenting the data . (NCT00674817)
Timeframe: 0-4h and 0-27h for maximum change and 0-4 h for weighted mean change

Number of Participants With Adverse Events and Serious Adverse Events

Intervention	Millimeters of mercury (Least Squares Mean)
	MC from BL, DBP, 0-4h	MC from BL, DBP, 0-27h	WMC from BL, DBP, 0-4h
GSK961081 1200 mg Plus IPR	-5.49	-8.72	-0.80
GSK961081 1200 mg Plus Placebo	-4.42	-9.18	-0.44
GSK961081 1200 mg Plus SAL	-5.76	-9.20	-1.25
GSK961081 400 mg Plus IPR	-3.26	-9.12	0.75
GSK961081 400 mg Plus Placebo	-4.96	-9.66	-0.12
GSK961081 400 mg Plus SAL	-5.53	-10.04	-1.30

An adverse event (AE) is any untoward medical occurrence in a participant temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. A serious AE (SAE) is any untoward medical occurrence that, at any dose results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, or is a congenital anomaly/birth defect. (NCT00674817)
Timeframe: Upto 82 days

Number of Participants With Laboratory Abnormalities of Potential Clinical Concern (PCC)

Intervention	Participants (Number)
	Participants with any AE	Participants with any SAE
GSK961081 1200 mg Plus IPR	9	0
GSK961081 1200 mg Plus Placebo	11	0
GSK961081 1200 mg Plus SAL	13	1
GSK961081 400 mg Plus IPR	15	1
GSK961081 400 mg Plus Placebo	6	0
GSK961081 400 mg Plus SAL	13	0

The normal ranges of laboratory parameters were hemoglobin: 130-167 grams per deciliter (g/dL), platelets: 173-383 Giga per liter (GI/L), lymphocytes: 20.1-44.5 %, glucose: 3.8857-6.106 millimoles per liter (mmol/L), creatinine: 44.2-132.6 micromoles per liter (uM/L) , aspartate transaminases (AST): 12-32 international units per liter (IU/L), total bilirubin (TB): 4.275-25.65 uM/L and potassium: 3.4-4.7 mmol/L, respectively. Laboratory values recorded outside the normal range were considered of potential clinical concern (PCC). (NCT00674817)
Timeframe: Up to 42 days

Number of Participants With Maximum Change From Baseline 12-LED Electrocardiogram (ECG) Findings

Analysis QTc interval of ECG was performed by Bazett's formula (QTc B) and Fridericia's correction (QTc F). Number of participants with abnormal ECG findings were recorded. Any participant with QTc(B) or QTc(F) >500 milliseconds (msec) or uncorrected QT >600 msec (machine or manual over read) was withdrawn from the study. Participants that had right bundle branch block with QTc(B) or QTc(F) >530 msec were also withdrawn from the study. (NCT00674817)
Timeframe: From dosing until 24h post-dose.

Time to Maximum Change From Baseline (Pre-dose on Day 1) for QTc(B), QTc(F), Heart Rate, Systolic BP, Glucose in Supine Position and Time to Minimum Change From Baseline for Potassium and Diastolic BP in Supine Position

Analysis of QT (B) or QTc (F) interval during ECG (taken in supine position) was performed using Bazett's method and Fridericia's method, respectively. Heart rate, BP, potassium, and glucose were measured in supine body position. Change from baseline is the value at indicated time point minus the value at Baseline. Weighted means are considered as LS mean values while presenting the data. (NCT00674817)
Timeframe: From dosing until 4 hours (0-4h)

Intervention	Participants (Number)
	Hemoglobin high	Platelets high	Platelets low	Lymphocytes low
GSK961081 1200 mg Plus IPR	0	0	0	1
GSK961081 1200 mg Plus Placebo	0	0	0	0
GSK961081 1200 mg Plus SAL	1	1	0	0
GSK961081 400 mg Plus IPR	0	0	0	0
GSK961081 400 mg Plus Placebo	0	0	0	0
GSK961081 400 mg Plus SAL	0	0	1	0

Intervention	Participants (Number)
	QTcB, <=30 msec	QTcB, >30 to <= 59 msec	QTcB, >=60 msec	QTcF, <=30 msec	QTcF, >30 to <= 59 msec	QTcF, >=60 msec
GSK961081 1200 mg Plus IPR	33	7	1	36	4	1
GSK961081 1200 mg Plus Placebo	31	6	2	35	2	2
GSK961081 1200 mg Plus SAL	31	9	1	31	9	1
GSK961081 400 mg Plus IPR	35	6	0	37	2	2
GSK961081 400 mg Plus Placebo	36	3	1	36	4	0
GSK961081 400 mg Plus SAL	26	12	1	34	5	0

