Two-part pharmacokinetic and pharmacodynamic study of LAS190792 in patients with asthma and COPD

Study identifier:M-190792-01

ClinicalTrials.gov identifier:NCT02059434

EudraCT identifier:2013-001758-93

CTIS identifier:N/A

Study Complete

Official Title

A 2-Part, Randomised, Placebo-Controlled, Safety, Tolerability, Pharmacokinetic And Pharmacodynamic Study Of LAS190792 Delivered By Inhalation In Asthmatic And Chronic Obstructive Pulmonary Disease (COPD) Subjects

Medical condition

Chronic obstructive pulmonary disease (COPD)

Phase

Phase 1

Healthy volunteers

Study drug

LAS190792 Dose 1, LAS190792 Dose 2, LAS190792 Dose 3, LAS190792 Dose 4, LAS190792 Dose 5, LAS190792 Dose 6, LAS190792 Dose 1 (Part 2), LAS190792 Dose 2 (Part 2), Tiotropium 18 μg, Indacaterol 150 μg, Placebo

Sex

All

Actual Enrollment

Study type

Interventional

Age

18 Years - 70 Years

Date

Study Start Date: 01 Sept 2013

Primary Completion Date: 06 Oct 2014

Study Completion Date: 06 Oct 2014

Study design

Allocation: Randomized
Endpoint Classification: Safety Study
Intervention Model: Crossover Assignment
Masking: Single Blind
Primary Purpose: Treatment

Verification:

Verified 01 Mar 2019 by AstraZeneca

Collaborators

Inclusion and exclusion criteria

Inclusion Criteria

(PART 1):
- Adult male subjects aged 18 to 70 years
- Body mass index (BMI) 18.5 to 30 kg/m2 at screening
- Clinical diagnosis of mild persistent asthma (according to GINA guidelines) for at least 6 months prior to screening
- Ability to change current asthma therapy, to discontinue previous prescribed medications after signature of informed consent as per required washout periods
- Screening FEV1 value of ≥70% of the predicted normal value after a washout of at least 5 h for short-acting beta2-agonists and 72 h for long-acting beta2-agonists
- FEV1 reversibility of ≥12% and an absolute increase of at least 200 mL over the baseline value within 30 min after inhalation of 400 µg of salbutamol
- Subjects using intermittent salbutamol and / or subjects on a stable dose or regimen of low dose ICS (as defined by the GINA guidelines) at least 4 weeks prior to screening
- Predose FEV1 value of first treatment period within the range of ±20% of the FEV1 measured at screening prior to salbutamol inhalation
- Subjects who are otherwise healthy as determined by medical history, physical examination, 12-lead ECG findings
- Normal blood pressure (defined as SBP between 100 and 140 mmHg, and DBP between 50 and 90 mmHg) at screening, measured after resting in supine position for 5 minutes.
- Subjects whose clinical laboratory test results are not clinically relevant and are acceptable to the Investigator
- Subjects who are negative for hepatitis B surface antigen (HBsAg), hepatitis B core (HBc) antibody (IgM), hepatitis C antibody and human immunodeficiency virus (HIV) I and II antibodies at screening
- Subjects who are able and willing to provide written informed consent
- Subjects able to perform repeatable pulmonary function testing for FEV1 according to the American Thoracic Society (ATS) / European Respiratory Society (ERS) 2005 criteria at screening
Inclusion Criteria (PART 2):
- Adult male and non-childbearing potential women subjects aged ≥40 years with a clinical diagnosis of stable moderate to severe COPD according to GOLD guidelines at screening
- Females must be of non-childbearing potential, confirmed at screening
- Post-salbutamol FEV1 <80% and ≥30% of the predicted normal value and post-salbutamol FEV1 / forced vital capacity (FVC) <70%
- Ability to change current COPD therapy, to discontinue previous prescribed medications after signature of informed consent
- No evidence of clinically significant respiratory and / or cardiovascular conditions or laboratory abnormalities
- No other relevant pulmonary disease or history of thoracic surgery
- No contraindication to the use of anticholinergic drugs such as known symptomatic prostatic hypertrophy, bladder neck obstruction, narrow-angle glaucoma, or beta2-agonists usage
- Subjects who are negative for HBsAg, HBc IgM, hepatitis C antibody and HIV I and II antibodies at screening
- Subjects who are able and willing to provide written informed consent
- Subjects able to perform repeatable pulmonary function testing for FEV1 according to the ATS / ERS 2005 criteria at screening

Exclusion Criteria

(PART 1 and 2):
- Subjects who do not conform to the above inclusion criteria
- Current smokers, subjects with a smoking history during the last 12 months or subjects with a smoking history of more than 10 pack-years
- Other relevant pulmonary disease or history of thoracic surgery
- Subjects with a BMI ≥40 kg/m2 (only applicable for Part 2)
- Subjects with any clinically relevant history or presence of abnormality from the medical history and/or physical examination (only applicable for Part 1)
- Current evidence or recent history of any clinically significant and unstable disease (other than COPD) or abnormality that could put the subject at risk or could confound the results of the study (only applicable for Part 2)
- Subjects with a surgical history clinically relevant for the purpose of the study
- History of malignancy of any organ system, treated or untreated within the past 5 years, with the exception of localised basal cell carcinoma of the skin
- Subjects with serious adverse reaction or serious hypersensitivity to Spiriva (for Part 2 only), indacaterol (for Part 2 only), or the formulation excipients (eg, lactose) or other drugs in the same pharmacologic class (for Part 1 and Part 2)
- Current diagnosis of COPD (for Part 1 only) or history of / or current diagnosis for asthma (for Part 2 only)
- Recent history of asthma / COPD exacerbation requiring hospitalisation or need for increased maintenance treatments for asthma / COPD within 6 weeks prior to screening or randomisation
- Use of daily oxygen therapy >10 h per day (for Part 2 only)
- Use of systemic steroids for respiratory reasons within 3 months prior to screening
- Lower respiratory tract infection within 6 weeks prior to screening or randomisation
- Upper respiratory tract infection requiring antibiotics within 4 weeks prior to screening or randomisation
- Current history of tuberculosis, bronchiectasis or other non-specific pulmonary disease
- QTcF interval >430 ms at screening or prior to randomisation, or history of long QT syndrome (for Part 1 only)
- QTcF interval, >450 ms for males and >470 ms for females at screening or prior to randomisation, or history of long QT syndrome (for Part 2 only)
- Subjects with a history of excessive use or abuse of alcohol or with a history of drug abuse within the past 2 years
- Subjects who are positive for drugs of abuse and alcohol tests at screening and prior to randomisation
- Donation or loss >400 ml of blood and plasma within the previous 3 months prior to screening
- Subjects consuming more than 14 (female subjects) or 21 (male subjects) units of alcohol a week
- Subjects with a significant infection or known inflammatory process at screening or prior to randomisation
- Subjects with acute gastrointestinal symptoms at the time of screening or prior to randomisation
- Subjects with an acute infection such as influenza at the time of screening or prior to randomisation
- Male subjects who do not agree to follow instructions to avoid pregnancies
- Subjects who are not able to adhere to the restrictions on prior and concomitant medications
- Subjects who intend to use any concomitant medication not permitted by the protocol or who have not undergone the required washout period for a particular prohibited medication
- Subjects who have used any investigational drug within 3 months prior to screening or within the equivalent time of 6 half-lives of receiving the last administration, whichever is longer
- Subjects who have received the last dose of investigational product more than 3 months ago but who are on an extended follow-up
- Subjects who are vegans or who have medical dietary restrictions
- Subjects unable to communicate reliably with the Investigator
- Subjects who are unlikely to co-operate with the requirements of the study

Location

Quintiles Drug Research Unit at Guy’s Hospital

London, United Kingdom, SE1 1YR

Location

Medicines Evaluation Unit Ltd (MEU)

Manchester, United Kingdom, M23 9QZ

Arms	Assigned Interventions
Experimental: LAS190792 Dose 1 (Part 1) Single dose, oral inhalation by Genuair® single-dose dry powder inhaler (DPI)	-
Experimental: LAS190792 Dose 2 (Part 1) Single dose, oral inhalation by Genuair® single-dose dry powder inhaler (DPI)	-
Experimental: LAS190792 Dose 3 (Part 1) Single dose, oral inhalation by Genuair® single-dose dry powder inhaler (DPI)	-
Experimental: LAS190792 Dose 4 (Part 1) Single dose, oral inhalation by Genuair® single-dose dry powder inhaler (DPI)	-
Experimental: LAS190792 Dose 5 (Part 1) Single dose, oral inhalation by Genuair® single-dose dry powder inhaler (DPI)	-
Experimental: LAS190792 Dose 6 (Part 1) Single dose, oral inhalation by Genuair® single-dose dry powder inhaler (DPI)	-
Placebo Comparator: Placebo (Part 1) Single dose, oral inhalation by Genuair® single-dose dry powder inhaler (DPI)	-
Experimental: LAS190792 Dose 1 (Part 2) Single dose, oral inhalation by Genuair® single-dose dry powder inhaler (DPI)	-
Experimental: LAS190792 Dose 2 (Part 2) Single dose, oral inhalation by Genuair® single-dose dry powder inhaler (DPI)	-
Active Comparator: Tiotropium 18 μg Single dose, oral inhalation by HandiHaler® single-dose DPI	-
Active Comparator: Indacaterol 150 μg Single dose, oral inhalation by Breezhaler® single-dose DPI	-
Placebo Comparator: Placebo (Part 2) Single dose, oral inhalation by Genuair® single-dose dry powder inhaler (DPI)	-

Participant Flow

Recruitment Details

Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
This study was conducted at 2 centres in the UK. In part 1 of the study, the first patient was screened in September 2013 and the last patient visit was in February 2014. In part 2 of the study, the first patient was screened in March 2014 and the last patient visit was in October 2014.

