Efficacy, Pharmacokinetics (PK), Safety and Tolerability Study of inhaled AZD8871

Study identifier:D6640C00004

ClinicalTrials.gov identifier:NCT02971293

EudraCT identifier:N/A

CTIS identifier:N/A

Study Complete

Official Title

A Phase IIa, Randomised, Multi-Centre, Double-Blind, Placebo-Controlled, 3 Periods, Crossover Study to Investigate the Efficacy, Pharmacokinetics, Safety and Tolerability of Inhaled AZD8871 Administered once daily for 2 Weeks in Patients with Moderate to Severe COPD.

Medical condition

Chronic Obstructive Pulmonary Disease COPD

Phase

Phase 2

Healthy volunteers

Study drug

AZD8871 100 µg, AZD8871 600 µg, Placebo

Sex

All

Actual Enrollment

Study type

Interventional

Age

40 Years - 80 Years

Date

Study Start Date: 15 Dec 2016

Primary Completion Date: 18 Aug 2017

Study Completion Date: 18 Aug 2017

Study design

Allocation: Randomized
Endpoint Classification: Safety/Efficacy
Intervention Model: Crossover Assignment
Masking: Double Blind
Primary Purpose: Treatment

Verification:

Verified 01 Jun 2019 by AstraZeneca

Collaborators

PAREXEL

Inclusion and exclusion criteria

Inclusion Criteria

1. Patient who provided of informed consent prior to any study-specific procedures
2. Male or female 40 to 80 years of age (both inclusive) at Screening (Visit 1). A female is eligible to enter and participate in the study if she is of non-childbearing potential.
Note: A female is considered to be of non-childbearing potential if she meets one of the following criteria:
•Permanently or surgically sterilised, including hysterectomy and/or bilateral oophorectomy and/or bilateral salpingectomy
•Post-menopausal; aged <50 years and amenorrhoeic for 12 months or more following cessation of exogenous hormonal treatments and with luteinizing hormone (LH) and follicle stimulating hormone (FSH) levels in the post-menopausal range of the local laboratory.
•Post-menopausal; aged ≥50 years and amenorrhoeic for 12 months or more, following cessation of all exogenous hormonal treatments.
3. Male patient should use a condom and spermicide to prevent pregnancy and drug exposure of a partner, regardless of the gender or childbearing potential of the partner from the day of the first administration of the investigational product (IP) until 3 months after the last administration of the IP.
4. COPD Diagnosis: Patient with an established clinical history of COPD for more than 1 year at Screening, according to the Global Initiative for Chronic Obstructive Lung Disease 2016 COPD guidelines.
5. Tobacco Use: Patient is a current or former smoker with a history of ≥10 pack-years of cigarette smoking. A former smoker is defined as one who has stopped smoking for at least 6 months prior to Screening.
6. Patient with post-bronchodilator FEV1/FVC (Forced vital capacity) ratio <70% based on the value reached after inhalation of salbutamol (400 µg) at Visit 2. If criterion is not met, the test can be repeated at the latest, up to Day 14.
7. Patient with post-bronchodilator FEV1 that must be ≥40% and <80% predicted normal value and must also be >750 mL at Visit 2. If criterion is not met, the test can be repeated at the latest, up to Day 14.
8. Patient who fulfils reversibility criteria to salbutamol at Visit 2. Reversibility is defined as ≥12% and ≥200 mL increase in FEV1 after inhalation of 4 puffs of salbutamol. (400 µg). If criterion is not met, the test can be repeated at the latest, up to Day 14.
9. Patient is willing and, in the opinion of the Investigator, able to change current COPD therapy as required by the protocol and willing to use ipratropium Four times a day (if needed, during run-in and wash-out periods) with or without Inhaled corticosteroid for maintenance therapy of COPD and as needed rescue salbutamol from Visit 1 up Visit 11.
10. Patient is free from any clinically active disease other than COPD that may impact study outcome, as determined by medical history, physical examination, laboratory testing, and 12-lead ECG findings, at Screening.
11. Patient is willing to remain at the study centre as required per protocol to complete all visit assessments.
12. Patient with body mass index (BMI) <40 kg/m2 at the time of screening.

