Two-part safety, tolerability, pharmacodynamic and –kinetic study of inhaled AZD8871 in asthmatic and COPD subjects

Study identifier:D6640C00001

ClinicalTrials.gov identifier:NCT02573155

EudraCT identifier:2015-002906-36

CTIS identifier:N/A

Study Complete

Official Title

A 2-part, randomised, placebo-controlled, safety, tolerability, pharmacokinetic and pharmacodynamic study of AZD8871 delivered by inhalation in asthmatic and chronic obstructive pulmonary disease (COPD) subjects

Medical condition

Asthma (Part 1)

Phase

Phase 1

Healthy volunteers

Study drug

Dose 1, AZD8871 50 μg (Part 1), Dose 2, AZD8871 100 μg (Part 1), Dose 3, AZD8871 300 μg (Part 1), Dose 4, AZD8871 600 µg (Part 1), Dose 5, AZD8871 1200 µg (Part 1), Dose 6, AZD8871 1800 μg (Part 1), Placebo, AZD8871 placebo (Part 1), Treatment A, AZD8871 dose A (Part 2), Treatment B, AZD8871 dose B (Part 2), Treatment C, Indacaterol 150 μg (Part 2), Treatment D, Tiotropium 18 μg (Part 2)

Sex

All

Actual Enrollment

134

Study type

Interventional

Age

18 Years - 130 Years

Date

Study Start Date: 01 Oct 2015

Primary Completion Date: 01 Aug 2016

Study Completion Date: 01 Aug 2016

Study design

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

Verification:

Verified 01 Apr 2018 by AstraZeneca

Collaborators

Inclusion and exclusion criteria

Inclusion Criteria

:Part 1
1. Subjects who are able and willing to provide written informed consent prior to conducting any study-related procedures, including withdrawal of medications
2. Adult male subjects aged 18 to 70 years (both inclusive)
3. Body mass index (BMI) from 18 to 32 kg/m2 at screening
4. Clinical diagnosis of asthma (according to the Global Initiative for Asthma [GINA] guidelines) for at least 6 months prior to screening
5. Ability to change current asthma therapy, to discontinue previous prescribed medications after signature of informed consent as per required washout periods
6. Screening FEV1 value of ≥70% of the predicted normal value
7. 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 (4 puffs) of salbutamol via a metered dose inhaler, with spacer device
8. Subjects using intermittent salbutamol and / or subjects on a stable dose of low dose Inhaled corticosteroid (as defined by the GINA guidelines) at least 4 weeks prior to screening
9. Predose FEV1 value of first treatment period within the range of ± 20% of the FEV1 measured at screening prior to salbutamol inhalation
10. No current smokers, no subjects with a smoking history during the last 12 months and no subjects with a total smoking history of more than 10 pack-years
11. No other relevant pulmonary disease or history of thoracic surgery
12. Subjects who are otherwise healthy as determined by medical history, physical examination, 12-lead ECG findings
13. Normal blood pressure (defined as Systolic blood pressure [SBP] between 100 and 140 mmHg for subjects ≤59 years of age and between 100 and 150 mmHg for subjects ≥60 years of age, and Diastolic blood pressure [DBP] between 40 and 90 mmHg) at screening
14. Subjects whose clinical laboratory test results are not clinically relevant and are acceptable to the Investigator.
15. 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
16. Subjects who are negative for drugs of abuse and alcohol tests at screening and admission
17. Subjects able to perform repeatable pulmonary function testing for FEV1 according to the American Thoracic Society (ATS) / European Respiratory Society (ERS) 2005(9) criteria at screening
Inclusion Criteria: Part 2
1. Adult male and non-childbearing female subjects aged ≥40 years with a clinical diagnosis of stable moderate to severe COPD according to GOLD guidelines at screening
2. Females must be of non-childbearing potential, confirmed at screening by fulfilling study predefined criteria
3. Post-salbutamol FEV1 <80% and ≥30% of the predicted normal value and post-salbutamol FEV1 / forced vital capacity (FVC) <70%
4. BMI < 40 kg/m2 at screening
5. Ability to change current COPD therapy, to discontinue previous prescribed medications after signature of informed consent as per required washout periods
6. Current or ex-smokers with a smoking history of ≥10 pack years
7. No evidence of clinically significant respiratory and / or cardiovascular conditions (e.g. uncontrolled hypertension) or laboratory abnormalities
8. No other relevant pulmonary disease or history of thoracic surgery
9. Subjects who are negative for HBsAg, HBc IgM, hepatitis C antibody and HIV I and II antibodies at screening
10. Subjects who are able and willing to provide written informed consent prior to conducting any study-related procedures, including withdrawal of medications
11. Medical history must be verified by either a personal physician or medical practitioner as appropriate
12. Subjects able to perform repeatable pulmonary function testing for FEV1 according to the ATS / ERS 2005(9) criteria at screening

Exclusion Criteria

(Part 1 & 2):
1. Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site)
2. Previous enrolment or randomisation of treatment in the present study
3. Current evidence or recent history of any clinically significant and unstable disease (other than asthma/COPD) or abnormality that could put the subject at risk or could confound the results of the study
4. Subjects with a surgical history clinically relevant for the purpose of the study
5. 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
6. Subjects with serious adverse reaction or serious hypersensitivity to Tiotropium (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)
7. Current diagnosis of COPD (for Part 1 only) or history of / or current diagnosis for asthma (for Part 2 only)
8. Recent history of asthma / COPD exacerbation requiring hospitalisation or need for increased maintenance treatments for asthma / COPD within 6 weeks prior to screening or prior to randomisation
9. Use of daily oxygen therapy >10 h per day (for Part 2 only)
10. Use of systemic steroids for respiratory reasons within 6 weeks prior to screening
11. Lower respiratory tract infection within 6 weeks prior to screening or prior to randomisation
12. Upper respiratory tract infection requiring antibiotics within 6 weeks prior to screening or prior to randomisation
13. Current history of tuberculosis, bronchiectasis or other non-specific pulmonary disease
14. Subject with significant cardiovascular disease that may be vulnerable to cardiovascular instability
15. QTcF (QT interval corrected, Fridericia formula QT[msec]/RR[s]) interval, >450 ms for males and >470 ms for females at screening or prior to randomisation, or history of long QT syndrome
16. PR (duration in milliseconds from the beginning of wave P to onset of ventricular depolarisation [Q or R]) interval >200 ms at screening or prior to randomisation (for Part 1 only)
Note: 4- 6 hours of ECG rhythm monitoring with telemetry will be performed on Day-1 to identify patients that may have any clinical significant abnormality prior to randomisation. If this occurs, patients should not participate in the study
17. Subjects with serum potassium concentration < 3.5mmol/l at screening
18. Subjects with a history of excessive use or abuse of alcohol within the past 2 years
19. Subjects with a history of drug abuse within the past 2 years
20. Subjects who are positive for drugs of abuse and alcohol tests at screening and prior to randomisation. Subjects consuming more than 14 (female subjects) or 21 (male subjects) units of alcohol a week
21. Donation or loss >400 ml of blood and plasma within the previous 3 months prior to screening
22. Subjects with a significant infection or known inflammatory process at screening or prior to randomisation
23. Subjects with acute gastrointestinal symptoms at the time of screening or prior to randomisation (eg, nausea, vomiting, diarrhoea, heartburn)
24. Subjects with an acute infection such as influenza at the time of screening or prior to randomisation
25. Male subjects who do not agree to follow instructions to avoid pregnancies
26. Subjects who are not able to adhere to the restrictions on prior and concomitant medications
27. Subjects who intend to use any concomitant medication not permitted by this protocol or who have not undergone the required washout period for a particular prohibited medication
28. 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
29. Subjects who have received the last dose of investigational product more than 3 months ago but who are on an extended follow-up
30. Subjects who are unlikely to co-operate with the requirements of the study, or the study center or the subjects who are unwilling or unable to follow the instructions of the principal investigator