Pre-Assignment Details

Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
This was a 2-part study. Part 1: incomplete crossover, single ascending dose study of 2 cohorts randomised to fixed sequences of LAS190792 or placebo in 3 treatment periods. Part 2: 5-way complete crossover, single dose study of LAS190792 (100/400 μg), placebo, or active controls (indacaterol 150 μg, tiotropium 18 μg) in 5 treatment periods.

Reporting Groups

	Description
Part 1 - Cohort 1 LAS190792 5 μg, 50 μg, 200 μg	All individuals in Part 1 - Cohort 1 who were randomised to treatment sequence LAS190792 5 μg, 50 μg, 200 μg in 3 treatment periods separated by washout periods of 28-42 days.
Part 1 - Cohort 1 Placebo, then LAS190792 50 μg, 200 μg	All individuals in Part 1 - Cohort 1 who were randomised to treatment sequence Placebo, then LAS190792 50 μg, 200 μg in 3 treatment periods separated by washout periods of 28-42 days.
Part 1 - Cohort 1 LAS190792 5 μg, Placebo, LAS190792 200 μg	All individuals in Part 1 - Cohort 1 who were randomised to treatment sequence LAS190792 5 μg, Placebo, LAS190792 200 μg in 3 treatment periods separated by washout periods of 28-42 days.
Part 1 - Cohort 1 LAS190792 5 μg, 50 μg, then Placebo	All individuals in Part 1 - Cohort 1 who were randomised to treatment sequence LAS190792 5 μg, 50 μg, then Placebo in 3 treatment periods separated by washout periods of 28-42 days.
Part 1 - Cohort 2 LAS190792 20 μg, 100 μg, 400 μg	All individuals in Part 1 - Cohort 2 who were randomised to treatment sequence LAS190792 20 μg, 100 μg, 400 μg in 3 treatment periods separated by washout periods of 28-42 days.
Part 1 - Cohort 2 Placebo, then LAS190792 100 μg, 400 μg	All individuals in Part 1 - Cohort 2 who were randomised to treatment sequence Placebo, then LAS190792 100 μg, 400 μg in 3 treatment periods separated by washout periods of 28-42 days.
Part 1 - Cohort 2 LAS190792 20 μg, Placebo, LAS190792 400 μg	All individuals in Part 1 - Cohort 2 who were randomised to treatment sequence LAS190792 20 μg, Placebo, LAS190792 400 μg in 3 treatment periods separated by washout periods of 28-42 days.
Part 1 - Cohort 2 LAS190792 20 μg, 100 μg, then Placebo	All individuals in Part 1 - Cohort 2 who were randomised to treatment sequence LAS190792 20 μg, 100 μg, then Placebo in 3 treatment periods separated by washout periods of 28-42 days.
Overall population - Part 2	All individuals involved in Part 2 (single-dose study of two doses of LAS190792 [100 and 400 μg], indacaterol, tiotropium or placebo, in 5 treatment periods separated by washout periods of 7-14 days).

Participant Flow for 14 periods

Period 1: Period 1 (after screening/run-in period)

	Part 1 - Cohort 1 LAS190792 5 μg, 50 μg, 200 μg	Part 1 - Cohort 1 Placebo, then LAS190792 50 μg, 200 μg	Part 1 - Cohort 1 LAS190792 5 μg, Placebo, LAS190792 200 μg	Part 1 - Cohort 1 LAS190792 5 μg, 50 μg, then Placebo	Part 1 - Cohort 2 LAS190792 20 μg, 100 μg, 400 μg	Part 1 - Cohort 2 Placebo, then LAS190792 100 μg, 400 μg	Part 1 - Cohort 2 LAS190792 20 μg, Placebo, LAS190792 400 μg	Part 1 - Cohort 2 LAS190792 20 μg, 100 μg, then Placebo	Overall population - Part 2
STARTED	2	2	2	2	2	2	2	3	0^[2]
COMPLETED	2	2	2	2	2	2	2	3	0^[3]
NOT COMPLETED	0	0	0	0	0	0	0	0	0

[2]	Part 2 followed Part 1, and comprised 5 treatment periods
[3]	Part 2 followed Part 1, and comprised 5 treatment periods

Period 2: Washout between Periods 1 and 2

	Part 1 - Cohort 1 LAS190792 5 μg, 50 μg, 200 μg	Part 1 - Cohort 1 Placebo, then LAS190792 50 μg, 200 μg	Part 1 - Cohort 1 LAS190792 5 μg, Placebo, LAS190792 200 μg	Part 1 - Cohort 1 LAS190792 5 μg, 50 μg, then Placebo	Part 1 - Cohort 2 LAS190792 20 μg, 100 μg, 400 μg	Part 1 - Cohort 2 Placebo, then LAS190792 100 μg, 400 μg	Part 1 - Cohort 2 LAS190792 20 μg, Placebo, LAS190792 400 μg	Part 1 - Cohort 2 LAS190792 20 μg, 100 μg, then Placebo	Overall population - Part 2
STARTED	2	2	2	2	2	2	2	3	0^[2]
COMPLETED	2	2	2	2	2	2	2	2	0^[3]
NOT COMPLETED	0	0	0	0	0	0	0	1	0
Physician Decision	0	0	0	0	0	0	0	1	0

[2]	Part 2 followed Part 1, and comprised 5 treatment periods
[3]	Part 2 followed Part 1, and comprised 5 treatment periods

Period 3: Period 2

	Part 1 - Cohort 1 LAS190792 5 μg, 50 μg, 200 μg	Part 1 - Cohort 1 Placebo, then LAS190792 50 μg, 200 μg	Part 1 - Cohort 1 LAS190792 5 μg, Placebo, LAS190792 200 μg	Part 1 - Cohort 1 LAS190792 5 μg, 50 μg, then Placebo	Part 1 - Cohort 2 LAS190792 20 μg, 100 μg, 400 μg	Part 1 - Cohort 2 Placebo, then LAS190792 100 μg, 400 μg	Part 1 - Cohort 2 LAS190792 20 μg, Placebo, LAS190792 400 μg	Part 1 - Cohort 2 LAS190792 20 μg, 100 μg, then Placebo	Overall population - Part 2
STARTED	2	2	2	2	2	2	2	2	0^[2]
COMPLETED	2	2	2	2	2	2	2	2	0^[3]
NOT COMPLETED	0	0	0	0	0	0	0	0	0

[2]	Part 2 followed Part 1, and comprised 5 treatment periods
[3]	Part 2 followed Part 1, and comprised 5 treatment periods

Period 4: Washout between Periods 2 and 3

	Part 1 - Cohort 1 LAS190792 5 μg, 50 μg, 200 μg	Part 1 - Cohort 1 Placebo, then LAS190792 50 μg, 200 μg	Part 1 - Cohort 1 LAS190792 5 μg, Placebo, LAS190792 200 μg	Part 1 - Cohort 1 LAS190792 5 μg, 50 μg, then Placebo	Part 1 - Cohort 2 LAS190792 20 μg, 100 μg, 400 μg	Part 1 - Cohort 2 Placebo, then LAS190792 100 μg, 400 μg	Part 1 - Cohort 2 LAS190792 20 μg, Placebo, LAS190792 400 μg	Part 1 - Cohort 2 LAS190792 20 μg, 100 μg, then Placebo	Overall population - Part 2
STARTED	2	2	2	2	2	2	2	2	0^[2]
COMPLETED	2	2	2	2	2	2	2	2	0^[3]
NOT COMPLETED	0	0	0	0	0	0	0	0	0

