Trial Outcomes & Findings for A Dose Ranging Study With CHF 1531 in Subjects With Asthma (FLASH) (NCT NCT03086460)

Last Updated: 2021-08-16

Results Overview

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

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

67 participants

Primary outcome timeframe

Baseline, Day 14 post-dose

Results posted on

2021-08-16

Participant Flow

Adult patients with confirmed diagnosis of asthma were recruited into the study according to the trial inclusion and exclusion criteria and were randomized into one of the 6 treatment groups. The total daily dose (TDD) of the trial investigational drug CHF 1531 pressurized metered dose Inhaler (pMDI), inhalation solution (IS) of the direct comparator, or matched placebo is indicated for each treatment group.

Participant milestones

Participant milestones
Measure	Overall Study Group Each eligible patient was randomly assigned to one of the 12 treatments sequences. The study had an incomplete cross-over design. Patients were planned to take 4 out of 6 treatments, according to one of 12 possible sequences using a balanced incomplete block randomization scheme. Treatment intervals were separated by 2-week wash-out periods. For clarity, a summary of study participants who received treatment A, B, C, D, E, and F is presented below as milestones and also as periods.
Study Participants STARTED	67
Study Participants Treatment A	39
Study Participants Treatment B	35
Study Participants Treatment C	37
Study Participants Treatment D	40
Study Participants Treatment E	40
Study Participants Treatment F	41
Study Participants COMPLETED	58
Study Participants NOT COMPLETED	9
Treatment A STARTED	39
Treatment A COMPLETED	35
Treatment A NOT COMPLETED	4
Treatment B STARTED	35
Treatment B COMPLETED	35
Treatment B NOT COMPLETED	0
Treatment C STARTED	37
Treatment C COMPLETED	35
Treatment C NOT COMPLETED	2
Treatment D STARTED	40
Treatment D COMPLETED	40
Treatment D NOT COMPLETED	0
Treatment E STARTED	40
Treatment E COMPLETED	36
Treatment E NOT COMPLETED	4
Treatment F STARTED	41
Treatment F COMPLETED	41
Treatment F NOT COMPLETED	0

Reasons for withdrawal

Reasons for withdrawal
Measure	Overall Study Group Each eligible patient was randomly assigned to one of the 12 treatments sequences. The study had an incomplete cross-over design. Patients were planned to take 4 out of 6 treatments, according to one of 12 possible sequences using a balanced incomplete block randomization scheme. Treatment intervals were separated by 2-week wash-out periods. For clarity, a summary of study participants who received treatment A, B, C, D, E, and F is presented below as milestones and also as periods.
Study Participants Lost to Follow-up	2
Study Participants Protocol Violation	1
Study Participants Withdrawal by Subject	6
Treatment A Lost to Follow-up	1
Treatment A Protocol Violation	1
Treatment A Withdrawal by Subject	2
Treatment C Withdrawal by Subject	2
Treatment E Lost to Follow-up	1
Treatment E Withdrawal by Subject	3

Baseline Characteristics

Only 9 trial participants had smoked (ex-smokers); thus, results on 9 participants are reported.

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Trial Participants n=67 Participants All trial participants had diagnosed asthma and were randomized to 6 treatments in a cross-over study design.
Age, Categorical <=18 years	0 Participants n=67 Participants
Age, Categorical Between 18 and 65 years	55 Participants n=67 Participants
Age, Categorical >=65 years	12 Participants n=67 Participants
Age, Continuous	46.0 years STANDARD_DEVIATION 15.8 • n=67 Participants
Sex: Female, Male Female	42 Participants n=67 Participants
Sex: Female, Male Male	25 Participants n=67 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	4 Participants n=67 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	63 Participants n=67 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=67 Participants
Race (NIH/OMB) American Indian or Alaska Native	1 Participants n=67 Participants
Race (NIH/OMB) Asian	1 Participants n=67 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=67 Participants
Race (NIH/OMB) Black or African American	31 Participants n=67 Participants
Race (NIH/OMB) White	34 Participants n=67 Participants
Race (NIH/OMB) More than one race	0 Participants n=67 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=67 Participants
Region of Enrollment United States	67 participants n=67 Participants
Weight	89.8 kg STANDARD_DEVIATION 23.1 • n=67 Participants
Height	167.6 cm STANDARD_DEVIATION 10.1 • n=67 Participants
Body Mass Index (BMI)	32.0 kg/m^2 STANDARD_DEVIATION 8.1 • n=67 Participants
Time since first diagnosis of asthma	335.2 months n=67 Participants
Age at first diagnosis of asthma	17.3 years STANDARD_DEVIATION 17.4 • n=67 Participants
Asthma medication category at study entry Short-acting beta2-agonist (SABA [albuterol])	62 Participants n=67 Participants
Asthma medication category at study entry Leukotriene modifiers (LTRM)	7 Participants n=67 Participants
Asthma medication category at study entry Theophylline	0 Participants n=67 Participants
Asthma medication category at study entry Inhaled corticosteroid (ICS) alone	27 Participants n=67 Participants
Asthma medication category at study entry ICS/Long-acting muscarinic antagonist (LABA), (free or fixed combination)	39 Participants n=67 Participants
Asthma medication category at study entry ICS/Long-acting muscarinic antagonist (LAMA), (free combination)	1 Participants n=67 Participants
Asthma medication category at study entry ICS/LABA/LAMA	0 Participants n=67 Participants
Smoking habits Current smoker	0 Participants n=67 Participants
Smoking habits Ex-smoker	9 Participants n=67 Participants
Smoking habits Non-smoker	58 Participants n=67 Participants
Duration of smoking	8.0 years STANDARD_DEVIATION 4.5 • n=9 Participants • Only 9 trial participants had smoked (ex-smokers); thus, results on 9 participants are reported.
Number of pack-years	2.5 pack-years n=9 Participants • Only 9 trial participants had smoked (ex-smokers).
FEV1 at screening (pre-bronchodilator)	2.128 Litre STANDARD_DEVIATION 0.620 • n=67 Participants
FEV1 % of the normal predicted value (pre-bronchodilator)	70.2 percent STANDARD_DEVIATION 6.3 • n=67 Participants
FEV1 at screening (post-bronchodilator)	2.548 Litre STANDARD_DEVIATION 0.738 • n=67 Participants
FEV1 % of the normal predicted value (post-bronchodilator)	84.2 percent STANDARD_DEVIATION 8.1 • n=67 Participants
FVC at screening (pre-bronchodilator)	3.066 Litre STANDARD_DEVIATION 0.993 • n=67 Participants
FVC at screening (post-bronchodilator)	3.450 Litre STANDARD_DEVIATION 1.028 • n=67 Participants
Reversibility FEV1 (mL) at screening	420 millilitre STANDARD_DEVIATION 178 • n=67 Participants
Reversibility FEV1 (%) at screening	20.1 percent STANDARD_DEVIATION 7.1 • n=67 Participants

PRIMARY outcome

Timeframe: Baseline, Day 14 post-dose

Outcome measures

Outcome measures
Measure	Treatment A n=38 Participants Treatment A, CHF 1531 pMDI: 6 μg TDD	Treatment B n=35 Participants Treatment B, CHF 1531 pMDI: 12 μg TDD	Treatment C n=34 Participants Treatment C, CHF 1531 pMDI: 24 μg TDD	Treatment D n=40 Participants Treatment D, CHF 1531 pMDI: 48 μg TDD	Treatment E n=35 Participants Treatment E, Matched placebo	Treatment F n=41 Participants Treatment F, Formoterol fumarate IS Perforomist®: 40 μg TDD
FEV1 Area Under the Curve Between 0 and 12 h [AUC(0-12h)], Normalized by Time -- Change From Baseline to Post Dose Day 14	0.174 Litres Interval 0.141 to 0.208	0.221 Litres Interval 0.186 to 0.257	0.197 Litres Interval 0.161 to 0.232	0.231 Litres Interval 0.199 to 0.263	0.064 Litres Interval 0.03 to 0.098	0.208 Litres Interval 0.175 to 0.24

PRIMARY outcome

Timeframe: Baseline, Day 14 post-dose

The primary analysis was repeated, considering patients "as randomized" and including only the first instance of each treatment. Patients receiving the same treatment in more than one period were included in the analysis with only data from the first instance of each treatment.

Outcome measures

Outcome measures
Measure	Treatment A n=38 Participants Treatment A, CHF 1531 pMDI: 6 μg TDD	Treatment B n=35 Participants Treatment B, CHF 1531 pMDI: 12 μg TDD	Treatment C n=34 Participants Treatment C, CHF 1531 pMDI: 24 μg TDD	Treatment D n=40 Participants Treatment D, CHF 1531 pMDI: 48 μg TDD	Treatment E n=35 Participants Treatment E, Matched placebo	Treatment F n=41 Participants Treatment F, Formoterol fumarate IS Perforomist®: 40 μg TDD
Sensitivity Analysis 1: FEV1 AUC(0-12h), Normalized by Time -- Change From Baseline to Post Dose Day 14	0.169 Litres Interval 0.134 to 0.205	0.224 Litres Interval 0.187 to 0.26	0.196 Litres Interval 0.158 to 0.233	0.232 Litres Interval 0.198 to 0.265	0.058 Litres Interval 0.021 to 0.094	0.206 Litres Interval 0.173 to 0.239

PRIMARY outcome

Timeframe: Baseline, Day 14 post-dose

The primary analysis was repeated, considering only patients and treatment periods for which treatment was assigned on or after the randomization error occurred. The number of patients shown represents those with at least one post-baseline assessment available.

Outcome measures

Outcome measures
Measure	Treatment A n=31 Participants Treatment A, CHF 1531 pMDI: 6 μg TDD	Treatment B n=27 Participants Treatment B, CHF 1531 pMDI: 12 μg TDD	Treatment C n=28 Participants Treatment C, CHF 1531 pMDI: 24 μg TDD	Treatment D n=34 Participants Treatment D, CHF 1531 pMDI: 48 μg TDD	Treatment E n=32 Participants Treatment E, Matched placebo	Treatment F n=30 Participants Treatment F, Formoterol fumarate IS Perforomist®: 40 μg TDD
Sensitivity Analysis 2: FEV1 AUC(0-12h), Normalized by Time -- Change From Baseline to Post Dose Day 14	0.129 Litres Interval 0.089 to 0.17	0.180 Litres Interval 0.136 to 0.223	0.159 Litres Interval 0.116 to 0.201	0.179 Litres Interval 0.141 to 0.217	-0.006 Litres Interval -0.047 to 0.034	0.170 Litres Interval 0.129 to 0.211

PRIMARY outcome

Timeframe: Baseline, Day 14 post-dose

Patients receiving the same treatment during two treatment periods are considered twice in the ANCOVA model (once for each period attended). Patients considered in this analysis are those with at least one available post-baseline assessment.