Location

Research Site

Harrow, United Kingdom

Location

Research Site

Manchester, United Kingdom

Arms	Assigned Interventions
Experimental: Sequence 1, Part 1 Period 1: Dose 1 Period 2: Dose 3 Period 3: Dose 5	Drug: Dose 1, AZD8871 50 μg (Part 1) 50 µg of AZD8871 on Day 1; each dose of AZD8871 inhalation powder will be administered via single-dose dry powder inhaler (Genuair®) Drug: Dose 3, AZD8871 300 μg (Part 1) 300 µg of AZD8871 on Day 1; each dose of AZD8871 inhalation powder will be administered via single-dose dry powder inhaler (Genuair®) Drug: Dose 5, AZD8871 1200 µg (Part 1) 1200 µg of AZD8871 on Day 1; each dose of AZD8871 inhalation powder will be administered via single-dose dry powder inhaler (Genuair®)
Experimental: Sequence 2, Part 1 Period 1: Placebo Period 2: Dose 3 Period 3: Dose 5	Drug: Dose 3, AZD8871 300 μg (Part 1) 300 µg of AZD8871 on Day 1; each dose of AZD8871 inhalation powder will be administered via single-dose dry powder inhaler (Genuair®) Drug: Dose 5, AZD8871 1200 µg (Part 1) 1200 µg of AZD8871 on Day 1; each dose of AZD8871 inhalation powder will be administered via single-dose dry powder inhaler (Genuair®) Drug: Placebo, AZD8871 placebo (Part 1) AZD8871 placebo on Day 1; each dose of AZD8871 placebo inhalation powder will be administered via single-dose dry powder inhaler (Genuair®)
Experimental: Sequence 3, Part 1 Period 1: Dose 1 Period 2: Placebo Period 3: Dose 5	Drug: Dose 1, AZD8871 50 μg (Part 1) 50 µg of AZD8871 on Day 1; each dose of AZD8871 inhalation powder will be administered via single-dose dry powder inhaler (Genuair®) Drug: Dose 5, AZD8871 1200 µg (Part 1) 1200 µg of AZD8871 on Day 1; each dose of AZD8871 inhalation powder will be administered via single-dose dry powder inhaler (Genuair®) Drug: Placebo, AZD8871 placebo (Part 1) AZD8871 placebo on Day 1; each dose of AZD8871 placebo inhalation powder will be administered via single-dose dry powder inhaler (Genuair®)
Experimental: Sequence 4, Part 1 Period 1: Dose 1 Period 2: Dose 3 Period 3: Placebo	Drug: Dose 1, AZD8871 50 μg (Part 1) 50 µg of AZD8871 on Day 1; each dose of AZD8871 inhalation powder will be administered via single-dose dry powder inhaler (Genuair®) Drug: Dose 3, AZD8871 300 μg (Part 1) 300 µg of AZD8871 on Day 1; each dose of AZD8871 inhalation powder will be administered via single-dose dry powder inhaler (Genuair®) Drug: Placebo, AZD8871 placebo (Part 1) AZD8871 placebo on Day 1; each dose of AZD8871 placebo inhalation powder will be administered via single-dose dry powder inhaler (Genuair®)
Experimental: Sequence 5, Part 1 Period 1: Dose 2 Period 2: Dose 4 Period 3: Dose 6	Drug: Dose 2, AZD8871 100 μg (Part 1) 100 µg of AZD8871 on Day 1; each dose of AZD8871 inhalation powder will be administered via single-dose dry powder inhaler (Genuair®) Drug: Dose 4, AZD8871 600 µg (Part 1) 600 µg of AZD8871 on Day 1; each dose of AZD8871 inhalation powder will be administered via single-dose dry powder inhaler (Genuair®) Drug: Dose 6, AZD8871 1800 μg (Part 1) 1800 µg of AZD8871 on Day 1; each dose of AZD8871 inhalation powder will be administered via single-dose dry powder inhaler (Genuair®)
Experimental: Sequence 6, Part 1 Period 1: Placebo Period 2: Dose 4 Period 3: Dose 6	Drug: Dose 4, AZD8871 600 µg (Part 1) 600 µg of AZD8871 on Day 1; each dose of AZD8871 inhalation powder will be administered via single-dose dry powder inhaler (Genuair®) Drug: Dose 6, AZD8871 1800 μg (Part 1) 1800 µg of AZD8871 on Day 1; each dose of AZD8871 inhalation powder will be administered via single-dose dry powder inhaler (Genuair®) Drug: Placebo, AZD8871 placebo (Part 1) AZD8871 placebo on Day 1; each dose of AZD8871 placebo inhalation powder will be administered via single-dose dry powder inhaler (Genuair®)
Experimental: Sequence 7, Part 1 Period 1: Dose 2 Period 2: Placebo Period 3: Dose 6	Drug: Dose 2, AZD8871 100 μg (Part 1) 100 µg of AZD8871 on Day 1; each dose of AZD8871 inhalation powder will be administered via single-dose dry powder inhaler (Genuair®) Drug: Dose 6, AZD8871 1800 μg (Part 1) 1800 µg of AZD8871 on Day 1; each dose of AZD8871 inhalation powder will be administered via single-dose dry powder inhaler (Genuair®) Drug: Placebo, AZD8871 placebo (Part 1) AZD8871 placebo on Day 1; each dose of AZD8871 placebo inhalation powder will be administered via single-dose dry powder inhaler (Genuair®)
Experimental: Sequence 8, Part 1 Period 1: Dose 2 Period 2: Dose 4 Period 3: Placebo	Drug: Dose 2, AZD8871 100 μg (Part 1) 100 µg of AZD8871 on Day 1; each dose of AZD8871 inhalation powder will be administered via single-dose dry powder inhaler (Genuair®) Drug: Dose 4, AZD8871 600 µg (Part 1) 600 µg of AZD8871 on Day 1; each dose of AZD8871 inhalation powder will be administered via single-dose dry powder inhaler (Genuair®) Drug: Placebo, AZD8871 placebo (Part 1) AZD8871 placebo on Day 1; each dose of AZD8871 placebo inhalation powder will be administered via single-dose dry powder inhaler (Genuair®)
Experimental: Sequence 1, Part 2 Period 1: Treatment A Period 2: Treatment B Period 3: Treatment E Period 4: Treatment C Period 5: Treatment D	Drug: Treatment A, AZD8871 dose A (Part 2) AZD8871 dose A once on Day 1; each dose of AZD8871 placebo inhalation powder will be administered via single-dose dry powder inhaler (Genuair®) Drug: Treatment B, AZD8871 dose B (Part 2) AZD8871 dose B once on Day 1; each dose of AZD8871 placebo inhalation powder will be administered via single-dose dry powder inhaler(Genuair®) Drug: Treatment C, Indacaterol 150 μg (Part 2) 150 μg of Indacaterol once on Day 1; each dose of Indacaterol dry inhalation powder will be administered via a dry powder inhaler (Onbrez Breezhaler®) as 1 hard capsule Drug: Treatment D, Tiotropium 18 μg (Part 2) 18 μg of Tiotropium once on Day 1; each dose of Indacaterol dry inhalation powder will be administered via a dry powder inhaler (HandiHaler®) as 1 hard capsule
Experimental: Sequence 2, Part 2 Period 1: Treatment B Period 2: Treatment C Period 3: Treatment A Period 4: Treatment D Period 5: Treatment E	Drug: Treatment A, AZD8871 dose A (Part 2) AZD8871 dose A once on Day 1; each dose of AZD8871 placebo inhalation powder will be administered via single-dose dry powder inhaler (Genuair®) Drug: Treatment B, AZD8871 dose B (Part 2) AZD8871 dose B once on Day 1; each dose of AZD8871 placebo inhalation powder will be administered via single-dose dry powder inhaler(Genuair®) Drug: Treatment C, Indacaterol 150 μg (Part 2) 150 μg of Indacaterol once on Day 1; each dose of Indacaterol dry inhalation powder will be administered via a dry powder inhaler (Onbrez Breezhaler®) as 1 hard capsule Drug: Treatment D, Tiotropium 18 μg (Part 2) 18 μg of Tiotropium once on Day 1; each dose of Indacaterol dry inhalation powder will be administered via a dry powder inhaler (HandiHaler®) as 1 hard capsule
Experimental: Sequence 3, Part 2 Period 1: Treatment C Period 2: Treatment D Period 3: Treatment B Period 4: Treatment E Period 5: Treatment A	Drug: Treatment A, AZD8871 dose A (Part 2) AZD8871 dose A once on Day 1; each dose of AZD8871 placebo inhalation powder will be administered via single-dose dry powder inhaler (Genuair®) Drug: Treatment B, AZD8871 dose B (Part 2) AZD8871 dose B once on Day 1; each dose of AZD8871 placebo inhalation powder will be administered via single-dose dry powder inhaler(Genuair®) Drug: Treatment C, Indacaterol 150 μg (Part 2) 150 μg of Indacaterol once on Day 1; each dose of Indacaterol dry inhalation powder will be administered via a dry powder inhaler (Onbrez Breezhaler®) as 1 hard capsule Drug: Treatment D, Tiotropium 18 μg (Part 2) 18 μg of Tiotropium once on Day 1; each dose of Indacaterol dry inhalation powder will be administered via a dry powder inhaler (HandiHaler®) as 1 hard capsule
Experimental: Sequence 4, Part 2 Period 1: Treatment D Period 2: Treatment E Period 3: Treatment C Period 4: Treatment A Period 5: Treatment B	Drug: Treatment A, AZD8871 dose A (Part 2) AZD8871 dose A once on Day 1; each dose of AZD8871 placebo inhalation powder will be administered via single-dose dry powder inhaler (Genuair®) Drug: Treatment B, AZD8871 dose B (Part 2) AZD8871 dose B once on Day 1; each dose of AZD8871 placebo inhalation powder will be administered via single-dose dry powder inhaler(Genuair®) Drug: Treatment C, Indacaterol 150 μg (Part 2) 150 μg of Indacaterol once on Day 1; each dose of Indacaterol dry inhalation powder will be administered via a dry powder inhaler (Onbrez Breezhaler®) as 1 hard capsule Drug: Treatment D, Tiotropium 18 μg (Part 2) 18 μg of Tiotropium once on Day 1; each dose of Indacaterol dry inhalation powder will be administered via a dry powder inhaler (HandiHaler®) as 1 hard capsule
Experimental: Sequence 5, Part 2 Period 1: Treatment E Period 2: Treatment A Period 3: Treatment D Period 4: Treatment B Period 5: Treatment C	Drug: Treatment A, AZD8871 dose A (Part 2) AZD8871 dose A once on Day 1; each dose of AZD8871 placebo inhalation powder will be administered via single-dose dry powder inhaler (Genuair®) Drug: Treatment B, AZD8871 dose B (Part 2) AZD8871 dose B once on Day 1; each dose of AZD8871 placebo inhalation powder will be administered via single-dose dry powder inhaler(Genuair®) Drug: Treatment C, Indacaterol 150 μg (Part 2) 150 μg of Indacaterol once on Day 1; each dose of Indacaterol dry inhalation powder will be administered via a dry powder inhaler (Onbrez Breezhaler®) as 1 hard capsule Drug: Treatment D, Tiotropium 18 μg (Part 2) 18 μg of Tiotropium once on Day 1; each dose of Indacaterol dry inhalation powder will be administered via a dry powder inhaler (HandiHaler®) as 1 hard capsule
Experimental: Sequence 6, Part 2 Period 1: Treatment D Period 2: Treatment C Period 3: Treatment E Period 4: Treatment B Period 5: Treatment A	Drug: Treatment A, AZD8871 dose A (Part 2) AZD8871 dose A once on Day 1; each dose of AZD8871 placebo inhalation powder will be administered via single-dose dry powder inhaler (Genuair®) Drug: Treatment B, AZD8871 dose B (Part 2) AZD8871 dose B once on Day 1; each dose of AZD8871 placebo inhalation powder will be administered via single-dose dry powder inhaler(Genuair®) Drug: Treatment C, Indacaterol 150 μg (Part 2) 150 μg of Indacaterol once on Day 1; each dose of Indacaterol dry inhalation powder will be administered via a dry powder inhaler (Onbrez Breezhaler®) as 1 hard capsule Drug: Treatment D, Tiotropium 18 μg (Part 2) 18 μg of Tiotropium once on Day 1; each dose of Indacaterol dry inhalation powder will be administered via a dry powder inhaler (HandiHaler®) as 1 hard capsule
Experimental: Sequence 7, Part 2 Period 1: Treatment E Period 2: Treatment D Period 3: Treatment A Period 4: Treatment C Period 5: Treatment B	Drug: Treatment A, AZD8871 dose A (Part 2) AZD8871 dose A once on Day 1; each dose of AZD8871 placebo inhalation powder will be administered via single-dose dry powder inhaler (Genuair®) Drug: Treatment B, AZD8871 dose B (Part 2) AZD8871 dose B once on Day 1; each dose of AZD8871 placebo inhalation powder will be administered via single-dose dry powder inhaler(Genuair®) Drug: Treatment C, Indacaterol 150 μg (Part 2) 150 μg of Indacaterol once on Day 1; each dose of Indacaterol dry inhalation powder will be administered via a dry powder inhaler (Onbrez Breezhaler®) as 1 hard capsule Drug: Treatment D, Tiotropium 18 μg (Part 2) 18 μg of Tiotropium once on Day 1; each dose of Indacaterol dry inhalation powder will be administered via a dry powder inhaler (HandiHaler®) as 1 hard capsule
Experimental: Sequence 8, Part 2 Period 1: Treatment A Period 2: Treatment E Period 3: Treatment B Period 4: Treatment D Period 5: Treatment C	Drug: Treatment A, AZD8871 dose A (Part 2) AZD8871 dose A once on Day 1; each dose of AZD8871 placebo inhalation powder will be administered via single-dose dry powder inhaler (Genuair®) Drug: Treatment B, AZD8871 dose B (Part 2) AZD8871 dose B once on Day 1; each dose of AZD8871 placebo inhalation powder will be administered via single-dose dry powder inhaler(Genuair®) Drug: Treatment C, Indacaterol 150 μg (Part 2) 150 μg of Indacaterol once on Day 1; each dose of Indacaterol dry inhalation powder will be administered via a dry powder inhaler (Onbrez Breezhaler®) as 1 hard capsule Drug: Treatment D, Tiotropium 18 μg (Part 2) 18 μg of Tiotropium once on Day 1; each dose of Indacaterol dry inhalation powder will be administered via a dry powder inhaler (HandiHaler®) as 1 hard capsule
Experimental: Sequence 9, Part 2 Period 1: Treatment B Period 2: Treatment A Period 3: Treatment C Period 4: Treatment E Period 5: Treatment D	Drug: Treatment A, AZD8871 dose A (Part 2) AZD8871 dose A once on Day 1; each dose of AZD8871 placebo inhalation powder will be administered via single-dose dry powder inhaler (Genuair®) Drug: Treatment B, AZD8871 dose B (Part 2) AZD8871 dose B once on Day 1; each dose of AZD8871 placebo inhalation powder will be administered via single-dose dry powder inhaler(Genuair®) Drug: Treatment C, Indacaterol 150 μg (Part 2) 150 μg of Indacaterol once on Day 1; each dose of Indacaterol dry inhalation powder will be administered via a dry powder inhaler (Onbrez Breezhaler®) as 1 hard capsule Drug: Treatment D, Tiotropium 18 μg (Part 2) 18 μg of Tiotropium once on Day 1; each dose of Indacaterol dry inhalation powder will be administered via a dry powder inhaler (HandiHaler®) as 1 hard capsule
Experimental: Sequence 10, Part 2 Period 1: Treatment C Period 2: Treatment B Period 3: Treatment D Period 4: Treatment A Period 5: Treatment E	Drug: Treatment A, AZD8871 dose A (Part 2) AZD8871 dose A once on Day 1; each dose of AZD8871 placebo inhalation powder will be administered via single-dose dry powder inhaler (Genuair®) Drug: Treatment B, AZD8871 dose B (Part 2) AZD8871 dose B once on Day 1; each dose of AZD8871 placebo inhalation powder will be administered via single-dose dry powder inhaler(Genuair®) Drug: Treatment C, Indacaterol 150 μg (Part 2) 150 μg of Indacaterol once on Day 1; each dose of Indacaterol dry inhalation powder will be administered via a dry powder inhaler (Onbrez Breezhaler®) as 1 hard capsule Drug: Treatment D, Tiotropium 18 μg (Part 2) 18 μg of Tiotropium once on Day 1; each dose of Indacaterol dry inhalation powder will be administered via a dry powder inhaler (HandiHaler®) as 1 hard capsule

