Trial Outcomes & Findings for Pharmacodynamic and Pharmacokinetic Dose Ranging Study of Tiotropium Bromide Administered Via Inhalation Solution in Patients With Chronic Obstructive Pulmonary Disease (COPD) (NCT NCT03118765)

NCT ID: NCT03118765

Last Updated: 2019-08-01

Results Overview

The PK endpoint in plasma to assess the relative bioavailability was peak concentrations of tiotropium during the dosing interval at steady-state (CmaxSS)

• Recruitment status: COMPLETED
• Study phase: PHASE2
• Target enrollment: 155 participants
• Primary outcome timeframe: Plasma concentrations on day 21 according to the below schedule: Pre-dose (0 hour), and at 2, 4, 6, 10, 15, 30, and 45, 60, 75, and 90 minutes post-dose, as well as 2, 4, 6, 8, 12, 16, 20 and 24 hours post-dose.
• Results posted on: 2019-08-01

Participant Flow

A total of 155 subjects were randomized to study treatments.

Participant milestones

Measure	GSP304 10 μg Oral inhalation, once daily (morning) for 21 days	GSP304 20 μg Oral inhalation, once daily (morning) for 21 days	GSP304 40 μg Oral inhalation, once daily (morning) for 21 days	Placebo Oral inhalation, once daily (morning) for 21 days	SPIRIVA RESPIMAT 5 μg Oral inhalation, once daily (morning) for 21 days
Overall Study STARTED	30	32	31	32	30
Overall Study COMPLETED	26	30	26	29	28
Overall Study NOT COMPLETED	4	2	5	3	2

Reasons for withdrawal

Measure	GSP304 10 μg Oral inhalation, once daily (morning) for 21 days	GSP304 20 μg Oral inhalation, once daily (morning) for 21 days	GSP304 40 μg Oral inhalation, once daily (morning) for 21 days	Placebo Oral inhalation, once daily (morning) for 21 days	SPIRIVA RESPIMAT 5 μg Oral inhalation, once daily (morning) for 21 days
Overall Study Withdrawal by Subject	0	0	1	0	0
Overall Study Adverse Event	1	1	1	1	1
Overall Study Non compliance with Study Procedures	0	0	0	1	0
Overall Study Violation of Inclusion/ExclusionCriteria	0	1	1	0	0
Overall Study COPD Exacerbation	1	0	0	1	0
Overall Study Lost to Follow-up	1	0	1	0	0
Overall Study Sponsor Decision	1	0	1	0	1

Baseline Characteristics

Pharmacodynamic and Pharmacokinetic Dose Ranging Study of Tiotropium Bromide Administered Via Inhalation Solution in Patients With Chronic Obstructive Pulmonary Disease (COPD)

Baseline characteristics by cohort

Measure	GSP304 10 μg n=30 Participants Oral inhalation, once daily (morning) for 21 days	GSP304 20 μg n=32 Participants Oral inhalation, once daily (morning) for 21 days	GSP304 40 μg n=31 Participants Oral inhalation, once daily (morning) for 21 days	Placebo n=32 Participants Oral inhalation, once daily (morning) for 21 days	SPIRIVA RESPIMAT 5 μg n=30 Participants Oral inhalation, once daily (morning) for 21 days	Total n=155 Participants Total of all reporting groups
Age, Continuous	63.2 years STANDARD_DEVIATION 7.12 • n=5 Participants	61.6 years STANDARD_DEVIATION 10.34 • n=7 Participants	65.4 years STANDARD_DEVIATION 10.02 • n=5 Participants	65.0 years STANDARD_DEVIATION 9.51 • n=4 Participants	62.0 years STANDARD_DEVIATION 9.42 • n=21 Participants	63.4 years STANDARD_DEVIATION 9.38 • n=10 Participants
Sex: Female, Male Female	13 Participants n=5 Participants	11 Participants n=7 Participants	14 Participants n=5 Participants	17 Participants n=4 Participants	20 Participants n=21 Participants	75 Participants n=10 Participants
Sex: Female, Male Male	17 Participants n=5 Participants	21 Participants n=7 Participants	17 Participants n=5 Participants	15 Participants n=4 Participants	10 Participants n=21 Participants	80 Participants n=10 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	2 Participants n=5 Participants	3 Participants n=7 Participants	4 Participants n=5 Participants	1 Participants n=4 Participants	2 Participants n=21 Participants	12 Participants n=10 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	28 Participants n=5 Participants	29 Participants n=7 Participants	27 Participants n=5 Participants	31 Participants n=4 Participants	28 Participants n=21 Participants	143 Participants n=10 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants	0 Participants n=10 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants	0 Participants n=10 Participants
Race (NIH/OMB) Asian	1 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants	1 Participants n=10 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants	0 Participants n=10 Participants
Race (NIH/OMB) Black or African American	2 Participants n=5 Participants	7 Participants n=7 Participants	2 Participants n=5 Participants	1 Participants n=4 Participants	1 Participants n=21 Participants	13 Participants n=10 Participants
Race (NIH/OMB) White	27 Participants n=5 Participants	25 Participants n=7 Participants	29 Participants n=5 Participants	31 Participants n=4 Participants	29 Participants n=21 Participants	141 Participants n=10 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants	0 Participants n=10 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants	0 Participants n=10 Participants
BMI	25.848 kg/m^2 STANDARD_DEVIATION 2.8936 • n=5 Participants	26.150 kg/m^2 STANDARD_DEVIATION 4.0007 • n=7 Participants	24.799 kg/m^2 STANDARD_DEVIATION 3.7138 • n=5 Participants	25.409 kg/m^2 STANDARD_DEVIATION 3.5321 • n=4 Participants	25.503 kg/m^2 STANDARD_DEVIATION 3.1809 • n=21 Participants	25.543 kg/m^2 STANDARD_DEVIATION 3.4803 • n=10 Participants

PRIMARY outcome

Timeframe: Plasma concentrations on day 21 according to the below schedule: Pre-dose (0 hour), and at 2, 4, 6, 10, 15, 30, and 45, 60, 75, and 90 minutes post-dose, as well as 2, 4, 6, 8, 12, 16, 20 and 24 hours post-dose.

