Trial Outcomes & Findings for Formoterol Dose Ranging Study (ACHIEVE Duaklir USA Phase IIb) (NCT NCT02796651)

NCT ID: NCT02796651

Last Updated: 2018-02-07

Results Overview

To assess the bronchodilation of 3 doses of formoterol fumarate (6 μg, 12 μg and 24 μg) twice daily (BID administered via Pressair® compared to placebo and to open-label nebulised formoterol fumarate(20 μg). Pre-dose spirometry was performed before the morning daily dose at Day 1 and Day 7 of each treatment period. Two sets of measurements were performed during the hour preceding the scheduled morning study drug administration, allowing approximately 30 minutes between them. Note: Perforomist® 40 μg treatment periods lasted for 1 day only. Hence, was not included in the calculation.

• Recruitment status: COMPLETED
• Study phase: PHASE2
• Target enrollment: 132 participants
• Primary outcome timeframe: Day 7: 30 min, 1 to 4 hours, 6 hours, 9 hours and 12 hours post-dose
• Results posted on: 2018-02-07

Participant Flow

This study was carried on 132 participants with moderate to severe chronic obstructive pulmonary disease (COPD) & reversible airway disease in the United States of America (USA; 21 sites) & were randomized to one of treatment sequences (each with 5 periods of different treatment, separated by wash-out period of 7 (+/1) days after treatment period).

After signature of the informed consent, participants who were taking prohibited medication performed a wash-out period and were given Atrovent (2 puffs 4 times/day) before Screening and during the run-in period. All participants were provided with rescue drug (albuterol) and Atrovent to be taken during the wash-out between treatment periods.

Participant milestones

Measure	Total Participants All patients were randomized in a treatment sequence containing 5 treatment periods. All patients received FF12 and Perforomist 20 mcg, 90% received FF6, FF24 and Perforomist 40 mcg, and only 30% received placebo. Treatment was double blind for FF in Pressair, and open label for Perforomist. If treatment was FF6, FF12, FF24 or placebo, patients received two identical Pressair dry powder inhalers (DPI) and were instructed to take 1 puff from each of the inhalers in the morning and in the evening for 7 days. If treatment was Perforomist 20 mcg, patients were instructed to take 1 vial in the morning and 1 vial in the evening for 7 days. Treatment with Perforomist 40 mcg was a single dose administration. Note: 132 participants were randomized. But, one participant was excluded from the ITT analysis set as the participant did not have a post-baseline forced expiratory volume in 1 second (FEV1) measurement.
Overall Study STARTED	132
Overall Study Formoterol Fumarate (FF) 6 μg	107
Overall Study Formoterol Fumarate (FF) 12 μg	121
Overall Study Formoterol Fumarate (FF) 24 μg	105
Overall Study Perforomist 20 μg	118
Overall Study Perforomist 40 μg	108
Overall Study Placebo (Lactose Monohydrate)	38
Overall Study COMPLETED	106
Overall Study NOT COMPLETED	26

Reasons for withdrawal

Measure	Total Participants All patients were randomized in a treatment sequence containing 5 treatment periods. All patients received FF12 and Perforomist 20 mcg, 90% received FF6, FF24 and Perforomist 40 mcg, and only 30% received placebo. Treatment was double blind for FF in Pressair, and open label for Perforomist. If treatment was FF6, FF12, FF24 or placebo, patients received two identical Pressair dry powder inhalers (DPI) and were instructed to take 1 puff from each of the inhalers in the morning and in the evening for 7 days. If treatment was Perforomist 20 mcg, patients were instructed to take 1 vial in the morning and 1 vial in the evening for 7 days. Treatment with Perforomist 40 mcg was a single dose administration. Note: 132 participants were randomized. But, one participant was excluded from the ITT analysis set as the participant did not have a post-baseline forced expiratory volume in 1 second (FEV1) measurement.
Overall Study Adverse Event	6
Overall Study Lost to Follow-up	1
Overall Study Withdrawal by Subject	4
Overall Study Protocol Violation	4
Overall Study Lack of Efficacy	1
Overall Study Other	10

Baseline Characteristics

Formoterol Dose Ranging Study (ACHIEVE Duaklir USA Phase IIb)

Baseline characteristics by cohort

Measure	Overall Study Total n=131 Participants All patients were randomized in a treatment sequence containing 5 treatment periods. All patients received FF12 and Perforomist 20 mcg, 90% received FF6, FF24 and Perforomist 40 mcg, and only 30% received placebo. Treatment was double blind for FF in Pressair, and open label for Perforomist. If treatment was FF6, FF12, FF24 or placebo, patients received two identical Pressair DPI and were instructed to take 1 puff from each of the inhalers in the morning and in the evening for 7 days. If treatment was Perforomist 20 mcg, patients were instructed to take 1 vial in the morning and 1 vial in the evening for 7 days. Treatment with Perforomist 40 mcg was a single dose administration. Note: 132 participants were randomized. But, one participant was excluded from the ITT analysis set as the participant did not have a post-baseline forced expiratory volume in 1 second (FEV1) measurement.
Age, Continuous	62.3 Years STANDARD_DEVIATION 7.5 • n=5 Participants
Age, Customized <50 years	5 Participants n=5 Participants
Age, Customized ≥50 to <65 years	78 Participants n=5 Participants
Age, Customized ≥65 years	48 Participants n=5 Participants
Sex: Female, Male Female	66 Participants n=5 Participants
Sex: Female, Male Male	65 Participants n=5 Participants

PRIMARY outcome

Timeframe: Day 7: 30 min, 1 to 4 hours, 6 hours, 9 hours and 12 hours post-dose

Population: The ITT analysis set consisted of all randomized participants who received at least 1 dose of investigational product (IP) and had a baseline FEV1 value and at least 1 post-baseline FEV1 measurement, regardless of a participant's adherence to the randomized treatment.

To assess the bronchodilation of 3 doses of formoterol fumarate (6 μg, 12 μg and 24 μg) twice daily (BID administered via Pressair® compared to placebo and to open-label nebulised formoterol fumarate(20 μg).

Pre-dose spirometry was performed before the morning daily dose at Day 1 and Day 7 of each treatment period. Two sets of measurements were performed during the hour preceding the scheduled morning study drug administration, allowing approximately 30 minutes between them.

Note: Perforomist® 40 μg treatment periods lasted for 1 day only. Hence, was not included in the calculation.