[2]	Part 2 followed Part 1, and comprised 5 treatment periods
[3]	Part 2 followed Part 1, and comprised 5 treatment periods

Period 5: Period 3

	Part 1 - Cohort 1 LAS190792 5 μg, 50 μg, 200 μg	Part 1 - Cohort 1 Placebo, then LAS190792 50 μg, 200 μg	Part 1 - Cohort 1 LAS190792 5 μg, Placebo, LAS190792 200 μg	Part 1 - Cohort 1 LAS190792 5 μg, 50 μg, then Placebo	Part 1 - Cohort 2 LAS190792 20 μg, 100 μg, 400 μg	Part 1 - Cohort 2 Placebo, then LAS190792 100 μg, 400 μg	Part 1 - Cohort 2 LAS190792 20 μg, Placebo, LAS190792 400 μg	Part 1 - Cohort 2 LAS190792 20 μg, 100 μg, then Placebo	Overall population - Part 2
STARTED	2	2	2	2	2	2	2	2	0^[2]
COMPLETED	2	2	2	2	2	2	2	2	0^[3]
NOT COMPLETED	0	0	0	0	0	0	0	0	0

[2]	Part 2 followed Part 1, and comprised 5 treatment periods
[3]	Part 2 followed Part 1, and comprised 5 treatment periods

Period 6: Period 4 (after screening/run-in period)

	Part 1 - Cohort 1 LAS190792 5 μg, 50 μg, 200 μg	Part 1 - Cohort 1 Placebo, then LAS190792 50 μg, 200 μg	Part 1 - Cohort 1 LAS190792 5 μg, Placebo, LAS190792 200 μg	Part 1 - Cohort 1 LAS190792 5 μg, 50 μg, then Placebo	Part 1 - Cohort 2 LAS190792 20 μg, 100 μg, 400 μg	Part 1 - Cohort 2 Placebo, then LAS190792 100 μg, 400 μg	Part 1 - Cohort 2 LAS190792 20 μg, Placebo, LAS190792 400 μg	Part 1 - Cohort 2 LAS190792 20 μg, 100 μg, then Placebo	Overall population - Part 2
STARTED	0^[1]	0^[2]	0^[2]	0^[3]	0^[4]	0^[5]	0^[6]	0^[7]	38
COMPLETED	0^[9]	0^[10]	0^[10]	0^[11]	0^[12]	0^[13]	0^[14]	0^[15]	38
NOT COMPLETED	0	0	0	0	0	0	0	0	0

[1]	Part 1 comprised 3 treatment periods only
[2]	Part 1 comprised 3 treatment periods only
[2]	Part 1 comprised 3 treatment periods only
[3]	Part 1 comprised 3 treatment periods only
[4]	Part 1 comprised 3 treatment periods only
[5]	Part 1 comprised 3 treatment periods only
[6]	Part 1 comprised 3 treatment periods only
[7]	Part 1 comprised 3 treatment periods only
[9]	Part 1 comprised 3 treatment periods only
[10]	Part 1 comprised 3 treatment periods only
[10]	Part 1 comprised 3 treatment periods only
[11]	Part 1 comprised 3 treatment periods only
[12]	Part 1 comprised 3 treatment periods only
[13]	Part 1 comprised 3 treatment periods only
[14]	Part 1 comprised 3 treatment periods only
[15]	Part 1 comprised 3 treatment periods only

Period 7: Washout between Periods 4 and 5

	Part 1 - Cohort 1 LAS190792 5 μg, 50 μg, 200 μg	Part 1 - Cohort 1 Placebo, then LAS190792 50 μg, 200 μg	Part 1 - Cohort 1 LAS190792 5 μg, Placebo, LAS190792 200 μg	Part 1 - Cohort 1 LAS190792 5 μg, 50 μg, then Placebo	Part 1 - Cohort 2 LAS190792 20 μg, 100 μg, 400 μg	Part 1 - Cohort 2 Placebo, then LAS190792 100 μg, 400 μg	Part 1 - Cohort 2 LAS190792 20 μg, Placebo, LAS190792 400 μg	Part 1 - Cohort 2 LAS190792 20 μg, 100 μg, then Placebo	Overall population - Part 2
STARTED	0^[1]	0^[2]	0^[2]	0^[3]	0^[4]	0^[5]	0^[6]	0^[7]	38
COMPLETED	0^[9]	0^[10]	0^[10]	0^[11]	0^[12]	0^[13]	0^[14]	0^[15]	37
NOT COMPLETED	0	0	0	0	0	0	0	0	1
Adverse Event	0	0	0	0	0	0	0	0	1

[1]	Part 1 comprised 3 treatment periods only
[2]	Part 1 comprised 3 treatment periods only
[2]	Part 1 comprised 3 treatment periods only
[3]	Part 1 comprised 3 treatment periods only
[4]	Part 1 comprised 3 treatment periods only
[5]	Part 1 comprised 3 treatment periods only
[6]	Part 1 comprised 3 treatment periods only
[7]	Part 1 comprised 3 treatment periods only
[9]	Part 1 comprised 3 treatment periods only
[10]	Part 1 comprised 3 treatment periods only
[10]	Part 1 comprised 3 treatment periods only
[11]	Part 1 comprised 3 treatment periods only
[12]	Part 1 comprised 3 treatment periods only
[13]	Part 1 comprised 3 treatment periods only
[14]	Part 1 comprised 3 treatment periods only
[15]	Part 1 comprised 3 treatment periods only

Period 8: Period 5

	Part 1 - Cohort 1 LAS190792 5 μg, 50 μg, 200 μg	Part 1 - Cohort 1 Placebo, then LAS190792 50 μg, 200 μg	Part 1 - Cohort 1 LAS190792 5 μg, Placebo, LAS190792 200 μg	Part 1 - Cohort 1 LAS190792 5 μg, 50 μg, then Placebo	Part 1 - Cohort 2 LAS190792 20 μg, 100 μg, 400 μg	Part 1 - Cohort 2 Placebo, then LAS190792 100 μg, 400 μg	Part 1 - Cohort 2 LAS190792 20 μg, Placebo, LAS190792 400 μg	Part 1 - Cohort 2 LAS190792 20 μg, 100 μg, then Placebo	Overall population - Part 2
STARTED	0^[1]	0^[2]	0^[2]	0^[3]	0^[4]	0^[5]	0^[6]	0^[7]	37
COMPLETED	0^[9]	0^[10]	0^[10]	0^[11]	0^[12]	0^[13]	0^[14]	0^[15]	37
NOT COMPLETED	0	0	0	0	0	0	0	0	0

[1]	Part 1 comprised 3 treatment periods only
[2]	Part 1 comprised 3 treatment periods only
[2]	Part 1 comprised 3 treatment periods only
[3]	Part 1 comprised 3 treatment periods only
[4]	Part 1 comprised 3 treatment periods only
[5]	Part 1 comprised 3 treatment periods only
[6]	Part 1 comprised 3 treatment periods only
[7]	Part 1 comprised 3 treatment periods only
[9]	Part 1 comprised 3 treatment periods only
[10]	Part 1 comprised 3 treatment periods only
[10]	Part 1 comprised 3 treatment periods only
[11]	Part 1 comprised 3 treatment periods only
[12]	Part 1 comprised 3 treatment periods only
[13]	Part 1 comprised 3 treatment periods only
[14]	Part 1 comprised 3 treatment periods only
[15]	Part 1 comprised 3 treatment periods only

Period 9: Washout between Periods 5 and 6

	Part 1 - Cohort 1 LAS190792 5 μg, 50 μg, 200 μg	Part 1 - Cohort 1 Placebo, then LAS190792 50 μg, 200 μg	Part 1 - Cohort 1 LAS190792 5 μg, Placebo, LAS190792 200 μg	Part 1 - Cohort 1 LAS190792 5 μg, 50 μg, then Placebo	Part 1 - Cohort 2 LAS190792 20 μg, 100 μg, 400 μg	Part 1 - Cohort 2 Placebo, then LAS190792 100 μg, 400 μg	Part 1 - Cohort 2 LAS190792 20 μg, Placebo, LAS190792 400 μg	Part 1 - Cohort 2 LAS190792 20 μg, 100 μg, then Placebo	Overall population - Part 2
STARTED	0^[1]	0^[2]	0^[2]	0^[3]	0^[4]	0^[5]	0^[6]	0^[7]	37
COMPLETED	0^[9]	0^[10]	0^[10]	0^[11]	0^[12]	0^[13]	0^[14]	0^[15]	37
NOT COMPLETED	0	0	0	0	0	0	0	0	0