Population: The PK analysis set consisted of all subjects who were randomized, received at least 1 dose of study treatment, and had at least 1 quantifiable PK sample and did not have an exclusionary major protocol deviation.

The PK endpoint in plasma to assess the relative bioavailability was peak concentrations of tiotropium during the dosing interval at steady-state (CmaxSS)

Outcome measures

Measure	GSP304 10 μg n=26 Participants Oral inhalation, once daily (morning) for 21 days	GSP304 20 μg n=30 Participants Oral inhalation, once daily (morning) for 21 days	GSP304 40 μg n=26 Participants Oral inhalation, once daily (morning) for 21 days	SPIRIVA RESPIMAT 5 μg n=26 Participants Oral inhalation, once daily (morning) for 21 days	SPIRIVA RESPIMAT 5 μg Oral inhalation, once daily (morning) for 21 days
Relative Bioavailability of Tiotropium With GSP304 in Comparison to SPIRIVA RESPIMAT 5 μg Based on CmaxSS	4.10 pg/mL Standard Error 1.152	8.00 pg/mL Standard Error 1.140	21.80 pg/mL Standard Error 1.152	14.00 pg/mL Standard Error 1.152	—

PRIMARY outcome

Timeframe: Plasma concentrations on day 21 according to the below schedule: Pre-dose (0 hour), and at 2, 4, 6, 10, 15, 30, and 45, 60, 75, and 90 minutes post-dose, as well as 2, 4, 6, 8, 12, 16, 20 and 24 hours post-dose.

Population: The PK analysis set consisted of all subjects who were randomized, received at least 1 dose of study treatment, and had at least 1 quantifiable PK sample and did not have an exclusionary major protocol deviation.

The PK endpoint in plasma to assess the relative bioavailability was area under the plasma concentration-time curve of tiotropium over the dosing interval at steady state (AUC0-tauSS)

Outcome measures

Measure	GSP304 10 μg n=26 Participants Oral inhalation, once daily (morning) for 21 days	GSP304 20 μg n=29 Participants Oral inhalation, once daily (morning) for 21 days	GSP304 40 μg n=26 Participants Oral inhalation, once daily (morning) for 21 days	SPIRIVA RESPIMAT 5 μg n=26 Participants Oral inhalation, once daily (morning) for 21 days	SPIRIVA RESPIMAT 5 μg Oral inhalation, once daily (morning) for 21 days
Relative Bioavailability of Tiotropium With GSP 304 in Comparison to SPIRIVA RESPIMAT 5 μg Based on AUC0-tauSS	22.90 h*pg/mL Standard Error 1.130	49.10 h*pg/mL Standard Error 1.123	122.00 h*pg/mL Standard Error 1.130	57.70 h*pg/mL Standard Error 1.130	—

PRIMARY outcome

Timeframe: 21 days (Pre- dose trough FEV1 is mean FEV1 at -45 mins and -15 mins pre-morning dose at Day 1. Trough FEV1 is mean FEV1 obtained 23 hrs 15 mins and 23 hrs 45 mins post-morning dose of day 21).

Change from baseline (Day 1) at Day 21 (Week 3) in trough FEV1 response at approximately 24 hours after the last dose (average of 23 hours 15 minutes and 23 hours 45 minutes postdose measurements), in comparison with placebo.

Outcome measures

Measure	GSP304 10 μg n=30 Participants Oral inhalation, once daily (morning) for 21 days	GSP304 20 μg n=32 Participants Oral inhalation, once daily (morning) for 21 days	GSP304 40 μg n=31 Participants Oral inhalation, once daily (morning) for 21 days	SPIRIVA RESPIMAT 5 μg n=32 Participants Oral inhalation, once daily (morning) for 21 days	SPIRIVA RESPIMAT 5 μg n=30 Participants Oral inhalation, once daily (morning) for 21 days
Change From Baseline (Day 1) in Trough FEV1 at 24 Hours After the Last Dose of Treatment on Day 21 in Comparison to Placebo.	0.14 L Standard Error 0.04	0.10 L Standard Error 0.04	0.09 L Standard Error 0.04	0.08 L Standard Error 0.04	0.14 L Standard Error 0.04

SECONDARY outcome

Timeframe: Day 1

Population: Overall Number of Participants Analyzed is the number of subjects with data in the Pharmacokinetic Analysis Set (PKAS). PKAS included all subjects who were randomized, received at least 1 dose of study drug, and had at least 1 quantifiable PK sample and did not have exclusionary major protocol deviations.

Descriptive statistics for tiotropium urine PK parameter - Amount (Aetau) of tiotropium excreted in urine over the dosing interval on Day 1

Outcome measures

Measure	GSP304 10 μg n=25 Participants Oral inhalation, once daily (morning) for 21 days	GSP304 20 μg n=23 Participants Oral inhalation, once daily (morning) for 21 days	GSP304 40 μg n=24 Participants Oral inhalation, once daily (morning) for 21 days	SPIRIVA RESPIMAT 5 μg n=19 Participants Oral inhalation, once daily (morning) for 21 days	SPIRIVA RESPIMAT 5 μg Oral inhalation, once daily (morning) for 21 days
Amount (Aetau) (Cumulative Amount of Unchanged Drug Excreted Into the Urine Over the Dosing Interval) of Tiotropium Excreted in Urine Over the Dosing Interval on Day 1	138600 pg Standard Deviation 76830	336100 pg Standard Deviation 233800	602900 pg Standard Deviation 422400	247400 pg Standard Deviation 219600	—

SECONDARY outcome

Timeframe: Day 21

Population: Overall Number of Participants Analyzed is the number of subjects with data in the Pharmacokinetic Analysis Set (PKAS). PKAS included all subjects who were randomized, received at least 1 dose of study drug, and had at least 1 quantifiable PK sample and did not have exclusionary major protocol deviations.