Outcome measures

Measure	Formoterol Fumarate 6 μg n=105 Participants Randomized participants received 2 puffs of Formoterol Fumarate 6 μg oral inhalation powder using Pressair® dry powder inhaler (DPI) in the morning and evening for 7 (±1) days	Formoterol Fumarate (FF) 12 μg n=118 Participants Randomized participants received two identical Pressair dry powder inhaler (DPI; FF 12 μg and placebo) and were instructed to take one puff from each of the two Pressair DPI in the morning and in the evening for 7 days	Formoterol Fumarate (FF) 24 μg n=104 Participants Randomized participants received two identical Pressair dry powder inhaler (DPI; FF 24 μg and placebo) and were instructed to take one puff from each of the two Pressair DPI in the morning and in the evening for 7 days	Perforomist 20 μg n=116 Participants Randomized participants received 1 vial of Perforomist 20 μg oral nebulization solution via a jet nebulizer in the morning and evening for 7 (±1) days	Placebo (Lactose Monohydrate) n=35 Participants Randomized participants received two identical Pressair dry powder inhaler (DPI; FF 6/12/24 μg and placebo) and were instructed to take one puff from each of the two Pressair DPI in the morning and in the evening for 7 days	Placebo (Lactose Monohydrate) Randomized participants received two identical Pressair dry powder inhaler (DPI; FF 6/12/24 μg and placebo) and were instructed to take one puff from each of the two Pressair DPI in the morning and in the evening for 7 days
Change From Baseline in Normalized Forced Expiratory Volume in 1 Second (FEV1) Area Under the Curve (AUC) Over the 12 h Period Immediately After Morning Study Drug Administration, AUC0-12/12h at Day 7 on Treatment	0.108 Litre/Hour Interval 0.073 to 0.143	0.117 Litre/Hour Interval 0.082 to 0.151	0.161 Litre/Hour Interval 0.125 to 0.197	0.122 Litre/Hour Interval 0.087 to 0.156	0.000 Litre/Hour Interval -0.055 to 0.054	—

SECONDARY outcome

Timeframe: Day 1: zero time to 6 hours post-dose

Population: The ITT analysis set consisted of all randomized participants who received at least 1 dose of investigational product (IP) and had a baseline FEV1 value and at least 1 post-baseline FEV1 measurement, regardless of a participant's adherence to the randomized treatment.

To assess the bronchodilation of 3 doses of formoterol fumarate (6 μg, 12 μg and 24 μg) BID administered via Pressair® compared to placebo and to open-label nebulised formoterol fumarate (20 μg and 40 μg). 6-hour serial spirometry was performed at Day 1 of each treatment period: spirometry was performed post-dose at 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours and 6 hours post-dose.

Outcome measures

Measure	Formoterol Fumarate 6 μg n=106 Participants Randomized participants received 2 puffs of Formoterol Fumarate 6 μg oral inhalation powder using Pressair® dry powder inhaler (DPI) in the morning and evening for 7 (±1) days	Formoterol Fumarate (FF) 12 μg n=121 Participants Randomized participants received two identical Pressair dry powder inhaler (DPI; FF 12 μg and placebo) and were instructed to take one puff from each of the two Pressair DPI in the morning and in the evening for 7 days	Formoterol Fumarate (FF) 24 μg n=104 Participants Randomized participants received two identical Pressair dry powder inhaler (DPI; FF 24 μg and placebo) and were instructed to take one puff from each of the two Pressair DPI in the morning and in the evening for 7 days	Perforomist 20 μg n=118 Participants Randomized participants received 1 vial of Perforomist 20 μg oral nebulization solution via a jet nebulizer in the morning and evening for 7 (±1) days	Placebo (Lactose Monohydrate) n=108 Participants Randomized participants received two identical Pressair dry powder inhaler (DPI; FF 6/12/24 μg and placebo) and were instructed to take one puff from each of the two Pressair DPI in the morning and in the evening for 7 days	Placebo (Lactose Monohydrate) n=38 Participants Randomized participants received two identical Pressair dry powder inhaler (DPI; FF 6/12/24 μg and placebo) and were instructed to take one puff from each of the two Pressair DPI in the morning and in the evening for 7 days
Change From Baseline in FEV1 AUC0-6/6h at Day 1 on Treatment	0.111 Litre/Hour Interval 0.077 to 0.145	0.148 Litre/Hour Interval 0.115 to 0.182	0.205 Litre/Hour Interval 0.171 to 0.239	0.195 Litre/Hour Interval 0.162 to 0.229	0.246 Litre/Hour Interval 0.212 to 0.28	-0.019 Litre/Hour Interval -0.063 to 0.025

SECONDARY outcome

Timeframe: Day 7: zero time to 6 hours post-dose

Population: The ITT analysis set consisted of all randomized participants who received at least 1 dose of investigational product (IP) and had a baseline FEV1 value and at least 1 post-baseline FEV1 measurement, regardless of a participant's adherence to the randomized treatment.

To assess the bronchodilation of 3 doses of formoterol fumarate (6 μg, 12 μg and 24 μg) BID administered via Pressair® compared to placebo and to open-label nebulised formoterol fumarate (20 μg). 6-hour serial spirometry was performed at Day 7 of each treatment period: spirometry was performed post-dose at 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours and 6 hours post-dose Note: Perforomist® 40 μg treatment periods lasted for 1 day only. Hence, was not included in the calculation

Outcome measures

Measure	Formoterol Fumarate 6 μg n=105 Participants Randomized participants received 2 puffs of Formoterol Fumarate 6 μg oral inhalation powder using Pressair® dry powder inhaler (DPI) in the morning and evening for 7 (±1) days	Formoterol Fumarate (FF) 12 μg n=119 Participants Randomized participants received two identical Pressair dry powder inhaler (DPI; FF 12 μg and placebo) and were instructed to take one puff from each of the two Pressair DPI in the morning and in the evening for 7 days	Formoterol Fumarate (FF) 24 μg n=104 Participants Randomized participants received two identical Pressair dry powder inhaler (DPI; FF 24 μg and placebo) and were instructed to take one puff from each of the two Pressair DPI in the morning and in the evening for 7 days	Perforomist 20 μg n=117 Participants Randomized participants received 1 vial of Perforomist 20 μg oral nebulization solution via a jet nebulizer in the morning and evening for 7 (±1) days	Placebo (Lactose Monohydrate) n=36 Participants Randomized participants received two identical Pressair dry powder inhaler (DPI; FF 6/12/24 μg and placebo) and were instructed to take one puff from each of the two Pressair DPI in the morning and in the evening for 7 days	Placebo (Lactose Monohydrate) Randomized participants received two identical Pressair dry powder inhaler (DPI; FF 6/12/24 μg and placebo) and were instructed to take one puff from each of the two Pressair DPI in the morning and in the evening for 7 days
Change From Baseline in FEV1 AUC0-6/6h at Day 7 on Treatment	0.166 Litre/Hour Interval 0.127 to 0.205	0.177 Litre/Hour Interval 0.139 to 0.215	0.225 Litre/Hour Interval 0.186 to 0.265	0.186 Litre/Hour Interval 0.147 to 0.225	0.007 Litre/Hour Interval -0.05 to 0.064	—