[1]	Part 1 comprised 3 treatment periods only
[2]	Part 1 comprised 3 treatment periods only
[2]	Part 1 comprised 3 treatment periods only
[3]	Part 1 comprised 3 treatment periods only
[4]	Part 1 comprised 3 treatment periods only
[5]	Part 1 comprised 3 treatment periods only
[6]	Part 1 comprised 3 treatment periods only
[7]	Part 1 comprised 3 treatment periods only
[9]	Part 1 comprised 3 treatment periods only
[10]	Part 1 comprised 3 treatment periods only
[10]	Part 1 comprised 3 treatment periods only
[11]	Part 1 comprised 3 treatment periods only
[12]	Part 1 comprised 3 treatment periods only
[13]	Part 1 comprised 3 treatment periods only
[14]	Part 1 comprised 3 treatment periods only
[15]	Part 1 comprised 3 treatment periods only

Period 10: Period 6

	Part 1 - Cohort 1 LAS190792 5 μg, 50 μg, 200 μg	Part 1 - Cohort 1 Placebo, then LAS190792 50 μg, 200 μg	Part 1 - Cohort 1 LAS190792 5 μg, Placebo, LAS190792 200 μg	Part 1 - Cohort 1 LAS190792 5 μg, 50 μg, then Placebo	Part 1 - Cohort 2 LAS190792 20 μg, 100 μg, 400 μg	Part 1 - Cohort 2 Placebo, then LAS190792 100 μg, 400 μg	Part 1 - Cohort 2 LAS190792 20 μg, Placebo, LAS190792 400 μg	Part 1 - Cohort 2 LAS190792 20 μg, 100 μg, then Placebo	Overall population - Part 2
STARTED	0^[1]	0^[2]	0^[2]	0^[3]	0^[4]	0^[5]	0^[6]	0^[7]	37
COMPLETED	0^[9]	0^[10]	0^[10]	0^[11]	0^[12]	0^[13]	0^[14]	0^[15]	37
NOT COMPLETED	0	0	0	0	0	0	0	0	0

[1]	Part 1 comprised 3 treatment periods only
[2]	Part 1 comprised 3 treatment periods only
[2]	Part 1 comprised 3 treatment periods only
[3]	Part 1 comprised 3 treatment periods only
[4]	Part 1 comprised 3 treatment periods only
[5]	Part 1 comprised 3 treatment periods only
[6]	Part 1 comprised 3 treatment periods only
[7]	Part 1 comprised 3 treatment periods only
[9]	Part 1 comprised 3 treatment periods only
[10]	Part 1 comprised 3 treatment periods only
[10]	Part 1 comprised 3 treatment periods only
[11]	Part 1 comprised 3 treatment periods only
[12]	Part 1 comprised 3 treatment periods only
[13]	Part 1 comprised 3 treatment periods only
[14]	Part 1 comprised 3 treatment periods only
[15]	Part 1 comprised 3 treatment periods only

Period 11: Washout between Periods 6 and 7

	Part 1 - Cohort 1 LAS190792 5 μg, 50 μg, 200 μg	Part 1 - Cohort 1 Placebo, then LAS190792 50 μg, 200 μg	Part 1 - Cohort 1 LAS190792 5 μg, Placebo, LAS190792 200 μg	Part 1 - Cohort 1 LAS190792 5 μg, 50 μg, then Placebo	Part 1 - Cohort 2 LAS190792 20 μg, 100 μg, 400 μg	Part 1 - Cohort 2 Placebo, then LAS190792 100 μg, 400 μg	Part 1 - Cohort 2 LAS190792 20 μg, Placebo, LAS190792 400 μg	Part 1 - Cohort 2 LAS190792 20 μg, 100 μg, then Placebo	Overall population - Part 2
STARTED	0^[1]	0^[2]	0^[2]	0^[3]	0^[4]	0^[5]	0^[6]	0^[7]	37
COMPLETED	0^[9]	0^[10]	0^[10]	0^[11]	0^[12]	0^[13]	0^[14]	0^[15]	36
NOT COMPLETED	0	0	0	0	0	0	0	0	1
Physician Decision	0	0	0	0	0	0	0	0	1

[1]	Part 1 comprised 3 treatment periods only
[2]	Part 1 comprised 3 treatment periods only
[2]	Part 1 comprised 3 treatment periods only
[3]	Part 1 comprised 3 treatment periods only
[4]	Part 1 comprised 3 treatment periods only
[5]	Part 1 comprised 3 treatment periods only
[6]	Part 1 comprised 3 treatment periods only
[7]	Part 1 comprised 3 treatment periods only
[9]	Part 1 comprised 3 treatment periods only
[10]	Part 1 comprised 3 treatment periods only
[10]	Part 1 comprised 3 treatment periods only
[11]	Part 1 comprised 3 treatment periods only
[12]	Part 1 comprised 3 treatment periods only
[13]	Part 1 comprised 3 treatment periods only
[14]	Part 1 comprised 3 treatment periods only
[15]	Part 1 comprised 3 treatment periods only

Period 12: Period 7

	Part 1 - Cohort 1 LAS190792 5 μg, 50 μg, 200 μg	Part 1 - Cohort 1 Placebo, then LAS190792 50 μg, 200 μg	Part 1 - Cohort 1 LAS190792 5 μg, Placebo, LAS190792 200 μg	Part 1 - Cohort 1 LAS190792 5 μg, 50 μg, then Placebo	Part 1 - Cohort 2 LAS190792 20 μg, 100 μg, 400 μg	Part 1 - Cohort 2 Placebo, then LAS190792 100 μg, 400 μg	Part 1 - Cohort 2 LAS190792 20 μg, Placebo, LAS190792 400 μg	Part 1 - Cohort 2 LAS190792 20 μg, 100 μg, then Placebo	Overall population - Part 2
STARTED	0^[1]	0^[2]	0^[2]	0^[3]	0^[4]	0^[5]	0^[6]	0^[7]	36
COMPLETED	0^[9]	0^[10]	0^[10]	0^[11]	0^[12]	0^[13]	0^[14]	0^[15]	36
NOT COMPLETED	0	0	0	0	0	0	0	0	0

[1]	Part 1 comprised 3 treatment periods only
[2]	Part 1 comprised 3 treatment periods only
[2]	Part 1 comprised 3 treatment periods only
[3]	Part 1 comprised 3 treatment periods only
[4]	Part 1 comprised 3 treatment periods only
[5]	Part 1 comprised 3 treatment periods only
[6]	Part 1 comprised 3 treatment periods only
[7]	Part 1 comprised 3 treatment periods only
[9]	Part 1 comprised 3 treatment periods only
[10]	Part 1 comprised 3 treatment periods only
[10]	Part 1 comprised 3 treatment periods only
[11]	Part 1 comprised 3 treatment periods only
[12]	Part 1 comprised 3 treatment periods only
[13]	Part 1 comprised 3 treatment periods only
[14]	Part 1 comprised 3 treatment periods only
[15]	Part 1 comprised 3 treatment periods only

Period 13: Washout between Periods 7 and 8

	Part 1 - Cohort 1 LAS190792 5 μg, 50 μg, 200 μg	Part 1 - Cohort 1 Placebo, then LAS190792 50 μg, 200 μg	Part 1 - Cohort 1 LAS190792 5 μg, Placebo, LAS190792 200 μg	Part 1 - Cohort 1 LAS190792 5 μg, 50 μg, then Placebo	Part 1 - Cohort 2 LAS190792 20 μg, 100 μg, 400 μg	Part 1 - Cohort 2 Placebo, then LAS190792 100 μg, 400 μg	Part 1 - Cohort 2 LAS190792 20 μg, Placebo, LAS190792 400 μg	Part 1 - Cohort 2 LAS190792 20 μg, 100 μg, then Placebo	Overall population - Part 2
STARTED	0^[1]	0^[2]	0^[2]	0^[3]	0^[4]	0^[5]	0^[6]	0^[7]	36
COMPLETED	0^[9]	0^[10]	0^[10]	0^[11]	0^[12]	0^[13]	0^[14]	0^[15]	34
NOT COMPLETED	0	0	0	0	0	0	0	0	2
Adverse Event	0	0	0	0	0	0	0	0	1
Withdrawal by Subject	0	0	0	0	0	0	0	0	1