Descriptive statistics for tiotropium urine PK parameter - Amount (Aetau) of Tiotropium Excreted in Urine Over the Dosing Interval on Day 21

Outcome measures

Measure	GSP304 10 μg n=26 Participants Oral inhalation, once daily (morning) for 21 days	GSP304 20 μg n=29 Participants Oral inhalation, once daily (morning) for 21 days	GSP304 40 μg n=26 Participants Oral inhalation, once daily (morning) for 21 days	SPIRIVA RESPIMAT 5 μg n=25 Participants Oral inhalation, once daily (morning) for 21 days	SPIRIVA RESPIMAT 5 μg Oral inhalation, once daily (morning) for 21 days
Amount (Aetau) of Tiotropium Excreted in Urine Over the Dosing Interval on Day 21	375400 pg Standard Deviation 286900	647100 pg Standard Deviation 460000	1611000 pg Standard Deviation 1013000	775500 pg Standard Deviation 458000	—

SECONDARY outcome

Timeframe: Day 1

Population: Overall Number of Participants Analyzed is the number of subjects with data in the Pharmacokinetic Analysis Set (PKAS). PKAS included all subjects who were randomized, received at least 1 dose of study drug, and had at least 1 quantifiable PK sample and did not have exclusionary major protocol deviations.

Descriptive statistics for tiotropium urine PK parameter - Fraction of dose (Fe) of tiotropium excreted in urine over the dosing interval on Day 1

Outcome measures

Measure	GSP304 10 μg n=25 Participants Oral inhalation, once daily (morning) for 21 days	GSP304 20 μg n=23 Participants Oral inhalation, once daily (morning) for 21 days	GSP304 40 μg n=24 Participants Oral inhalation, once daily (morning) for 21 days	SPIRIVA RESPIMAT 5 μg n=19 Participants Oral inhalation, once daily (morning) for 21 days	SPIRIVA RESPIMAT 5 μg Oral inhalation, once daily (morning) for 21 days
Fraction of Dose (Fe) of Tiotropium Excreted in Urine Over the Dosing Interval on Day 1	1.386 percentage of dose Standard Deviation 0.7683	1.681 percentage of dose Standard Deviation 1.169	1.507 percentage of dose Standard Deviation 1.056	4.948 percentage of dose Standard Deviation 4.391	—

SECONDARY outcome

Timeframe: Day 21

Population: Overall Number of Participants Analyzed is the number of subjects with data in the Pharmacokinetic Analysis Set (PKAS). PKAS included all subjects who were randomized, received at least 1 dose of study drug, and had at least 1 quantifiable PK sample and did not have exclusionary major protocol deviations.

Descriptive statistics for tiotropium urine PK parameter-Fraction of Dose (Fe) of Tiotropium Excreted in Urine Over the Dosing Interval on Day 21

Outcome measures

Measure	GSP304 10 μg n=26 Participants Oral inhalation, once daily (morning) for 21 days	GSP304 20 μg n=29 Participants Oral inhalation, once daily (morning) for 21 days	GSP304 40 μg n=26 Participants Oral inhalation, once daily (morning) for 21 days	SPIRIVA RESPIMAT 5 μg n=25 Participants Oral inhalation, once daily (morning) for 21 days	SPIRIVA RESPIMAT 5 μg Oral inhalation, once daily (morning) for 21 days
Fraction of Dose (Fe) of Tiotropium Excreted in Urine Over the Dosing Interval on Day 21	3.754 percentage of dose Standard Deviation 2.869	3.236 percentage of dose Standard Deviation 2.300	4.026 percentage of dose Standard Deviation 2.532	15.51 percentage of dose Standard Deviation 9.161	—

SECONDARY outcome

Timeframe: Day 1

Population: Overall Number of Participants Analyzed is the number of subjects with data in the Pharmacokinetic Analysis Set (PKAS). PKAS included all subjects who were randomized, received at least 1 dose of study drug, and had at least 1 quantifiable PK sample and did not have exclusionary major protocol deviations.

Descriptive statistics for tiotropium plasma PK parameters - (Cmax) on Day 1

Outcome measures

Measure	GSP304 10 μg n=28 Participants Oral inhalation, once daily (morning) for 21 days	GSP304 20 μg n=27 Participants Oral inhalation, once daily (morning) for 21 days	GSP304 40 μg n=28 Participants Oral inhalation, once daily (morning) for 21 days	SPIRIVA RESPIMAT 5 μg n=22 Participants Oral inhalation, once daily (morning) for 21 days	SPIRIVA RESPIMAT 5 μg Oral inhalation, once daily (morning) for 21 days
Peak Concentrations During the Dosing Interval (Cmax) on Day 1	2.632 pg/mL Standard Deviation 1.690	7.119 pg/mL Standard Deviation 7.368	14.06 pg/mL Standard Deviation 11.98	10.25 pg/mL Standard Deviation 7.944	—

SECONDARY outcome

Timeframe: Day 1

Population: Overall Number of Participants Analyzed is the number of subjects with data in the Pharmacokinetic Analysis Set (PKAS). PKAS included all subjects who were randomized, received at least 1 dose of study drug, and had at least 1 quantifiable PK sample and did not have exclusionary major protocol deviations.