SECONDARY outcome

Timeframe: At baseline and Day 7

Population: The ITT analysis set consisted of all randomized participants who received at least 1 dose of investigational product (IP) and had a baseline FEV1 value and at least 1 post-baseline FEV1 measurement, regardless of a participant's adherence to the randomized treatment.

To assess the bronchodilation of 3 doses of formoterol fumarate (6 μg, 12 μg and 24 μg) BID administered via Pressair® compared to placebo and to open-label nebulised formoterol fumarate (20 μg). Trough value was defined as the mean of the 2 pre-dose measurements on Day 7. If 1 of the 2 measurements was missing, the non-missing measurement was used as the trough value.

Note: Perforomist® 40 μg treatment periods lasted for 1 day only. Hence, was not included in the calculation.

Outcome measures

Measure	Formoterol Fumarate 6 μg n=105 Participants Randomized participants received 2 puffs of Formoterol Fumarate 6 μg oral inhalation powder using Pressair® dry powder inhaler (DPI) in the morning and evening for 7 (±1) days	Formoterol Fumarate (FF) 12 μg n=119 Participants Randomized participants received two identical Pressair dry powder inhaler (DPI; FF 12 μg and placebo) and were instructed to take one puff from each of the two Pressair DPI in the morning and in the evening for 7 days	Formoterol Fumarate (FF) 24 μg n=104 Participants Randomized participants received two identical Pressair dry powder inhaler (DPI; FF 24 μg and placebo) and were instructed to take one puff from each of the two Pressair DPI in the morning and in the evening for 7 days	Perforomist 20 μg n=117 Participants Randomized participants received 1 vial of Perforomist 20 μg oral nebulization solution via a jet nebulizer in the morning and evening for 7 (±1) days	Placebo (Lactose Monohydrate) n=36 Participants Randomized participants received two identical Pressair dry powder inhaler (DPI; FF 6/12/24 μg and placebo) and were instructed to take one puff from each of the two Pressair DPI in the morning and in the evening for 7 days	Placebo (Lactose Monohydrate) Randomized participants received two identical Pressair dry powder inhaler (DPI; FF 6/12/24 μg and placebo) and were instructed to take one puff from each of the two Pressair DPI in the morning and in the evening for 7 days
Change From Baseline in Morning Pre-dose (Trough) FEV1 at Day 7 on Treatment	0.077 Litre Interval 0.044 to 0.109	0.067 Litre Interval 0.035 to 0.098	0.102 Litre Interval 0.069 to 0.135	0.061 Litre Interval 0.029 to 0.092	0.002 Litre Interval -0.059 to 0.063	—

Adverse Events

Formoterol Fumarate 6 μg

Serious events: 1 serious events

Other events: 3 other events

Deaths: 0 deaths

Formoterol Fumarate (FF) 12 μg

Serious events: 2 serious events

Other events: 4 other events

Deaths: 1 deaths

Formoterol Fumarate (FF) 24 μg

Serious events: 0 serious events

Other events: 1 other events

Deaths: 0 deaths

Perforomist 20 μg

Serious events: 0 serious events

Other events: 7 other events

Deaths: 0 deaths

Perforomist 40 μg

Serious events: 1 serious events

Other events: 0 other events

Deaths: 0 deaths

Placebo (Lactose Monohydrate)