[1]	Part 1 comprised 3 treatment periods only
[2]	Part 1 comprised 3 treatment periods only
[2]	Part 1 comprised 3 treatment periods only
[3]	Part 1 comprised 3 treatment periods only
[4]	Part 1 comprised 3 treatment periods only
[5]	Part 1 comprised 3 treatment periods only
[6]	Part 1 comprised 3 treatment periods only
[7]	Part 1 comprised 3 treatment periods only
[9]	Part 1 comprised 3 treatment periods only
[10]	Part 1 comprised 3 treatment periods only
[10]	Part 1 comprised 3 treatment periods only
[11]	Part 1 comprised 3 treatment periods only
[12]	Part 1 comprised 3 treatment periods only
[13]	Part 1 comprised 3 treatment periods only
[14]	Part 1 comprised 3 treatment periods only
[15]	Part 1 comprised 3 treatment periods only

Period 14: Period 8

	Part 1 - Cohort 1 LAS190792 5 μg, 50 μg, 200 μg	Part 1 - Cohort 1 Placebo, then LAS190792 50 μg, 200 μg	Part 1 - Cohort 1 LAS190792 5 μg, Placebo, LAS190792 200 μg	Part 1 - Cohort 1 LAS190792 5 μg, 50 μg, then Placebo	Part 1 - Cohort 2 LAS190792 20 μg, 100 μg, 400 μg	Part 1 - Cohort 2 Placebo, then LAS190792 100 μg, 400 μg	Part 1 - Cohort 2 LAS190792 20 μg, Placebo, LAS190792 400 μg	Part 1 - Cohort 2 LAS190792 20 μg, 100 μg, then Placebo	Overall population - Part 2
STARTED	0^[1]	0^[2]	0^[2]	0^[3]	0^[4]	0^[5]	0^[6]	0^[7]	34
COMPLETED	0^[9]	0^[10]	0^[10]	0^[11]	0^[12]	0^[13]	0^[14]	0^[15]	34
NOT COMPLETED	0	0	0	0	0	0	0	0	0

[1]	Part 1 comprised 3 treatment periods only
[2]	Part 1 comprised 3 treatment periods only
[2]	Part 1 comprised 3 treatment periods only
[3]	Part 1 comprised 3 treatment periods only
[4]	Part 1 comprised 3 treatment periods only
[5]	Part 1 comprised 3 treatment periods only
[6]	Part 1 comprised 3 treatment periods only
[7]	Part 1 comprised 3 treatment periods only
[9]	Part 1 comprised 3 treatment periods only
[10]	Part 1 comprised 3 treatment periods only
[10]	Part 1 comprised 3 treatment periods only
[11]	Part 1 comprised 3 treatment periods only
[12]	Part 1 comprised 3 treatment periods only
[13]	Part 1 comprised 3 treatment periods only
[14]	Part 1 comprised 3 treatment periods only
[15]	Part 1 comprised 3 treatment periods only

Baseline Characteristics

Analysis Population Description -- Explanation of how the number of participants for analysis was determined.

Number of participants randomised in Part 1 – Cohorts 1 and 2 treatment sequences (incomplete crossover design) and overall in Part 2 (due to 5-way crossover design), respectively. Parts 1 and 2 were independent: there was no intention to compare the results of the 2 parts of the study.

Reporting Groups

	Description
Part 1 - Cohort 1 LAS190792 5 μg, 50 μg, 200 μg	All individuals in Part 1 - Cohort 1 who were randomised to treatment sequence LAS190792 5 μg, 50 μg, 200 μg in 3 treatment periods separated by washout periods of 28-42 days.
Part 1 - Cohort 1 Placebo, then LAS190792 50 μg, 200 μg	All individuals in Part 1 - Cohort 1 who were randomised to treatment sequence Placebo, then LAS190792 50 μg, 200 μg in 3 treatment periods separated by washout periods of 28-42 days.
Part 1 - Cohort 1 LAS190792 5 μg, Placebo, LAS190792 200 μg	All individuals in Part 1 - Cohort 1 who were randomised to treatment sequence LAS190792 5 μg, Placebo, LAS190792 200 μg in 3 treatment periods separated by washout periods of 28-42 days.
Part 1 - Cohort 1 LAS190792 5 μg, 50 μg, then Placebo	All individuals in Part 1 - Cohort 1 who were randomised to treatment sequence LAS190792 5 μg, 50 μg, then Placebo in 3 treatment periods separated by washout periods of 28-42 days.
Part 1 - Cohort 2 LAS190792 20 μg, 100 μg, 400 μg	All individuals in Part 1 - Cohort 2 who were randomised to treatment sequence LAS190792 20 μg, 100 μg, 400 μg in 3 treatment periods separated by washout periods of 28-42 days.
Part 1 - Cohort 2 Placebo, then LAS190792 100 μg, 400 μg	All individuals in Part 1 - Cohort 2 who were randomised to treatment sequence Placebo, then LAS190792 100 μg, 400 μg in 3 treatment periods separated by washout periods of 28-42 days.
Part 1 - Cohort 2 LAS190792 20 μg, Placebo, LAS190792 400 μg	All individuals in Part 1 - Cohort 2 who were randomised to treatment sequence LAS190792 20 μg, Placebo, LAS190792 400 μg in 3 treatment periods separated by washout periods of 28-42 days.
Part 1 - Cohort 2 LAS190792 20 μg, 100 μg, then Placebo	All individuals in Part 1 - Cohort 2 who were randomised to treatment sequence LAS190792 20 μg, 100 μg, then Placebo in 3 treatment periods separated by washout periods of 28-42 days.
Overall population - Part 2	All individuals involved in Part 2 (single-dose study of two doses of LAS190792 [100 and 400 μg], indacaterol, tiotropium or placebo, in 5 treatment periods separated by washout periods of 7-14 days).

Baseline Measures

	Part 1 - Cohort 1 LAS190792 5 μg, 50 μg, 200 μg	Part 1 - Cohort 1 Placebo, then LAS190792 50 μg, 200 μg	Part 1 - Cohort 1 LAS190792 5 μg, Placebo, LAS190792 200 μg	Part 1 - Cohort 1 LAS190792 5 μg, 50 μg, then Placebo	Part 1 - Cohort 2 LAS190792 20 μg, 100 μg, 400 μg	Part 1 - Cohort 2 Placebo, then LAS190792 100 μg, 400 μg	Part 1 - Cohort 2 LAS190792 20 μg, Placebo, LAS190792 400 μg	Part 1 - Cohort 2 LAS190792 20 μg, 100 μg, then Placebo	Overall population - Part 2	Total
Number of Participants [units: Participants]	2	2	2	2	2	2	2	3	38	55
Age Continuous [units: Years] Mean ± Standard Deviation
Part 1	35 ± 8.5	34.5 ± 20.5	35 ± 4.2	37 ± 19.8	32.5 ± 6.4	41.5 ± 29.0	28 ± 1.4	34.3 ± 12.7		34.7 ± 12.0
Part 2									60.4 ± 5.9	60.4 ± 5.9
Sex: Female, Male [units: ]
Part 1
Female	0	0	0	0	0	0	0	0	0	0
Male	2	2	2	2	2	2	2	3	0	17
Part 2
Female	0	0	0	0	0	0	0	0	18	18
Male	0	0	0	0	0	0	0	0	20	20

Outcome Measures

1. Primary Outcome Measure: Subjects with ≥1 treatment-emergent adverse event [ Time Frame: 30 Days ]

Measure Type	Primary
Measure Name	Subjects with ≥1 treatment-emergent adverse event
Measure Description	Adverse events (AEs) are any unfavorable and unintended medical occurrence during the subject’s participation in the study (including deterioration of a pre-existing medical condition, an abnormal value in a laboratory assessment, an ECG abnormality, a 12-lead 24-hour ECG-Holter abnormality, a blood pressure abnormal value, paradoxal bronchospasm or an abnormal finding in the physical examination) and will be coded using the current Medical Dictionary for Regulatory Activities (MedDRA).
Time Frame	30 Days
Safety Issue?	Yes

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Safety Population: defined as all randomized subjects who received at least one dose of the investigational product

Reporting Groups

	Description
LAS190792 5 µg (Part 1)	Single dose, oral inhalation by Genuair® single-dose dry powder inhaler (DPI)
LAS190792 20 µg (Part 1)	Single dose, oral inhalation by Genuair® single-dose dry powder inhaler (DPI)
LAS190792 50 µg (Part 1)	Single dose, oral inhalation by Genuair® single-dose dry powder inhaler (DPI)
LAS190792 100 µg (Part 1)	Single dose, oral inhalation by Genuair® single-dose dry powder inhaler (DPI)
LAS190792 200 µg (Part 1)	Single dose, oral inhalation by Genuair® single-dose dry powder inhaler (DPI)
LAS190792 400 µg (Part 1)	Single dose, oral inhalation by Genuair® single-dose dry powder inhaler (DPI)
Placebo (Part 1)	Single dose, oral inhalation by Genuair® single-dose dry powder inhaler (DPI)
LAS190792 100 µg (Part 2)	Single dose, oral inhalation by Genuair® single-dose dry powder inhaler (DPI)
LAS190792 400 µg (Part 2)	Single dose, oral inhalation by Genuair® single-dose dry powder inhaler (DPI)
Tiotropium 18 μg	Single dose, oral inhalation by HandiHaler® single-dose dry powder inhaler (DPI)
Indacaterol 150 μg	Single dose, oral inhalation by Breezhaler® single-dose dry powder inhaler (DPI)
Placebo (Part 2)	Single dose, oral inhalation by Genuair® single-dose dry powder inhaler (DPI)