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 (one for each part). In part 1 of the study, the first patient was screened in October 2015 and the last patient visit was in March 2016. In part 2 of the study, the first patient was screened in April 2016 and the last patient visit was in August 2016.

Pre-Assignment Details

Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
2-part study: Part 1: single ascending doses of AZD8871 (planned 50, 100, 300, 600, 1200, 1800 μg; actual dose 50, 200, 400, 900, 1800, 2100 μg) or placebo over 3 treatment periods; 2 cohorts (male; mild persistent asthma). Part 2: 5-way complete cross-over, single-dose; M/F, moderate/severe COPD; 2 doses of AZD8871, placebo, or 2 active controls.

Reporting Groups

	Description
Overall population - Part 1	All individuals in Part 1 (patients who received single doses of AZD8871 [50, 400, 1800 μg for Cohort 1; 200, 900, 2100 μg for Cohort 2], or placebo, in 3 treatment periods separated by washout periods of 14 days).
Overall population - Part 2	All individuals involved in Part 2 (patients who received single doses of AZD8871 [400 and 1800 μg], placebo, indacaterol 150 μg, or tiotropium 18 μg, in 5 treatment periods separated by washout periods of 7-21 days.

Participant Flow for 9 periods

Period 1: Treatment Period 1

	Overall population - Part 1	Overall population - Part 2
STARTED	16	38
COMPLETED	16	38
NOT COMPLETED	0	0

Period 2: Washout between Treatment Period 1 and 2

	Overall population - Part 1	Overall population - Part 2
STARTED	16	38
COMPLETED	16	33
NOT COMPLETED	0	5
Physician Decision	0	1
Withdrawal by Subject	0	1
Adverse Event	0	3

Period 3: Period 2

	Overall population - Part 1	Overall population - Part 2
STARTED	16	33
COMPLETED	16	33
NOT COMPLETED	0	0

Period 4: Washout between Treatment Period 2 and 3

	Overall population - Part 1	Overall population - Part 2
STARTED	16	33
COMPLETED	15	31
NOT COMPLETED	1	2
Sponsor's decision	1	0
Adverse Event	0	2

Period 5: Period 3

	Overall population - Part 1	Overall population - Part 2
STARTED	15	31
COMPLETED	15	31
NOT COMPLETED	0	0

Period 6: Washout between Treatment Period 3 and 4

	Overall population - Part 1	Overall population - Part 2
STARTED	0^[1]	31
COMPLETED	0^[2]	29
NOT COMPLETED	0	2
Stability/variability criteria not met	0	1
Adverse Event	0	1

[1]	Part 1 comprised 3 treatment periods only
[2]	Part 1 comprised 3 treatment periods only

Period 7: Period 4

	Overall population - Part 1	Overall population - Part 2
STARTED	0^[1]	29
COMPLETED	0^[2]	29
NOT COMPLETED	0	0

[1]	Part 1 comprised 3 treatment periods only
[2]	Part 1 comprised 3 treatment periods only

Period 8: Washout between Treatment Period 4 and 5

	Overall population - Part 1	Overall population - Part 2
STARTED	0^[1]	29
COMPLETED	0^[2]	28
NOT COMPLETED	0	1
Adverse Event	0	1

[1]	Part 1 comprised 3 treatment periods only
[2]	Part 1 comprised 3 treatment periods only

Period 9: Period 5

	Overall population - Part 1	Overall population - Part 2
STARTED	0^[1]	28
COMPLETED	0^[2]	28
NOT COMPLETED	0	0

[1]	Part 1 comprised 3 treatment periods only
[2]	Part 1 comprised 3 treatment periods only

Baseline Characteristics

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

All randomized subjects who received at least 1 dose of the investigational product in Parts 1 and 2, respectively.

Reporting Groups

	Description
Overall population - Part 1	All individuals in Part 1 (patients who received single doses of AZD8871 [50, 400, 1800 μg for Cohort 1; 200, 900, 2100 μg for Cohort 2], or placebo, in 3 treatment periods separated by washout periods of 14 days).
Overall population - Part 2	All individuals involved in Part 2 (patients who received single doses of AZD8871 [400 and 1800 μg], placebo, indacaterol 150 μg, or tiotropium 18 μg, in 5 treatment periods separated by washout periods of 7-21 days.

Baseline Measures

	Overall population - Part 1	Overall population - Part 2	Total
Number of Participants [units: Participants]	16	38	54
Age Continuous [units: Years] Mean ± Standard Deviation	39.0 ± 11.8	65.6 ± 6.4	NA ± NA ^[1]
Sex: Female, Male [units: ]
Female	0	16	16
Male	16	22	38

Outcome Measures

1. Primary Outcome Measure: The number of participants with mild persistent asthma (Part 1) and COPD (Part 2) with at least 1 treatment-emergent adverse event [ Time Frame: From the time of informed consent up to 14 (±2) days after the last dose of investigational product. Unresolved AEs were followed up by the investigator for as long as medically indicated. ]

Measure Type	Primary
Measure Name	The number of participants with mild persistent asthma (Part 1) and COPD (Part 2) with at least 1 treatment-emergent adverse event
Measure Description	An adverse event is 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, signs, or the abnormal results of laboratory parameters (haematology, blood chemistry, urinalysis, physical examination, 12-lead ECGs and telemetry, and vital signs). AEs were coded using the Medical Dictionary for Regulatory Activities (MedDRA) version 18.1.
Time Frame	From the time of informed consent up to 14 (±2) days after the last dose of investigational product. Unresolved AEs were followed up by the investigator for as long as medically indicated.
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.
Safety population: all randomized subjects who received at least 1 dose of the investigational product.

Reporting Groups

	Description
AZD8871 50 μg (Part 1)	Single-dose, oral inhalation by Genuair® single-dose dry powder inhaler (DPI)
AZD8871 200 μg (Part 1)	Single-dose, oral inhalation by Genuair® single-dose dry powder inhaler (DPI)
AZD8871 400 μg (Part 1)	Single-dose, oral inhalation by Genuair® single-dose dry powder inhaler (DPI)
AZD8871 900 μg (Part 1)	Single-dose, oral inhalation by Genuair® single-dose dry powder inhaler (DPI)
AZD8871 1800 μg (Part 1)	Single-dose, oral inhalation by Genuair® single-dose dry powder inhaler (DPI)
AZD8871 2100 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)
AZD8871 400 μg (Part 2)	Single-dose, oral inhalation by Genuair® single-dose dry powder inhaler (DPI)
AZD8871 1800 μg (Part 2)	Single-dose, oral inhalation by Genuair® single-dose dry powder inhaler (DPI)
Indacaterol 150 μg (Part 2)	Single-dose, oral inhalation by Onbrez Breezhaler® single-dose dry powder inhaler (DPI)
Tiotropium 18 μg (Part 2)	Single-dose, oral inhalation by HandiHaler® single-dose dry powder inhaler (DPI)
Placebo (Part 2)	Single-dose, oral inhalation by Genuair® single-dose dry powder inhaler (DPI)