Serious events: 1 serious events

Other events: 3 other events

Deaths: 0 deaths

Serious adverse events

Measure	Formoterol Fumarate 6 μg n=107 participants at risk Randomized participants received 2 puffs of Formoterol Fumarate 6 μg oral inhalation powder using Pressair® dry powder inhaler (DPI) in the morning and evening for 7 (±1) days	Formoterol Fumarate (FF) 12 μg n=121 participants at risk Randomized participants received two identical Pressair dry powder inhaler (DPI; FF 12 μg and placebo) and were instructed to take one puff from each of the two Pressair DPI in the morning and in the evening for 7 days	Formoterol Fumarate (FF) 24 μg n=105 participants at risk Randomized participants received two identical Pressair dry powder inhaler (DPI; FF 24 μg and placebo) and were instructed to take one puff from each of the two Pressair DPI in the morning and in the evening for 7 days	Perforomist 20 μg n=118 participants at risk Randomized participants received 1 vial of Perforomist 20 μg oral nebulization solution via a jet nebulizer in the morning and evening for 7 (±1) days	Perforomist 40 μg n=109 participants at risk Randomized participants received single dose of 2 vials of Perforomist 20 μg oral nebulization solution via a jet nebulizer in the morning of Day 1 of assigned treatment period.	Placebo (Lactose Monohydrate) n=38 participants at risk Randomized participants received two identical Pressair dry powder inhaler (DPI; FF 6/12/24 μg and placebo) and were instructed to take one puff from each of the two Pressair DPI in the morning and in the evening for 7 days
Cardiac disorders Myocardial infarction	0.00% 0/107 • From the time of signature of informed consent throughout the treatment period and including the follow-up period (i.e. 2 weeks after the last IP). Adverse event: The development of an undesirable medical condition or the deterioration of a pre-existing medical condition following or during exposure to a pharmaceutical product, whether or not considered causally related to the product. An undesirable medical condition can be symptoms (e.g., nausea, chest pain), signs (e.g., tachycardia, enlarged liver) or the abnormal results of an investigation (e.g., laboratory findings, electrocardiogram)	0.83% 1/121 • From the time of signature of informed consent throughout the treatment period and including the follow-up period (i.e. 2 weeks after the last IP). Adverse event: The development of an undesirable medical condition or the deterioration of a pre-existing medical condition following or during exposure to a pharmaceutical product, whether or not considered causally related to the product. An undesirable medical condition can be symptoms (e.g., nausea, chest pain), signs (e.g., tachycardia, enlarged liver) or the abnormal results of an investigation (e.g., laboratory findings, electrocardiogram)	0.00% 0/105 • From the time of signature of informed consent throughout the treatment period and including the follow-up period (i.e. 2 weeks after the last IP). Adverse event: The development of an undesirable medical condition or the deterioration of a pre-existing medical condition following or during exposure to a pharmaceutical product, whether or not considered causally related to the product. An undesirable medical condition can be symptoms (e.g., nausea, chest pain), signs (e.g., tachycardia, enlarged liver) or the abnormal results of an investigation (e.g., laboratory findings, electrocardiogram)	0.00% 0/118 • From the time of signature of informed consent throughout the treatment period and including the follow-up period (i.e. 2 weeks after the last IP). Adverse event: The development of an undesirable medical condition or the deterioration of a pre-existing medical condition following or during exposure to a pharmaceutical product, whether or not considered causally related to the product. An undesirable medical condition can be symptoms (e.g., nausea, chest pain), signs (e.g., tachycardia, enlarged liver) or the abnormal results of an investigation (e.g., laboratory findings, electrocardiogram)	0.00% 0/109 • From the time of signature of informed consent throughout the treatment period and including the follow-up period (i.e. 2 weeks after the last IP). Adverse event: The development of an undesirable medical condition or the deterioration of a pre-existing medical condition following or during exposure to a pharmaceutical product, whether or not considered causally related to the product. An undesirable medical condition can be symptoms (e.g., nausea, chest pain), signs (e.g., tachycardia, enlarged liver) or the abnormal results of an investigation (e.g., laboratory findings, electrocardiogram)	0.00% 0/38 • From the time of signature of informed consent throughout the treatment period and including the follow-up period (i.e. 2 weeks after the last IP). Adverse event: The development of an undesirable medical condition or the deterioration of a pre-existing medical condition following or during exposure to a pharmaceutical product, whether or not considered causally related to the product. An undesirable medical condition can be symptoms (e.g., nausea, chest pain), signs (e.g., tachycardia, enlarged liver) or the abnormal results of an investigation (e.g., laboratory findings, electrocardiogram)
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Squamous cell carcinoma of lung	0.00% 0/107 • From the time of signature of informed consent throughout the treatment period and including the follow-up period (i.e. 2 weeks after the last IP). Adverse event: The development of an undesirable medical condition or the deterioration of a pre-existing medical condition following or during exposure to a pharmaceutical product, whether or not considered causally related to the product. An undesirable medical condition can be symptoms (e.g., nausea, chest pain), signs (e.g., tachycardia, enlarged liver) or the abnormal results of an investigation (e.g., laboratory findings, electrocardiogram)	0.00% 0/121 • From the time of signature of informed consent throughout the treatment period and including the follow-up period (i.e. 2 weeks after the last IP). Adverse event: The development of an undesirable medical condition or the deterioration of a pre-existing medical condition following or during exposure to a pharmaceutical product, whether or not considered causally related to the product. An undesirable medical condition can be symptoms (e.g., nausea, chest pain), signs (e.g., tachycardia, enlarged liver) or the abnormal results of an investigation (e.g., laboratory findings, electrocardiogram)	0.00% 0/105 • From the time of signature of informed consent throughout the treatment period and including the follow-up period (i.e. 2 weeks after the last IP). Adverse event: The development of an undesirable medical condition or the deterioration of a pre-existing medical condition following or during exposure to a pharmaceutical product, whether or not considered causally related to the product. An undesirable medical condition can be symptoms (e.g., nausea, chest pain), signs (e.g., tachycardia, enlarged liver) or the abnormal results of an investigation (e.g., laboratory findings, electrocardiogram)	0.00% 0/118 • From the time of signature of informed consent throughout the treatment period and including the follow-up period (i.e. 2 weeks after the last IP). Adverse event: The development of an undesirable medical condition or the deterioration of a pre-existing medical condition following or during exposure to a pharmaceutical product, whether or not considered causally related to the product. An undesirable medical condition can be symptoms (e.g., nausea, chest pain), signs (e.g., tachycardia, enlarged liver) or the abnormal results of an investigation (e.g., laboratory findings, electrocardiogram)	0.92% 1/109 • From the time of signature of informed consent throughout the treatment period and including the follow-up period (i.e. 2 weeks after the last IP). Adverse event: The development of an undesirable medical condition or the deterioration of a pre-existing medical condition following or during exposure to a pharmaceutical product, whether or not considered causally related to the product. An undesirable medical condition can be symptoms (e.g., nausea, chest pain), signs (e.g., tachycardia, enlarged liver) or the abnormal results of an investigation (e.g., laboratory findings, electrocardiogram)	0.00% 0/38 • From the time of signature of informed consent throughout the treatment period and including the follow-up period (i.e. 2 weeks after the last IP). Adverse event: The development of an undesirable medical condition or the deterioration of a pre-existing medical condition following or during exposure to a pharmaceutical product, whether or not considered causally related to the product. An undesirable medical condition can be symptoms (e.g., nausea, chest pain), signs (e.g., tachycardia, enlarged liver) or the abnormal results of an investigation (e.g., laboratory findings, electrocardiogram)