Outcome measures

Outcome measures
Measure	Treatment A n=38 Participants Treatment A, CHF 1531 pMDI: 6 μg TDD	Treatment B n=35 Participants Treatment B, CHF 1531 pMDI: 12 μg TDD	Treatment C n=34 Participants Treatment C, CHF 1531 pMDI: 24 μg TDD	Treatment D n=40 Participants Treatment D, CHF 1531 pMDI: 48 μg TDD	Treatment E n=35 Participants Treatment E, Matched placebo	Treatment F n=41 Participants Treatment F, Formoterol fumarate IS Perforomist®: 40 μg TDD
Sensitivity Analysis 3: FEV1 AUC(0-12h), Normalized by Time -- Change From Baseline to Post Dose Day 14	0.144 Litres Interval 0.103 to 0.186	0.194 Litres Interval 0.151 to 0.237	0.170 Litres Interval 0.128 to 0.213	0.198 Litres Interval 0.157 to 0.238	0.037 Litres Interval -0.004 to 0.079	0.184 Litres Interval 0.143 to 0.225

SECONDARY outcome

Timeframe: Baseline, Day 1 post-dose

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

Outcome measures

Outcome measures
Measure	Treatment A n=39 Participants Treatment A, CHF 1531 pMDI: 6 μg TDD	Treatment B n=34 Participants Treatment B, CHF 1531 pMDI: 12 μg TDD	Treatment C n=37 Participants Treatment C, CHF 1531 pMDI: 24 μg TDD	Treatment D n=40 Participants Treatment D, CHF 1531 pMDI: 48 μg TDD	Treatment E n=40 Participants Treatment E, Matched placebo	Treatment F n=39 Participants Treatment F, Formoterol fumarate IS Perforomist®: 40 μg TDD
FEV1 AUC(0-12h), Normalized by Time -- Change From Baseline to Post Dose Day 1	0.181 Litres Interval 0.143 to 0.219	0.221 Litres Interval 0.179 to 0.262	0.260 Litres Interval 0.221 to 0.298	0.282 Litres Interval 0.245 to 0.319	0.067 Litres Interval 0.03 to 0.103	0.239 Litres Interval 0.201 to 0.277

SECONDARY outcome

Timeframe: Baseline, Day 1, Day 14 post-dose

Population: Intention-to-treat (ITT): All randomized patients who received at least one dose of the study treatment within the given treatment period and with at least one available evaluation of efficacy (primary or secondary efficacy variables) after the baseline and within the given treatment period. Due to an error in the randomization system during the trial, some patients received the same treatment in several treatment period, as summarized in section Participant Flow.

Outcome measures

Outcome measures
Measure	Treatment A n=39 Participants Treatment A, CHF 1531 pMDI: 6 μg TDD	Treatment B n=35 Participants Treatment B, CHF 1531 pMDI: 12 μg TDD	Treatment C n=37 Participants Treatment C, CHF 1531 pMDI: 24 μg TDD	Treatment D n=40 Participants Treatment D, CHF 1531 pMDI: 48 μg TDD	Treatment E n=40 Participants Treatment E, Matched placebo	Treatment F n=41 Participants Treatment F, Formoterol fumarate IS Perforomist®: 40 μg TDD
FEV1 AUC(0-4h), Normalized by Time -- Change From Baseline to Post Dose Day 1 and Day 14 Day 1	0.220 Litres Interval 0.18 to 0.26	0.250 Litres Interval 0.207 to 0.293	0.270 Litres Interval 0.229 to 0.311	0.317 Litres Interval 0.279 to 0.356	0.047 Litres Interval 0.009 to 0.085	0.288 Litres Interval 0.249 to 0.328
FEV1 AUC(0-4h), Normalized by Time -- Change From Baseline to Post Dose Day 1 and Day 14 Day 14	0.214 Litres Interval 0.174 to 0.254	0.251 Litres Interval 0.21 to 0.293	0.231 Litres Interval 0.19 to 0.273	0.278 Litres Interval 0.241 to 0.316	0.061 Litres Interval 0.021 to 0.101	0.259 Litres Interval 0.221 to 0.298

SECONDARY outcome

Timeframe: Baseline, Day 1, Day 14 post-dose

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

Outcome measures

Outcome measures
Measure	Treatment A n=39 Participants Treatment A, CHF 1531 pMDI: 6 μg TDD	Treatment B n=35 Participants Treatment B, CHF 1531 pMDI: 12 μg TDD	Treatment C n=37 Participants Treatment C, CHF 1531 pMDI: 24 μg TDD	Treatment D n=40 Participants Treatment D, CHF 1531 pMDI: 48 μg TDD	Treatment E n=40 Participants Treatment E, Matched placebo	Treatment F n=41 Participants Treatment F, Formoterol fumarate IS Perforomist®: 40 μg TDD
FEV1 Peak(0-4h), Normalized by Time -- Change From Baseline to Post Dose Day 1 and Day 14 Day 1	0.359 Litres Interval 0.317 to 0.401	0.370 Litres Interval 0.326 to 0.414	0.393 Litres Interval 0.351 to 0.436	0.430 Litres Interval 0.39 to 0.47	0.178 Litres Interval 0.138 to 0.218	0.416 Litres Interval 0.375 to 0.457
FEV1 Peak(0-4h), Normalized by Time -- Change From Baseline to Post Dose Day 1 and Day 14 Day 14	0.346 Litres Interval 0.303 to 0.39	0.373 Litres Interval 0.328 to 0.419	0.349 Litres Interval 0.304 to 0.394	0.389 Litres Interval 0.348 to 0.43	0.183 Litres Interval 0.14 to 0.227	0.367 Litres Interval 0.325 to 0.409

SECONDARY outcome

Timeframe: Baseline, Day 1, Day 14 post-dose

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

Outcome measures

Outcome measures
Measure	Treatment A n=39 Participants Treatment A, CHF 1531 pMDI: 6 μg TDD	Treatment B n=35 Participants Treatment B, CHF 1531 pMDI: 12 μg TDD	Treatment C n=37 Participants Treatment C, CHF 1531 pMDI: 24 μg TDD	Treatment D n=40 Participants Treatment D, CHF 1531 pMDI: 48 μg TDD	Treatment E n=40 Participants Treatment E, Matched placebo	Treatment F n=41 Participants Treatment F, Formoterol fumarate IS Perforomist®: 40 μg TDD
FVC AUC(0-12h), Normalized by Time -- Change From Baseline to Post Dose Day 1 and Day 14 Day 1	0.111 Litres Interval 0.068 to 0.154	0.156 Litres Interval 0.109 to 0.203	0.160 Litres Interval 0.116 to 0.204	0.182 Litres Interval 0.14 to 0.224	0.059 Litres Interval 0.018 to 0.1	0.172 Litres Interval 0.128 to 0.215
FVC AUC(0-12h), Normalized by Time -- Change From Baseline to Post Dose Day 1 and Day 14 Day 14	0.103 Litres Interval 0.064 to 0.142	0.134 Litres Interval 0.093 to 0.174	0.120 Litres Interval 0.079 to 0.16	0.142 Litres Interval 0.105 to 0.178	0.060 Litres Interval 0.02 to 0.099	0.134 Litres Interval 0.096 to 0.171

SECONDARY outcome

Timeframe: Baseline, Day 1, Day 14 post-dose

Outcome measures

Outcome measures
Measure	Treatment A n=39 Participants Treatment A, CHF 1531 pMDI: 6 μg TDD	Treatment B n=35 Participants Treatment B, CHF 1531 pMDI: 12 μg TDD	Treatment C n=37 Participants Treatment C, CHF 1531 pMDI: 24 μg TDD	Treatment D n=40 Participants Treatment D, CHF 1531 pMDI: 48 μg TDD	Treatment E n=40 Participants Treatment E, Matched placebo	Treatment F n=41 Participants Treatment F, Formoterol fumarate IS Perforomist®: 40 μg TDD
FVC AUC(0-4h), Normalized by Time -- Change From Baseline to Post Dose Day 1 and Day 14 Day 1	0.158 Litres Interval 0.112 to 0.203	0.186 Litres Interval 0.136 to 0.235	0.159 Litres Interval 0.113 to 0.206	0.215 Litres Interval 0.171 to 0.26	0.036 Litres Interval -0.007 to 0.079	0.213 Litres Interval 0.168 to 0.257
FVC AUC(0-4h), Normalized by Time -- Change From Baseline to Post Dose Day 1 and Day 14 Day 14	0.135 Litres Interval 0.089 to 0.181	0.146 Litres Interval 0.098 to 0.195	0.136 Litres Interval 0.089 to 0.184	0.194 Litres Interval 0.151 to 0.238	0.050 Litres Interval 0.004 to 0.095	0.177 Litres Interval 0.132 to 0.221

SECONDARY outcome

Timeframe: Baseline, Day 1, Day 14 post-dose

Outcome measures

Outcome measures
Measure	Treatment A n=39 Participants Treatment A, CHF 1531 pMDI: 6 μg TDD	Treatment B n=35 Participants Treatment B, CHF 1531 pMDI: 12 μg TDD	Treatment C n=37 Participants Treatment C, CHF 1531 pMDI: 24 μg TDD	Treatment D n=40 Participants Treatment D, CHF 1531 pMDI: 48 μg TDD	Treatment E n=40 Participants Treatment E, Matched placebo	Treatment F n=41 Participants Treatment F, Formoterol fumarate IS Perforomist®: 40 μg TDD
FVC Peak(0-4h), Normalized by Time -- Change From Baseline to Post Dose Day 1 and Day 14 Day 1	0.331 Litres Interval 0.277 to 0.384	0.347 Litres Interval 0.29 to 0.404	0.354 Litres Interval 0.299 to 0.408	0.367 Litres Interval 0.315 to 0.419	0.216 Litres Interval 0.166 to 0.267	0.385 Litres Interval 0.333 to 0.437
FVC Peak(0-4h), Normalized by Time -- Change From Baseline to Post Dose Day 1 and Day 14 Day 14	0.310 Litres Interval 0.259 to 0.361	0.331 Litres Interval 0.277 to 0.385	0.304 Litres Interval 0.251 to 0.358	0.350 Litres Interval 0.301 to 0.399	0.198 Litres Interval 0.147 to 0.25	0.340 Litres Interval 0.29 to 0.39