Descriptive statistics for tiotropium plasma PK parameter - Area under the plasma concentration-time curve over the dosing interval (AUC0-tau) on Day 1

Outcome measures

Measure	GSP304 10 μg n=27 Participants Oral inhalation, once daily (morning) for 21 days	GSP304 20 μg n=26 Participants Oral inhalation, once daily (morning) for 21 days	GSP304 40 μg n=27 Participants Oral inhalation, once daily (morning) for 21 days	SPIRIVA RESPIMAT 5 μg n=22 Participants Oral inhalation, once daily (morning) for 21 days	SPIRIVA RESPIMAT 5 μg Oral inhalation, once daily (morning) for 21 days
Area Under the Plasma Concentration-time Curve Over the Dosing Interval (AUC0-tau) on Day 1	10.65 pg*h/mL Standard Deviation 7.049	22.94 pg*h/mL Standard Deviation 13.09	52.11 pg*h/mL Standard Deviation 34.7	22.64 pg*h/mL Standard Deviation 10.69	—

SECONDARY outcome

Timeframe: Day 1

Population: Overall Number of Participants Analyzed is the number of subjects with data in the Pharmacokinetic Analysis Set (PKAS). PKAS included all subjects who were randomized, received at least 1 dose of study drug, and had at least 1 quantifiable PK sample and did not have exclusionary major protocol deviations.

Descriptive statistics for tiotropium plasma PK parameter - Time of peak drug concentration over the dosing interval (tmax) on Day 1

Outcome measures

Measure	GSP304 10 μg n=28 Participants Oral inhalation, once daily (morning) for 21 days	GSP304 20 μg n=27 Participants Oral inhalation, once daily (morning) for 21 days	GSP304 40 μg n=28 Participants Oral inhalation, once daily (morning) for 21 days	SPIRIVA RESPIMAT 5 μg n=22 Participants Oral inhalation, once daily (morning) for 21 days	SPIRIVA RESPIMAT 5 μg Oral inhalation, once daily (morning) for 21 days
Time of Peak Drug Concentration Over the Dosing Interval (Tmax) on Day 1	0.067 hour Interval 0.03 to 0.18	0.100 hour Interval 0.03 to 8.02	0.108 hour Interval 0.03 to 0.75	0.100 hour Interval 0.03 to 3.98	—

SECONDARY outcome

Timeframe: Day 21

Population: Overall Number of Participants Analyzed is the number of subjects with data in the Pharmacokinetic Analysis Set (PKAS). PKAS included all subjects who were randomized, received at least 1 dose of study drug, and had at least 1 quantifiable PK sample and did not have exclusionary major protocol deviations.

Descriptive statistics for tiotropium plasma PK parameter - Time of peak drug concentration over the dosing interval (tmax) on Day 21

Outcome measures

Measure	GSP304 10 μg n=26 Participants Oral inhalation, once daily (morning) for 21 days	GSP304 20 μg n=30 Participants Oral inhalation, once daily (morning) for 21 days	GSP304 40 μg n=26 Participants Oral inhalation, once daily (morning) for 21 days	SPIRIVA RESPIMAT 5 μg n=26 Participants Oral inhalation, once daily (morning) for 21 days	SPIRIVA RESPIMAT 5 μg Oral inhalation, once daily (morning) for 21 days
Time of Peak Drug Concentration Over the Dosing Interval (Tmax) on Day 21	0.075 hour Interval 0.03 to 0.25	0.150 hour Interval 0.04 to 16.0	0.108 hour Interval 0.05 to 1.0	0.100 hour Interval 0.03 to 0.75	—

SECONDARY outcome

Timeframe: Day 21

Population: Overall Number of Participants Analyzed is the number of subjects with data in the Pharmacokinetic Analysis Set (PKAS). PKAS included all subjects who were randomized, received at least 1 dose of study drug, and had at least 1 quantifiable PK sample and did not have exclusionary major protocol deviations.

Descriptive statistics for tiotropium plasma PK parameter - Average concentration during a dosing interval at steady state (CavSS) on day 21

Outcome measures

Measure	GSP304 10 μg n=26 Participants Oral inhalation, once daily (morning) for 21 days	GSP304 20 μg n=30 Participants Oral inhalation, once daily (morning) for 21 days	GSP304 40 μg n=26 Participants Oral inhalation, once daily (morning) for 21 days	SPIRIVA RESPIMAT 5 μg n=26 Participants Oral inhalation, once daily (morning) for 21 days	SPIRIVA RESPIMAT 5 μg Oral inhalation, once daily (morning) for 21 days
Average Concentration During a Dosing Interval at Steady State (CavSS) on Day 21	1.120 pg/mL Standard Deviation 0.8301	2.436 pg/mL Standard Deviation 1.623	6.273 pg/mL Standard Deviation 4.052	2.725 pg/mL Standard Deviation 1.289	—

SECONDARY outcome

Timeframe: Day 21

Population: Overall Number of Participants Analyzed is the number of subjects with data in the Pharmacokinetic Analysis Set (PKAS). PKAS included all subjects who were randomized, received at least 1 dose of study drug, and had at least 1 quantifiable PK sample and did not have exclusionary major protocol deviations.

Descriptive statistics for tiotropium plasma PK parameter-Accumulation ratio Rac(auc). Rac(auc) was calculated as AUC0-tauSS/AUC0-tau.

Outcome measures

Measure	GSP304 10 μg n=26 Participants Oral inhalation, once daily (morning) for 21 days	GSP304 20 μg n=26 Participants Oral inhalation, once daily (morning) for 21 days	GSP304 40 μg n=25 Participants Oral inhalation, once daily (morning) for 21 days	SPIRIVA RESPIMAT 5 μg n=25 Participants Oral inhalation, once daily (morning) for 21 days	SPIRIVA RESPIMAT 5 μg Oral inhalation, once daily (morning) for 21 days
Accumulation Ratio Rac(Auc)	2.966 ratio Standard Deviation 1.561	5.328 ratio Standard Deviation 13.53	3.667 ratio Standard Deviation 2.873	3.699 ratio Standard Deviation 2.897	—

SECONDARY outcome

Timeframe: Day 21

Population: Overall Number of Participants Analyzed is the number of subjects with data in the Pharmacokinetic Analysis Set (PKAS). PKAS included all subjects who were randomized, received at least 1 dose of study drug, and had at least 1 quantifiable PK sample and did not have exclusionary major protocol deviations.