Respiratory, thoracic and mediastinal disorders Chronic obstructive pulmonary disease	0.00% 0/107 • From the time of signature of informed consent throughout the treatment period and including the follow-up period (i.e. 2 weeks after the last IP). Adverse event: The development of an undesirable medical condition or the deterioration of a pre-existing medical condition following or during exposure to a pharmaceutical product, whether or not considered causally related to the product. An undesirable medical condition can be symptoms (e.g., nausea, chest pain), signs (e.g., tachycardia, enlarged liver) or the abnormal results of an investigation (e.g., laboratory findings, electrocardiogram)	0.00% 0/121 • From the time of signature of informed consent throughout the treatment period and including the follow-up period (i.e. 2 weeks after the last IP). Adverse event: The development of an undesirable medical condition or the deterioration of a pre-existing medical condition following or during exposure to a pharmaceutical product, whether or not considered causally related to the product. An undesirable medical condition can be symptoms (e.g., nausea, chest pain), signs (e.g., tachycardia, enlarged liver) or the abnormal results of an investigation (e.g., laboratory findings, electrocardiogram)	0.00% 0/105 • From the time of signature of informed consent throughout the treatment period and including the follow-up period (i.e. 2 weeks after the last IP). Adverse event: The development of an undesirable medical condition or the deterioration of a pre-existing medical condition following or during exposure to a pharmaceutical product, whether or not considered causally related to the product. An undesirable medical condition can be symptoms (e.g., nausea, chest pain), signs (e.g., tachycardia, enlarged liver) or the abnormal results of an investigation (e.g., laboratory findings, electrocardiogram)	0.00% 0/118 • From the time of signature of informed consent throughout the treatment period and including the follow-up period (i.e. 2 weeks after the last IP). Adverse event: The development of an undesirable medical condition or the deterioration of a pre-existing medical condition following or during exposure to a pharmaceutical product, whether or not considered causally related to the product. An undesirable medical condition can be symptoms (e.g., nausea, chest pain), signs (e.g., tachycardia, enlarged liver) or the abnormal results of an investigation (e.g., laboratory findings, electrocardiogram)	0.00% 0/109 • From the time of signature of informed consent throughout the treatment period and including the follow-up period (i.e. 2 weeks after the last IP). Adverse event: The development of an undesirable medical condition or the deterioration of a pre-existing medical condition following or during exposure to a pharmaceutical product, whether or not considered causally related to the product. An undesirable medical condition can be symptoms (e.g., nausea, chest pain), signs (e.g., tachycardia, enlarged liver) or the abnormal results of an investigation (e.g., laboratory findings, electrocardiogram)	2.6% 1/38 • From the time of signature of informed consent throughout the treatment period and including the follow-up period (i.e. 2 weeks after the last IP). Adverse event: The development of an undesirable medical condition or the deterioration of a pre-existing medical condition following or during exposure to a pharmaceutical product, whether or not considered causally related to the product. An undesirable medical condition can be symptoms (e.g., nausea, chest pain), signs (e.g., tachycardia, enlarged liver) or the abnormal results of an investigation (e.g., laboratory findings, electrocardiogram)
General disorders Vascular stent occlusion	0.00% 0/107 • From the time of signature of informed consent throughout the treatment period and including the follow-up period (i.e. 2 weeks after the last IP). Adverse event: The development of an undesirable medical condition or the deterioration of a pre-existing medical condition following or during exposure to a pharmaceutical product, whether or not considered causally related to the product. An undesirable medical condition can be symptoms (e.g., nausea, chest pain), signs (e.g., tachycardia, enlarged liver) or the abnormal results of an investigation (e.g., laboratory findings, electrocardiogram)	0.83% 1/121 • From the time of signature of informed consent throughout the treatment period and including the follow-up period (i.e. 2 weeks after the last IP). Adverse event: The development of an undesirable medical condition or the deterioration of a pre-existing medical condition following or during exposure to a pharmaceutical product, whether or not considered causally related to the product. An undesirable medical condition can be symptoms (e.g., nausea, chest pain), signs (e.g., tachycardia, enlarged liver) or the abnormal results of an investigation (e.g., laboratory findings, electrocardiogram)	0.00% 0/105 • From the time of signature of informed consent throughout the treatment period and including the follow-up period (i.e. 2 weeks after the last IP). Adverse event: The development of an undesirable medical condition or the deterioration of a pre-existing medical condition following or during exposure to a pharmaceutical product, whether or not considered causally related to the product. An undesirable medical condition can be symptoms (e.g., nausea, chest pain), signs (e.g., tachycardia, enlarged liver) or the abnormal results of an investigation (e.g., laboratory findings, electrocardiogram)	0.00% 0/118 • From the time of signature of informed consent throughout the treatment period and including the follow-up period (i.e. 2 weeks after the last IP). Adverse event: The development of an undesirable medical condition or the deterioration of a pre-existing medical condition following or during exposure to a pharmaceutical product, whether or not considered causally related to the product. An undesirable medical condition can be symptoms (e.g., nausea, chest pain), signs (e.g., tachycardia, enlarged liver) or the abnormal results of an investigation (e.g., laboratory findings, electrocardiogram)	0.00% 0/109 • From the time of signature of informed consent throughout the treatment period and including the follow-up period (i.e. 2 weeks after the last IP). Adverse event: The development of an undesirable medical condition or the deterioration of a pre-existing medical condition following or during exposure to a pharmaceutical product, whether or not considered causally related to the product. An undesirable medical condition can be symptoms (e.g., nausea, chest pain), signs (e.g., tachycardia, enlarged liver) or the abnormal results of an investigation (e.g., laboratory findings, electrocardiogram)	0.00% 0/38 • From the time of signature of informed consent throughout the treatment period and including the follow-up period (i.e. 2 weeks after the last IP). Adverse event: The development of an undesirable medical condition or the deterioration of a pre-existing medical condition following or during exposure to a pharmaceutical product, whether or not considered causally related to the product. An undesirable medical condition can be symptoms (e.g., nausea, chest pain), signs (e.g., tachycardia, enlarged liver) or the abnormal results of an investigation (e.g., laboratory findings, electrocardiogram)
Injury, poisoning and procedural complications Multiple injuries	0.93% 1/107 • From the time of signature of informed consent throughout the treatment period and including the follow-up period (i.e. 2 weeks after the last IP). Adverse event: The development of an undesirable medical condition or the deterioration of a pre-existing medical condition following or during exposure to a pharmaceutical product, whether or not considered causally related to the product. An undesirable medical condition can be symptoms (e.g., nausea, chest pain), signs (e.g., tachycardia, enlarged liver) or the abnormal results of an investigation (e.g., laboratory findings, electrocardiogram)	0.00% 0/121 • From the time of signature of informed consent throughout the treatment period and including the follow-up period (i.e. 2 weeks after the last IP). Adverse event: The development of an undesirable medical condition or the deterioration of a pre-existing medical condition following or during exposure to a pharmaceutical product, whether or not considered causally related to the product. An undesirable medical condition can be symptoms (e.g., nausea, chest pain), signs (e.g., tachycardia, enlarged liver) or the abnormal results of an investigation (e.g., laboratory findings, electrocardiogram)	0.00% 0/105 • From the time of signature of informed consent throughout the treatment period and including the follow-up period (i.e. 2 weeks after the last IP). Adverse event: The development of an undesirable medical condition or the deterioration of a pre-existing medical condition following or during exposure to a pharmaceutical product, whether or not considered causally related to the product. An undesirable medical condition can be symptoms (e.g., nausea, chest pain), signs (e.g., tachycardia, enlarged liver) or the abnormal results of an investigation (e.g., laboratory findings, electrocardiogram)	0.00% 0/118 • From the time of signature of informed consent throughout the treatment period and including the follow-up period (i.e. 2 weeks after the last IP). Adverse event: The development of an undesirable medical condition or the deterioration of a pre-existing medical condition following or during exposure to a pharmaceutical product, whether or not considered causally related to the product. An undesirable medical condition can be symptoms (e.g., nausea, chest pain), signs (e.g., tachycardia, enlarged liver) or the abnormal results of an investigation (e.g., laboratory findings, electrocardiogram)	0.00% 0/109 • From the time of signature of informed consent throughout the treatment period and including the follow-up period (i.e. 2 weeks after the last IP). Adverse event: The development of an undesirable medical condition or the deterioration of a pre-existing medical condition following or during exposure to a pharmaceutical product, whether or not considered causally related to the product. An undesirable medical condition can be symptoms (e.g., nausea, chest pain), signs (e.g., tachycardia, enlarged liver) or the abnormal results of an investigation (e.g., laboratory findings, electrocardiogram)	0.00% 0/38 • From the time of signature of informed consent throughout the treatment period and including the follow-up period (i.e. 2 weeks after the last IP). Adverse event: The development of an undesirable medical condition or the deterioration of a pre-existing medical condition following or during exposure to a pharmaceutical product, whether or not considered causally related to the product. An undesirable medical condition can be symptoms (e.g., nausea, chest pain), signs (e.g., tachycardia, enlarged liver) or the abnormal results of an investigation (e.g., laboratory findings, electrocardiogram)