Intervention	hours (Median)
	Heart rate	Systlic BP	Diastolic BP	QTcF	QTcB	Glucose	Potassium
GSK961081 1200 mg Plus IPR	1.517	2.100	0.933	2.100	2.100	0.967	1.950
GSK961081 1200 mg Plus Placebo	1.567	3.008	0.925	2.117	2.100	0.967	1.933
GSK961081 1200 mg Plus SAL	1.850	2.100	1.967	2.100	2.100	1.950	1.933
GSK961081 400 mg Plus IPR	1.517	2.100	2.100	2.167	2.100	0.967	1.933
GSK961081 400 mg Plus Placebo	1.567	2.008	1.983	2.133	2.100	1.150	1.942
GSK961081 400 mg Plus SAL	1.850	0.917	2.100	2.183	2.100	1.933	1.967

Article	Year
Emerging Treatments for COPD: Evidence to Date on Revefenacin. COPD, 2020, Volume: 17, Issue:1 Topics: Benzamides; Carbamates; Drug Administration Schedule; Forced Expiratory Volume; Humans; Medication A	2020
Revefenacin for the treatment of chronic obstructive pulmonary disease. Expert review of respiratory medicine, 2020, Volume: 14, Issue:3 Topics: Administration, Inhalation; Benzamides; Carbamates; Clinical Trials as Topic; Humans; Nebulizers and	2020
Revefenacin, a once-daily, long-acting muscarinic antagonist, for nebulized maintenance therapy in patients with chronic obstructive pulmonary disease. American journal of health-system pharmacy : AJHP : official journal of the American Society of Health-System Pharmacists, 2021, 06-23, Volume: 78, Issue:13 Topics: Administration, Inhalation; Benzamides; Bronchodilator Agents; Carbamates; Humans; Muscarinic Antago	2021
Revefenacin: First Global Approval. Drugs, 2019, Volume: 79, Issue:1 Topics: Administration, Inhalation; Adult; Aged; Benzamides; Bronchodilator Agents; Carbamates; Drug Approva	2019
Revefenacin for the treatment of chronic obstructive pulmonary disease. Expert review of clinical pharmacology, 2019, Volume: 12, Issue:4 Topics: Acetylcholine; Animals; Benzamides; Bronchodilator Agents; Carbamates; Forced Expiratory Volume; Hum	2019
Revefenacin (Yupelri) for COPD. The Medical letter on drugs and therapeutics, 2019, Jan-28, Volume: 61, Issue:1564 Topics: Administration, Inhalation; Benzamides; Bronchodilator Agents; Carbamates; Humans; Pulmonary Disease	2019