Exclusion Criteria

1. Patient previously enrolled in the present study.
2. Patient has significant diseases other than COPD, ie, disease or condition or an abnormality in laboratory, ECG, medical history or physical examination which, in the opinion of the Investigator, may put the patient at risk because of participation in the study or may influence either the results of the study or the patient’spatient's ability to participate in the study.
3. Childbearing potential female, pregnant or lactating.
4. Patient who, in the opinion of the Investigator, has a current diagnosis of asthma.
5. Patient has alpha-1 antitrypsin deficiency as the cause of COPD.
6. Patient has other active pulmonary disease such as active tuberculosis, lung cancer, bronchiectasis sarcoidosis, idiopathic interstitial pulmonary fibrosis, primary pulmonary hypertension, or uncontrolled sleep apnoea. Allergic rhinitis is not exclusionary.
7. Lung surgery for volume reduction or lung transplantation: Patient has undergone lung volume reduction surgery, lobectomy, or bronchoscopic lung volume reduction (endobronchial blockers, airway bypass, endobronchial valves, thermal vapour ablation, biological sealants, massive pulmonary embolism and airway implants) within 1 year of Screening (Visit 1).
8. Patient is using nocturnal positive pressure (eg, continuous positive airway pressure or bi level positive airway pressure). Patient is using any non-invasive positive pressure ventilation device.
Note: A patient using continuous positive airway pressure or bi level positive airway pressure for Sleep Apnoea Syndrome is allowed in the study.
9. Patient has been hospitalised due to poorly controlled COPD within 3 months of Screening.
10. Patient has acute worsening of COPD that requires treatment with corticosteroids or antibiotics in the 6 week interval prior to Screening (Visit 1), or during the Screening Period (between Visits 1 and 3).
11. Patient has had lower respiratory tract infections that required antibiotics within 6 weeks prior to Screening.
12. Patient cannot perform acceptable spirometry, ie, meet American Thoracic Society (ATS)/European Respiratory Society (ERS) acceptability criteria.
13. Patient has changed their smoking status (ie, start or stop smoking) or initiation of a smoking cessation program within 6 weeks prior to Screening.
14. Patient has participated in the acute phase of a pulmonary rehabilitation program within 4 weeks prior to Screening or who will enter the acute phase of a pulmonary rehabilitation program during the study. A patient in the maintenance phase of a pulmonary rehabilitation program is not to be excluded.
15. Cardiac disease: Subject with significant cardiovascular disease cardiovascular instability. Patient with heart rate <50 beats per minute. Patient has clinically significant uncontrolled hypertension as assessed by the investigator.
16. Neurological: Patient with seizures or history of seizures requiring anticonvulsants within 12 months prior to Screening. Patient is taking selective serotonin reuptake inhibitors or serotonin–-norepinephrine reuptake inhibitors whose dose has not been stable for at least 4 weeks prior to Screening, or exceeds the maximum recommended dose.
17. Renal: Patient with symptomatic bladder neck obstruction, acute urinary retention or symptomatic non-stable prostate hypertrophy. 35.23. Patient with a serum potassium value <3.5 mmol/L at Screening and on repeat testing. Note: however potassium replacement and rescreening is allowed if serum potassium concentration was < 3.5mmol/l at screening.
18. Others:
-Any laboratory abnormality or suspicion of any clinically relevant disease or disorder (on history or examination), including uncontrolled hypertension or uncontrolled diabetes, which, in the opinion of the Investigator, may either put the patient at risk because of participation in the study, or influence the results or the patient's ability to participate in the study, or any other safety concerns in the opinion of the Investigator.
- History of malignancy of any organ system, treated or untreated within the past 5 years, with the exception of localized basal cell carcinoma of the skin
-Patient with known narrow-angle glaucoma.
-Patient has a history of hypersensitivity to β2-agonists, muscarinic anticholinergics or lactose/milk protein. Lactose intolerance is not an exclusion criterion.
-The patient has a known or suspected history of alcohol or drug of abuse within the past 2-year period years or consuming more than 14 (female subjects) or 21 (male subjects) units of alcohol a week, or shows positive for drugs of abuse and alcohol tests at screening and prior to randomization.
-Patient who, in the opinion of the Investigator, would be unable to abstain from protocol-defined prohibited medications during the study.
-Patient who received a live attenuated vaccination within 30 days prior to Screening.
-Patient involved in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site).
-Patient treated with investigational drug or device in another clinical trial within the last 30 days or five half-lives (whichever is longer) prior to Screening.
-Patient who donated or lost >500 mL of blood and plasma within the previous 3 months prior to screening.
-Patient is unlikely to co-operate with the requirements of the study, instructions of the Principal Investigator., or have e-dairy completion rate of < 70% during the run in period.
-Patient with known human immunodeficiency virus (HIV) infection or chronic hepatitis B or C infection.