Measured Values

	AZD8871 50 μg (Part 1)	AZD8871 200 μg (Part 1)	AZD8871 400 μg (Part 1)	AZD8871 900 μg (Part 1)	AZD8871 1800 μg (Part 1)	AZD8871 2100 μg (Part 1)	Placebo (Part 1)	AZD8871 400 μg (Part 2)	AZD8871 1800 μg (Part 2)	Indacaterol 150 μg (Part 2)	Tiotropium 18 μg (Part 2)	Placebo (Part 2)
Number of Participants Analyzed [units:participants]	6	6	6	6	6	5	12	34	31	32	30	32
The number of participants with mild persistent asthma (Part 1) and COPD (Part 2) with at least 1 treatment-emergent adverse event [units: Participants]	5	5	3	3	3	2	7	18	7	12	11	11

No statistical analysis provided for The number of participants with mild persistent asthma (Part 1) and COPD (Part 2) with at least 1 treatment-emergent adverse event

2. Primary Outcome Measure: Number of participants with clinically relevant abnormalities in blood pressure [ Time Frame: From the time of informed consent up to 36 hours after last dose of IP. ]

Measure Type	Primary
Measure Name	Number of participants with clinically relevant abnormalities in blood pressure
Measure Description	Blood pressure (BP) measurements (diastolic [DBP] and systolic BP [SBP]) taken after ~5 minutes rest in supine position, at screening, baseline (≤1 hour before IP administration), 10 and 30 minutes, 1, 2, 3, 4, 8, 12 hours (Day 1) and 24 and 36 hours (Day 2) after IP administration. Normal BP at screening: SBP 100–140 mmHg (subjects aged ≤59 years) and 100–150 mmHg (subjects aged ≥60 years), and DBP 40–90 mmHg. Criteria for notable changes in BP: High SBP: (≥180 and increase over baseline (predose) ≥20) or (≥200 and baseline <200) Low SBP: (≤ 90 and decrease over baseline ≥20) or (≤75 and baseline >75) High DBP: (≥105 and increase over baseline ≥15) or (≥115 and baseline <115) Low DBP: (≤50 and decrease over baseline ≥15) or (≤40 and baseline >40) All out of range values were flagged to the principal investigator who assessed clinical relevance based on medical criteria at individual subject level. Clinically relevant findings were assessed until considered non-clinically relevant.
Time Frame	From the time of informed consent up to 36 hours after last dose of IP.
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.
Safety population: all randomized subjects who received at least 1 dose of the investigational product

Reporting Groups

	Description
AZD8871 50 μg (Part 1)	Single-dose, oral inhalation by Genuair® single-dose dry powder inhaler (DPI)
AZD8871 200 μg (Part 1)	Single-dose, oral inhalation by Genuair® single-dose dry powder inhaler (DPI)
AZD8871 400 μg (Part 1)	Single-dose, oral inhalation by Genuair® single-dose dry powder inhaler (DPI)
AZD8871 900 μg (Part 1)	Single-dose, oral inhalation by Genuair® single-dose dry powder inhaler (DPI)
AZD8871 1800 μg (Part 1)	Single-dose, oral inhalation by Genuair® single-dose dry powder inhaler (DPI)
AZD8871 2100 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)
AZD8871 400 μg (Part 2)	Single-dose, oral inhalation by Genuair® single-dose dry powder inhaler (DPI)
AZD8871 1800 μg (Part 2)	Single-dose, oral inhalation by Genuair® single-dose dry powder inhaler (DPI)
Indacaterol 150 μg (Part 2)	Single-dose, oral inhalation by Onbrez Breezhaler® single-dose dry powder inhaler (DPI)
Tiotropium 18 μg (Part 2)	Single-dose, oral inhalation by HandiHaler® single-dose dry powder inhaler (DPI)
Placebo (Part 2)	Single-dose, oral inhalation by Genuair® single-dose dry powder inhaler (DPI)

Measured Values

	AZD8871 50 μg (Part 1)	AZD8871 200 μg (Part 1)	AZD8871 400 μg (Part 1)	AZD8871 900 μg (Part 1)	AZD8871 1800 μg (Part 1)	AZD8871 2100 μg (Part 1)	Placebo (Part 1)	AZD8871 400 μg (Part 2)	AZD8871 1800 μg (Part 2)	Indacaterol 150 μg (Part 2)	Tiotropium 18 μg (Part 2)	Placebo (Part 2)
Number of Participants Analyzed [units:participants]	6	6	6	6	6	5	12	34	31	32	30	32
Number of participants with clinically relevant abnormalities in blood pressure [units: Participants]	0	0	0	0	0	0	0	0	0	0	0	0

No statistical analysis provided for Number of participants with clinically relevant abnormalities in blood pressure

3. Primary Outcome Measure: Number of participants with clinically relevant abnormalities in electrocardiograms (HR, QTcF and Other ECG parameters). [ Time Frame: From the time of informed consent up to 36 hours after last dose of IP. ]

Measure Type	Primary
Measure Name	Number of participants with clinically relevant abnormalities in electrocardiograms (HR, QTcF and Other ECG parameters).
Measure Description	HR, QTcF and other ECG abnormalities were assessed by local digital 12-lead ECG performed in triplicate at the time points indicated: ECG (Parts 1 and 2) was assessed at Screening, Day 1 baseline, 10 min, 30 min, 1 hour (h), 2 h, 3 h, 4 h, 8 h, 12 h, 24 h, 36 h after dosing. Telemetry (Part 1), assessed with at least 2 lead real time display, was recorded at Day -1 (4–6 hours continuous recording, at the time this was more convenient for the logistics of the unit) and on Day 1 from the time of the IP administration up to at least 24 hours, but if advised by the Investigator or designee, then up to 36 hours after IP administration. Abnormal findings were flagged to the principal investigator who assessed clinical relevance based on medical criteria at individual subject level. Clinically relevant findings were assessed until the abnormality was considered non-clinically relevant.
Time Frame	From the time of informed consent up to 36 hours after last dose of IP.
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.
Safety population: all randomized subjects who received at least 1 dose of the investigational product

Reporting Groups

	Description
AZD8871 50 μg (Part 1)	Single-dose, oral inhalation by Genuair® single-dose dry powder inhaler (DPI)
AZD8871 200 μg (Part 1)	Single-dose, oral inhalation by Genuair® single-dose dry powder inhaler (DPI)
AZD8871 400 μg (Part 1)	Single-dose, oral inhalation by Genuair® single-dose dry powder inhaler (DPI)
AZD8871 900 μg (Part 1)	Single-dose, oral inhalation by Genuair® single-dose dry powder inhaler (DPI)
AZD8871 1800 μg (Part 1)	Single-dose, oral inhalation by Genuair® single-dose dry powder inhaler (DPI)
AZD8871 2100 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)
AZD8871 400 μg (Part 2)	Single-dose, oral inhalation by Genuair® single-dose dry powder inhaler (DPI)
AZD8871 1800 μg (Part 2)	Single-dose, oral inhalation by Genuair® single-dose dry powder inhaler (DPI)
Indacaterol 150 μg (Part 2)	Single-dose, oral inhalation by Onbrez Breezhaler® single-dose dry powder inhaler (DPI)
Tiotropium 18 μg (Part 2)	Single-dose, oral inhalation by HandiHaler® single-dose dry powder inhaler (DPI)
Placebo (Part 2)	Single-dose, oral inhalation by Genuair® single-dose dry powder inhaler (DPI)

Measured Values

	AZD8871 50 μg (Part 1)	AZD8871 200 μg (Part 1)	AZD8871 400 μg (Part 1)	AZD8871 900 μg (Part 1)	AZD8871 1800 μg (Part 1)	AZD8871 2100 μg (Part 1)	Placebo (Part 1)	AZD8871 400 μg (Part 2)	AZD8871 1800 μg (Part 2)	Indacaterol 150 μg (Part 2)	Tiotropium 18 μg (Part 2)	Placebo (Part 2)
Number of Participants Analyzed [units:participants]	6	6	6	6	6	5	12	34	31	32	30	32
Number of participants with clinically relevant abnormalities in electrocardiograms (HR, QTcF and Other ECG parameters). [units: Participants]	0	0	0	0	0	0	0	0	0	0	0	0

No statistical analysis provided for Number of participants with clinically relevant abnormalities in electrocardiograms (HR, QTcF and Other ECG parameters).

4. Primary Outcome Measure: Number of participants with clinically relevant abnormalities in clinical biochemistry, hematology and urinalysis [ Time Frame: From the time of informed consent up to 7 days after the last dose of IP. ]

Measure Type	Primary
Measure Name	Number of participants with clinically relevant abnormalities in clinical biochemistry, hematology and urinalysis
Measure Description	A composite of clinically relevant abnormalities in clinical biochemistry, hematology and urinalysis laboratory evaluations. Laboratory tests (haematology, blood chemistry, and urinalysis) were performed at screening, at Day -1 (Part 1 only), at 24 hours (Day 2) and at follow-up (7 [±2] days) after IP administration. Coagulation was only performed at screening; TSH, T4 only at screening, at Day-1 and at follow-up. Abnormal findings were flagged to the principal investigator who assessed clinical relevance based on medical criteria at individual subject level. Clinically relevant findings were assessed until the abnormality was considered non-clinically relevant.
Time Frame	From the time of informed consent up to 7 days after the last dose of IP.
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.
Safety population: all randomized subjects who received at least 1 dose of the investigational product

Reporting Groups

	Description
AZD8871 50 μg (Part 1)	Single-dose, oral inhalation by Genuair® single-dose dry powder inhaler (DPI)
AZD8871 200 μg (Part 1)	Single-dose, oral inhalation by Genuair® single-dose dry powder inhaler (DPI)
AZD8871 400 μg (Part 1)	Single-dose, oral inhalation by Genuair® single-dose dry powder inhaler (DPI)
AZD8871 900 μg (Part 1)	Single-dose, oral inhalation by Genuair® single-dose dry powder inhaler (DPI)
AZD8871 1800 μg (Part 1)	Single-dose, oral inhalation by Genuair® single-dose dry powder inhaler (DPI)
AZD8871 2100 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)
AZD8871 400 μg (Part 2)	Single-dose, oral inhalation by Genuair® single-dose dry powder inhaler (DPI)
AZD8871 1800 μg (Part 2)	Single-dose, oral inhalation by Genuair® single-dose dry powder inhaler (DPI)
Indacaterol 150 μg (Part 2)	Single-dose, oral inhalation by Onbrez Breezhaler® single-dose dry powder inhaler (DPI)
Tiotropium 18 μg (Part 2)	Single-dose, oral inhalation by HandiHaler® single-dose dry powder inhaler (DPI)
Placebo (Part 2)	Single-dose, oral inhalation by Genuair® single-dose dry powder inhaler (DPI)