Article	Year
Maintained therapeutic effect of revefenacin over 52 weeks in moderate to very severe Chronic Obstructive Pulmonary Disease (COPD). Respiratory research, 2019, Oct-30, Volume: 20, Issue:1 Topics: Aged; Benzamides; Bronchodilator Agents; Carbamates; Double-Blind Method; Drug Administration Schedu	2019
A randomized, controlled, repeat-dose study of batefenterol/fluticasone furoate compared with placebo in the treatment of COPD. BMC pulmonary medicine, 2020, May-04, Volume: 20, Issue:1 Topics: Administration, Inhalation; Aged; Androstadienes; Carbamates; Double-Blind Method; Drug Combinations	2020
Efficacy of revefenacin, a long-acting muscarinic antagonist for nebulized therapy, in patients with markers of more severe COPD: a post hoc subgroup analysis. BMC pulmonary medicine, 2020, May-11, Volume: 20, Issue:1 Topics: Administration, Inhalation; Aged; Aged, 80 and over; Benzamides; Bronchodilator Agents; Carbamates;	2020
Efficacy of revefenacin, a long-acting muscarinic antagonist for nebulized therapy, in patients with markers of more severe COPD: a post hoc subgroup analysis. BMC pulmonary medicine, 2020, May-11, Volume: 20, Issue:1 Topics: Administration, Inhalation; Aged; Aged, 80 and over; Benzamides; Bronchodilator Agents; Carbamates;	2020
Efficacy of revefenacin, a long-acting muscarinic antagonist for nebulized therapy, in patients with markers of more severe COPD: a post hoc subgroup analysis. BMC pulmonary medicine, 2020, May-11, Volume: 20, Issue:1 Topics: Administration, Inhalation; Aged; Aged, 80 and over; Benzamides; Bronchodilator Agents; Carbamates;	2020
Efficacy of revefenacin, a long-acting muscarinic antagonist for nebulized therapy, in patients with markers of more severe COPD: a post hoc subgroup analysis. BMC pulmonary medicine, 2020, May-11, Volume: 20, Issue:1 Topics: Administration, Inhalation; Aged; Aged, 80 and over; Benzamides; Bronchodilator Agents; Carbamates;	2020
Pharmacodynamics, pharmacokinetics and safety of revefenacin (TD-4208), a long-acting muscarinic antagonist, in patients with chronic obstructive pulmonary disease (COPD): Results of two randomized, double-blind, phase 2 studies. Pulmonary pharmacology & therapeutics, 2018, Volume: 48 Topics: Administration, Inhalation; Aged; Benzamides; Bronchodilator Agents; Carbamates; Cross-Over Studies;	2018
Pharmacodynamics, pharmacokinetics and safety of revefenacin (TD-4208), a long-acting muscarinic antagonist, in patients with chronic obstructive pulmonary disease (COPD): Results of two randomized, double-blind, phase 2 studies. Pulmonary pharmacology & therapeutics, 2018, Volume: 48 Topics: Administration, Inhalation; Aged; Benzamides; Bronchodilator Agents; Carbamates; Cross-Over Studies;	2018
Pharmacodynamics, pharmacokinetics and safety of revefenacin (TD-4208), a long-acting muscarinic antagonist, in patients with chronic obstructive pulmonary disease (COPD): Results of two randomized, double-blind, phase 2 studies. Pulmonary pharmacology & therapeutics, 2018, Volume: 48 Topics: Administration, Inhalation; Aged; Benzamides; Bronchodilator Agents; Carbamates; Cross-Over Studies;	2018
Pharmacodynamics, pharmacokinetics and safety of revefenacin (TD-4208), a long-acting muscarinic antagonist, in patients with chronic obstructive pulmonary disease (COPD): Results of two randomized, double-blind, phase 2 studies. Pulmonary pharmacology & therapeutics, 2018, Volume: 48 Topics: Administration, Inhalation; Aged; Benzamides; Bronchodilator Agents; Carbamates; Cross-Over Studies;	2018
Revefenacin, a once-daily, lung-selective, long-acting muscarinic antagonist for nebulized therapy: Safety and tolerability results of a 52-week phase 3 trial in moderate to very severe chronic obstructive pulmonary disease. Respiratory medicine, 2019, Volume: 153 Topics: Administration, Inhalation; Adrenergic beta-2 Receptor Agonists; Aged; Benzamides; Bronchodilator Ag	2019
Revefenacin, a once-daily, lung-selective, long-acting muscarinic antagonist for nebulized therapy: Safety and tolerability results of a 52-week phase 3 trial in moderate to very severe chronic obstructive pulmonary disease. Respiratory medicine, 2019, Volume: 153 Topics: Administration, Inhalation; Adrenergic beta-2 Receptor Agonists; Aged; Benzamides; Bronchodilator Ag	2019
Revefenacin, a once-daily, lung-selective, long-acting muscarinic antagonist for nebulized therapy: Safety and tolerability results of a 52-week phase 3 trial in moderate to very severe chronic obstructive pulmonary disease. Respiratory medicine, 2019, Volume: 153 Topics: Administration, Inhalation; Adrenergic beta-2 Receptor Agonists; Aged; Benzamides; Bronchodilator Ag	2019
Revefenacin, a once-daily, lung-selective, long-acting muscarinic antagonist for nebulized therapy: Safety and tolerability results of a 52-week phase 3 trial in moderate to very severe chronic obstructive pulmonary disease. Respiratory medicine, 2019, Volume: 153 Topics: Administration, Inhalation; Adrenergic beta-2 Receptor Agonists; Aged; Benzamides; Bronchodilator Ag	2019
Cardiovascular safety of revefenacin, a once-daily, lung-selective, long-acting muscarinic antagonist for nebulized therapy of chronic obstructive pulmonary disease: Evaluation in phase 3 clinical trials. Pulmonary pharmacology & therapeutics, 2019, Volume: 57 Topics: Administration, Inhalation; Adult; Aged; Aged, 80 and over; Benzamides; Bronchodilator Agents; Carba	2019
A new class of bronchodilator improves lung function in COPD: a trial with GSK961081. The European respiratory journal, 2013, Volume: 42, Issue:4 Topics: Aged; Albuterol; Bronchodilator Agents; Carbamates; Double-Blind Method; Drug Administration Schedul	2013
Bronchodilation and safety of supratherapeutic doses of salbutamol or ipratropium bromide added to single dose GSK961081 in patients with moderate to severe COPD. Pulmonary pharmacology & therapeutics, 2013, Volume: 26, Issue:5 Topics: Aged; Albuterol; Bronchodilator Agents; Carbamates; Cross-Over Studies; Delayed-Action Preparations;	2013
Pharmacodynamics of GSK961081, a bi-functional molecule, in patients with COPD. Pulmonary pharmacology & therapeutics, 2013, Volume: 26, Issue:5 Topics: Adrenergic beta-2 Receptor Agonists; Adult; Aged; Albuterol; Bronchodilator Agents; Carbamates; Cros	2013
Population Pharmacokinetics and Pharmacodynamics of GSK961081 (Batefenterol), a Muscarinic Antagonist and β2-Agonist, in Moderate-to-Severe COPD Patients: Substudy of a Randomized Trial. Drugs in R&D, 2015, Volume: 15, Issue:3 Topics: Adrenergic beta-2 Receptor Agonists; Adult; Aged; Carbamates; Dose-Response Relationship, Drug; Doub	2015