SECONDARY outcome

Timeframe: Baseline, Day 14 post-dose

Outcome measures

Outcome measures
Measure	Treatment A n=39 Participants Treatment A, CHF 1531 pMDI: 6 μg TDD	Treatment B n=35 Participants Treatment B, CHF 1531 pMDI: 12 μg TDD	Treatment C n=35 Participants Treatment C, CHF 1531 pMDI: 24 μg TDD	Treatment D n=40 Participants Treatment D, CHF 1531 pMDI: 48 μg TDD	Treatment E n=37 Participants Treatment E, Matched placebo	Treatment F n=41 Participants Treatment F, Formoterol fumarate IS Perforomist®: 40 μg TDD
Pre-dose Morning FEV1 (L) -- Change From Baseline to Post Dose Day 14	0.071 Litres Interval 0.021 to 0.12	0.102 Litres Interval 0.049 to 0.155	0.073 Litres Interval 0.021 to 0.125	0.149 Litres Interval 0.101 to 0.197	0.037 Litres Interval -0.013 to 0.087	0.126 Litres Interval 0.077 to 0.175

SECONDARY outcome

Timeframe: Baseline, Day 14 post-dose

Outcome measures

Outcome measures
Measure	Treatment A n=39 Participants Treatment A, CHF 1531 pMDI: 6 μg TDD	Treatment B n=35 Participants Treatment B, CHF 1531 pMDI: 12 μg TDD	Treatment C n=35 Participants Treatment C, CHF 1531 pMDI: 24 μg TDD	Treatment D n=40 Participants Treatment D, CHF 1531 pMDI: 48 μg TDD	Treatment E n=37 Participants Treatment E, Matched placebo	Treatment F n=41 Participants Treatment F, Formoterol fumarate IS Perforomist®: 40 μg TDD
Pre-dose Morning FVC -- Change From Baseline to Post Dose Day 14	0.048 Litres Interval -0.005 to 0.102	0.044 Litres Interval -0.013 to 0.101	0.048 Litres Interval -0.009 to 0.104	0.114 Litres Interval 0.062 to 0.166	0.053 Litres Interval 0.0 to 0.107	0.114 Litres Interval 0.061 to 0.166

SECONDARY outcome

Timeframe: Baseline, Day 1 post-dose

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

Outcome measures

Outcome measures
Measure	Treatment A n=39 Participants Treatment A, CHF 1531 pMDI: 6 μg TDD	Treatment B n=35 Participants Treatment B, CHF 1531 pMDI: 12 μg TDD	Treatment C n=37 Participants Treatment C, CHF 1531 pMDI: 24 μg TDD	Treatment D n=40 Participants Treatment D, CHF 1531 pMDI: 48 μg TDD	Treatment E n=40 Participants Treatment E, Matched placebo	Treatment F n=41 Participants Treatment F, Formoterol fumarate IS Perforomist®: 40 μg TDD
Time to Onset of Action -- Change From Baseline in Post-dose FEV1 ≥12% and ≥200 mL to Post Dose Day 1	358.8 minutes Interval 43.1 to NA: Censoring for patients not achieving onset of action	60.3 minutes Interval 31.3 to NA: Censoring for patients not achieving onset of action	33.6 minutes Interval 16.0 to 118.8	44.3 minutes Interval 16.0 to 240.1	NA minutes NA: Censoring for patients not achieving onset of action	45.5 minutes Interval 32.6 to 66.8

SECONDARY outcome

Timeframe: Baseline, Day 1 post-dose

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

Outcome measures

Outcome measures
Measure	Treatment A n=39 Participants Treatment A, CHF 1531 pMDI: 6 μg TDD	Treatment B n=35 Participants Treatment B, CHF 1531 pMDI: 12 μg TDD	Treatment C n=37 Participants Treatment C, CHF 1531 pMDI: 24 μg TDD	Treatment D n=40 Participants Treatment D, CHF 1531 pMDI: 48 μg TDD	Treatment E n=40 Participants Treatment E, Matched placebo	Treatment F n=41 Participants Treatment F, Formoterol fumarate IS Perforomist®: 40 μg TDD
Patients Achieving Onset of Action -- Change From Baseline in Post-dose FEV1 ≥12% and ≥200 mL to Post Dose Day 1	23 Participants	22 Participants	30 Participants	29 Participants	11 Participants	31 Participants

SECONDARY outcome

Timeframe: Baseline, Day 1 and Day 14 post-dose

Population: Safety population: All randomized patients who received at least one dose of study treatment within the given period.