Other adverse events

Measure	Formoterol Fumarate 6 μg n=107 participants at risk Randomized participants received 2 puffs of Formoterol Fumarate 6 μg oral inhalation powder using Pressair® dry powder inhaler (DPI) in the morning and evening for 7 (±1) days	Formoterol Fumarate (FF) 12 μg n=121 participants at risk Randomized participants received two identical Pressair dry powder inhaler (DPI; FF 12 μg and placebo) and were instructed to take one puff from each of the two Pressair DPI in the morning and in the evening for 7 days	Formoterol Fumarate (FF) 24 μg n=105 participants at risk Randomized participants received two identical Pressair dry powder inhaler (DPI; FF 24 μg and placebo) and were instructed to take one puff from each of the two Pressair DPI in the morning and in the evening for 7 days	Perforomist 20 μg n=118 participants at risk Randomized participants received 1 vial of Perforomist 20 μg oral nebulization solution via a jet nebulizer in the morning and evening for 7 (±1) days	Perforomist 40 μg n=109 participants at risk Randomized participants received single dose of 2 vials of Perforomist 20 μg oral nebulization solution via a jet nebulizer in the morning of Day 1 of assigned treatment period.	Placebo (Lactose Monohydrate) n=38 participants at risk Randomized participants received two identical Pressair dry powder inhaler (DPI; FF 6/12/24 μg and placebo) and were instructed to take one puff from each of the two Pressair DPI in the morning and in the evening for 7 days
Respiratory, thoracic and mediastinal disorders Chronic obstructive pulmonary disease	0.00% 0/107 • From the time of signature of informed consent throughout the treatment period and including the follow-up period (i.e. 2 weeks after the last IP). Adverse event: The development of an undesirable medical condition or the deterioration of a pre-existing medical condition following or during exposure to a pharmaceutical product, whether or not considered causally related to the product. An undesirable medical condition can be symptoms (e.g., nausea, chest pain), signs (e.g., tachycardia, enlarged liver) or the abnormal results of an investigation (e.g., laboratory findings, electrocardiogram)	0.00% 0/121 • From the time of signature of informed consent throughout the treatment period and including the follow-up period (i.e. 2 weeks after the last IP). Adverse event: The development of an undesirable medical condition or the deterioration of a pre-existing medical condition following or during exposure to a pharmaceutical product, whether or not considered causally related to the product. An undesirable medical condition can be symptoms (e.g., nausea, chest pain), signs (e.g., tachycardia, enlarged liver) or the abnormal results of an investigation (e.g., laboratory findings, electrocardiogram)	0.00% 0/105 • From the time of signature of informed consent throughout the treatment period and including the follow-up period (i.e. 2 weeks after the last IP). Adverse event: The development of an undesirable medical condition or the deterioration of a pre-existing medical condition following or during exposure to a pharmaceutical product, whether or not considered causally related to the product. An undesirable medical condition can be symptoms (e.g., nausea, chest pain), signs (e.g., tachycardia, enlarged liver) or the abnormal results of an investigation (e.g., laboratory findings, electrocardiogram)	0.00% 0/118 • From the time of signature of informed consent throughout the treatment period and including the follow-up period (i.e. 2 weeks after the last IP). Adverse event: The development of an undesirable medical condition or the deterioration of a pre-existing medical condition following or during exposure to a pharmaceutical product, whether or not considered causally related to the product. An undesirable medical condition can be symptoms (e.g., nausea, chest pain), signs (e.g., tachycardia, enlarged liver) or the abnormal results of an investigation (e.g., laboratory findings, electrocardiogram)	0.00% 0/109 • From the time of signature of informed consent throughout the treatment period and including the follow-up period (i.e. 2 weeks after the last IP). Adverse event: The development of an undesirable medical condition or the deterioration of a pre-existing medical condition following or during exposure to a pharmaceutical product, whether or not considered causally related to the product. An undesirable medical condition can be symptoms (e.g., nausea, chest pain), signs (e.g., tachycardia, enlarged liver) or the abnormal results of an investigation (e.g., laboratory findings, electrocardiogram)	7.9% 3/38 • From the time of signature of informed consent throughout the treatment period and including the follow-up period (i.e. 2 weeks after the last IP). Adverse event: The development of an undesirable medical condition or the deterioration of a pre-existing medical condition following or during exposure to a pharmaceutical product, whether or not considered causally related to the product. An undesirable medical condition can be symptoms (e.g., nausea, chest pain), signs (e.g., tachycardia, enlarged liver) or the abnormal results of an investigation (e.g., laboratory findings, electrocardiogram)
Nervous system disorders Headache	0.00% 0/107 • From the time of signature of informed consent throughout the treatment period and including the follow-up period (i.e. 2 weeks after the last IP). Adverse event: The development of an undesirable medical condition or the deterioration of a pre-existing medical condition following or during exposure to a pharmaceutical product, whether or not considered causally related to the product. An undesirable medical condition can be symptoms (e.g., nausea, chest pain), signs (e.g., tachycardia, enlarged liver) or the abnormal results of an investigation (e.g., laboratory findings, electrocardiogram)	2.5% 3/121 • From the time of signature of informed consent throughout the treatment period and including the follow-up period (i.e. 2 weeks after the last IP). Adverse event: The development of an undesirable medical condition or the deterioration of a pre-existing medical condition following or during exposure to a pharmaceutical product, whether or not considered causally related to the product. An undesirable medical condition can be symptoms (e.g., nausea, chest pain), signs (e.g., tachycardia, enlarged liver) or the abnormal results of an investigation (e.g., laboratory findings, electrocardiogram)	0.95% 1/105 • From the time of signature of informed consent throughout the treatment period and including the follow-up period (i.e. 2 weeks after the last IP). Adverse event: The development of an undesirable medical condition or the deterioration of a pre-existing medical condition following or during exposure to a pharmaceutical product, whether or not