Article	Year
Revefenacin (Yupelri) for the Treatment of Chronic Obstructive Pulmonary Disease. American family physician, 2020, 01-15, Volume: 101, Issue:2 Topics: Benzamides; Bronchodilator Agents; Carbamates; Humans; Nebulizers and Vaporizers; Pulmonary Disease,	2020
Evaluating revefenacin as a therapeutic option for chronic obstructive pulmonary disease. Expert opinion on pharmacotherapy, 2020, Volume: 21, Issue:9 Topics: Benzamides; Carbamates; Humans; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive	2020
Population Pharmacokinetics of Revefenacin in Patients with Chronic Obstructive Pulmonary Disease. Clinical pharmacokinetics, 2021, Volume: 60, Issue:3 Topics: Adult; Aged; Aged, 80 and over; Benzamides; Bronchodilator Agents; Carbamates; Female; Humans; Male;	2021
Population Pharmacokinetics of Revefenacin in Patients with Chronic Obstructive Pulmonary Disease. Clinical pharmacokinetics, 2021, Volume: 60, Issue:3 Topics: Adult; Aged; Aged, 80 and over; Benzamides; Bronchodilator Agents; Carbamates; Female; Humans; Male;	2021
Population Pharmacokinetics of Revefenacin in Patients with Chronic Obstructive Pulmonary Disease. Clinical pharmacokinetics, 2021, Volume: 60, Issue:3 Topics: Adult; Aged; Aged, 80 and over; Benzamides; Bronchodilator Agents; Carbamates; Female; Humans; Male;	2021
Population Pharmacokinetics of Revefenacin in Patients with Chronic Obstructive Pulmonary Disease. Clinical pharmacokinetics, 2021, Volume: 60, Issue:3 Topics: Adult; Aged; Aged, 80 and over; Benzamides; Bronchodilator Agents; Carbamates; Female; Humans; Male;	2021
Population Pharmacokinetics of Revefenacin in Patients with Chronic Obstructive Pulmonary Disease. Clinical pharmacokinetics, 2021, Volume: 60, Issue:3 Topics: Adult; Aged; Aged, 80 and over; Benzamides; Bronchodilator Agents; Carbamates; Female; Humans; Male;	2021
Population Pharmacokinetics of Revefenacin in Patients with Chronic Obstructive Pulmonary Disease. Clinical pharmacokinetics, 2021, Volume: 60, Issue:3 Topics: Adult; Aged; Aged, 80 and over; Benzamides; Bronchodilator Agents; Carbamates; Female; Humans; Male;	2021
Population Pharmacokinetics of Revefenacin in Patients with Chronic Obstructive Pulmonary Disease. Clinical pharmacokinetics, 2021, Volume: 60, Issue:3 Topics: Adult; Aged; Aged, 80 and over; Benzamides; Bronchodilator Agents; Carbamates; Female; Humans; Male;	2021
Population Pharmacokinetics of Revefenacin in Patients with Chronic Obstructive Pulmonary Disease. Clinical pharmacokinetics, 2021, Volume: 60, Issue:3 Topics: Adult; Aged; Aged, 80 and over; Benzamides; Bronchodilator Agents; Carbamates; Female; Humans; Male;	2021
Population Pharmacokinetics of Revefenacin in Patients with Chronic Obstructive Pulmonary Disease. Clinical pharmacokinetics, 2021, Volume: 60, Issue:3 Topics: Adult; Aged; Aged, 80 and over; Benzamides; Bronchodilator Agents; Carbamates; Female; Humans; Male;	2021
Population Pharmacokinetics of Revefenacin in Patients with Chronic Obstructive Pulmonary Disease. Clinical pharmacokinetics, 2021, Volume: 60, Issue:3 Topics: Adult; Aged; Aged, 80 and over; Benzamides; Bronchodilator Agents; Carbamates; Female; Humans; Male;	2021
Population Pharmacokinetics of Revefenacin in Patients with Chronic Obstructive Pulmonary Disease. Clinical pharmacokinetics, 2021, Volume: 60, Issue:3 Topics: Adult; Aged; Aged, 80 and over; Benzamides; Bronchodilator Agents; Carbamates; Female; Humans; Male;	2021
Population Pharmacokinetics of Revefenacin in Patients with Chronic Obstructive Pulmonary Disease. Clinical pharmacokinetics, 2021, Volume: 60, Issue:3 Topics: Adult; Aged; Aged, 80 and over; Benzamides; Bronchodilator Agents; Carbamates; Female; Humans; Male;	2021
Population Pharmacokinetics of Revefenacin in Patients with Chronic Obstructive Pulmonary Disease. Clinical pharmacokinetics, 2021, Volume: 60, Issue:3 Topics: Adult; Aged; Aged, 80 and over; Benzamides; Bronchodilator Agents; Carbamates; Female; Humans; Male;	2021
Population Pharmacokinetics of Revefenacin in Patients with Chronic Obstructive Pulmonary Disease. Clinical pharmacokinetics, 2021, Volume: 60, Issue:3 Topics: Adult; Aged; Aged, 80 and over; Benzamides; Bronchodilator Agents; Carbamates; Female; Humans; Male;	2021