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

Outcome measures

Outcome measures
Measure	Treatment A n=39 Participants Treatment A, CHF 1531 pMDI: 6 μg TDD	Treatment B n=35 Participants Treatment B, CHF 1531 pMDI: 12 μg TDD	Treatment C n=37 Participants Treatment C, CHF 1531 pMDI: 24 μg TDD	Treatment D n=40 Participants Treatment D, CHF 1531 pMDI: 48 μg TDD	Treatment E n=40 Participants Treatment E, Matched placebo	Treatment F n=41 Participants Treatment F, Formoterol fumarate IS Perforomist®: 40 μg TDD
Vital Signs (Systolic Blood Pressure [SBP] and Diastolic Blood Pressure [DBP]) -- Change From Baseline for Post-dose on Day 1 and on Day 14 DBP, Day 1, 8 h post-dose	-1.5 mmHg Interval -15.0 to 10.0	-0.9 mmHg Interval -10.0 to 15.0	-0.4 mmHg Interval -13.0 to 10.0	-1.9 mmHg Interval -16.0 to 11.0	-1.7 mmHg Interval -13.0 to 9.0	0.4 mmHg Interval -17.0 to 12.0
Vital Signs (Systolic Blood Pressure [SBP] and Diastolic Blood Pressure [DBP]) -- Change From Baseline for Post-dose on Day 1 and on Day 14 SBP, Day 1, 12 h post-dose	1.8 mmHg Interval -13.0 to 21.0	2.1 mmHg Interval -17.0 to 18.0	3.0 mmHg Interval -24.0 to 28.0	1.4 mmHg Interval -11.0 to 18.0	-0.1 mmHg Interval -16.0 to 16.0	3.4 mmHg Interval -12.0 to 28.0
Vital Signs (Systolic Blood Pressure [SBP] and Diastolic Blood Pressure [DBP]) -- Change From Baseline for Post-dose on Day 1 and on Day 14 SBP, Day 1, 30 min post-dose	-1.2 mmHg Interval -14.0 to 9.0	0.2 mmHg Interval -23.0 to 11.0	-0.8 mmHg Interval -35.0 to 19.0	-1.2 mmHg Interval -21.0 to 17.0	-0.5 mmHg Interval -12.0 to 9.0	-0.8 mmHg Interval -15.0 to 11.0
Vital Signs (Systolic Blood Pressure [SBP] and Diastolic Blood Pressure [DBP]) -- Change From Baseline for Post-dose on Day 1 and on Day 14 SBP, Day 1, 1 h post-dose	-0.1 mmHg Interval -15.0 to 17.0	0.5 mmHg Interval -18.0 to 14.0	-0.6 mmHg Interval -31.0 to 11.0	-0.6 mmHg Interval -18.0 to 15.0	-0.8 mmHg Interval -17.0 to 16.0	-0.8 mmHg Interval -13.0 to 11.0
Vital Signs (Systolic Blood Pressure [SBP] and Diastolic Blood Pressure [DBP]) -- Change From Baseline for Post-dose on Day 1 and on Day 14 SBP, Day 1, 4 h post-dose	1.7 mmHg Interval -11.0 to 20.0	0.4 mmHg Interval -13.0 to 15.0	-0.9 mmHg Interval -32.0 to 16.0	0.9 mmHg Interval -12.0 to 17.0	0.2 mmHg Interval -14.0 to 17.0	0.5 mmHg Interval -25.0 to 11.0
Vital Signs (Systolic Blood Pressure [SBP] and Diastolic Blood Pressure [DBP]) -- Change From Baseline for Post-dose on Day 1 and on Day 14 SBP, Day 1, 8 h post-dose	0.8 mmHg Interval -16.0 to 18.0	0.2 mmHg Interval -19.0 to 19.0	1.1 mmHg Interval -23.0 to 31.0	0.7 mmHg Interval -15.0 to 13.0	0.5 mmHg Interval -18.0 to 14.0	2.5 mmHg Interval -13.0 to 26.0
Vital Signs (Systolic Blood Pressure [SBP] and Diastolic Blood Pressure [DBP]) -- Change From Baseline for Post-dose on Day 1 and on Day 14 SBP, Day 14, pre-dose	1.0 mmHg Interval -15.0 to 15.0	-1.8 mmHg Interval -19.0 to 20.0	0.0 mmHg Interval -17.0 to 23.0	-0.4 mmHg Interval -22.0 to 23.0	-2.5 mmHg Interval -19.0 to 22.0	-0.3 mmHg Interval -14.0 to 18.0
Vital Signs (Systolic Blood Pressure [SBP] and Diastolic Blood Pressure [DBP]) -- Change From Baseline for Post-dose on Day 1 and on Day 14 SBP, Day 14, 30 min post-dose	0.3 mmHg Interval -23.0 to 23.0	-3.1 mmHg Interval -24.0 to 15.0	-0.7 mmHg Interval -25.0 to 24.0	-0.7 mmHg Interval -27.0 to 36.0	-3.6 mmHg Interval -16.0 to 15.0	-2.5 mmHg Interval -19.0 to 12.0
Vital Signs (Systolic Blood Pressure [SBP] and Diastolic Blood Pressure [DBP]) -- Change From Baseline for Post-dose on Day 1 and on Day 14 SBP, Day 14, 12 h post-dose	1.2 mmHg Interval -18.0 to 17.0	1.0 mmHg Interval -23.0 to 29.0	1.5 mmHg Interval -26.0 to 26.0	4.4 mmHg Interval -18.0 to 39.0	-0.3 mmHg Interval -20.0 to 43.0	2.5 mmHg Interval -11.0 to 19.0
Vital Signs (Systolic Blood Pressure [SBP] and Diastolic Blood Pressure [DBP]) -- Change From Baseline for Post-dose on Day 1 and on Day 14 DBP, Day 1, 30 min post-dose	-2.1 mmHg Interval -19.0 to 10.0	-1.5 mmHg Interval -19.0 to 10.0	-1.2 mmHg Interval -21.0 to 8.0	-2.0 mmHg Interval -20.0 to 13.0	-0.3 mmHg Interval -11.0 to 14.0	-1.2 mmHg Interval -17.0 to 12.0
Vital Signs (Systolic Blood Pressure [SBP] and Diastolic Blood Pressure [DBP]) -- Change From Baseline for Post-dose on Day 1 and on Day 14 SBP, Day 14, 1 h post-dose	0.1 mmHg Interval -17.0 to 16.0	-1.8 mmHg Interval -29.0 to 25.0	-1.8 mmHg Interval -29.0 to 36.0	-1.9 mmHg Interval -29.0 to 33.0	-1.7 mmHg Interval -18.0 to 12.0	-1.1 mmHg Interval -14.0 to 17.0
Vital Signs (Systolic Blood Pressure [SBP] and Diastolic Blood Pressure [DBP]) -- Change From Baseline for Post-dose on Day 1 and on Day 14 SBP, Day 14, 4 h post-dose	0.9 mmHg Interval -26.0 to 19.0	0.1 mmHg Interval -26.0 to 26.0	-1.4 mmHg Interval -20.0 to 15.0	1.0 mmHg Interval -13.0 to 25.0	-0.5 mmHg Interval -26.0 to 49.0	-0.8 mmHg Interval -20.0 to 22.0
Vital Signs (Systolic Blood Pressure [SBP] and Diastolic Blood Pressure [DBP]) -- Change From Baseline for Post-dose on Day 1 and on Day 14 SBP, Day 14, 8 h post-dose	0.7 mmHg Interval -20.0 to 23.0	1.3 mmHg Interval -13.0 to 16.0	1.1 mmHg Interval -20.0 to 25.0	0.6 mmHg Interval -16.0 to 28.0	-3.3 mmHg Interval -27.0 to 27.0	0.6 mmHg Interval -13.0 to 13.0
Vital Signs (Systolic Blood Pressure [SBP] and Diastolic Blood Pressure [DBP]) -- Change From Baseline for Post-dose on Day 1 and on Day 14 DBP, Day 14, 12 h post-dose	0.0 mmHg Interval -11.0 to 18.0	-0.7 mmHg Interval -15.0 to 21.0	0.7 mmHg Interval -10.0 to 13.0	-0.6 mmHg Interval -19.0 to 14.0	1.4 mmHg Interval -15.0 to 25.0	-0.1 mmHg Interval -10.0 to 14.0
Vital Signs (Systolic Blood Pressure [SBP] and Diastolic Blood Pressure [DBP]) -- Change From Baseline for Post-dose on Day 1 and on Day 14 DBP, Day 1, 1 h post-dose	0.0 mmHg Interval -8.0 to 9.0	-1.9 mmHg Interval -18.0 to 12.0	-0.4 mmHg Interval -14.0 to 17.0	-1.6 mmHg Interval -17.0 to 11.0	-2.5 mmHg Interval -12.0 to 8.0	-1.7 mmHg Interval -15.0 to 15.0
Vital Signs (Systolic Blood Pressure [SBP] and Diastolic Blood Pressure [DBP]) -- Change From Baseline for Post-dose on Day 1 and on Day 14 DBP, Day 1, 4 h post-dose	-0.6 mmHg Interval -11.0 to 9.0	-1.4 mmHg Interval -13.0 to 9.0	-0.4 mmHg Interval -11.0 to 14.0	-1.0 mmHg Interval -20.0 to 15.0	-1.6 mmHg Interval -13.0 to 8.0	-1.0 mmHg Interval -16.0 to 14.0
Vital Signs (Systolic Blood Pressure [SBP] and Diastolic Blood Pressure [DBP]) -- Change From Baseline for Post-dose on Day 1 and on Day 14 DBP, Day 1, 12 h post-dose	-0.5 mmHg Interval -11.0 to 16.0	-0.1 mmHg Interval -14.0 to 15.0	0.4 mmHg Interval -14.0 to 11.0	-1.0 mmHg Interval -11.0 to 14.0	-0.3 mmHg Interval -14.0 to 9.0	0.0 mmHg Interval -13.0 to 13.0
Vital Signs (Systolic Blood Pressure [SBP] and Diastolic Blood Pressure [DBP]) -- Change From Baseline for Post-dose on Day 1 and on Day 14 DBP, Day 14, pre-dose	-1.2 mmHg Interval -13.0 to 8.0	0.1 mmHg Interval -10.0 to 19.0	1.1 mmHg Interval -13.0 to 10.0	-0.1 mmHg Interval -16.0 to 14.0	-0.6 mmHg Interval -13.0 to 10.0	-0.7 mmHg Interval -13.0 to 17.0
Vital Signs (Systolic Blood Pressure [SBP] and Diastolic Blood Pressure [DBP]) -- Change From Baseline for Post-dose on Day 1 and on Day 14 DBP, Day 14, 30 min post-dose	-0.2 mmHg Interval -14.0 to 17.0	-2.1 mmHg Interval -21.0 to 20.0	-0.8 mmHg Interval -20.0 to 8.0	-2.9 mmHg Interval -20.0 to 16.0	-1.5 mmHg Interval -12.0 to 10.0	-2.0 mmHg Interval -14.0 to 14.0
Vital Signs (Systolic Blood Pressure [SBP] and Diastolic Blood Pressure [DBP]) -- Change From Baseline for Post-dose on Day 1 and on Day 14 DBP, Day 14, 1 h post-dose	-0.3 mmHg Interval -13.0 to 13.0	-2.4 mmHg Interval -24.0 to 24.0	-0.5 mmHg Interval -14.0 to 12.0	-2.4 mmHg Interval -24.0 to 25.0	-1.8 mmHg Interval -12.0 to 16.0	-1.6 mmHg Interval -18.0 to 14.0
Vital Signs (Systolic Blood Pressure [SBP] and Diastolic Blood Pressure [DBP]) -- Change From Baseline for Post-dose on Day 1 and on Day 14 DBP, Day 14, 4 h post-dose	-1.0 mmHg Interval -15.0 to 9.0	-1.5 mmHg Interval -18.0 to 19.0	-1.7 mmHg Interval -12.0 to 9.0	-2.5 mmHg Interval -17.0 to 10.0	0.4 mmHg Interval -12.0 to 24.0	-2.3 mmHg Interval -16.0 to 24.0
Vital Signs (Systolic Blood Pressure [SBP] and Diastolic Blood Pressure [DBP]) -- Change From Baseline for Post-dose on Day 1 and on Day 14 DBP, Day 14, 8 h post-dose	-1.1 mmHg Interval -15.0 to 15.0	-1.0 mmHg Interval -18.0 to 18.0	0.3 mmHg Interval -11.0 to 13.0	-2.6 mmHg Interval -20.0 to 14.0	-1.7 mmHg Interval -19.0 to 15.0	-1.3 mmHg Interval -14.0 to 13.0

SECONDARY outcome

Timeframe: Baseline, Day 1, Day 14 post-dose

Population: Safety population: All randomized patients who received at least one dose of study treatment within the given period.

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

Outcome measures

Outcome measures
Measure	Treatment A n=39 Participants Treatment A, CHF 1531 pMDI: 6 μg TDD	Treatment B n=35 Participants Treatment B, CHF 1531 pMDI: 12 μg TDD	Treatment C n=37 Participants Treatment C, CHF 1531 pMDI: 24 μg TDD	Treatment D n=40 Participants Treatment D, CHF 1531 pMDI: 48 μg TDD	Treatment E n=40 Participants Treatment E, Matched placebo	Treatment F n=41 Participants Treatment F, Formoterol fumarate IS Perforomist®: 40 μg TDD
12-lead ECG Parameter -- Heart Rate (HR) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 Day 1, 8h post-dose	5.0 bpm Interval -19.0 to 27.0	2.4 bpm Interval -16.0 to 21.0	5.0 bpm Interval -8.0 to 15.0	3.9 bpm Interval -12.0 to 23.0	0.5 bpm Interval -21.0 to 18.0	2.1 bpm Interval -18.0 to 23.0
12-lead ECG Parameter -- Heart Rate (HR) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 Day 1, 12h post-dose	5.1 bpm Interval -13.0 to 28.0	5.5 bpm Interval -13.0 to 32.0	5.5 bpm Interval -15.0 to 24.0	7.6 bpm Interval -12.0 to 28.0	2.4 bpm Interval -18.0 to 25.0	5.2 bpm Interval -15.0 to 24.0
12-lead ECG Parameter -- Heart Rate (HR) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 Day 14, 12h post-dose	7.4 bpm Interval -17.0 to 34.0	7.5 bpm Interval -17.0 to 30.0	6.7 bpm Interval -15.0 to 19.0	5.4 bpm Interval -16.0 to 27.0	0.5 bpm Interval -23.0 to 16.0	5.1 bpm Interval -19.0 to 30.0
12-lead ECG Parameter -- Heart Rate (HR) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 Day 14, pre-dose	2.5 bpm Interval -14.0 to 22.0	0.1 bpm Interval -13.0 to 13.0	3.1 bpm Interval -6.0 to 17.0	2.0 bpm Interval -12.0 to 16.0	0.7 bpm Interval -26.0 to 15.0	0.4 bpm Interval -11.0 to 16.0
12-lead ECG Parameter -- Heart Rate (HR) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 Day 14, 30 min post-dose	2.9 bpm Interval -12.0 to 25.0	-0.8 bpm Interval -21.0 to 18.0	1.6 bpm Interval -9.0 to 12.0	4.3 bpm Interval -10.0 to 20.0	-1.5 bpm Interval -28.0 to 19.0	1.3 bpm Interval -19.0 to 32.0
12-lead ECG Parameter -- Heart Rate (HR) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 Day 14, 1h post-dose	1.9 bpm Interval -16.0 to 26.0	-1.2 bpm Interval -18.0 to 15.0	1.6 bpm Interval -11.0 to 12.0	3.2 bpm Interval -12.0 to 19.0	-1.2 bpm Interval -31.0 to 29.0	0.4 bpm Interval -22.0 to 30.0
12-lead ECG Parameter -- Heart Rate (HR) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 Day 14, 4h post-dose	2.8 bpm Interval -14.0 to 24.0	2.3 bpm Interval -19.0 to 14.0	6.7 bpm Interval -7.0 to 25.0	3.4 bpm Interval -14.0 to 19.0	1.8 bpm Interval -22.0 to 15.0	2.3 bpm Interval -25.0 to 19.0
12-lead ECG Parameter -- Heart Rate (HR) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 Day 14, 8h post-dose	5.5 bpm Interval -16.0 to 26.0	3.5 bpm Interval -22.0 to 19.0	4.9 bpm Interval -16.0 to 19.0	3.8 bpm Interval -12.0 to 24.0	1.6 bpm Interval -21.0 to 23.0	2.6 bpm Interval -22.0 to 22.0
12-lead ECG Parameter -- Heart Rate (HR) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 Day 1, 30 min post-dose	0.3 bpm Interval -14.0 to 23.0	1.2 bpm Interval -11.0 to 21.0	1.7 bpm Interval -7.0 to 22.0	2.5 bpm Interval -10.0 to 15.0	-2.4 bpm Interval -21.0 to 15.0	-0.3 bpm Interval -20.0 to 13.0
12-lead ECG Parameter -- Heart Rate (HR) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 Day 1, 1h post-dose	-1.3 bpm Interval -15.0 to 15.0	0.3 bpm Interval -17.0 to 20.0	2.7 bpm Interval -9.0 to 18.0	1.5 bpm Interval -11.0 to 13.0	-1.8 bpm Interval -22.0 to 13.0	-1.2 bpm Interval -18.0 to 15.0
12-lead ECG Parameter -- Heart Rate (HR) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 Day 1, 4h post-dose	2.1 bpm Interval -12.0 to 14.0	1.5 bpm Interval -19.0 to 16.0	3.3 bpm Interval -10.0 to 15.0	5.3 bpm Interval -10.0 to 21.0	0.2 bpm Interval -17.0 to 19.0	3.2 bpm Interval -16.0 to 27.0