Descriptive statistics for tiotropium plasma PK parameter-Accumulation ratio Rac(cmax). Rac(Cmax) was calculated as CmaxSS/Cmax.

Outcome measures

Measure	GSP304 10 μg n=26 Participants Oral inhalation, once daily (morning) for 21 days	GSP304 20 μg n=29 Participants Oral inhalation, once daily (morning) for 21 days	GSP304 40 μg n=26 Participants Oral inhalation, once daily (morning) for 21 days	SPIRIVA RESPIMAT 5 μg n=25 Participants Oral inhalation, once daily (morning) for 21 days	SPIRIVA RESPIMAT 5 μg Oral inhalation, once daily (morning) for 21 days
Accumulation Ratio Rac(Cmax)	2.063 ratio Standard Deviation 0.7187	3.492 ratio Standard Deviation 7.436	2.622 ratio Standard Deviation 2.059	2.835 ratio Standard Deviation 2.612	—

SECONDARY outcome

Timeframe: Day 1 (Pre-dose FEV1 at -45 mins and 15 mins prior to dosing on Day 1. On Day 1 FEV1 at post-dose at 5 mins ±3, 15 mins ±2, 30 mins ±5, 60 mins, 90 mins, and 2 hours; and post-dose at 4, 6, 8, 10, 12 hours after the morning dose).

Population: Full Analysis Set (FAS) included all subjects who were randomized, had received at least 1 dose of study drug and had at least 1 post-baseline PD assessment.

The least square mean change from baseline to peak FEV1 within 12 hours postdose on Day 1. Change from baseline in peak FEV1 within 12 hours postdose on Day 1 was derived from the serial readings taken through 12 hours postdose and calculating the change from baseline.

Outcome measures

Measure	GSP304 10 μg n=30 Participants Oral inhalation, once daily (morning) for 21 days	GSP304 20 μg n=32 Participants Oral inhalation, once daily (morning) for 21 days	GSP304 40 μg n=31 Participants Oral inhalation, once daily (morning) for 21 days	SPIRIVA RESPIMAT 5 μg n=32 Participants Oral inhalation, once daily (morning) for 21 days	SPIRIVA RESPIMAT 5 μg n=30 Participants Oral inhalation, once daily (morning) for 21 days
Change From Baseline in Peak FEV1 Within 12 Hours Post-dose on Day 1	0.34 Litre Standard Error 0.03	0.38 Litre Standard Error 0.03	0.33 Litre Standard Error 0.04	0.21 Litre Standard Error 0.03	0.38 Litre Standard Error 0.03

SECONDARY outcome

Timeframe: Day 21(Pre-dose FEV1 at -45 mins and 15 mins prior to dosing on Day 21. On Day 21, FEV1 at post-dose at 5 mins ±3, 15 mins ±2, 30 mins ±5, 60 mins, 90 mins, and 2 hours; and post-dose at 4, 6, 8, 10, 12 hours after the morning dose).

Population: Full Analysis Set (FAS) included all subjects who were randomized, had received at least 1 dose of study drug and had at least 1 post-baseline PD assessment.

The least square mean change from baseline to peak FEV1 within 12 hours postdose on Day 21. Change from baseline in peak FEV1 within 12 hours postdose on Day 21 was derived from the serial readings taken through 12 hours postdose and calculating the change from baseline.

Outcome measures

Measure	GSP304 10 μg n=30 Participants Oral inhalation, once daily (morning) for 21 days	GSP304 20 μg n=32 Participants Oral inhalation, once daily (morning) for 21 days	GSP304 40 μg n=31 Participants Oral inhalation, once daily (morning) for 21 days	SPIRIVA RESPIMAT 5 μg n=32 Participants Oral inhalation, once daily (morning) for 21 days	SPIRIVA RESPIMAT 5 μg n=30 Participants Oral inhalation, once daily (morning) for 21 days
Change From Baseline in Peak FEV1 Within 12 Hours Post-dose on Day 21	0.37 Litre Standard Error 0.04	0.34 Litre Standard Error 0.04	0.31 Litre Standard Error 0.04	0.20 Litre Standard Error 0.04	0.37 Litre Standard Error 0.04

SECONDARY outcome

Timeframe: Day 1 (Pre-dose FVC at -45 mins and 15 mins prior to dosing on Day 1. Postdose timing were relative to the end of dosing.The window for 1 hour spirometry and thereafter was ±5 minutes).

Population: Full Analysis Set (FAS) included all subjects who were randomized, had received at least 1 dose of study drug and had at least 1 post-baseline PD assessment.

Least Square Mean change from baseline in forced vital capacity (FVC) to end of Day 1.

Outcome measures

Measure	GSP304 10 μg n=29 Participants Oral inhalation, once daily (morning) for 21 days	GSP304 20 μg n=32 Participants Oral inhalation, once daily (morning) for 21 days	GSP304 40 μg n=31 Participants Oral inhalation, once daily (morning) for 21 days	SPIRIVA RESPIMAT 5 μg n=31 Participants Oral inhalation, once daily (morning) for 21 days	SPIRIVA RESPIMAT 5 μg n=30 Participants Oral inhalation, once daily (morning) for 21 days
Change From Baseline in Forced Vital Capacity (FVC) on Day 1	0.21 Litre Standard Error 0.05	0.21 Litre Standard Error 0.05	0.18 Litre Standard Error 0.05	0.13 Litre Standard Error 0.05	0.16 Litre Standard Error 0.05

SECONDARY outcome

Timeframe: Day 21 (Pre-dose FVC at -45 mins and 15 mins prior to dosing on Day 21. Postdose timing were relative to the end of dosing. The window for 1 hour spirometry and thereafter was ±5 minutes).

Population: Full Analysis Set (FAS) included all subjects who were randomized, had received at least 1 dose of study drug and had at least 1 post-baseline PD assessment.