Population Pharmacokinetics of Revefenacin in Patients with Chronic Obstructive Pulmonary Disease. Clinical pharmacokinetics, 2021, Volume: 60, Issue:3 Topics: Adult; Aged; Aged, 80 and over; Benzamides; Bronchodilator Agents; Carbamates; Female; Humans; Male;	2021
Population Pharmacokinetics of Revefenacin in Patients with Chronic Obstructive Pulmonary Disease. Clinical pharmacokinetics, 2021, Volume: 60, Issue:3 Topics: Adult; Aged; Aged, 80 and over; Benzamides; Bronchodilator Agents; Carbamates; Female; Humans; Male;	2021
Population Pharmacokinetics of Revefenacin in Patients with Chronic Obstructive Pulmonary Disease. Clinical pharmacokinetics, 2021, Volume: 60, Issue:3 Topics: Adult; Aged; Aged, 80 and over; Benzamides; Bronchodilator Agents; Carbamates; Female; Humans; Male;	2021
Population Pharmacokinetics of Revefenacin in Patients with Chronic Obstructive Pulmonary Disease. Clinical pharmacokinetics, 2021, Volume: 60, Issue:3 Topics: Adult; Aged; Aged, 80 and over; Benzamides; Bronchodilator Agents; Carbamates; Female; Humans; Male;	2021
Population Pharmacokinetics of Revefenacin in Patients with Chronic Obstructive Pulmonary Disease. Clinical pharmacokinetics, 2021, Volume: 60, Issue:3 Topics: Adult; Aged; Aged, 80 and over; Benzamides; Bronchodilator Agents; Carbamates; Female; Humans; Male;	2021
Population Pharmacokinetics of Revefenacin in Patients with Chronic Obstructive Pulmonary Disease. Clinical pharmacokinetics, 2021, Volume: 60, Issue:3 Topics: Adult; Aged; Aged, 80 and over; Benzamides; Bronchodilator Agents; Carbamates; Female; Humans; Male;	2021
Population Pharmacokinetics of Revefenacin in Patients with Chronic Obstructive Pulmonary Disease. Clinical pharmacokinetics, 2021, Volume: 60, Issue:3 Topics: Adult; Aged; Aged, 80 and over; Benzamides; Bronchodilator Agents; Carbamates; Female; Humans; Male;	2021
Population Pharmacokinetics of Revefenacin in Patients with Chronic Obstructive Pulmonary Disease. Clinical pharmacokinetics, 2021, Volume: 60, Issue:3 Topics: Adult; Aged; Aged, 80 and over; Benzamides; Bronchodilator Agents; Carbamates; Female; Humans; Male;	2021
Population Pharmacokinetics of Revefenacin in Patients with Chronic Obstructive Pulmonary Disease. Clinical pharmacokinetics, 2021, Volume: 60, Issue:3 Topics: Adult; Aged; Aged, 80 and over; Benzamides; Bronchodilator Agents; Carbamates; Female; Humans; Male;	2021
Population Pharmacokinetics of Revefenacin in Patients with Chronic Obstructive Pulmonary Disease. Clinical pharmacokinetics, 2021, Volume: 60, Issue:3 Topics: Adult; Aged; Aged, 80 and over; Benzamides; Bronchodilator Agents; Carbamates; Female; Humans; Male;	2021
Population Pharmacokinetics of Revefenacin in Patients with Chronic Obstructive Pulmonary Disease. Clinical pharmacokinetics, 2021, Volume: 60, Issue:3 Topics: Adult; Aged; Aged, 80 and over; Benzamides; Bronchodilator Agents; Carbamates; Female; Humans; Male;	2021
The MABA approach: a new option to improve bronchodilator therapy. The European respiratory journal, 2013, Volume: 42, Issue:4 Topics: Bronchodilator Agents; Carbamates; Female; Humans; Male; Pulmonary Disease, Chronic Obstructive; Qui	2013
Discovery of (R)-1-(3-((2-chloro-4-(((2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)-5-methoxyphenyl)amino)-3-oxopropyl)piperidin-4-yl [1,1'-biphenyl]-2-ylcarbamate (TD-5959, GSK961081, batefenterol): first-in-class dual pharmac Journal of medicinal chemistry, 2015, Mar-26, Volume: 58, Issue:6 Topics: Administration, Inhalation; Adrenergic beta-2 Receptor Agonists; Animals; Carbamates; CHO Cells; Cri	2015
Chronic exposures to cholinesterase-inhibiting pesticides adversely affect respiratory health of agricultural workers in India. Journal of occupational health, 2009, Volume: 51, Issue:6 Topics: Adult; Agricultural Workers' Diseases; Carbamates; Case-Control Studies; Cholinesterase Inhibitors;	2009
Discovery of novel 8-azoniabicyclo[3.2.1]octane carbamates as muscarinic acetylcholine receptor antagonists. Bioorganic & medicinal chemistry letters, 2007, Nov-15, Volume: 17, Issue:22 Topics: Animals; Bridged Bicyclo Compounds, Heterocyclic; Bronchodilator Agents; Carbamates; Drug Evaluation	2007