SECONDARY outcome

Timeframe: Baseline, Day 1, Day 14 post-dose

Population: Safety population: All randomized patients who received at least one dose of study treatment within the given period.

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

Outcome measures

Outcome measures
Measure	Treatment A n=39 Participants Treatment A, CHF 1531 pMDI: 6 μg TDD	Treatment B n=35 Participants Treatment B, CHF 1531 pMDI: 12 μg TDD	Treatment C n=37 Participants Treatment C, CHF 1531 pMDI: 24 μg TDD	Treatment D n=40 Participants Treatment D, CHF 1531 pMDI: 48 μg TDD	Treatment E n=40 Participants Treatment E, Matched placebo	Treatment F n=41 Participants Treatment F, Formoterol fumarate IS Perforomist®: 40 μg TDD
Heart Rate (HR) AUC(0-4h), Normalized by Time -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 Day 1	0.2 bpm Interval -0.9 to 1.3	0.8 bpm Interval -1.0 to 2.6	2.7 bpm Interval 1.4 to 4.0	3.0 bpm Interval 1.7 to 4.2	-1.0 bpm Interval -2.8 to 0.7	0.3 bpm Interval -1.2 to 1.7
Heart Rate (HR) AUC(0-4h), Normalized by Time -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 Day 14	2.3 bpm Interval 0.3 to 4.3	0.2 bpm Interval -1.7 to 2.2	3.5 bpm Interval 1.9 to 5.1	3.3 bpm Interval 1.4 to 5.3	-0.1 bpm Interval -2.5 to 2.2	1.2 bpm Interval -0.9 to 3.3

SECONDARY outcome

Timeframe: Baseline, Day 1, Day 14 post-dose

Population: Safety population: All randomized patients who received at least one dose of study treatment within the given period.

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

Outcome measures

Outcome measures
Measure	Treatment A n=39 Participants Treatment A, CHF 1531 pMDI: 6 μg TDD	Treatment B n=35 Participants Treatment B, CHF 1531 pMDI: 12 μg TDD	Treatment C n=37 Participants Treatment C, CHF 1531 pMDI: 24 μg TDD	Treatment D n=40 Participants Treatment D, CHF 1531 pMDI: 48 μg TDD	Treatment E n=40 Participants Treatment E, Matched placebo	Treatment F n=41 Participants Treatment F, Formoterol fumarate IS Perforomist®: 40 μg TDD
Heart Rate (HR) Peak(0-4h), Normalized by Time -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 Day 1	4.7 bpm Interval 3.1 to 6.2	4.4 bpm Interval 2.2 to 6.6	6.5 bpm Interval 4.7 to 8.3	7.5 bpm Interval 5.9 to 9.0	2.9 bpm Interval 0.8 to 5.0	5.1 bpm Interval 3.3 to 6.9
Heart Rate (HR) Peak(0-4h), Normalized by Time -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 Day 14	6.1 bpm Interval 3.8 to 8.5	4.8 bpm Interval 2.5 to 7.1	8.3 bpm Interval 6.2 to 10.3	7.3 bpm Interval 5.4 to 9.2	4.4 bpm Interval 1.6 to 7.1	5.2 bpm Interval 2.9 to 7.5

SECONDARY outcome

Timeframe: Baseline, Day 14 post-dose

Population: Safety population: All randomized patients who received at least one dose of study treatment within the given period.

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

Outcome measures

Outcome measures
Measure	Treatment A n=39 Participants Treatment A, CHF 1531 pMDI: 6 μg TDD	Treatment B n=35 Participants Treatment B, CHF 1531 pMDI: 12 μg TDD	Treatment C n=37 Participants Treatment C, CHF 1531 pMDI: 24 μg TDD	Treatment D n=40 Participants Treatment D, CHF 1531 pMDI: 48 μg TDD	Treatment E n=40 Participants Treatment E, Matched placebo	Treatment F n=41 Participants Treatment F, Formoterol fumarate IS Perforomist®: 40 μg TDD
Heart Rate (HR) AUC(0-4h) and Peak(0-4h), Normalized by Time -- Change From Pre-dose to Post Dose Day 14 HR AUC(0-4h)	-0.4 bpm Interval -1.7 to 1.0	0.5 bpm Interval -1.0 to 2.1	0.4 bpm Interval -0.9 to 1.7	1.3 bpm Interval -0.1 to 2.7	-0.2 bpm Interval -1.7 to 1.3	0.9 bpm Interval -0.6 to 2.3
Heart Rate (HR) AUC(0-4h) and Peak(0-4h), Normalized by Time -- Change From Pre-dose to Post Dose Day 14 HR peak(0-4h)	3.5 bpm Interval 1.6 to 5.4	5.1 bpm Interval 3.2 to 6.9	5.1 bpm Interval 3.3 to 6.9	5.3 bpm Interval 3.8 to 6.7	4.3 bpm Interval 2.3 to 6.2	4.8 bpm Interval 3.1 to 6.6

SECONDARY outcome

Timeframe: Baseline, Day 1, Day 14 post-dose

Population: Safety population: All randomized patients who received at least one dose of study treatment within the given period.

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

Outcome measures

Outcome measures
Measure	Treatment A n=39 Participants Treatment A, CHF 1531 pMDI: 6 μg TDD	Treatment B n=35 Participants Treatment B, CHF 1531 pMDI: 12 μg TDD	Treatment C n=37 Participants Treatment C, CHF 1531 pMDI: 24 μg TDD	Treatment D n=40 Participants Treatment D, CHF 1531 pMDI: 48 μg TDD	Treatment E n=40 Participants Treatment E, Matched placebo	Treatment F n=41 Participants Treatment F, Formoterol fumarate IS Perforomist®: 40 μg TDD
12-lead Electrocardiogram (ECG) Parameter (QTcF Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 Day 1, 30 min post-dose	3.9 msec Interval -28.0 to 29.0	3.8 msec Interval -5.0 to 29.0	2.7 msec Interval -22.0 to 23.0	4.9 msec Interval -27.0 to 24.0	-0.2 msec Interval -30.0 to 25.0	1.4 msec Interval -27.0 to 67.0
12-lead Electrocardiogram (ECG) Parameter (QTcF Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 Day 1, 1h post-dose	2.1 msec Interval -44.0 to 19.0	1.4 msec Interval -29.0 to 27.0	3.9 msec Interval -16.0 to 25.0	4.2 msec Interval -21.0 to 31.0	0.4 msec Interval -55.0 to 26.0	-0.9 msec Interval -24.0 to 28.0
12-lead Electrocardiogram (ECG) Parameter (QTcF Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 Day 1, 4h post-dose	2.5 msec Interval -39.0 to 24.0	1.5 msec Interval -30.0 to 25.0	0.8 msec Interval -28.0 to 28.0	2.4 msec Interval -17.0 to 22.0	-2.4 msec Interval -42.0 to 16.0	-1.3 msec Interval -30.0 to 16.0
12-lead Electrocardiogram (ECG) Parameter (QTcF Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 Day 1, 8h post-dose	2.4 msec Interval -25.0 to 15.0	1.1 msec Interval -14.0 to 31.0	0.6 msec Interval -27.0 to 24.0	0.8 msec Interval -18.0 to 23.0	-0.2 msec Interval -20.0 to 25.0	-2.4 msec Interval -37.0 to 19.0
12-lead Electrocardiogram (ECG) Parameter (QTcF Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 Day 1, 12h post-dose	2.0 msec Interval -26.0 to 25.0	0.9 msec Interval -21.0 to 32.0	-0.3 msec Interval -25.0 to 21.0	1.1 msec Interval -21.0 to 33.0	-1.5 msec Interval -25.0 to 30.0	-2.2 msec Interval -44.0 to 20.0
12-lead Electrocardiogram (ECG) Parameter (QTcF Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 Day 14, pre-dose	1.5 msec Interval -26.0 to 30.0	-0.4 msec Interval -30.0 to 33.0	1.6 msec Interval -20.0 to 28.0	5.8 msec Interval -22.0 to 68.0	-2.3 msec Interval -17.0 to 27.0	1.2 msec Interval -46.0 to 29.0
12-lead Electrocardiogram (ECG) Parameter (QTcF Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 Day 14, 30 min post-dose	4.4 msec Interval -28.0 to 30.0	1.0 msec Interval -29.0 to 37.0	3.5 msec Interval -28.0 to 31.0	10.4 msec Interval -23.0 to 41.0	1.9 msec Interval -29.0 to 22.0	1.7 msec Interval -29.0 to 29.0
12-lead Electrocardiogram (ECG) Parameter (QTcF Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 Day 14, 1h post-dose	4.0 msec Interval -19.0 to 23.0	1.0 msec Interval -45.0 to 37.0	1.9 msec Interval -32.0 to 31.0	7.7 msec Interval -25.0 to 44.0	0.9 msec Interval -44.0 to 28.0	0.6 msec Interval -36.0 to 29.0
12-lead Electrocardiogram (ECG) Parameter (QTcF Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 Day 14, 4h post-dose	3.8 msec Interval -9.0 to 29.0	0.9 msec Interval -26.0 to 37.0	1.1 msec Interval -33.0 to 30.0	5.0 msec Interval -37.0 to 40.0	-1.1 msec Interval -28.0 to 28.0	-1.1 msec Interval -48.0 to 25.0
12-lead Electrocardiogram (ECG) Parameter (QTcF Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 Day 14, 8h post-dose	3.4 msec Interval -21.0 to 30.0	1.7 msec Interval -23.0 to 29.0	1.7 msec Interval -35.0 to 28.0	2.2 msec Interval -37.0 to 44.0	1.5 msec Interval -28.0 to 34.0	0.4 msec Interval -38.0 to 30.0
12-lead Electrocardiogram (ECG) Parameter (QTcF Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 Day 14, 12h post-dose	3.7 msec Interval -15.0 to 29.0	1.7 msec Interval -21.0 to 25.0	-0.9 msec Interval -20.0 to 32.0	3.7 msec Interval -17.0 to 34.0	-0.6 msec Interval -22.0 to 20.0	-1.6 msec Interval -36.0 to 29.0