Measured Values

	AZD8871 50 μg (Part 1)	AZD8871 200 μg (Part 1)	AZD8871 400 μg (Part 1)	AZD8871 900 μg (Part 1)	AZD8871 1800 μg (Part 1)	AZD8871 2100 μg (Part 1)	Placebo (Part 1)	AZD8871 400 μg (Part 2)	AZD8871 1800 μg (Part 2)	Indacaterol 150 μg (Part 2)	Tiotropium 18 μg (Part 2)	Placebo (Part 2)
Number of Participants Analyzed [units:participants]	6	6	6	6	6	5	12	34	31	32	30	32
Number of participants with clinically relevant abnormalities in clinical biochemistry, hematology and urinalysis [units: Participants]	0	0	0	0	0	0	0	0	0	0	0	0

No statistical analysis provided for Number of participants with clinically relevant abnormalities in clinical biochemistry, hematology and urinalysis

5. Primary Outcome Measure: Change from baseline in trough forced expiratory volume in 1 second (FEV1) on Day 2 [ Time Frame: Baseline (Day 1) to 36 hours post-dose (Day 2) ]

Measure Type	Primary
Measure Name	Change from baseline in trough forced expiratory volume in 1 second (FEV1) on Day 2
Measure Description	Pharmacodynamics of AZD8871 before (-45 min and -15 min pre-dose) and after single dosing of AZD8871 Forced expiratory volume in 1 second (FEV1) on Day 2 (defined as the average of the values 23:00 and 24:00 hours after the morning dose of investigational product)
Time Frame	Baseline (Day 1) to 36 hours post-dose (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.
The PP population is defined as all randomised subjects who satisfied the main I/E criteria, received IP, completed at least 1 treatment period, and did not present major violations to the protocol

Reporting Groups

	Description
AZD8871 50 μg (Part 1)	Single-dose, oral inhalation by Genuair® single-dose dry powder inhaler (DPI)
AZD8871 200 μg (Part 1)	Single-dose, oral inhalation by Genuair® single-dose dry powder inhaler (DPI)
AZD8871 400 μg (Part 1)	Single-dose, oral inhalation by Genuair® single-dose dry powder inhaler (DPI)
AZD8871 900 μg (Part 1)	Single-dose, oral inhalation by Genuair® single-dose dry powder inhaler (DPI)
AZD8871 1800 μg (Part 1)	Single-dose, oral inhalation by Genuair® single-dose dry powder inhaler (DPI)
AZD8871 2100 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)
AZD8871 400 μg (Part 2)	Single-dose, oral inhalation by Genuair® single-dose dry powder inhaler (DPI)
AZD8871 1800 μg (Part 2)	Single-dose, oral inhalation by Genuair® single-dose dry powder inhaler (DPI)
Indacaterol 150 μg (Part 2)	Single-dose, oral inhalation by Onbrez Breezhaler® single-dose dry powder inhaler (DPI)
Tiotropium 18 μg (Part 2)	Single-dose, oral inhalation by HandiHaler® single-dose dry powder inhaler (DPI)
Placebo (Part 2)	Single-dose, oral inhalation by Genuair® single-dose dry powder inhaler (DPI)

Measured Values

	AZD8871 50 μg (Part 1)	AZD8871 200 μg (Part 1)	AZD8871 400 μg (Part 1)	AZD8871 900 μg (Part 1)	AZD8871 1800 μg (Part 1)	AZD8871 2100 μg (Part 1)	Placebo (Part 1)	AZD8871 400 μg (Part 2)	AZD8871 1800 μg (Part 2)	Indacaterol 150 μg (Part 2)	Tiotropium 18 μg (Part 2)	Placebo (Part 2)
Number of Participants Analyzed [units:participants]	6	6	6	6	6	5	12	34	31	32	30	32
Change from baseline in trough forced expiratory volume in 1 second (FEV1) on Day 2 [units: Liters] Mean (Standard Deviation)	-0.0375 (0.3449)	0.2183 (0.1631)	0.2883 (0.1418)	0.1858 (0.3528)	0.3275 (0.0708)	0.4630 (0.2065)	-0.0600 (0.3099)	0.0738 (0.1212)	0.1731 (0.1761)	0.1036 (0.1286)	0.1055 (0.1922)	-0.0294 (0.0768)

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

Groups^[1]	AZD8871 400 μg (Part 2), Placebo (Part 2)
Method^[3]	ANCOVA
P-Value^[4]	<0.0001
Other^[5]	0.111
Standard Error of the mean	± 0.0265
95% Confidence Interval	( 0.0585 to 0.163 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[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:
	No text entered.
[5]	Other relevant estimation information:
	No text entered.

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

Groups^[1]	AZD8871 1800 μg (Part 2), Placebo (Part 2)
Method^[3]	ANCOVA
P-Value^[4]	<0.0001
Other^[5]	0.210
Standard Error of the mean	± 0.0272
95% Confidence Interval	( 0.156 to 0.264 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[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:
	No text entered.
[5]	Other relevant estimation information:
	No text entered.

6. Secondary Outcome Measure: Cmax of AZD8871 in Parts 1 and 2 [ Time Frame: Pre-dose, and 5 min, 15 min, 30 min, 45 min, 1 h, 2 h, 3 h, 4 h, 6 h, 8 h, 12 h (Day 1), 24 h, and 36 h (Day 2) post-dose ]

Measure Type	Secondary
Measure Name	Cmax of AZD8871 in Parts 1 and 2
Measure Description	Cmax (maximum observed plasma drug concentrations) of AZD8871 on Day 1 of each treatment period.
Time Frame	Pre-dose, and 5 min, 15 min, 30 min, 45 min, 1 h, 2 h, 3 h, 4 h, 6 h, 8 h, 12 h (Day 1), 24 h, and 36 h (Day 2) post-dose
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 randomised subjects who have received at least 1 dose of investigational product in at least 1 treatment period and have evaluable PK parameters. AZD8871 plasma PK assessed following dosing with AZD8871 only (not placebo, indacaterol, or tiotropium).

Reporting Groups

	Description
AZD8871 50 μg (Part 1)	Single-dose, oral inhalation by Genuair® single-dose dry powder inhaler (DPI)
AZD8871 200 μg (Part 1)	Single-dose, oral inhalation by Genuair® single-dose dry powder inhaler (DPI)
AZD8871 400 μg (Part 1)	Single-dose, oral inhalation by Genuair® single-dose dry powder inhaler (DPI)
AZD8871 900 μg (Part 1)	Single-dose, oral inhalation by Genuair® single-dose dry powder inhaler (DPI)
AZD8871 1800 μg (Part 1)	Single-dose, oral inhalation by Genuair® single-dose dry powder inhaler (DPI)
AZD8871 2100 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)
AZD8871 400 μg (Part 2)	Single-dose, oral inhalation by Genuair® single-dose dry powder inhaler (DPI)
AZD8871 1800 μg (Part 2)	Single-dose, oral inhalation by Genuair® single-dose dry powder inhaler (DPI)
Indacaterol 150 μg (Part 2)	Single-dose, oral inhalation by Onbrez Breezhaler® single-dose dry powder inhaler (DPI)
Tiotropium 18 μg (Part 2)	Single-dose, oral inhalation by HandiHaler® single-dose dry powder inhaler (DPI)
Placebo (Part 2)	Single-dose, oral inhalation by Genuair® single-dose dry powder inhaler (DPI)

Measured Values

	AZD8871 50 μg (Part 1)	AZD8871 200 μg (Part 1)	AZD8871 400 μg (Part 1)	AZD8871 900 μg (Part 1)	AZD8871 1800 μg (Part 1)	AZD8871 2100 μg (Part 1)	Placebo (Part 1)	AZD8871 400 μg (Part 2)	AZD8871 1800 μg (Part 2)	Indacaterol 150 μg (Part 2)	Tiotropium 18 μg (Part 2)	Placebo (Part 2)
Number of Participants Analyzed [units:participants]	6	6	6	6	6	5	0	18	15	0	0	0
Cmax of AZD8871 in Parts 1 and 2 [units: pg/mL] Geometric Mean (Geometric Coefficient of Variation)	34.77 (60.77%)	174.1 (43.74%)	313.4 (46.56%)	797.3 (20.99%)	1351 (20.32%)	1243 (24.33%)		199.3 (37.40%)	810.8 (36.59%)

No statistical analysis provided for Cmax of AZD8871 in Parts 1 and 2

7. Secondary Outcome Measure: tmax of AZD8871 in Parts 1 and 2 [ Time Frame: Pre-dose, and 5 min, 15 min, 30 min, 45 min, 1 h, 2 h, 3 h, 4 h, 6 h, 8 h, 12 h (Day 1), 24 h, and 36 h (Day 2) post-dose ]

Measure Type	Secondary
Measure Name	tmax of AZD8871 in Parts 1 and 2
Measure Description	tmax (time to reach maximum concentration) of AZD8871 on Day 1 of each treatment period.
Time Frame	Pre-dose, and 5 min, 15 min, 30 min, 45 min, 1 h, 2 h, 3 h, 4 h, 6 h, 8 h, 12 h (Day 1), 24 h, and 36 h (Day 2) post-dose
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 randomised subjects who have received at least 1 dose of investigational product in at least 1 treatment period and have evaluable PK parameters. AZD8871 plasma PK assessed following dosing with AZD8871 only (not placebo, indacaterol, or tiotropium).