carbamates and Airflow Obstruction, Chronic

Research Excerpts

Research

Studies (23)

Authors

Clinical Trials (11)

Trial Overview

Trial Outcomes

Change From Baseline in 0 to 4 Hours Post-dose Weighted Mean Heart Rate at Day 42, Derived From Electrocardiograms (ECGs)

Change From Baseline in Trough FEV1 on Day 85

Percentage of Albuterol Rescue-free 24-hour Periods

St. George's Respiratory Questionnaire (SGRQ) Proportion of Responders on Day 85

Summary of Change From Baseline to Peak FEV1 After First Dose

Summary of Rescue Medication Use: Puffs Per Day

Summary of Trough FEV1 Overall Treatment Effect From Day 15 to Day 85

Change From Baseline in Trough FEV1 on Day 85

Percentage of Albuterol Rescue-free 24-hour Periods

St. George's Respiratory Questionnaire (SGRQ) Proportion of Responders on Day 85

Summary of Change From Baseline to Peak FEV1 After First Dose

Summary of Rescue Medication Use: Puffs Per Day

Summary of Trough FEV1 Overall Treatment Effect From Day 15 to Day 85

Area Under the Forced Vital Capacity (FVC) vs. Time Curve

Peak Forced Expiratory Volume in One Second (FEV1) Relative to Baseline

Area Under the FEV1 vs. Peak FEV1, Time-matched Difference From Placebo

Area Under the FEV1 vs. Time Curve, Time-matched Difference From Placebo

Forced Expiratory Flow From 25% to 75% of Vital Capacity (FEF25-75), as Related to FEV1