SECONDARY outcome

Timeframe: Baseline, Day 1, Day 14 post-dose

Population: Safety population: All randomized patients who received at least one dose of study treatment within the given period.

Outcome measures

Outcome measures
Measure	Treatment A n=39 Participants Treatment A, CHF 1531 pMDI: 6 μg TDD	Treatment B n=35 Participants Treatment B, CHF 1531 pMDI: 12 μg TDD	Treatment C n=37 Participants Treatment C, CHF 1531 pMDI: 24 μg TDD	Treatment D n=40 Participants Treatment D, CHF 1531 pMDI: 48 μg TDD	Treatment E n=40 Participants Treatment E, Matched placebo	Treatment F n=41 Participants Treatment F, Formoterol fumarate IS Perforomist®: 40 μg TDD
12-lead Electrocardiogram (ECG) Parameter (PR Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 Day 14, 1h post-dose	1.0 msec Interval -24.0 to 30.0	5.7 msec Interval -13.0 to 35.0	0.1 msec Interval -19.0 to 25.0	-1.6 msec Interval -93.0 to 19.0	5.2 msec Interval -8.0 to 67.0	6.1 msec Interval -14.0 to 62.0
12-lead Electrocardiogram (ECG) Parameter (PR Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 Day 14, 4h post-dose	-1.5 msec Interval -28.0 to 14.0	2.5 msec Interval -11.0 to 23.0	-2.5 msec Interval -22.0 to 14.0	-3.2 msec Interval -76.0 to 21.0	0.8 msec Interval -18.0 to 20.0	1.3 msec Interval -33.0 to 29.0
12-lead Electrocardiogram (ECG) Parameter (PR Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 Day 14, 8h post-dose	-2.6 msec Interval -32.0 to 17.0	1.5 msec Interval -13.0 to 46.0	-3.2 msec Interval -25.0 to 22.0	-5.4 msec Interval -71.0 to 8.0	-1.1 msec Interval -20.0 to 16.0	0.8 msec Interval -28.0 to 23.0
12-lead Electrocardiogram (ECG) Parameter (PR Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 Day 14, 12h post-dose	-5.0 msec Interval -40.0 to 11.0	1.7 msec Interval -22.0 to 59.0	-4.8 msec Interval -24.0 to 19.0	-1.4 msec Interval -27.0 to 27.0	0.1 msec Interval -20.0 to 34.0	-0.3 msec Interval -18.0 to 19.0
12-lead Electrocardiogram (ECG) Parameter (PR Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 Day 1, 30 min post-dose	-0.1 msec Interval -33.0 to 22.0	1.6 msec Interval -12.0 to 18.0	-1.3 msec Interval -10.0 to 9.0	-3.6 msec Interval -71.0 to 15.0	1.0 msec Interval -13.0 to 15.0	3.2 msec Interval -11.0 to 24.0
12-lead Electrocardiogram (ECG) Parameter (PR Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 Day 1, 1h post-dose	1.1 msec Interval -13.0 to 16.0	2.2 msec Interval -16.0 to 21.0	-1.1 msec Interval -27.0 to 17.0	-0.7 msec Interval -66.0 to 13.0	0.4 msec Interval -13.0 to 18.0	2.0 msec Interval -11.0 to 20.0
12-lead Electrocardiogram (ECG) Parameter (PR Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 Day 1, 4h post-dose	-1.2 msec Interval -14.0 to 11.0	1.6 msec Interval -17.0 to 24.0	-1.5 msec Interval -16.0 to 16.0	-4.0 msec Interval -88.0 to 14.0	-1.6 msec Interval -33.0 to 21.0	1.9 msec Interval -13.0 to 37.0
12-lead Electrocardiogram (ECG) Parameter (PR Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 Day 1, 8h post-dose	-1.9 msec Interval -16.0 to 23.0	-0.5 msec Interval -14.0 to 20.0	-3.0 msec Interval -16.0 to 10.0	-2.6 msec Interval -74.0 to 10.0	-2.4 msec Interval -29.0 to 16.0	-0.0 msec Interval -13.0 to 27.0
12-lead Electrocardiogram (ECG) Parameter (PR Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 Day 1, 12h post-dose	-3.4 msec Interval -17.0 to 14.0	-2.3 msec Interval -18.0 to 18.0	-3.8 msec Interval -15.0 to 17.0	-3.0 msec Interval -46.0 to 28.0	-2.6 msec Interval -15.0 to 19.0	-1.7 msec Interval -14.0 to 21.0
12-lead Electrocardiogram (ECG) Parameter (PR Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 Day 14, pre-dose	1.3 msec Interval -16.0 to 23.0	3.7 msec Interval -17.0 to 25.0	-1.7 msec Interval -22.0 to 15.0	-2.9 msec Interval -53.0 to 18.0	0.1 msec Interval -13.0 to 15.0	2.2 msec Interval -15.0 to 28.0
12-lead Electrocardiogram (ECG) Parameter (PR Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 Day 14, 30 min post-dose	-0.2 msec Interval -24.0 to 22.0	4.5 msec Interval -12.0 to 27.0	-1.5 msec Interval -20.0 to 17.0	-3.1 msec Interval -85.0 to 19.0	3.4 msec Interval -15.0 to 26.0	5.1 msec Interval -19.0 to 67.0

SECONDARY outcome

Timeframe: Baseline, Day 1, Day 14 post-dose

Population: Safety population: All randomized patients who received at least one dose of study treatment within the given period.

Outcome measures

Outcome measures
Measure	Treatment A n=39 Participants Treatment A, CHF 1531 pMDI: 6 μg TDD	Treatment B n=35 Participants Treatment B, CHF 1531 pMDI: 12 μg TDD	Treatment C n=37 Participants Treatment C, CHF 1531 pMDI: 24 μg TDD	Treatment D n=40 Participants Treatment D, CHF 1531 pMDI: 48 μg TDD	Treatment E n=40 Participants Treatment E, Matched placebo	Treatment F n=41 Participants Treatment F, Formoterol fumarate IS Perforomist®: 40 μg TDD
12-lead Electrocardiogram (ECG) Parameter (QRS Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 Day 1, 30 min post-dose	1.2 msec Interval -9.0 to 9.0	1.2 msec Interval -8.0 to 11.0	1.7 msec Interval -6.0 to 8.0	1.1 msec Interval -8.0 to 10.0	0.8 msec Interval -7.0 to 7.0	1.3 msec Interval -7.0 to 7.0
12-lead Electrocardiogram (ECG) Parameter (QRS Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 Day 1, 1h post-dose	1.3 msec Interval -7.0 to 11.0	1.0 msec Interval -9.0 to 11.0	1.2 msec Interval -6.0 to 13.0	1.6 msec Interval -8.0 to 13.0	1.0 msec Interval -5.0 to 8.0	1.4 msec Interval -6.0 to 8.0
12-lead Electrocardiogram (ECG) Parameter (QRS Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 Day 1, 4h post-dose	1.2 msec Interval -6.0 to 13.0	2.1 msec Interval -11.0 to 14.0	2.2 msec Interval -6.0 to 18.0	2.1 msec Interval -6.0 to 12.0	1.0 msec Interval -6.0 to 11.0	1.1 msec Interval -6.0 to 12.0
12-lead Electrocardiogram (ECG) Parameter (QRS Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 Day 1, 8h post-dose	0.6 msec Interval -9.0 to 9.0	0.9 msec Interval -8.0 to 10.0	1.3 msec Interval -6.0 to 13.0	0.5 msec Interval -9.0 to 11.0	-0.2 msec Interval -9.0 to 10.0	0.5 msec Interval -10.0 to 8.0
12-lead Electrocardiogram (ECG) Parameter (QRS Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 Day 1, 12h post-dose	0.5 msec Interval -9.0 to 12.0	1.0 msec Interval -13.0 to 8.0	1.0 msec Interval -9.0 to 10.0	0.9 msec Interval -9.0 to 9.0	0.4 msec Interval -9.0 to 8.0	0.8 msec Interval -8.0 to 7.0
12-lead Electrocardiogram (ECG) Parameter (QRS Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 Day 14, pre-dose	0.5 msec Interval -9.0 to 13.0	1.0 msec Interval -12.0 to 10.0	-0.5 msec Interval -10.0 to 10.0	1.7 msec Interval -8.0 to 17.0	-0.9 msec Interval -12.0 to 7.0	0.8 msec Interval -8.0 to 8.0
12-lead Electrocardiogram (ECG) Parameter (QRS Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 Day 14, 30 min post-dose	1.4 msec Interval -7.0 to 14.0	1.6 msec Interval -10.0 to 12.0	0.5 msec Interval -7.0 to 11.0	2.4 msec Interval -5.0 to 12.0	-0.3 msec Interval -8.0 to 11.0	1.7 msec Interval -6.0 to 9.0
12-lead Electrocardiogram (ECG) Parameter (QRS Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 Day 14, 1h post-dose	1.3 msec Interval -5.0 to 15.0	0.9 msec Interval -10.0 to 11.0	0.4 msec Interval -7.0 to 9.0	2.3 msec Interval -9.0 to 11.0	0.0 msec Interval -12.0 to 13.0	1.0 msec Interval -10.0 to 9.0
12-lead Electrocardiogram (ECG) Parameter (QRS Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 Day 14, 4h post-dose	2.0 msec Interval -10.0 to 15.0	1.8 msec Interval -9.0 to 19.0	0.6 msec Interval -7.0 to 9.0	2.8 msec Interval -11.0 to 12.0	-0.2 msec Interval -9.0 to 8.0	1.1 msec Interval -6.0 to 11.0
12-lead Electrocardiogram (ECG) Parameter (QRS Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 Day 14, 8h post-dose	0.7 msec Interval -11.0 to 15.0	1.2 msec Interval -10.0 to 12.0	0.1 msec Interval -11.0 to 12.0	1.4 msec Interval -7.0 to 10.0	-0.8 msec Interval -10.0 to 9.0	0.9 msec Interval -12.0 to 12.0
12-lead Electrocardiogram (ECG) Parameter (QRS Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 Day 14, 12h post-dose	0.8 msec Interval -8.0 to 15.0	0.4 msec Interval -13.0 to 10.0	0.3 msec Interval -9.0 to 11.0	1.4 msec Interval -6.0 to 17.0	-1.0 msec Interval -9.0 to 8.0	0.5 msec Interval -10.0 to 14.0