Least Square Mean change from baseline in forced vital capacity (FVC) to end of Day 21

Outcome measures

Measure	GSP304 10 μg n=29 Participants Oral inhalation, once daily (morning) for 21 days	GSP304 20 μg n=32 Participants Oral inhalation, once daily (morning) for 21 days	GSP304 40 μg n=31 Participants Oral inhalation, once daily (morning) for 21 days	SPIRIVA RESPIMAT 5 μg n=31 Participants Oral inhalation, once daily (morning) for 21 days	SPIRIVA RESPIMAT 5 μg n=30 Participants Oral inhalation, once daily (morning) for 21 days
Change From Baseline in Forced Vital Capacity (FVC) on Day 21	0.16 Litre Standard Error 0.06	0.10 Litre Standard Error 0.06	0.11 Litre Standard Error 0.06	0.11 Litre Standard Error 0.06	0.16 Litre Standard Error 0.06

SECONDARY outcome

Timeframe: Day 1 (Pre-dose FEV1 at -45 mins and 15 mins prior to dosing on Day 1. On Day 1 FEV1 at post-dose at 5 mins ±3, 15 mins ±2, 30 mins ±5, 60 mins, 90 mins, and 2 hours; and post-dose at 4, 6, 8, 10, 12 hours after the morning dose).

Population: Full Analysis Set (FAS) included all subjects who were randomized, had received at least 1 dose of study drug and had at least 1 post-baseline PD assessment.

Least Square Mean (SE) change from baseline in time-normalized area under the curve for FEV1 measured over 12 hours on Day 1.

Outcome measures

Measure	GSP304 10 μg n=29 Participants Oral inhalation, once daily (morning) for 21 days	GSP304 20 μg n=32 Participants Oral inhalation, once daily (morning) for 21 days	GSP304 40 μg n=31 Participants Oral inhalation, once daily (morning) for 21 days	SPIRIVA RESPIMAT 5 μg n=31 Participants Oral inhalation, once daily (morning) for 21 days	SPIRIVA RESPIMAT 5 μg n=30 Participants Oral inhalation, once daily (morning) for 21 days
Change From Baseline in Time-normalized Area Under the Curve for FEV1 Measured Over 12 Hours on Day 1	0.22 Litre Standard Error 0.03	0.24 Litre Standard Error 0.03	0.24 Litre Standard Error 0.03	0.10 Litre Standard Error 0.03	0.26 Litre Standard Error 0.03

SECONDARY outcome

Timeframe: Day 21(Pre-dose FEV1 at -45 mins and 15 mins prior to dosing on Day 21. On Day 21, FEV1 at post-dose at 5 mins ±3, 15 mins ±2, 30 mins ±5, 60 mins, 90 mins, and 2 hours; and post-dose at 4, 6, 8, 10, 12 hours after the morning dose).

Population: Full Analysis Set (FAS) included all subjects who were randomized, had received at least 1 dose of study drug and had at least 1 post-baseline PD assessment.

Least Square Mean (SE) change from baseline in time-normalized area under the curve for FEV1 Measured Over 12 Hours on Day 21.

Outcome measures

Measure	GSP304 10 μg n=29 Participants Oral inhalation, once daily (morning) for 21 days	GSP304 20 μg n=32 Participants Oral inhalation, once daily (morning) for 21 days	GSP304 40 μg n=31 Participants Oral inhalation, once daily (morning) for 21 days	SPIRIVA RESPIMAT 5 μg n=31 Participants Oral inhalation, once daily (morning) for 21 days	SPIRIVA RESPIMAT 5 μg n=30 Participants Oral inhalation, once daily (morning) for 21 days
Change From Baseline in Time-normalized Area Under the Curve for FEV1 Measured Over 12 Hours on Day 21	0.23 Litre Standard Error 0.04	0.17 Litre Standard Error 0.03	0.15 Litre Standard Error 0.04	0.08 Litre Standard Error 0.04	0.23 Litre Standard Error 0.03