Forced Vital Capacity (FVC)

Peak Expiratory Flow Rate (PEFR) From 25% to 75% of Vital Capacity (FEF25-75), as Related to FEV1

Change From Baseline to Day 7 in Trough FEV1 (Forced Expiratory Volume in 1 Second)

Cmax

Plasma Half-life

Tmax

Change From Baseline in Trough FEV1 (Forced Expiratory Volume in One Second)

Adverse Events: Frequency and Severity

Area Under Plasma Concentration Time Curve (AUC) of GSK961081 to the Last Quantifiable Concentration

Maximum Change From Baseline (Pre-dose on Day 1) in QTc (F) in Supine Position From 0 to 27 Hours After Dosing

Maximum Change From Baseline (Pre-dose on Day 1) in QTc (F) in Supine Position From 0 to 4 Hours After Dosing

Maximum Plasma Concentration (Cmax) of GSK961081 Over Period Determined Directly From the Concentration-time Data

Time to Last Quantifiable Plasma Concentration (Tlast) of GSK961081 Over Period Determined Directly From the Concentration-time Data

Time to Maximum Plasma Concentration (Tmax) of GSK961081 Over Period Determined Directly From the Concentration-time Data

Weighted Mean Change From Baseline (Pre-dose on Day 1) in Heart Rate in Supine Position From 0 to 4 Hours

Weighted Mean Change From Baseline (Pre-dose on Day 1) in QTc(B) in Supine Position From 0 to 4 Hours

Weighted Mean Change From Baseline (Pre-dose on Day 1) in QTc(F) in Supine Position From 0 to 4 Hours

Change From Baseline (Pre-dose on Day 1) in Systolic and Diastolic Blood Pressure up to 27 Hours

Maximal Change in Forced Expiratory Volume in One Second (FEV1) From Baseline (Pre-dose on Day 1) in Combination With Short Acting Bronchodialator (Salbutamol or Ipratropium Bromide) at 1h,12h and 24h.

Maximal Change in Forced Vital Capacity (FVC) in One Second From Pre-dose in Combination With Short Acting Bronchodialator (Salbutamol or Ipratropium Bromide) at 1h, 12h and 24h.

Maximum Change From Baseline (Pre-dose on Day 1) in Glucose Over 4 and 27 Hours and Weighted Mean Change From Baseline in Glucose Over 4 Hours

Maximum Change From Baseline (Pre-dose on Day 1) in QTc(B) in Supine Position From 0 to 4 Hours and 0 to 27 Hours

Maximum Change From Baseline (Pre-dose on Day 1) in Supine Heart Rate From 0 to 4 Hours and From 0 to 27 Hours.

Maximum Change From Baseline (Pre-dose on Day 1) in Supine Systolic Blood Pressure (SBP) Over 4 and 27 Hours and Weighted Mean Change From Baseline in Supine SBP Over 4 Hours

Mean Change From Baseline (Pre-dose on Day 1) in Heart Rate Over 27 Hours

Minimum Change From Baseline (Pre-dose on Day 1) in Potassium Over 4 and 27 Hours and Weighted Mean Change From Baseline in Potassium Over 4 Hours

Minimum Change From Baseline (Pre-dose on Day 1) in Supine Diastolic Blood Pressure (DBP) Over 4 and 27 Hours and Weighted Mean Change From Baseline in Supine DBP Over 4 Hours

Number of Participants With Adverse Events and Serious Adverse Events

Number of Participants With Laboratory Abnormalities of Potential Clinical Concern (PCC)

Number of Participants With Maximum Change From Baseline 12-LED Electrocardiogram (ECG) Findings

Time to Maximum Change From Baseline (Pre-dose on Day 1) for QTc(B), QTc(F), Heart Rate, Systolic BP, Glucose in Supine Position and Time to Minimum Change From Baseline for Potassium and Diastolic BP in Supine Position

Reviews

Trials

Other Studies