SECONDARY outcome

Timeframe: Baseline, Day 1, Day 14 post-dose

Population: Safety population: All randomized patients who received at least one dose of study treatment within the given period.

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

Outcome measures

Outcome measures
Measure	Treatment A n=39 Participants Treatment A, CHF 1531 pMDI: 6 μg TDD	Treatment B n=35 Participants Treatment B, CHF 1531 pMDI: 12 μg TDD	Treatment C n=37 Participants Treatment C, CHF 1531 pMDI: 24 μg TDD	Treatment D n=40 Participants Treatment D, CHF 1531 pMDI: 48 μg TDD	Treatment E n=40 Participants Treatment E, Matched placebo	Treatment F n=41 Participants Treatment F, Formoterol fumarate IS Perforomist®: 40 μg TDD
Serum Potassium -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 Day 1; 1.5h post-dose	-0.01 mmol/L Interval -0.9 to 0.8	-0.05 mmol/L Interval -1.1 to 0.7	-0.08 mmol/L Interval -1.2 to 0.6	-0.17 mmol/L Interval -0.7 to 0.3	-0.06 mmol/L Interval -0.9 to 0.6	-0.18 mmol/L Interval -1.0 to 0.6
Serum Potassium -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 Day 1; 3h post-dose	-0.06 mmol/L Interval -0.9 to 1.0	-0.08 mmol/L Interval -0.8 to 0.5	-0.23 mmol/L Interval -1.3 to 0.3	-0.28 mmol/L Interval -1.5 to 0.4	0.03 mmol/L Interval -0.7 to 0.9	-0.21 mmol/L Interval -1.0 to 0.9
Serum Potassium -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 Day 1; 5h post-dose	-0.14 mmol/L Interval -0.6 to 0.5	-0.03 mmol/L Interval -0.6 to 1.2	-0.12 mmol/L Interval -1.0 to 0.6	-0.19 mmol/L Interval -1.6 to 1.0	-0.04 mmol/L Interval -0.9 to 0.5	-0.20 mmol/L Interval -1.3 to 0.5
Serum Potassium -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 Day 1; 7h post-dose	-0.02 mmol/L Interval -0.6 to 0.8	-0.00 mmol/L Interval -0.9 to 0.7	-0.05 mmol/L Interval -0.8 to 0.8	-0.16 mmol/L Interval -1.8 to 0.6	0.04 mmol/L Interval -0.7 to 0.9	-0.14 mmol/L Interval -1.4 to 1.0
Serum Potassium -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 Day 1; 11h post-dose	0.07 mmol/L Interval -0.7 to 1.0	0.02 mmol/L Interval -0.5 to 1.1	-0.08 mmol/L Interval -1.2 to 0.9	-0.10 mmol/L Interval -0.8 to 0.7	0.01 mmol/L Interval -1.0 to 0.6	-0.13 mmol/L Interval -1.4 to 0.7
Serum Potassium -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 Day 14; pre-dose	0.06 mmol/L Interval -1.1 to 0.9	-0.02 mmol/L Interval -1.2 to 0.4	0.08 mmol/L Interval -0.9 to 0.9	-0.14 mmol/L Interval -1.5 to 1.3	0.05 mmol/L Interval -0.5 to 1.4	-0.13 mmol/L Interval -0.9 to 0.8
Serum Potassium -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 Day 14; 1.5h post-dose	-0.02 mmol/L Interval -0.7 to 1.5	-0.03 mmol/L Interval -1.0 to 1.2	-0.10 mmol/L Interval -1.0 to 0.9	-0.23 mmol/L Interval -1.7 to 1.0	-0.03 mmol/L Interval -0.7 to 1.7	-0.15 mmol/L Interval -1.0 to 1.1
Serum Potassium -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 Day 14; 3h post-dose	-0.04 mmol/L Interval -0.6 to 0.6	-0.09 mmol/L Interval -1.0 to 0.7	-0.13 mmol/L Interval -0.9 to 0.6	-0.24 mmol/L Interval -1.9 to 0.6	-0.00 mmol/L Interval -0.6 to 1.7	-0.15 mmol/L Interval -1.0 to 0.6
Serum Potassium -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 Day 14; 5h post-dose	-0.02 mmol/L Interval -0.8 to 1.0	-0.05 mmol/L Interval -1.1 to 1.7	-0.01 mmol/L Interval -1.2 to 0.8	-0.26 mmol/L Interval -1.9 to 0.5	0.00 mmol/L Interval -0.6 to 1.5	-0.15 mmol/L Interval -1.1 to 0.8
Serum Potassium -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 Day 14; 7h post-dose	0.05 mmol/L Interval -0.5 to 1.4	0.06 mmol/L Interval -0.8 to 1.2	0.09 mmol/L Interval -0.9 to 1.1	-0.19 mmol/L Interval -1.5 to 0.5	0.02 mmol/L Interval -0.7 to 1.3	-0.09 mmol/L Interval -1.1 to 1.0
Serum Potassium -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 Day 14; 11h post-dose	0.11 mmol/L Interval -0.4 to 1.3	0.05 mmol/L Interval -1.3 to 1.1	0.03 mmol/L Interval -1.0 to 1.1	-0.06 mmol/L Interval -1.4 to 1.2	0.01 mmol/L Interval -1.0 to 1.0	-0.02 mmol/L Interval -1.1 to 1.2

SECONDARY outcome

Timeframe: Baseline, Day 1, Day 14 post-dose

Population: Safety population: All randomized patients who received at least one dose of study treatment within the given period.