considered causally related to the product. An undesirable medical condition can be symptoms (e.g., nausea, chest pain), signs (e.g., tachycardia, enlarged liver) or the abnormal results of an investigation (e.g., laboratory findings, electrocardiogram)	1.7% 2/118 • From the time of signature of informed consent throughout the treatment period and including the follow-up period (i.e. 2 weeks after the last IP). Adverse event: The development of an undesirable medical condition or the deterioration of a pre-existing medical condition following or during exposure to a pharmaceutical product, whether or not considered causally related to the product. An undesirable medical condition can be symptoms (e.g., nausea, chest pain), signs (e.g., tachycardia, enlarged liver) or the abnormal results of an investigation (e.g., laboratory findings, electrocardiogram)	0.00% 0/109 • From the time of signature of informed consent throughout the treatment period and including the follow-up period (i.e. 2 weeks after the last IP). Adverse event: The development of an undesirable medical condition or the deterioration of a pre-existing medical condition following or during exposure to a pharmaceutical product, whether or not considered causally related to the product. An undesirable medical condition can be symptoms (e.g., nausea, chest pain), signs (e.g., tachycardia, enlarged liver) or the abnormal results of an investigation (e.g., laboratory findings, electrocardiogram)	0.00% 0/38 • From the time of signature of informed consent throughout the treatment period and including the follow-up period (i.e. 2 weeks after the last IP). Adverse event: The development of an undesirable medical condition or the deterioration of a pre-existing medical condition following or during exposure to a pharmaceutical product, whether or not considered causally related to the product. An undesirable medical condition can be symptoms (e.g., nausea, chest pain), signs (e.g., tachycardia, enlarged liver) or the abnormal results of an investigation (e.g., laboratory findings, electrocardiogram)
Infections and infestations Upper respiratory tract infection	0.93% 1/107 • From the time of signature of informed consent throughout the treatment period and including the follow-up period (i.e. 2 weeks after the last IP). Adverse event: The development of an undesirable medical condition or the deterioration of a pre-existing medical condition following or during exposure to a pharmaceutical product, whether or not considered causally related to the product. An undesirable medical condition can be symptoms (e.g., nausea, chest pain), signs (e.g., tachycardia, enlarged liver) or the abnormal results of an investigation (e.g., laboratory findings, electrocardiogram)	0.00% 0/121 • From the time of signature of informed consent throughout the treatment period and including the follow-up period (i.e. 2 weeks after the last IP). Adverse event: The development of an undesirable medical condition or the deterioration of a pre-existing medical condition following or during exposure to a pharmaceutical product, whether or not considered causally related to the product. An undesirable medical condition can be symptoms (e.g., nausea, chest pain), signs (e.g., tachycardia, enlarged liver) or the abnormal results of an investigation (e.g., laboratory findings, electrocardiogram)	0.00% 0/105 • From the time of signature of informed consent throughout the treatment period and including the follow-up period (i.e. 2 weeks after the last IP). Adverse event: The development of an undesirable medical condition or the deterioration of a pre-existing medical condition following or during exposure to a pharmaceutical product, whether or not considered causally related to the product. An undesirable medical condition can be symptoms (e.g., nausea, chest pain), signs (e.g., tachycardia, enlarged liver) or the abnormal results of an investigation (e.g., laboratory findings, electrocardiogram)	1.7% 2/118 • From the time of signature of informed consent throughout the treatment period and including the follow-up period (i.e. 2 weeks after the last IP). Adverse event: The development of an undesirable medical condition or the deterioration of a pre-existing medical condition following or during exposure to a pharmaceutical product, whether or not considered causally related to the product. An undesirable medical condition can be symptoms (e.g., nausea, chest pain), signs (e.g., tachycardia, enlarged liver) or the abnormal results of an investigation (e.g., laboratory findings, electrocardiogram)	0.00% 0/109 • From the time of signature of informed consent throughout the treatment period and including the follow-up period (i.e. 2 weeks after the last IP). Adverse event: The development of an undesirable medical condition or the deterioration of a pre-existing medical condition following or during exposure to a pharmaceutical product, whether or not considered causally related to the product. An undesirable medical condition can be symptoms (e.g., nausea, chest pain), signs (e.g., tachycardia, enlarged liver) or the abnormal results of an investigation (e.g., laboratory findings, electrocardiogram)	0.00% 0/38 • From the time of signature of informed consent throughout the treatment period and including the follow-up period (i.e. 2 weeks after the last IP). Adverse event: The development of an undesirable medical condition or the deterioration of a pre-existing medical condition following or during exposure to a pharmaceutical product, whether or not considered causally related to the product. An undesirable medical condition can be symptoms (e.g., nausea, chest pain), signs (e.g., tachycardia, enlarged liver) or the abnormal results of an investigation (e.g., laboratory findings, electrocardiogram)
Infections and infestations Urinary tract infection	1.9% 2/107 • From the time of signature of informed consent throughout the treatment period and including the follow-up period (i.e. 2 weeks after the last IP). Adverse event: The development of an undesirable medical condition or the deterioration of a pre-existing medical condition following or during exposure to a pharmaceutical product, whether or not considered causally related to the product. An undesirable medical condition can be symptoms (e.g., nausea, chest pain), signs (e.g., tachycardia, enlarged liver) or the abnormal results of an investigation (e.g., laboratory findings, electrocardiogram)	0.83% 1/121 • From the time of signature of informed consent throughout the treatment period and including the follow-up period (i.e. 2 weeks after the last IP). Adverse event: The development of an undesirable medical condition or the deterioration of a pre-existing medical condition following or during exposure to a pharmaceutical product, whether or not considered causally related to the product. An