Reporting Groups

	Description
AZD8871 50 μg (Part 1)	Single-dose, oral inhalation by Genuair® single-dose dry powder inhaler (DPI)
AZD8871 200 μg (Part 1)	Single-dose, oral inhalation by Genuair® single-dose dry powder inhaler (DPI)
AZD8871 400 μg (Part 1)	Single-dose, oral inhalation by Genuair® single-dose dry powder inhaler (DPI)
AZD8871 900 μg (Part 1)	Single-dose, oral inhalation by Genuair® single-dose dry powder inhaler (DPI)
AZD8871 1800 μg (Part 1)	Single-dose, oral inhalation by Genuair® single-dose dry powder inhaler (DPI)
AZD8871 2100 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)
AZD8871 400 μg (Part 2)	Single-dose, oral inhalation by Genuair® single-dose dry powder inhaler (DPI)
AZD8871 1800 μg (Part 2)	Single-dose, oral inhalation by Genuair® single-dose dry powder inhaler (DPI)
Indacaterol 150 μg (Part 2)	Single-dose, oral inhalation by Onbrez Breezhaler® single-dose dry powder inhaler (DPI)
Tiotropium 18 μg (Part 2)	Single-dose, oral inhalation by HandiHaler® single-dose dry powder inhaler (DPI)
Placebo (Part 2)	Single-dose, oral inhalation by Genuair® single-dose dry powder inhaler (DPI)

Measured Values

	AZD8871 50 μg (Part 1)	AZD8871 200 μg (Part 1)	AZD8871 400 μg (Part 1)	AZD8871 900 μg (Part 1)	AZD8871 1800 μg (Part 1)	AZD8871 2100 μg (Part 1)	Placebo (Part 1)	AZD8871 400 μg (Part 2)	AZD8871 1800 μg (Part 2)	Indacaterol 150 μg (Part 2)	Tiotropium 18 μg (Part 2)	Placebo (Part 2)
Number of Participants Analyzed [units:participants]	6	6	6	6	6	5	0	18	15	0	0	0
tmax of AZD8871 in Parts 1 and 2 [units: Hours] Median (Full Range)	0.88 (0.52 to 1.03)	0.86 (0.48 to 1.00)	1.00 (0.75 to 1.05)	1.00 (0.98 to 1.02)	1.49 (0.73 to 2.03)	1.02 (1.00 to 2.00)		1.00 (0.75 to 3.00)	2.00 (0.75 to 3.00)

No statistical analysis provided for tmax of AZD8871 in Parts 1 and 2

8. Secondary Outcome Measure: AUC(0-t) of AZD8871 in Parts 1 and 2 [ Time Frame: Pre-dose, and 5 min, 15 min, 30 min, 45 min, 1 h, 2 h, 3 h, 4 h, 6 h, 8 h, 12 h (Day 1), 24 h, and 36 h (Day 2) post-dose ]

Measure Type	Secondary
Measure Name	AUC(0-t) of AZD8871 in Parts 1 and 2
Measure Description	AUC(0-t) (area under the concentration–time curve from time zero to time of the last quantifiable measurable concentration) of AZD8871 on Day 1 of each treatment period.
Time Frame	Pre-dose, and 5 min, 15 min, 30 min, 45 min, 1 h, 2 h, 3 h, 4 h, 6 h, 8 h, 12 h (Day 1), 24 h, and 36 h (Day 2) post-dose
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 randomised subjects who have received at least 1 dose of investigational product in at least 1 treatment period and have evaluable PK parameters. AZD8871 plasma PK assessed following dosing with AZD8871 only (not placebo, indacaterol, or tiotropium).

Reporting Groups

	Description
AZD8871 50 μg (Part 1)	Single-dose, oral inhalation by Genuair® single-dose dry powder inhaler (DPI)
AZD8871 200 μg (Part 1)	Single-dose, oral inhalation by Genuair® single-dose dry powder inhaler (DPI)
AZD8871 400 μg (Part 1)	Single-dose, oral inhalation by Genuair® single-dose dry powder inhaler (DPI)
AZD8871 900 μg (Part 1)	Single-dose, oral inhalation by Genuair® single-dose dry powder inhaler (DPI)
AZD8871 1800 μg (Part 1)	Single-dose, oral inhalation by Genuair® single-dose dry powder inhaler (DPI)
AZD8871 2100 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)
AZD8871 400 μg (Part 2)	Single-dose, oral inhalation by Genuair® single-dose dry powder inhaler (DPI)
AZD8871 1800 μg (Part 2)	Single-dose, oral inhalation by Genuair® single-dose dry powder inhaler (DPI)
Indacaterol 150 μg (Part 2)	Single-dose, oral inhalation by Onbrez Breezhaler® single-dose dry powder inhaler (DPI)
Tiotropium 18 μg (Part 2)	Single-dose, oral inhalation by HandiHaler® single-dose dry powder inhaler (DPI)
Placebo (Part 2)	Single-dose, oral inhalation by Genuair® single-dose dry powder inhaler (DPI)

Measured Values

	AZD8871 50 μg (Part 1)	AZD8871 200 μg (Part 1)	AZD8871 400 μg (Part 1)	AZD8871 900 μg (Part 1)	AZD8871 1800 μg (Part 1)	AZD8871 2100 μg (Part 1)	Placebo (Part 1)	AZD8871 400 μg (Part 2)	AZD8871 1800 μg (Part 2)	Indacaterol 150 μg (Part 2)	Tiotropium 18 μg (Part 2)	Placebo (Part 2)
Number of Participants Analyzed [units:participants]	6	6	6	6	6	5	0	16	15	0	0	0
AUC(0-t) of AZD8871 in Parts 1 and 2 [units: pg*h/mL] Geometric Mean (Geometric Coefficient of Variation)	110 (69.17%)	631.3 (30.40%)	1397 (31.41%)	3299 (27.00%)	6055 (24.98%)	6418 (35.13%)		1239 (37.70%)	6159 (44.30%)

No statistical analysis provided for AUC(0-t) of AZD8871 in Parts 1 and 2

9. Secondary Outcome Measure: AUC(0-24) of AZD8871 in Parts 1 and 2 [ Time Frame: Pre-dose, and 5 min, 15 min, 30 min, 45 min, 1 h, 2 h, 3 h, 4 h, 6 h, 8 h, 12 h (Day 1), 24 h, and 36 h (Day 2) post-dose ]

Measure Type	Secondary
Measure Name	AUC(0-24) of AZD8871 in Parts 1 and 2
Measure Description	AUC(0-24) (area under the concentration–time curve from zero to 24h) of AZD8871 on Day 1 of each treatment period.
Time Frame	Pre-dose, and 5 min, 15 min, 30 min, 45 min, 1 h, 2 h, 3 h, 4 h, 6 h, 8 h, 12 h (Day 1), 24 h, and 36 h (Day 2) post-dose
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 randomised subjects who have received at least 1 dose of investigational product in at least 1 treatment period and have evaluable PK parameters. AZD8871 plasma PK assessed following dosing with AZD8871 only (not placebo, indacaterol, or tiotropium).

Reporting Groups

	Description
AZD8871 50 μg (Part 1)	Single-dose, oral inhalation by Genuair® single-dose dry powder inhaler (DPI)
AZD8871 200 μg (Part 1)	Single-dose, oral inhalation by Genuair® single-dose dry powder inhaler (DPI)
AZD8871 400 μg (Part 1)	Single-dose, oral inhalation by Genuair® single-dose dry powder inhaler (DPI)
AZD8871 900 μg (Part 1)	Single-dose, oral inhalation by Genuair® single-dose dry powder inhaler (DPI)
AZD8871 1800 μg (Part 1)	Single-dose, oral inhalation by Genuair® single-dose dry powder inhaler (DPI)
AZD8871 2100 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)
AZD8871 400 μg (Part 2)	Single-dose, oral inhalation by Genuair® single-dose dry powder inhaler (DPI)
AZD8871 1800 μg (Part 2)	Single-dose, oral inhalation by Genuair® single-dose dry powder inhaler (DPI)
Indacaterol 150 μg (Part 2)	Single-dose, oral inhalation by Onbrez Breezhaler® single-dose dry powder inhaler (DPI)
Tiotropium 18 μg (Part 2)	Single-dose, oral inhalation by HandiHaler® single-dose dry powder inhaler (DPI)
Placebo (Part 2)	Single-dose, oral inhalation by Genuair® single-dose dry powder inhaler (DPI)

Measured Values

	AZD8871 50 μg (Part 1)	AZD8871 200 μg (Part 1)	AZD8871 400 μg (Part 1)	AZD8871 900 μg (Part 1)	AZD8871 1800 μg (Part 1)	AZD8871 2100 μg (Part 1)	Placebo (Part 1)	AZD8871 400 μg (Part 2)	AZD8871 1800 μg (Part 2)	Indacaterol 150 μg (Part 2)	Tiotropium 18 μg (Part 2)	Placebo (Part 2)
Number of Participants Analyzed [units:participants]	6	6	6	6	6	5	0	18	15	0	0	0
AUC(0-24) of AZD8871 in Parts 1 and 2 [units: pg*h/mL] Geometric Mean (Geometric Coefficient of Variation)	118.9 (60.19%)	567.9 (29.74%)	1265 (32.44%)	3020 (25.71%)	5587 (25.40%)	5922 (34.32%)		1195 (38.91%)	5659 (43.68%)

No statistical analysis provided for AUC(0-24) of AZD8871 in Parts 1 and 2

10. Other Pre-specified Outcome Measure: AUC of AZD8871 in Parts 1 and 2 [ Time Frame: Predose, and 5 min, 15 min, 30 min, and 45 min, at 1 h, 2 h, 3 h, 4 h, 6 h, 8 h, 12 h (Day 1), 24 h and 36 h (Day 2) post-dose ]

Measure Type	Other Pre-specified
Measure Name	AUC of AZD8871 in Parts 1 and 2
Measure Description	AUC (area under the concentration-time curve from time 0 to infinity) of AZD8871 on Day 1 of each treatment period
Time Frame	Predose, and 5 min, 15 min, 30 min, and 45 min, at 1 h, 2 h, 3 h, 4 h, 6 h, 8 h, 12 h (Day 1), 24 h and 36 h (Day 2) post-dose
Safety Issue?

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 randomised subjects who have received at least 1 dose of investigational product in at least 1 treatment period and have evaluable PK parameters. AZD8871 plasma PK assessed following dosing with AZD8871 only (not placebo, indacaterol, or tiotropium).

Reporting Groups

	Description
AZD8871 50 μg (Part 1)	Single-dose, oral inhalation by Genuair® single-dose dry powder inhaler (DPI)
AZD8871 200 μg (Part 1)	Single-dose, oral inhalation by Genuair® single-dose dry powder inhaler (DPI)
AZD8871 400 μg (Part 1)	Single-dose, oral inhalation by Genuair® single-dose dry powder inhaler (DPI)
AZD8871 900 μg (Part 1)	Single-dose, oral inhalation by Genuair® single-dose dry powder inhaler (DPI)
AZD8871 1800 μg (Part 1)	Single-dose, oral inhalation by Genuair® single-dose dry powder inhaler (DPI)
AZD8871 2100 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)
AZD8871 400 μg (Part 2)	Single-dose, oral inhalation by Genuair® single-dose dry powder inhaler (DPI)
AZD8871 1800 μg (Part 2)	Single-dose, oral inhalation by Genuair® single-dose dry powder inhaler (DPI)
Indacaterol 150 μg (Part 2)	Single-dose, oral inhalation by Onbrez Breezhaler® single-dose dry powder inhaler (DPI)
Tiotropium 18 μg (Part 2)	Single-dose, oral inhalation by HandiHaler® single-dose dry powder inhaler (DPI)
Placebo (Part 2)	Single-dose, oral inhalation by Genuair® single-dose dry powder inhaler (DPI)