Adverse Events

GSP304 10 μg

Serious events: 0 serious events

Other events: 3 other events

Deaths: 0 deaths

GSP304 20 μg

Serious events: 0 serious events

Other events: 6 other events

Deaths: 0 deaths

GSP304 40 μg

Serious events: 0 serious events

Other events: 5 other events

Deaths: 0 deaths

Placebo

Serious events: 0 serious events

Other events: 4 other events

Deaths: 0 deaths

SPIRIVA RESPIMAT 5 μg

Serious events: 0 serious events

Other events: 6 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Measure	GSP304 10 μg n=30 participants at risk Oral inhalation, once daily (morning) for 21 days	GSP304 20 μg n=32 participants at risk Oral inhalation, once daily (morning) for 21 days	GSP304 40 μg n=31 participants at risk Oral inhalation, once daily (morning) for 21 days	Placebo n=33 participants at risk Oral inhalation, once daily (morning) for 21 days	SPIRIVA RESPIMAT 5 μg n=30 participants at risk Oral inhalation, once daily (morning) for 21 days
Respiratory, thoracic and mediastinal disorders Cough	3.3% 1/30 • Number of events 1 • The AEs and SAEs were collected from the time of signing the informed consent form until the end of study and the follow-up contact which was approximately 9 weeks i.e., upto 2 weeks of screening, 2 weeks of run-in period, 3 weeks of treatment and follow up of 2 weeks. GSP304 placebo: One subject not randomized to study treatment inadvertently received placebo and therefore included in SAF in Placebo arm.	3.1% 1/32 • Number of events 1 • The AEs and SAEs were collected from the time of signing the informed consent form until the end of study and the follow-up contact which was approximately 9 weeks i.e., upto 2 weeks of screening, 2 weeks of run-in period, 3 weeks of treatment and follow up of 2 weeks. GSP304 placebo: One subject not randomized to study treatment inadvertently received placebo and therefore included in SAF in Placebo arm.	0.00% 0/31 • The AEs and SAEs were collected from the time of signing the informed consent form until the end of study and the follow-up contact which was approximately 9 weeks i.e., upto 2 weeks of screening, 2 weeks of run-in period, 3 weeks of treatment and follow up of 2 weeks. GSP304 placebo: One subject not randomized to study treatment inadvertently received placebo and therefore included in SAF in Placebo arm.	0.00% 0/33 • The AEs and SAEs were collected from the time of signing the informed consent form until the end of study and the follow-up contact which was approximately 9 weeks i.e., upto 2 weeks of screening, 2 weeks of run-in period, 3 weeks of treatment and follow up of 2 weeks. GSP304 placebo: One subject not randomized to study treatment inadvertently received placebo and therefore included in SAF in Placebo arm.	10.0% 3/30 • Number of events 3 • The AEs and SAEs were collected from the time of signing the informed consent form until the end of study and the follow-up contact which was approximately 9 weeks i.e., upto 2 weeks of screening, 2 weeks of run-in period, 3 weeks of treatment and follow up of 2 weeks. GSP304 placebo: One subject not randomized to study treatment inadvertently received placebo and therefore included in SAF in Placebo arm.
Nervous system disorders Headache	3.3% 1/30 • Number of events 1 • The AEs and SAEs were collected from the time of signing the informed consent form until the end of study and the follow-up contact which was approximately 9 weeks i.e., upto 2 weeks of screening, 2 weeks of run-in period, 3 weeks of treatment and follow up of 2 weeks. GSP304 placebo: One subject not randomized to study treatment inadvertently received placebo and therefore included in SAF in Placebo arm.	6.2% 2/32 • Number of events 2 • The AEs and SAEs were collected from the time of signing the informed consent form until the end of study and the follow-up contact which was approximately 9 weeks i.e., upto 2 weeks of screening, 2 weeks of run-in period, 3 weeks of treatment and follow up of 2 weeks. GSP304 placebo: One subject not randomized to study treatment inadvertently received placebo and therefore included in SAF in Placebo arm.	0.00% 0/31 • The AEs and SAEs were collected from the time of signing the informed consent form until the end of study and the follow-up contact which was approximately 9 weeks i.e., upto 2 weeks of screening, 2 weeks of run-in period, 3 weeks of treatment and follow up of 2 weeks. GSP304 placebo: One subject not randomized to study treatment inadvertently received placebo and therefore included in SAF in Placebo arm.	3.0% 1/33 • Number of events 1 • The AEs and SAEs were collected from the time of signing the informed consent form until the end of study and the follow-up contact which was approximately 9 weeks i.e., upto 2 weeks of screening, 2 weeks of run-in period, 3 weeks of treatment and follow up of 2 weeks. GSP304 placebo: One subject not randomized to study treatment inadvertently received placebo and therefore included in SAF in Placebo arm.	10.0% 3/30 • Number of events 3 • The AEs and SAEs were collected from the time of signing the informed consent form until the end of study and the follow-up contact which was approximately 9 weeks i.e., upto 2 weeks of screening, 2 weeks of run-in period, 3 weeks of treatment and follow up of 2 weeks. GSP304 placebo: One subject not randomized to study treatment inadvertently received placebo and therefore included in SAF in Placebo arm.
Nervous system disorders Dizziness	0.00% 0/30 • The AEs and SAEs were collected from the time of signing the informed consent form until the end of study and the follow-up contact which was approximately 9 weeks i.e., upto 2 weeks of screening, 2 weeks of run-in period, 3 weeks of treatment and follow up of 2 weeks. GSP304 placebo: One subject not randomized to study treatment inadvertently received placebo and therefore included in SAF in Placebo arm.	0.00% 0/32 • The AEs and SAEs were collected from the time of signing the informed consent form until the end of study and the follow-up contact which was approximately 9 weeks i.e., upto 2 weeks of screening, 2 weeks of run-in period, 3 weeks of treatment and follow up of 2 weeks. GSP304 placebo: One subject not randomized to study treatment inadvertently received placebo and therefore included in SAF in Placebo arm.	3.2% 1/31 • Number of events 1 • The AEs and SAEs were collected from the time of signing the informed consent form until the end of study and the follow-up contact which was approximately 9 weeks i.e., upto 2 weeks of screening, 2 weeks of run-in period, 3 weeks of treatment and follow up of 2 weeks. GSP304 placebo: One subject not randomized to study treatment inadvertently received placebo and therefore included in SAF in Placebo arm.	6.1% 2/33 • Number of events 2 • The AEs and SAEs were collected from the time of signing the informed consent form until the end of study and the follow-up contact which was approximately 9 weeks i.e., upto 2 weeks of screening, 2 weeks of run-in period, 3 weeks of treatment and follow up of 2 weeks. GSP304 placebo: One subject not randomized to study treatment inadvertently received placebo and therefore included in SAF in Placebo arm.	3.3% 1/30 • Number of events 1 • The AEs and SAEs were collected from the time of signing the informed consent form until the end of study and the follow-up contact which was approximately 9 weeks i.e., upto 2 weeks of screening, 2 weeks of run-in period, 3 weeks of treatment and follow up of 2 weeks. GSP304 placebo: One subject not randomized to study treatment inadvertently received placebo and therefore included in SAF in Placebo arm.