Measured Values

	LAS190792 5 µg (Part 1)	LAS190792 20 µg (Part 1)	LAS190792 50 µg (Part 1)	LAS190792 100 µg (Part 1)	LAS190792 200 µg (Part 1)	LAS190792 400 µg (Part 1)	Placebo (Part 1)	LAS190792 100 µg (Part 2)	LAS190792 400 µg (Part 2)	Tiotropium 18 μg	Indacaterol 150 μg	Placebo (Part 2)
Number of Participants Analyzed [units:participants]	6	6	6	6	6	6	12	36	35	37	37	37
Subjects with ≥1 treatment-emergent adverse event [units: Participants]	2	3	2	2	2	4	3	12	12	14	21	15

No statistical analysis provided for Subjects with ≥1 treatment-emergent adverse event

2. Primary Outcome Measure: Change from baseline in trough FEV1 (forced expiratory volume in 1 second) [ Time Frame: Day 2 ]

Measure Type	Primary
Measure Name	Change from baseline in trough FEV1 (forced expiratory volume in 1 second)
Measure Description	Trough is defined as the mean of the FEV1 values obtained at 23 hours and at 24 hours after morning investigational product administration.
Time Frame	Day 2
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Per Protocol Population: defined as all randomized subjects who satisfied the main inclusion / exclusion criteria, received investigational product, completed at least one treatment period, and did not present major violations to the protocol.

Reporting Groups

	Description
LAS190792 5 µg (Part 1)	Single dose, oral inhalation by Genuair® single-dose dry powder inhaler (DPI)
LAS190792 20 µg (Part 1)	Single dose, oral inhalation by Genuair® single-dose dry powder inhaler (DPI)
LAS190792 50 µg (Part 1)	Single dose, oral inhalation by Genuair® single-dose dry powder inhaler (DPI)
LAS190792 100 µg (Part 1)	Single dose, oral inhalation by Genuair® single-dose dry powder inhaler (DPI)
LAS190792 200 µg (Part 1)	Single dose, oral inhalation by Genuair® single-dose dry powder inhaler (DPI)
LAS190792 400 µg (Part 1)	Single dose, oral inhalation by Genuair® single-dose dry powder inhaler (DPI)
Placebo (Part 1)	Single dose, oral inhalation by Genuair® single-dose dry powder inhaler (DPI)
LAS190792 100 µg (Part 2)	Single dose, oral inhalation by Genuair® single-dose dry powder inhaler (DPI)
LAS190792 400 µg (Part 2)	Single dose, oral inhalation by Genuair® single-dose dry powder inhaler (DPI)
Tiotropium 18 μg	Single dose, oral inhalation by HandiHaler® single-dose dry powder inhaler (DPI)
Indacaterol 150 μg	Single dose, oral inhalation by Breezhaler® single-dose dry powder inhaler (DPI)
Placebo (Part 2)	Single dose, oral inhalation by Genuair® single-dose dry powder inhaler (DPI)

Measured Values

	LAS190792 5 µg (Part 1)	LAS190792 20 µg (Part 1)	LAS190792 50 µg (Part 1)	LAS190792 100 µg (Part 1)	LAS190792 200 µg (Part 1)	LAS190792 400 µg (Part 1)	Placebo (Part 1)	LAS190792 100 µg (Part 2)	LAS190792 400 µg (Part 2)	Tiotropium 18 μg	Indacaterol 150 μg	Placebo (Part 2)
Number of Participants Analyzed [units:participants]	6	6	6	6	6	6	12	36	35	37	37	37
Change from baseline in trough FEV1 (forced expiratory volume in 1 second) [units: Liters] Mean (Standard Deviation)	-0.013 (0.333)	0.161 (0.131)	0.523 (0.448)	0.536 (0.170)	0.371 (0.333)	0.599 (0.316)	0.029 (0.144)	1.369 (0.505)	1.360 (0.472)	1.379 (0.502)	1.361 (0.481)	1.338 (0.506)

Statistical Analysis 1 for Change from baseline in trough FEV1 (forced expiratory volume in 1 second)

Groups^[1]	LAS190792 100 µg (Part 2), Placebo (Part 2)
Method^[3]	ANCOVA
P-Value^[4]	<0.0001
Other^[5]	0.104
Standard Error of the mean	± 0.023
95% Confidence Interval	( 0.060 to 0.149 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Change from baseline to trough FEV1 was analyzed by means of an analysis of covariance (ANCOVA) for cross-over designs with sequence, treatment group and period as fixed effect factors, subject within sequence as random effect, and screening and baseline FEV1 value of each period as covariates
[3]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	All statistical comparisons were two-sided hypothesis tests, and the significance level was set at 0.05 without multiplicity adjustment
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 2 for Change from baseline in trough FEV1 (forced expiratory volume in 1 second)

Groups^[1]	LAS190792 400 µg (Part 2), Placebo (Part 2)
Method^[3]	ANCOVA
P-Value^[4]	<0.0001
Other^[5]	0.178
Standard Error of the mean	± 0.023
95% Confidence Interval	( 0.133 to 0.223 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Change from baseline to trough FEV1 was analyzed by means of an analysis of covariance (ANCOVA) for cross-over designs with sequence, treatment group and period as fixed effect factors, subject within sequence as random effect, and screening and baseline FEV1 value of each period as covariates
[3]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	All statistical comparisons were two-sided hypothesis tests, and the significance level was set at 0.05 without multiplicity adjustment
[5]	Other relevant estimation information:
	No text entered.

3. Secondary Outcome Measure: Maximum observed plasma concentration (Cmax) [ Time Frame: Up to 36 hours after investigational product administration ]

Measure Type	Secondary
Measure Name	Maximum observed plasma concentration (Cmax)
Measure Description
Time Frame	Up to 36 hours after investigational product administration
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Pharmacokinetic population: defined as all randomized subjects who received at least one dose of investigational product in at least one treatment period and have evaluable PK parameters

Reporting Groups

	Description
LAS190792 5 µg (Part 1)	Single dose, oral inhalation by Genuair® single-dose dry powder inhaler (DPI)
LAS190792 20 µg (Part 1)	Single dose, oral inhalation by Genuair® single-dose dry powder inhaler (DPI)
LAS190792 50 µg (Part 1)	Single dose, oral inhalation by Genuair® single-dose dry powder inhaler (DPI)
LAS190792 100 µg (Part 1)	Single dose, oral inhalation by Genuair® single-dose dry powder inhaler (DPI)
LAS190792 200 µg (Part 1)	Single dose, oral inhalation by Genuair® single-dose dry powder inhaler (DPI)
LAS190792 400 µg (Part 1)	Single dose, oral inhalation by Genuair® single-dose dry powder inhaler (DPI)
LAS190792 100 µg (Part 2)	Single dose, oral inhalation by Genuair® single-dose dry powder inhaler (DPI)
LAS190792 400 µg (Part 2)	Single dose, oral inhalation by Genuair® single-dose dry powder inhaler (DPI)

Measured Values

	LAS190792 5 µg (Part 1)	LAS190792 20 µg (Part 1)	LAS190792 50 µg (Part 1)	LAS190792 100 µg (Part 1)	LAS190792 200 µg (Part 1)	LAS190792 400 µg (Part 1)	LAS190792 100 µg (Part 2)	LAS190792 400 µg (Part 2)
Number of Participants Analyzed [units:participants]	6	6	6	6	6	6	12	10
Maximum observed plasma concentration (Cmax) [units: pg/mL] Mean (Standard Deviation)	NA (NA)^[1]	NA (NA)^[1]	8.79 (4.86)	19.5 (8.45)	43.9 (16.8)	59.7 (19.2)	15.4 (6.39)	56.2 (10.1)

No statistical analysis provided for Maximum observed plasma concentration (Cmax)

4. Secondary Outcome Measure: Time to maximum observed plasma concentration (Tmax) [ Time Frame: Up to 36 hours after investigational product administration ]