undesirable medical condition can be symptoms (e.g., nausea, chest pain), signs (e.g., tachycardia, enlarged liver) or the abnormal results of an investigation (e.g., laboratory findings, electrocardiogram)	0.00% 0/105 • From the time of signature of informed consent throughout the treatment period and including the follow-up period (i.e. 2 weeks after the last IP). Adverse event: The development of an undesirable medical condition or the deterioration of a pre-existing medical condition following or during exposure to a pharmaceutical product, whether or not considered causally related to the product. An undesirable medical condition can be symptoms (e.g., nausea, chest pain), signs (e.g., tachycardia, enlarged liver) or the abnormal results of an investigation (e.g., laboratory findings, electrocardiogram)	0.85% 1/118 • From the time of signature of informed consent throughout the treatment period and including the follow-up period (i.e. 2 weeks after the last IP). Adverse event: The development of an undesirable medical condition or the deterioration of a pre-existing medical condition following or during exposure to a pharmaceutical product, whether or not considered causally related to the product. An undesirable medical condition can be symptoms (e.g., nausea, chest pain), signs (e.g., tachycardia, enlarged liver) or the abnormal results of an investigation (e.g., laboratory findings, electrocardiogram)	0.00% 0/109 • From the time of signature of informed consent throughout the treatment period and including the follow-up period (i.e. 2 weeks after the last IP). Adverse event: The development of an undesirable medical condition or the deterioration of a pre-existing medical condition following or during exposure to a pharmaceutical product, whether or not considered causally related to the product. An undesirable medical condition can be symptoms (e.g., nausea, chest pain), signs (e.g., tachycardia, enlarged liver) or the abnormal results of an investigation (e.g., laboratory findings, electrocardiogram)	0.00% 0/38 • From the time of signature of informed consent throughout the treatment period and including the follow-up period (i.e. 2 weeks after the last IP). Adverse event: The development of an undesirable medical condition or the deterioration of a pre-existing medical condition following or during exposure to a pharmaceutical product, whether or not considered causally related to the product. An undesirable medical condition can be symptoms (e.g., nausea, chest pain), signs (e.g., tachycardia, enlarged liver) or the abnormal results of an investigation (e.g., laboratory findings, electrocardiogram)
Musculoskeletal and connective tissue disorders Muscle spasms	0.00% 0/107 • From the time of signature of informed consent throughout the treatment period and including the follow-up period (i.e. 2 weeks after the last IP). Adverse event: The development of an undesirable medical condition or the deterioration of a pre-existing medical condition following or during exposure to a pharmaceutical product, whether or not considered causally related to the product. An undesirable medical condition can be symptoms (e.g., nausea, chest pain), signs (e.g., tachycardia, enlarged liver) or the abnormal results of an investigation (e.g., laboratory findings, electrocardiogram)	0.00% 0/121 • From the time of signature of informed consent throughout the treatment period and including the follow-up period (i.e. 2 weeks after the last IP). Adverse event: The development of an undesirable medical condition or the deterioration of a pre-existing medical condition following or during exposure to a pharmaceutical product, whether or not considered causally related to the product. An undesirable medical condition can be symptoms (e.g., nausea, chest pain), signs (e.g., tachycardia, enlarged liver) or the abnormal results of an investigation (e.g., laboratory findings, electrocardiogram)	0.00% 0/105 • From the time of signature of informed consent throughout the treatment period and including the follow-up period (i.e. 2 weeks after the last IP). Adverse event: The development of an undesirable medical condition or the deterioration of a pre-existing medical condition following or during exposure to a pharmaceutical product, whether or not considered causally related to the product. An undesirable medical condition can be symptoms (e.g., nausea, chest pain), signs (e.g., tachycardia, enlarged liver) or the abnormal results of an investigation (e.g., laboratory findings, electrocardiogram)	1.7% 2/118 • From the time of signature of informed consent throughout the treatment period and including the follow-up period (i.e. 2 weeks after the last IP). Adverse event: The development of an undesirable medical condition or the deterioration of a pre-existing medical condition following or during exposure to a pharmaceutical product, whether or not considered causally related to the product. An undesirable medical condition can be symptoms (e.g., nausea, chest pain), signs (e.g., tachycardia, enlarged liver) or the abnormal results of an investigation (e.g., laboratory findings, electrocardiogram)	0.00% 0/109 • From the time of signature of informed consent throughout the treatment period and including the follow-up period (i.e. 2 weeks after the last IP). Adverse event: The development of an undesirable medical condition or the deterioration of a pre-existing medical condition following or during exposure to a pharmaceutical product, whether or not considered causally related to the product. An undesirable medical condition can be symptoms (e.g., nausea, chest pain), signs (e.g., tachycardia, enlarged liver) or the abnormal results of an investigation (e.g., laboratory findings, electrocardiogram)	0.00% 0/38 • From the time of signature of informed consent throughout the treatment period and including the follow-up period (i.e. 2 weeks after the last IP). Adverse event: The development of an undesirable medical condition or the deterioration of a pre-existing medical condition following or during exposure to a pharmaceutical product, whether or not considered causally related to the product. An undesirable medical condition can be symptoms (e.g., nausea, chest pain), signs (e.g., tachycardia, enlarged liver) or the abnormal results of an investigation (e.g., laboratory findings, electrocardiogram)

Additional Information

Global Clinical Leader

AstraZeneca AB

Phone: +46 766 346712

Email: clinicaltrialtransparency@astrazeneca.com

Results disclosure agreements

• Principal investigator is a sponsor employee All clinical study findings and documents will be regarded as confidential. The investigator and members of his/her research team must not disclose such information without prior written approval from the sponsor.
• Publication restrictions are in place

Restriction type: OTHER