Measured Values

	AZD8871 50 μg (Part 1)	AZD8871 200 μg (Part 1)	AZD8871 400 μg (Part 1)	AZD8871 900 μg (Part 1)	AZD8871 1800 μg (Part 1)	AZD8871 2100 μg (Part 1)	Placebo (Part 1)	AZD8871 400 μg (Part 2)	AZD8871 1800 μg (Part 2)	Indacaterol 150 μg (Part 2)	Tiotropium 18 μg (Part 2)	Placebo (Part 2)
Number of Participants Analyzed [units:participants]	5	6	6	6	6	5	0	18	15	0	0	0
AUC of AZD8871 in Parts 1 and 2 [units: pg*h/mL] Geometric Mean (Geometric Coefficient of Variation)	123.1 (75.48%)	774.5 (32.64%)	1671 (28.54%)	3831 (28.72%)	6941 (22.23%)	7164 (34.10%)		1459 (39.19%)	6769 (44.65%)

No statistical analysis provided for AUC of AZD8871 in Parts 1 and 2

11. Other Pre-specified Outcome Measure: Elimination half-life of AZD8871 in Parts 1 and 2 [ Time Frame: Predose, and 5 min, 15 min, 30 min, and 45 min, at 1 h, 2 h, 3 h, 4 h, 6 h, 8 h, 12 h (Day 1), 24 h and 36 h (Day 2) post-dose ]

Measure Type	Other Pre-specified
Measure Name	Elimination half-life of AZD8871 in Parts 1 and 2
Measure Description	Elimination half-life (t½λz) for AZD8871 on Day 1 of each treatment period. t½λz was generally calculated over a period of less than 3 times the resultant half-life
Time Frame	Predose, and 5 min, 15 min, 30 min, and 45 min, at 1 h, 2 h, 3 h, 4 h, 6 h, 8 h, 12 h (Day 1), 24 h and 36 h (Day 2) post-dose
Safety Issue?

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 randomised subjects who have received at least 1 dose of investigational product in at least 1 treatment period and have evaluable PK parameters. AZD8871 plasma PK assessed following dosing with AZD8871 only (not placebo, indacaterol, or tiotropium).

Reporting Groups

	Description
AZD8871 50 μg (Part 1)	Single-dose, oral inhalation by Genuair® single-dose dry powder inhaler (DPI)
AZD8871 200 μg (Part 1)	Single-dose, oral inhalation by Genuair® single-dose dry powder inhaler (DPI)
AZD8871 400 μg (Part 1)	Single-dose, oral inhalation by Genuair® single-dose dry powder inhaler (DPI)
AZD8871 900 μg (Part 1)	Single-dose, oral inhalation by Genuair® single-dose dry powder inhaler (DPI)
AZD8871 1800 μg (Part 1)	Single-dose, oral inhalation by Genuair® single-dose dry powder inhaler (DPI)
AZD8871 2100 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)
AZD8871 400 μg (Part 2)	Single-dose, oral inhalation by Genuair® single-dose dry powder inhaler (DPI)
AZD8871 1800 μg (Part 2)	Single-dose, oral inhalation by Genuair® single-dose dry powder inhaler (DPI)
Indacaterol 150 μg (Part 2)	Single-dose, oral inhalation by Onbrez Breezhaler® single-dose dry powder inhaler (DPI)
Tiotropium 18 μg (Part 2)	Single-dose, oral inhalation by HandiHaler® single-dose dry powder inhaler (DPI)
Placebo (Part 2)	Single-dose, oral inhalation by Genuair® single-dose dry powder inhaler (DPI)

Measured Values

	AZD8871 50 μg (Part 1)	AZD8871 200 μg (Part 1)	AZD8871 400 μg (Part 1)	AZD8871 900 μg (Part 1)	AZD8871 1800 μg (Part 1)	AZD8871 2100 μg (Part 1)	Placebo (Part 1)	AZD8871 400 μg (Part 2)	AZD8871 1800 μg (Part 2)	Indacaterol 150 μg (Part 2)	Tiotropium 18 μg (Part 2)	Placebo (Part 2)
Number of Participants Analyzed [units:participants]	6	6	6	6	6	5	0	18	15	0	0	0
Elimination half-life of AZD8871 in Parts 1 and 2 [units: Hours] Mean (Standard Deviation)	9.439 (7.350)	23.10 (2.809)	20.81 (5.384)	18.86 (3.959)	19.29 (5.468)	15.96 (2.789)		14.20 (5.521)	12.89 (2.268)

No statistical analysis provided for Elimination half-life of AZD8871 in Parts 1 and 2

Serious Adverse Events

Time Frame	From the time of informed consent up to 14 (±2) days after the last dose of investigational product (IP). Treatment-emergent adverse events were those reported after the first dose of IP up to 14 (±2) days after the last dose of IP. Unresolved AEs were followed up by the investigator for as long as medically indicated.
Additional Description	The Safety population comprised all randomised subjects who received at least 1 dose of the IP.

Reporting Groups

	Description
AZD8871 50 μg (Part 1)	Single-dose, oral inhalation by Genuair® single-dose dry powder inhaler (DPI)
AZD8871 200 μg (Part 1)	Single-dose, oral inhalation by Genuair® single-dose dry powder inhaler (DPI)
AZD8871 400 μg (Part 1)	Single-dose, oral inhalation by Genuair® single-dose dry powder inhaler (DPI)
AZD8871 900 μg (Part 1)	Single-dose, oral inhalation by Genuair® single-dose dry powder inhaler (DPI)
AZD8871 1800 μg (Part 1)	Single-dose, oral inhalation by Genuair® single-dose dry powder inhaler (DPI)
AZD8871 2100 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)
AZD8871 400 μg (Part 2)	Single-dose, oral inhalation by Genuair® single-dose dry powder inhaler (DPI)
AZD8871 1800 μg (Part 2)	Single-dose, oral inhalation by Genuair® single-dose dry powder inhaler (DPI)
Indacaterol 150 μg (Part 2)	Single-dose, oral inhalation by Onbrez Breezhaler® single-dose dry powder inhaler (DPI)
Tiotropium 18 μg (Part 2)	Single-dose, oral inhalation by HandiHaler® single-dose dry powder inhaler (DPI)
Placebo (Part 2)	Single-dose, oral inhalation by Genuair® single-dose dry powder inhaler (DPI)

Serious Adverse Events

AZD8871 50 μg (Part 1)

AZD8871 200 μg (Part 1)

AZD8871 400 μg (Part 1)

AZD8871 900 μg (Part 1)

AZD8871 1800 μg (Part 1)

AZD8871 2100 μg (Part 1)

Placebo (Part 1)

AZD8871 400 μg (Part 2)

AZD8871 1800 μg (Part 2)

Indacaterol 150 μg (Part 2)

Tiotropium 18 μg (Part 2)

Placebo (Part 2)

Total, serious adverse events

# participants affected / at risk

0/6 (0.00%)

0/5 (0.00%)

0/12 (0.00%)

1/34 (2.94%)

0/31 (0.00%)

0/32 (0.00%)

1/30 (3.33%)

0/32 (0.00%)

Injury, poisoning and procedural complications

Spinal fracture¹,^†

# participants affected / at risk

0/6 (0.00%)

0/5 (0.00%)

0/12 (0.00%)

0/34 (0.00%)

0/31 (0.00%)

0/32 (0.00%)

1/30 (3.33%)

0/32 (0.00%)

# events

Social circumstances

Physical assault¹,^†

# participants affected / at risk

0/6 (0.00%)

0/5 (0.00%)

0/12 (0.00%)

1/34 (2.94%)

0/31 (0.00%)

0/32 (0.00%)

0/30 (0.00%)

0/32 (0.00%)

# events

†	Events were collected by systematic assessment
1	Term from vocabulary, MedDRA 18.1

Other Adverse Events

Time Frame	From the time of informed consent up to 14 (±2) days after the last dose of investigational product (IP). Treatment-emergent adverse events were those reported after the first dose of IP up to 14 (±2) days after the last dose of IP. Unresolved AEs were followed up by the investigator for as long as medically indicated.
Additional Description	The Safety population comprised all randomised subjects who received at least 1 dose of the IP.

Frequency Threshold

Threshold above which other adverse events are reported	5%

Reporting Groups

	Description
AZD8871 50 μg (Part 1)	Single-dose, oral inhalation by Genuair® single-dose dry powder inhaler (DPI)
AZD8871 200 μg (Part 1)	Single-dose, oral inhalation by Genuair® single-dose dry powder inhaler (DPI)
AZD8871 400 μg (Part 1)	Single-dose, oral inhalation by Genuair® single-dose dry powder inhaler (DPI)
AZD8871 900 μg (Part 1)	Single-dose, oral inhalation by Genuair® single-dose dry powder inhaler (DPI)
AZD8871 1800 μg (Part 1)	Single-dose, oral inhalation by Genuair® single-dose dry powder inhaler (DPI)
AZD8871 2100 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)
AZD8871 400 μg (Part 2)	Single-dose, oral inhalation by Genuair® single-dose dry powder inhaler (DPI)
AZD8871 1800 μg (Part 2)	Single-dose, oral inhalation by Genuair® single-dose dry powder inhaler (DPI)
Indacaterol 150 μg (Part 2)	Single-dose, oral inhalation by Onbrez Breezhaler® single-dose dry powder inhaler (DPI)
Tiotropium 18 μg (Part 2)	Single-dose, oral inhalation by HandiHaler® single-dose dry powder inhaler (DPI)
Placebo (Part 2)	Single-dose, oral inhalation by Genuair® single-dose dry powder inhaler (DPI)

Other Adverse Events

AZD8871 50 μg (Part 1)

AZD8871 200 μg (Part 1)

AZD8871 400 μg (Part 1)

AZD8871 900 μg (Part 1)

AZD8871 1800 μg (Part 1)

AZD8871 2100 μg (Part 1)

Placebo (Part 1)

AZD8871 400 μg (Part 2)

AZD8871 1800 μg (Part 2)

Indacaterol 150 μg (Part 2)

Tiotropium 18 μg (Part 2)

Placebo (Part 2)

Total, other (not including serious) adverse events

# participants affected / at risk

5/6 (83.33%)

3/6 (50.00%)

2/5 (40.00%)

12/12 (100.00%)

8/34 (23.53%)

4/31 (12.90%)

6/32 (18.75%)

8/30 (26.67%)

8/32 (25.00%)

Infections and infestations

Nasopharyngitis¹,^†

# participants affected / at risk

3/6 (50.00%)

1/6 (16.67%)

0/6 (0.00%)

2/5 (40.00%)

1/12 (8.33%)

1/34 (2.94%)

1/31 (3.23%)

2/32 (6.25%)

1/30 (3.33%)

1/32 (3.13%)

# events

Nervous system disorders

Headache¹,^†

# participants affected / at risk

3/6 (50.00%)

1/6 (16.67%)