Measure Type	Secondary
Measure Name	Time to maximum observed plasma concentration (Tmax)
Measure Description
Time Frame	Up to 36 hours after investigational product administration
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Pharmacokinetic population: defined as all randomized subjects who received at least one dose of investigational product in at least one treatment period and have evaluable PK parameters

Reporting Groups

	Description
LAS190792 5 µg (Part 1)	Single dose, oral inhalation by Genuair® single-dose dry powder inhaler (DPI)
LAS190792 20 µg (Part 1)	Single dose, oral inhalation by Genuair® single-dose dry powder inhaler (DPI)
LAS190792 50 µg (Part 1)	Single dose, oral inhalation by Genuair® single-dose dry powder inhaler (DPI)
LAS190792 100 µg (Part 1)	Single dose, oral inhalation by Genuair® single-dose dry powder inhaler (DPI)
LAS190792 200 µg (Part 1)	Single dose, oral inhalation by Genuair® single-dose dry powder inhaler (DPI)
LAS190792 400 µg (Part 1)	Single dose, oral inhalation by Genuair® single-dose dry powder inhaler (DPI)
LAS190792 100 µg (Part 2)	Single dose, oral inhalation by Genuair® single-dose dry powder inhaler (DPI)
LAS190792 400 µg (Part 2)	Single dose, oral inhalation by Genuair® single-dose dry powder inhaler (DPI)

Measured Values

	LAS190792 5 µg (Part 1)	LAS190792 20 µg (Part 1)	LAS190792 50 µg (Part 1)	LAS190792 100 µg (Part 1)	LAS190792 200 µg (Part 1)	LAS190792 400 µg (Part 1)	LAS190792 100 µg (Part 2)	LAS190792 400 µg (Part 2)
Number of Participants Analyzed [units:participants]	6	6	6	6	6	6	12	10
Time to maximum observed plasma concentration (Tmax) [units: Hours] Median (Full Range)	NA (NA to NA) ^[1]	NA (NA to NA) ^[1]	0.25 (0.25 to 0.5)	0.5 (0.28 to 0.75)	0.375 (0.25 to 0.5)	0.517 (0.25 to 0.75)	0.5 (0.25 to 0.75)	0.517 (0.317 to 1.0)

No statistical analysis provided for Time to maximum observed plasma concentration (Tmax)

5. Secondary Outcome Measure: Area under the concentration-time curve from zero to the time of the last measurable concentration [ Time Frame: Up to 36 hours after investigational product administration ]

Measure Type	Secondary
Measure Name	Area under the concentration-time curve from zero to the time of the last measurable concentration
Measure Description
Time Frame	Up to 36 hours after investigational product administration
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Pharmacokinetic population: defined as all randomized subjects who received at least one dose of investigational product in at least one treatment period and have evaluable PK parameters

Reporting Groups

	Description
LAS190792 5 µg (Part 1)	Single dose, oral inhalation by Genuair® single-dose dry powder inhaler (DPI)
LAS190792 20 µg (Part 1)	Single dose, oral inhalation by Genuair® single-dose dry powder inhaler (DPI)
LAS190792 50 µg (Part 1)	Single dose, oral inhalation by Genuair® single-dose dry powder inhaler (DPI)
LAS190792 100 µg (Part 1)	Single dose, oral inhalation by Genuair® single-dose dry powder inhaler (DPI)
LAS190792 200 µg (Part 1)	Single dose, oral inhalation by Genuair® single-dose dry powder inhaler (DPI)
LAS190792 400 µg (Part 1)	Single dose, oral inhalation by Genuair® single-dose dry powder inhaler (DPI)
LAS190792 100 µg (Part 2)	Single dose, oral inhalation by Genuair® single-dose dry powder inhaler (DPI)
LAS190792 400 µg (Part 2)	Single dose, oral inhalation by Genuair® single-dose dry powder inhaler (DPI)

Measured Values

	LAS190792 5 µg (Part 1)	LAS190792 20 µg (Part 1)	LAS190792 50 µg (Part 1)	LAS190792 100 µg (Part 1)	LAS190792 200 µg (Part 1)	LAS190792 400 µg (Part 1)	LAS190792 100 µg (Part 2)	LAS190792 400 µg (Part 2)
Number of Participants Analyzed [units:participants]	6	6	6	6	6	6	12	10
Area under the concentration-time curve from zero to the time of the last measurable concentration [units: pg.h/mL] Mean (Standard Deviation)	NA (NA)^[1]	0.106 (0.259)	5.50 (3.53)	20.1 (17.3)	82.7 (43.3)	122 (57.1)	20.5 (15.4)	127 (67.2)

No statistical analysis provided for Area under the concentration-time curve from zero to the time of the last measurable concentration

Serious Adverse Events

Time Frame	Up to 14 (±2) days after the last investigational product administration or after premature discontinuation.
Additional Description	The Safety population comprised all randomised participants who received at least one dose of investigational product.

Reporting Groups

	Description
LAS190792 5 µg (Part 1)	Single dose, oral inhalation by Genuair® single-dose dry powder inhaler (DPI)
LAS190792 20 µg (Part 1)	Single dose, oral inhalation by Genuair® single-dose dry powder inhaler (DPI)
LAS190792 50 µg (Part 1)	Single dose, oral inhalation by Genuair® single-dose dry powder inhaler (DPI)
LAS190792 100 µg (Part 1)	Single dose, oral inhalation by Genuair® single-dose dry powder inhaler (DPI)
LAS190792 200 µg (Part 1)	Single dose, oral inhalation by Genuair® single-dose dry powder inhaler (DPI)
LAS190792 400 µg (Part 1)	Single dose, oral inhalation by Genuair® single-dose dry powder inhaler (DPI)
Placebo (Part 1)	Single dose, oral inhalation by Genuair® single-dose dry powder inhaler (DPI)
LAS190792 100 µg (Part 2)	Single dose, oral inhalation by Genuair® single-dose dry powder inhaler (DPI)
LAS190792 400 µg (Part 2)	Single dose, oral inhalation by Genuair® single-dose dry powder inhaler (DPI)
Tiotropium 18 μg	Single dose, oral inhalation by HandiHaler® single-dose dry powder inhaler (DPI)
Indacaterol 150 μg	Single dose, oral inhalation by Breezhaler® single-dose dry powder inhaler (DPI)
Placebo (Part 2)	Single dose, oral inhalation by Genuair® single-dose dry powder inhaler (DPI)

Serious Adverse Events

LAS190792 5 µg (Part 1)

LAS190792 20 µg (Part 1)

LAS190792 50 µg (Part 1)

LAS190792 100 µg (Part 1)

LAS190792 200 µg (Part 1)

LAS190792 400 µg (Part 1)

Placebo (Part 1)

LAS190792 100 µg (Part 2)

LAS190792 400 µg (Part 2)

Tiotropium 18 μg

Indacaterol 150 μg

Placebo (Part 2)

Total, serious adverse events

# participants affected / at risk

0/6 (0.00%)

1/6 (16.67%)

0/6 (0.00%)

0/12 (0.00%)

0/36 (0.00%)

0/35 (0.00%)

0/37 (0.00%)

Infections and infestations

Scrotal abscess¹,^†

# participants affected / at risk

0/6 (0.00%)

1/6 (16.67%)

0/6 (0.00%)

0/12 (0.00%)

0/36 (0.00%)

0/35 (0.00%)

0/37 (0.00%)

# events

†	Events were collected by systematic assessment
1	Term from vocabulary, MedDRA 16.1

Other Adverse Events

Time Frame	Up to 14 (±2) days after the last investigational product administration or after premature discontinuation.
Additional Description	The Safety population comprised all randomised participants who received at least one dose of investigational product.