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

Outcome measures

Outcome measures
Measure	Treatment A n=39 Participants Treatment A, CHF 1531 pMDI: 6 μg TDD	Treatment B n=35 Participants Treatment B, CHF 1531 pMDI: 12 μg TDD	Treatment C n=37 Participants Treatment C, CHF 1531 pMDI: 24 μg TDD	Treatment D n=40 Participants Treatment D, CHF 1531 pMDI: 48 μg TDD	Treatment E n=40 Participants Treatment E, Matched placebo	Treatment F n=41 Participants Treatment F, Formoterol fumarate IS Perforomist®: 40 μg TDD
Serum Glucose -- Change From Baseline to Post-dose Day 1 and Day 14 Day 1; 1.5h post-dose	0.49 mmol/L Interval -3.0 to 5.3	0.34 mmol/L Interval -4.9 to 11.7	0.57 mmol/L Interval -1.7 to 6.2	1.19 mmol/L Interval -1.2 to 8.4	0.47 mmol/L Interval -2.0 to 4.7	-0.06 mmol/L Interval -7.5 to 3.6
Serum Glucose -- Change From Baseline to Post-dose Day 1 and Day 14 Day 1; 3h post-dose	0.45 mmol/L Interval -3.3 to 4.8	0.54 mmol/L Interval -6.0 to 13.9	1.10 mmol/L Interval -2.1 to 4.8	1.79 mmol/L Interval -2.2 to 5.7	0.26 mmol/L Interval -3.1 to 6.6	0.39 mmol/L Interval -7.2 to 4.6
Serum Glucose -- Change From Baseline to Post-dose Day 1 and Day 14 Day 1; 5h post-dose	0.83 mmol/L Interval -3.2 to 6.4	1.12 mmol/L Interval -3.6 to 20.5	1.11 mmol/L Interval -1.0 to 4.2	1.58 mmol/L Interval -1.2 to 7.6	0.51 mmol/L Interval -5.1 to 10.9	0.44 mmol/L Interval -1.6 to 6.3
Serum Glucose -- Change From Baseline to Post-dose Day 1 and Day 14 Day 1; 7h post-dose	0.81 mmol/L Interval -2.6 to 4.8	0.42 mmol/L Interval -4.7 to 5.8	1.24 mmol/L Interval -1.3 to 6.5	1.37 mmol/L Interval -1.6 to 8.1	0.84 mmol/L Interval -1.6 to 10.4	0.61 mmol/L Interval -1.2 to 8.0
Serum Glucose -- Change From Baseline to Post-dose Day 1 and Day 14 Day 1; 11h post-dose	0.98 mmol/L Interval -4.1 to 6.4	1.08 mmol/L Interval -3.6 to 16.1	1.89 mmol/L Interval -1.6 to 6.5	1.42 mmol/L Interval -2.2 to 8.7	1.40 mmol/L Interval -1.1 to 6.7	0.90 mmol/L Interval -2.3 to 5.2
Serum Glucose -- Change From Baseline to Post-dose Day 1 and Day 14 Day 14; pre-dose	-0.34 mmol/L Interval -8.7 to 2.9	0.00 mmol/L Interval -3.8 to 2.9	0.49 mmol/L Interval -0.7 to 3.3	0.49 mmol/L Interval -0.8 to 10.0	0.37 mmol/L Interval -0.6 to 4.1	-0.03 mmol/L Interval -2.8 to 2.6
Serum Glucose -- Change From Baseline to Post-dose Day 1 and Day 14 Day 14; 1.5h post-dose	0.09 mmol/L Interval -7.0 to 9.5	0.26 mmol/L Interval -3.3 to 5.1	0.97 mmol/L Interval -1.3 to 4.8	1.21 mmol/L Interval -0.8 to 8.9	0.35 mmol/L Interval -2.0 to 3.2	-0.03 mmol/L Interval -4.8 to 3.9
Serum Glucose -- Change From Baseline to Post-dose Day 1 and Day 14 Day 14; 3h post-dose	0.09 mmol/L Interval -10.9 to 6.3	0.77 mmol/L Interval -2.1 to 4.5	1.31 mmol/L Interval -1.1 to 6.0	1.51 mmol/L Interval -1.7 to 9.9	0.25 mmol/L Interval -2.4 to 2.7	0.16 mmol/L Interval -7.0 to 4.3
Serum Glucose -- Change From Baseline to Post-dose Day 1 and Day 14 Day 14; 5h post-dose	0.04 mmol/L Interval -10.8 to 5.9	0.90 mmol/L Interval -1.7 to 5.4	1.12 mmol/L Interval -1.9 to 4.7	1.16 mmol/L Interval -1.3 to 6.7	0.32 mmol/L Interval -1.8 to 4.4	0.53 mmol/L Interval -3.4 to 7.2
Serum Glucose -- Change From Baseline to Post-dose Day 1 and Day 14 Day 14; 7h post-dose	-0.04 mmol/L Interval -9.4 to 3.4	0.60 mmol/L Interval -2.5 to 7.6	0.73 mmol/L Interval -1.7 to 4.3	1.09 mmol/L Interval -0.7 to 12.0	0.25 mmol/L Interval -6.7 to 2.4	0.18 mmol/L Interval -4.6 to 2.6
Serum Glucose -- Change From Baseline to Post-dose Day 1 and Day 14 Day 14; 11h post-dose	0.39 mmol/L Interval -7.9 to 5.0	1.30 mmol/L Interval -1.3 to 14.1	1.50 mmol/L Interval -0.5 to 5.8	1.47 mmol/L Interval -1.1 to 8.9	1.03 mmol/L Interval -2.7 to 3.8	0.68 mmol/L Interval -2.5 to 4.8

Adverse Events

Treatment A

Serious events: 0 serious events

Other events: 2 other events

Deaths: 0 deaths

Treatment B

Serious events: 0 serious events

Other events: 1 other events

Deaths: 0 deaths

Treatment C

Serious events: 0 serious events

Other events: 2 other events

Deaths: 0 deaths

Treatment D

Serious events: 0 serious events

Other events: 2 other events

Deaths: 0 deaths

Treatment E

Serious events: 0 serious events

Other events: 0 other events

Deaths: 0 deaths

Treatment F

Serious events: 0 serious events

Other events: 1 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Other adverse events
Measure	Treatment A n=43 participants at risk Treatment A CHF 1531 pMDI: 6 μg TDD	Treatment B n=36 participants at risk Treatment B CHF 1531 pMDI: 12 μg TDD	Treatment C n=40 participants at risk Treatment C CHF 1531 pMDI: 24 μg TDD	Treatment D n=44 participants at risk Treatment D CHF 1531 pMDI: 48 μg TDD	Treatment E n=45 participants at risk Treatment E Matched placebo	Treatment F n=41 participants at risk Treatment F Formoterol fumarate IS Perforomist®: 40 μg TDD
Nervous system disorders Headache	4.7% 2/43 • Number of events 2 • From the first intake of study medication (Visit 2, Week 0) until study completion (Visit 10, Week 15) or study discontinuation. Safety population was used for the evaluation of treatment-emergent adverse event (TEAEs). The safety population is defined as all randomized patients who received at least one dose of study treatment within the given treatment period.	0.00% 0/36 • From the first intake of study medication (Visit 2, Week 0) until study completion (Visit 10, Week 15) or study discontinuation. Safety population was used for the evaluation of treatment-emergent adverse event (TEAEs). The safety population is defined as all randomized patients who received at least one dose of study treatment within the given treatment period.	0.00% 0/40 • From the first intake of study medication (Visit 2, Week 0) until study completion (Visit 10, Week 15) or study discontinuation. Safety population was used for the evaluation of treatment-emergent adverse event (TEAEs). The safety population is defined as all randomized patients who received at least one dose of study treatment within the given treatment period.	0.00% 0/44 • From the first intake of study medication (Visit 2, Week 0) until study completion (Visit 10, Week 15) or study discontinuation. Safety population was used for the evaluation of treatment-emergent adverse event (TEAEs). The safety population is defined as all randomized patients who received at least one dose of study treatment within the given treatment period.	0.00% 0/45 • From the first intake of study medication (Visit 2, Week 0) until study completion (Visit 10, Week 15) or study discontinuation. Safety population was used for the evaluation of treatment-emergent adverse event (TEAEs). The safety population is defined as all randomized patients who received at least one dose of study treatment within the given treatment period.	0.00% 0/41 • From the first intake of study medication (Visit 2, Week 0) until study completion (Visit 10, Week 15) or study discontinuation. Safety population was used for the evaluation of treatment-emergent adverse event (TEAEs). The safety population is defined as all randomized patients who received at least one dose of study treatment within the given treatment period.
Infections and infestations Upper respiratory tract infection	0.00% 0/43 • From the first intake of study medication (Visit 2, Week 0) until study completion (Visit 10, Week 15) or study discontinuation. Safety population was used for the evaluation of treatment-emergent adverse event (TEAEs). The safety population is defined as all randomized patients who received at least one dose of study treatment within the given treatment period.	2.8% 1/36 • Number of events 1 • From the first intake of study medication (Visit 2, Week 0) until study completion (Visit 10, Week 15) or study discontinuation. Safety population was used for the evaluation of treatment-emergent adverse event (TEAEs). The safety population is defined as all randomized patients who received at least one dose of study treatment within the given treatment period.	2.5% 1/40 • Number of events 1 • From the first intake of study medication (Visit 2, Week 0) until study completion (Visit 10, Week 15) or study discontinuation. Safety population was used for the evaluation of treatment-emergent adverse event (TEAEs). The safety population is defined as all randomized patients who received at least one dose of study treatment within the given treatment period.	4.5% 2/44 • Number of events 2 • From the first intake of study medication (Visit 2, Week 0) until study completion (Visit 10, Week 15) or study discontinuation. Safety population was used for the evaluation of treatment-emergent adverse event (TEAEs). The safety population is defined as all randomized patients who received at least one dose of study treatment within the given treatment period.	0.00% 0/45 • From the first intake of study medication (Visit 2, Week 0) until study completion (Visit 10, Week 15) or study discontinuation. Safety population was used for the evaluation of treatment-emergent adverse event (TEAEs). The safety population is defined as all randomized patients who received at least one dose of study treatment within the given treatment period.	0.00% 0/41 • From the first intake of study medication (Visit 2, Week 0) until study completion (Visit 10, Week 15) or study discontinuation. Safety population was used for the evaluation of treatment-emergent adverse event (TEAEs). The safety population is defined as all randomized patients who received at least one dose of study treatment within the given treatment period.
Vascular disorders Hypertension	0.00% 0/43 • From the first intake of study medication (Visit 2, Week 0) until study completion (Visit 10, Week 15) or study discontinuation. Safety population was used for the evaluation of treatment-emergent adverse event (TEAEs). The safety population is defined as all randomized patients who received at least one dose of study treatment within the given treatment period.	0.00% 0/36 • From the first intake of study medication (Visit 2, Week 0) until study completion (Visit 10, Week 15) or study discontinuation. Safety population was used for the evaluation of treatment-emergent adverse event (TEAEs). The safety population is defined as all randomized patients who received at least one dose of study treatment within the given treatment period.	5.0% 2/40 • Number of events 2 • From the first intake of study medication (Visit 2, Week 0) until study completion (Visit 10, Week 15) or study discontinuation. Safety population was used for the evaluation of treatment-emergent adverse event (TEAEs). The safety population is defined as all randomized patients who received at least one dose of study treatment within the given treatment period.	0.00% 0/44 • From the first intake of study medication (Visit 2, Week 0) until study completion (Visit 10, Week 15) or study discontinuation. Safety population was used for the evaluation of treatment-emergent adverse event (TEAEs). The safety population is defined as all randomized patients who received at least one dose of study treatment within the given treatment period.	0.00% 0/45 • From the first intake of study medication (Visit 2, Week 0) until study completion (Visit 10, Week 15) or study discontinuation. Safety population was used for the evaluation of treatment-emergent adverse event (TEAEs). The safety population is defined as all randomized patients who received at least one dose of study treatment within the given treatment period.	2.4% 1/41 • Number of events 1 • From the first intake of study medication (Visit 2, Week 0) until study completion (Visit 10, Week 15) or study discontinuation. Safety population was used for the evaluation of treatment-emergent adverse event (TEAEs). The safety population is defined as all randomized patients who received at least one dose of study treatment within the given treatment period.

Additional Information

Clinical Trial Transparency

Chiesi Farmaceutici S.p.A.

Phone: + 39 0521 2791

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee Chiesi can publish and/or present any results of this study at scientific meetings, and to submit the clinical trial data to national and international Regulatory Authorities. Chiesi reserves the right to use such data for industrial purposes. Investigators will inform Chiesi before using the results of the study for publication or presentation, and agree to provide the Sponsor with a copy of the proposed presentation. Data from individual study sites must not be published separately.
Publication restrictions are in place

Restriction type: OTHER