2/6 (33.33%)

1/6 (16.67%)

0/5 (0.00%)

3/12 (25.00%)

5/34 (14.71%)

3/31 (9.68%)

4/32 (12.50%)

7/30 (23.33%)

7/32 (21.88%)

# events

Respiratory, thoracic and mediastinal disorders

Chronic obstructive pulmonary disorder¹,^†

# participants affected / at risk

0/6 (0.00%)

0/5 (0.00%)

0/12 (0.00%)

2/34 (5.88%)

1/31 (3.23%)

1/32 (3.13%)

0/30 (0.00%)

0/32 (0.00%)

# events

Ear and labyrinth disorders

Ear pain¹,^†

# participants affected / at risk

0/6 (0.00%)

1/6 (16.67%)

0/6 (0.00%)

0/5 (0.00%)

0/12 (0.00%)

0/34 (0.00%)

0/31 (0.00%)

0/32 (0.00%)

0/30 (0.00%)

0/32 (0.00%)

# events

Gastrointestinal disorders

Dyspepsia¹,^†

# participants affected / at risk

0/6 (0.00%)

0/5 (0.00%)

1/12 (8.33%)

0/34 (0.00%)

0/31 (0.00%)

0/32 (0.00%)

0/30 (0.00%)

0/32 (0.00%)

# events

Gastrointestinal disorders

Nausea¹,^†

# participants affected / at risk

1/6 (16.67%)

0/6 (0.00%)

1/6 (16.67%)

0/5 (0.00%)

0/12 (0.00%)

0/34 (0.00%)

0/31 (0.00%)

0/32 (0.00%)

0/30 (0.00%)

0/32 (0.00%)

# events

General disorders

Feeling hot¹,^†

# participants affected / at risk

1/6 (16.67%)

0/6 (0.00%)

1/5 (20.00%)

1/12 (8.33%)

0/34 (0.00%)

0/31 (0.00%)

0/32 (0.00%)

0/30 (0.00%)

0/32 (0.00%)

# events

General disorders

Catheter site pain¹,^†

# participants affected / at risk

0/6 (0.00%)

0/5 (0.00%)

1/12 (8.33%)

0/34 (0.00%)

0/31 (0.00%)

0/32 (0.00%)

0/30 (0.00%)

0/32 (0.00%)

# events

General disorders

Chest discomfort¹,^†

# participants affected / at risk

1/6 (16.67%)

0/6 (0.00%)

0/5 (0.00%)

1/12 (8.33%)

0/34 (0.00%)

0/31 (0.00%)

0/32 (0.00%)

0/30 (0.00%)

0/32 (0.00%)

# events

General disorders

Chest pain¹,^†

# participants affected / at risk

0/6 (0.00%)

1/6 (16.67%)

0/6 (0.00%)

0/5 (0.00%)

0/12 (0.00%)

0/34 (0.00%)

0/31 (0.00%)

0/32 (0.00%)

0/30 (0.00%)

0/32 (0.00%)

# events

General disorders

Fatigue¹,^†

# participants affected / at risk

0/6 (0.00%)

0/5 (0.00%)

1/12 (8.33%)

0/34 (0.00%)

0/31 (0.00%)

0/32 (0.00%)

0/30 (0.00%)

0/32 (0.00%)

# events

Immune system disorders

Seasonal allergy¹,^†

# participants affected / at risk

0/6 (0.00%)

1/6 (16.67%)

0/6 (0.00%)

0/5 (0.00%)

1/12 (8.33%)

0/34 (0.00%)

0/31 (0.00%)

0/32 (0.00%)

0/30 (0.00%)

0/32 (0.00%)

# events

Infections and infestations

Abscess oral¹,^†

# participants affected / at risk

0/6 (0.00%)

1/6 (16.67%)

0/6 (0.00%)

0/5 (0.00%)

0/12 (0.00%)

0/34 (0.00%)

0/31 (0.00%)

0/32 (0.00%)

0/30 (0.00%)

0/32 (0.00%)

# events

Infections and infestations

Oral herpes¹,^†

# participants affected / at risk

0/6 (0.00%)

1/6 (16.67%)

0/6 (0.00%)

0/5 (0.00%)

0/12 (0.00%)

0/34 (0.00%)

0/31 (0.00%)

0/32 (0.00%)

0/30 (0.00%)

0/32 (0.00%)

# events

Infections and infestations

Bronchitis¹,^†

# participants affected / at risk

1/6 (16.67%)

0/6 (0.00%)

0/5 (0.00%)

0/12 (0.00%)

0/34 (0.00%)

0/31 (0.00%)

0/32 (0.00%)

0/30 (0.00%)

0/32 (0.00%)

# events

Infections and infestations

Pharyngitis¹,^†

# participants affected / at risk

0/6 (0.00%)

1/6 (16.67%)

0/6 (0.00%)

0/5 (0.00%)

0/12 (0.00%)

0/34 (0.00%)

0/31 (0.00%)

0/32 (0.00%)

0/30 (0.00%)

0/32 (0.00%)

# events

Infections and infestations

Bronchitis viral¹,^†

# participants affected / at risk

0/6 (0.00%)

1/5 (20.00%)

0/12 (0.00%)

0/34 (0.00%)

0/31 (0.00%)

0/32 (0.00%)

0/30 (0.00%)

0/32 (0.00%)

# events

Musculoskeletal and connective tissue disorders

Back pain¹,^†

# participants affected / at risk

1/6 (16.67%)

0/6 (0.00%)

1/6 (16.67%)

0/6 (0.00%)

0/5 (0.00%)

0/12 (0.00%)

0/34 (0.00%)

0/31 (0.00%)

0/32 (0.00%)

0/30 (0.00%)

0/32 (0.00%)

# events

Musculoskeletal and connective tissue disorders

Musculoskeletal pain¹,^†

# participants affected / at risk

1/6 (16.67%)

0/6 (0.00%)

0/5 (0.00%)

0/12 (0.00%)

0/34 (0.00%)

0/31 (0.00%)

0/32 (0.00%)

0/30 (0.00%)

0/32 (0.00%)

# events

Musculoskeletal and connective tissue disorders

Neck pain¹,^†

# participants affected / at risk

0/6 (0.00%)

1/6 (16.67%)

0/6 (0.00%)

1/6 (16.67%)

0/5 (0.00%)

0/12 (0.00%)

0/34 (0.00%)

0/31 (0.00%)

0/32 (0.00%)

0/30 (0.00%)

0/32 (0.00%)

# events

Nervous system disorders

Dizziness¹,^†

# participants affected / at risk

0/6 (0.00%)

1/6 (16.67%)

0/6 (0.00%)

0/5 (0.00%)

1/12 (8.33%)

0/34 (0.00%)

0/31 (0.00%)

0/32 (0.00%)

0/30 (0.00%)

0/32 (0.00%)

# events

Nervous system disorders

Dizziness postural¹,^†

# participants affected / at risk

0/6 (0.00%)

1/6 (16.67%)

0/6 (0.00%)

0/5 (0.00%)

0/12 (0.00%)

0/34 (0.00%)

0/31 (0.00%)

0/32 (0.00%)

0/30 (0.00%)

0/32 (0.00%)

# events

Nervous system disorders

Presyncope¹,^†

# participants affected / at risk

0/6 (0.00%)

0/5 (0.00%)

1/12 (8.33%)

0/34 (0.00%)

0/31 (0.00%)

0/32 (0.00%)

0/30 (0.00%)

0/32 (0.00%)

# events

Respiratory, thoracic and mediastinal disorders

Wheezing¹,^†

# participants affected / at risk

1/6 (16.67%)

0/6 (0.00%)

0/5 (0.00%)

1/12 (8.33%)

0/34 (0.00%)

0/31 (0.00%)

0/32 (0.00%)

0/30 (0.00%)

0/32 (0.00%)

# events

Respiratory, thoracic and mediastinal disorders

Cough¹,^†

# participants affected / at risk

1/6 (16.67%)

0/6 (0.00%)

1/6 (16.67%)

0/6 (0.00%)

0/5 (0.00%)

0/12 (0.00%)

0/34 (0.00%)

0/31 (0.00%)

0/32 (0.00%)

0/30 (0.00%)

0/32 (0.00%)

# events

Respiratory, thoracic and mediastinal disorders

Productive cough¹,^†

# participants affected / at risk

0/6 (0.00%)

1/6 (16.67%)

0/6 (0.00%)

0/5 (0.00%)

0/12 (0.00%)

0/34 (0.00%)

0/31 (0.00%)

0/32 (0.00%)

0/30 (0.00%)

0/32 (0.00%)

# events

Respiratory, thoracic and mediastinal disorders

Nasal congestion¹,^†

# participants affected / at risk

0/6 (0.00%)

1/6 (16.67%)

0/6 (0.00%)

0/5 (0.00%)

0/12 (0.00%)

0/34 (0.00%)

0/31 (0.00%)

0/32 (0.00%)

0/30 (0.00%)

0/32 (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%)

0/5 (0.00%)

0/12 (0.00%)

0/34 (0.00%)

0/31 (0.00%)

0/32 (0.00%)

0/30 (0.00%)

0/32 (0.00%)

# events

Skin and subcutaneous tissue disorders

Skin irritation¹,^†

# participants affected / at risk

1/6 (16.67%)

0/6 (0.00%)

1/6 (16.67%)

0/5 (0.00%)

0/12 (0.00%)

0/34 (0.00%)

0/31 (0.00%)

0/32 (0.00%)

0/30 (0.00%)

0/32 (0.00%)

# events

Skin and subcutaneous tissue disorders

Pruritus¹,^†

# participants affected / at risk

0/6 (0.00%)

1/6 (16.67%)

0/6 (0.00%)

1/6 (16.67%)

0/6 (0.00%)

0/5 (0.00%)

0/12 (0.00%)

0/34 (0.00%)

0/31 (0.00%)

0/32 (0.00%)

0/30 (0.00%)

0/32 (0.00%)

# events

†	Events were collected by systematic assessment
1	Term from vocabulary, MedDRA 18.1

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 of the results by the Principal Investigator (PI) will be subject to mutual agreement between the PI and the sponsor.

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
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Results Point of Contact

Name/Title:	Study Director
Organization:	AstraZeneca
E-mail:	[email protected]

Documents available

Trial Results Summaries
Available here

Contacts

Contact

AstraZeneca Clinical Study Information Center

1-877-240-9479

information.center@astrazeneca.com

Investigators

Principal Investigator

Muna Albayaty

PAREXEL Early Phase Clinical Unit, London, United Kingdom

Sponsors

Collaborators

Inclusion Criteria

Exclusion Criteria

Research Site

Research Site

Trial Results Summaries