Frequency Threshold

Threshold above which other adverse events are reported	5%

Reporting Groups

	Description
LAS190792 5 µg (Part 1)	Single dose, oral inhalation by Genuair® single-dose dry powder inhaler (DPI)
LAS190792 20 µg (Part 1)	Single dose, oral inhalation by Genuair® single-dose dry powder inhaler (DPI)
LAS190792 50 µg (Part 1)	Single dose, oral inhalation by Genuair® single-dose dry powder inhaler (DPI)
LAS190792 100 µg (Part 1)	Single dose, oral inhalation by Genuair® single-dose dry powder inhaler (DPI)
LAS190792 200 µg (Part 1)	Single dose, oral inhalation by Genuair® single-dose dry powder inhaler (DPI)
LAS190792 400 µg (Part 1)	Single dose, oral inhalation by Genuair® single-dose dry powder inhaler (DPI)
Placebo (Part 1)	Single dose, oral inhalation by Genuair® single-dose dry powder inhaler (DPI)
LAS190792 100 µg (Part 2)	Single dose, oral inhalation by Genuair® single-dose dry powder inhaler (DPI)
LAS190792 400 µg (Part 2)	Single dose, oral inhalation by Genuair® single-dose dry powder inhaler (DPI)
Tiotropium 18 μg	Single dose, oral inhalation by HandiHaler® single-dose dry powder inhaler (DPI)
Indacaterol 150 μg	Single dose, oral inhalation by Breezhaler® single-dose dry powder inhaler (DPI)
Placebo (Part 2)	Single dose, oral inhalation by Genuair® single-dose dry powder inhaler (DPI)

Other Adverse Events

LAS190792 5 µg (Part 1)

LAS190792 20 µg (Part 1)

LAS190792 50 µg (Part 1)

LAS190792 100 µg (Part 1)

LAS190792 200 µg (Part 1)

LAS190792 400 µg (Part 1)

Placebo (Part 1)

LAS190792 100 µg (Part 2)

LAS190792 400 µg (Part 2)

Tiotropium 18 μg

Indacaterol 150 μg

Placebo (Part 2)

Total, other (not including serious) adverse events

# participants affected / at risk

2/6 (33.33%)

3/6 (50.00%)

1/6 (16.67%)

2/6 (33.33%)

4/6 (66.67%)

3/12 (25.00%)

4/36 (11.11%)

9/35 (25.71%)

6/37 (16.22%)

15/37 (40.54%)

11/37 (29.73%)

Infections and infestations

Rhinitis¹,^†

# participants affected / at risk

0/6 (0.00%)

1/6 (16.67%)

0/6 (0.00%)

1/6 (16.67%)

0/12 (0.00%)

0/36 (0.00%)

1/35 (2.86%)

0/37 (0.00%)

# events

Injury, poisoning and procedural complications

Eye contusion¹,^†

# participants affected / at risk

0/6 (0.00%)

1/6 (16.67%)

0/6 (0.00%)

0/12 (0.00%)

0/36 (0.00%)

0/35 (0.00%)

0/37 (0.00%)

# events

Injury, poisoning and procedural complications

Ligament rupture¹,^†

# participants affected / at risk

0/6 (0.00%)

1/12 (8.33%)

0/36 (0.00%)

0/35 (0.00%)

0/37 (0.00%)

# events

Injury, poisoning and procedural complications

Tooth injury¹,^†

# participants affected / at risk

0/6 (0.00%)

1/6 (16.67%)

0/12 (0.00%)

0/36 (0.00%)

0/35 (0.00%)

0/37 (0.00%)

# events

Nervous system disorders

Headache¹,^†

# participants affected / at risk

1/6 (16.67%)

0/6 (0.00%)

2/6 (33.33%)

0/6 (0.00%)

2/6 (33.33%)

2/12 (16.67%)

3/36 (8.33%)

5/35 (14.29%)

6/37 (16.22%)

8/37 (21.62%)

4/37 (10.81%)

# events

Nervous system disorders

Presyncope¹,^†

# participants affected / at risk

0/6 (0.00%)

2/6 (33.33%)

0/6 (0.00%)

0/12 (0.00%)

0/36 (0.00%)

0/35 (0.00%)

1/37 (2.70%)

0/37 (0.00%)

# events

Nervous system disorders

Dizziness¹,^†

# participants affected / at risk

0/6 (0.00%)

1/6 (16.67%)

0/6 (0.00%)

0/12 (0.00%)

1/36 (2.78%)

0/35 (0.00%)

1/37 (2.70%)

0/37 (0.00%)

# events

Nervous system disorders

Dizziness postural¹,^†

# participants affected / at risk

0/6 (0.00%)

1/6 (16.67%)

0/6 (0.00%)

0/12 (0.00%)

0/36 (0.00%)

0/35 (0.00%)

0/37 (0.00%)

# events

Respiratory, thoracic and mediastinal disorders

Oropharyngeal pain¹,^†

# participants affected / at risk

0/6 (0.00%)

1/6 (16.67%)

0/6 (0.00%)

0/12 (0.00%)

0/36 (0.00%)

0/35 (0.00%)

1/37 (2.70%)

0/37 (0.00%)

# events

Respiratory, thoracic and mediastinal disorders

Rhinitis allergic¹,^†

# participants affected / at risk

0/6 (0.00%)

1/6 (16.67%)

0/6 (0.00%)

0/12 (0.00%)

0/36 (0.00%)

0/35 (0.00%)

0/37 (0.00%)

# events

Blood and lymphatic system disorders

Lymphadenopathy¹,^†

# participants affected / at risk

0/6 (0.00%)

1/6 (16.67%)

0/12 (0.00%)

0/36 (0.00%)

0/35 (0.00%)

0/37 (0.00%)

# events

Ear and labyrinth disorders

Ear pain¹,^†

# participants affected / at risk

1/6 (16.67%)

0/6 (0.00%)

0/12 (0.00%)

0/36 (0.00%)

0/35 (0.00%)

0/37 (0.00%)

1/37 (2.70%)

# events

Eye disorders

Eye pruritus¹,^†

# participants affected / at risk

0/6 (0.00%)

1/12 (8.33%)

0/36 (0.00%)

0/35 (0.00%)

0/37 (0.00%)

# events

Gastrointestinal disorders

Aphthous stomatitis¹,^†

# participants affected / at risk

1/6 (16.67%)

0/6 (0.00%)

0/12 (0.00%)

0/36 (0.00%)

0/35 (0.00%)

0/37 (0.00%)

# events

Vascular disorders

Thrombophlebitis¹,^†

# participants affected / at risk

0/6 (0.00%)

1/6 (16.67%)

0/12 (0.00%)

0/36 (0.00%)

0/35 (0.00%)

0/37 (0.00%)

# events

General disorders

Vessel puncture site bruise¹,^†

# participants affected / at risk

0/6 (0.00%)

0/12 (0.00%)

1/36 (2.78%)

0/35 (0.00%)

1/37 (2.70%)

2/37 (5.41%)

1/37 (2.70%)

# events

Injury, poisoning and procedural complications

Contusion¹,^†

# participants affected / at risk

0/6 (0.00%)

0/12 (0.00%)

0/36 (0.00%)

3/35 (8.57%)

1/37 (2.70%)

0/37 (0.00%)

1/37 (2.70%)

# events

Musculoskeletal and connective tissue disorders

Musculoskeletal pain¹,^†

# participants affected / at risk

0/6 (0.00%)

0/12 (0.00%)

0/36 (0.00%)

2/35 (5.71%)

0/37 (0.00%)

# events

Nervous system disorders

Tremor¹,^†

# participants affected / at risk

0/6 (0.00%)

0/12 (0.00%)

0/36 (0.00%)

2/35 (5.71%)

0/37 (0.00%)

# events

Respiratory, thoracic and mediastinal disorders

Cough¹,^†

# participants affected / at risk

0/6 (0.00%)

0/12 (0.00%)

2/36 (5.56%)

0/35 (0.00%)

1/37 (2.70%)

6/37 (16.22%)

2/37 (5.41%)

# events

Respiratory, thoracic and mediastinal disorders

Chronic obstructive pulmonary disease¹,^†

# participants affected / at risk

0/6 (0.00%)

0/12 (0.00%)

1/36 (2.78%)

0/35 (0.00%)

0/37 (0.00%)

2/37 (5.41%)

3/37 (8.11%)

# events

†	Events were collected by systematic assessment
1	Term from vocabulary, MedDRA 16.1

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

The agreement is:

	The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
	The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days . The sponsor cannot require changes to the communication and cannot extend the embargo.
	Other disclosure agreement that restricts the right of the PI to discuss or publish trial results after the trial is completed. Restriction Description: Publication and / or presentation whether complete or partial, of any part of the data or results of this study will not be allowed until global publication and study results disclosure by the sponsor as per EMA / FDA regulatory compliance obligations, and only after mutual agreement between the Investigator and AstraZemeca

Limitations and Caveats

Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
In Part 1, many plasma concentrations at 50-100µg dose levels were BLOQ; thus only limited PK data were obtained for AUC(0-t), with plasma concentrations generally detected up to 1h post-administration; and at 200-400µg, up to 6 or 12h, respectively

Results Point of Contact

Name/Title:	AstraZeneca Clinical Study Information Center
Organization:	AstraZeneca
E-mail:	[email protected]

Documents available

Trial Results Summaries
Available here

Contacts

Contact

AstraZeneca Clinical

1-877-240-9479

information.center@astrazeneca.com

Sponsors

Collaborators

Inclusion Criteria

Exclusion Criteria

Quintiles Drug Research Unit at Guy’s Hospital

Medicines Evaluation Unit Ltd (MEU)

Trial Results Summaries