Gastrointestinal disorders Dry mouth	0.00% 0/30 • The AEs and SAEs were collected from the time of signing the informed consent form until the end of study and the follow-up contact which was approximately 9 weeks i.e., upto 2 weeks of screening, 2 weeks of run-in period, 3 weeks of treatment and follow up of 2 weeks. GSP304 placebo: One subject not randomized to study treatment inadvertently received placebo and therefore included in SAF in Placebo arm.	3.1% 1/32 • Number of events 2 • The AEs and SAEs were collected from the time of signing the informed consent form until the end of study and the follow-up contact which was approximately 9 weeks i.e., upto 2 weeks of screening, 2 weeks of run-in period, 3 weeks of treatment and follow up of 2 weeks. GSP304 placebo: One subject not randomized to study treatment inadvertently received placebo and therefore included in SAF in Placebo arm.	12.9% 4/31 • Number of events 4 • The AEs and SAEs were collected from the time of signing the informed consent form until the end of study and the follow-up contact which was approximately 9 weeks i.e., upto 2 weeks of screening, 2 weeks of run-in period, 3 weeks of treatment and follow up of 2 weeks. GSP304 placebo: One subject not randomized to study treatment inadvertently received placebo and therefore included in SAF in Placebo arm.	0.00% 0/33 • The AEs and SAEs were collected from the time of signing the informed consent form until the end of study and the follow-up contact which was approximately 9 weeks i.e., upto 2 weeks of screening, 2 weeks of run-in period, 3 weeks of treatment and follow up of 2 weeks. GSP304 placebo: One subject not randomized to study treatment inadvertently received placebo and therefore included in SAF in Placebo arm.	0.00% 0/30 • The AEs and SAEs were collected from the time of signing the informed consent form until the end of study and the follow-up contact which was approximately 9 weeks i.e., upto 2 weeks of screening, 2 weeks of run-in period, 3 weeks of treatment and follow up of 2 weeks. GSP304 placebo: One subject not randomized to study treatment inadvertently received placebo and therefore included in SAF in Placebo arm.
Infections and infestations Urinary tract infection	3.3% 1/30 • Number of events 1 • The AEs and SAEs were collected from the time of signing the informed consent form until the end of study and the follow-up contact which was approximately 9 weeks i.e., upto 2 weeks of screening, 2 weeks of run-in period, 3 weeks of treatment and follow up of 2 weeks. GSP304 placebo: One subject not randomized to study treatment inadvertently received placebo and therefore included in SAF in Placebo arm.	0.00% 0/32 • The AEs and SAEs were collected from the time of signing the informed consent form until the end of study and the follow-up contact which was approximately 9 weeks i.e., upto 2 weeks of screening, 2 weeks of run-in period, 3 weeks of treatment and follow up of 2 weeks. GSP304 placebo: One subject not randomized to study treatment inadvertently received placebo and therefore included in SAF in Placebo arm.	0.00% 0/31 • The AEs and SAEs were collected from the time of signing the informed consent form until the end of study and the follow-up contact which was approximately 9 weeks i.e., upto 2 weeks of screening, 2 weeks of run-in period, 3 weeks of treatment and follow up of 2 weeks. GSP304 placebo: One subject not randomized to study treatment inadvertently received placebo and therefore included in SAF in Placebo arm.	3.0% 1/33 • Number of events 1 • The AEs and SAEs were collected from the time of signing the informed consent form until the end of study and the follow-up contact which was approximately 9 weeks i.e., upto 2 weeks of screening, 2 weeks of run-in period, 3 weeks of treatment and follow up of 2 weeks. GSP304 placebo: One subject not randomized to study treatment inadvertently received placebo and therefore included in SAF in Placebo arm.	6.7% 2/30 • Number of events 2 • The AEs and SAEs were collected from the time of signing the informed consent form until the end of study and the follow-up contact which was approximately 9 weeks i.e., upto 2 weeks of screening, 2 weeks of run-in period, 3 weeks of treatment and follow up of 2 weeks. GSP304 placebo: One subject not randomized to study treatment inadvertently received placebo and therefore included in SAF in Placebo arm.
Musculoskeletal and connective tissue disorders Back pain	0.00% 0/30 • The AEs and SAEs were collected from the time of signing the informed consent form until the end of study and the follow-up contact which was approximately 9 weeks i.e., upto 2 weeks of screening, 2 weeks of run-in period, 3 weeks of treatment and follow up of 2 weeks. GSP304 placebo: One subject not randomized to study treatment inadvertently received placebo and therefore included in SAF in Placebo arm.	6.2% 2/32 • Number of events 2 • The AEs and SAEs were collected from the time of signing the informed consent form until the end of study and the follow-up contact which was approximately 9 weeks i.e., upto 2 weeks of screening, 2 weeks of run-in period, 3 weeks of treatment and follow up of 2 weeks. GSP304 placebo: One subject not randomized to study treatment inadvertently received placebo and therefore included in SAF in Placebo arm.	0.00% 0/31 • The AEs and SAEs were collected from the time of signing the informed consent form until the end of study and the follow-up contact which was approximately 9 weeks i.e., upto 2 weeks of screening, 2 weeks of run-in period, 3 weeks of treatment and follow up of 2 weeks. GSP304 placebo: One subject not randomized to study treatment inadvertently received placebo and therefore included in SAF in Placebo arm.	3.0% 1/33 • Number of events 1 • The AEs and SAEs were collected from the time of signing the informed consent form until the end of study and the follow-up contact which was approximately 9 weeks i.e., upto 2 weeks of screening, 2 weeks of run-in period, 3 weeks of treatment and follow up of 2 weeks. GSP304 placebo: One subject not randomized to study treatment inadvertently received placebo and therefore included in SAF in Placebo arm.	0.00% 0/30 • The AEs and SAEs were collected from the time of signing the informed consent form until the end of study and the follow-up contact which was approximately 9 weeks i.e., upto 2 weeks of screening, 2 weeks of run-in period, 3 weeks of treatment and follow up of 2 weeks. GSP304 placebo: One subject not randomized to study treatment inadvertently received placebo and therefore included in SAF in Placebo arm.

Additional Information

Study Director

Glenmark Pharmaceuticals Ltd.

Phone: 201-684 8000

Email: clinicaltrialsdisclosuredesk@glenmarkpharma.com

Results disclosure agreements

• Principal investigator is a sponsor employee
• Publication restrictions are in place