This is a proof-of-concept, randomised, double-blind, placebo-controlled, 3-way, complete crossover William’s design, multiple dose study to investigate the efficacy, PK, safety, and tolerability of 2 dose levels of AZD8871 and placebo, administered using a dry powder inhaler (DPI) device once daily, for 2 weeks, in patients with moderate to severe COPD. AZD8871 is a new chemical entity with the combined properties of a LAMA and a LABA in a single molecule. AZD8871 is being developed as an inhaled long-acting bronchodilator for the maintenance treatment of COPD. The objective of the study is to assess the efficacy, safety and PK of AZD8871 after a 14-day treatment period at 2 different doses in patients with moderate to severe COPD. The target population includes male and female (non-childbearing potential) adult patients with clinical diagnosis of moderate to severe COPD. The crossover design has been chosen to avoid inter-patient variability and optimize sample size. By randomly assigning treatment sequence, differences in baseline characteristics of the treatment groups will be minimised. The inclusion of a placebo arm is considered the most reliable method to minimise patient and Investigator bias. The proposed dose levels of AZD8871 in this study are 100 and 600 µg of AZD8871 given by inhalation once daily for 14 days through a single dose DPI. Doses have been selected based on the safety, tolerability, PK and pharmacodynamics (PD) information generated in previous clinical trials with AZD8871. The wash-out period proposed for this current study is a minimum of 28 days and up to 35 days in order to avoid any carry over effect between periods. The broad dose range selected (6 fold range from 100 to 600 µg) has been chosen to span the likely therapeutic dose and facilitate the dose selection for future studies. Considering the expected efficacy in patients with COPD and the available data to date, it is anticipated the benefits will outweigh the risks and support the continued investigation of AZD8871 in clinical studies.

Location

Research Site

Berlin, Germany, 14050

Location

Research Site

Manchester, United Kingdom, M23 9QZ

Arms	Assigned Interventions
Experimental: AZD8871 100 µg The subjects will receive AZD8871 100 µg once daily, by dry powder inhaler (DPI) device. The treatment will be administered via single dose DPI that is an adaptation of the multi-dose Genuair™ used in approved inhalation products.	Drug: AZD8871 100 µg The subjects will receive one dose of AZD8871 100 µg single dose DPI.
Placebo Comparator: Placebo The placebo will be administered via single dose DPI that is an adaptation of the commercially available Genuair® with a smaller internal volume to enable delivery of single doses. To maintain blinding, each patient will receive one inhaled dose from placebo DPI provided to him/her on each day of the treatment period.	Drug: Placebo The subject will receive Placebo single dose DPI.
Experimental: AZD8871 600 µg The subjects will receive AZD8871 600 µg once daily by DPI device via single dose DPI that is an adaptation of the multi-dose Genuair™ used in approved inhalation products.	Drug: AZD8871 600 µg The subjects will receive AZD8871, 600 µg single dose 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 two centres, one each in Germany and the UK. The first patient was enrolled in December 2016 and the last patient last visit was in August 2017.

Pre-Assignment Details

Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
A total of 103 patients were screened; 42 patients were eligible to participate and were randomised.

Reporting Groups

	Description
All Participants	All subjects received AZD8871 100 µg, AZD8871 600 µg or placebo, once daily by DPI device via single dose DPI that is an adaptation of the multi-dose Genuair™ used in approved inhalation products. Each subject was randomized to one of three sequences in a 3-way, complete crossover William's design, and received all 3 treatments in turn, in three 14-day treatment periods, each (except the last one) followed by a wash-out period of 28-35 days.

Description

All Participants

All subjects received AZD8871 100 µg, AZD8871 600 µg or placebo, once daily by DPI device via single dose DPI that is an adaptation of the multi-dose Genuair™ used in approved inhalation products.
Each subject was randomized to one of three sequences in a 3-way, complete crossover William's design, and received all 3 treatments in turn, in three 14-day treatment periods, each (except the last one) followed by a wash-out period of 28-35 days.

Participant Flow: Overall Study

	All Participants
STARTED	42
COMPLETED	31
NOT COMPLETED	11

Baseline Characteristics

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

Safety analysis set: Includes all randomised participants who received at least one dose of investigational product.

Reporting Groups

	Description
Overall study population	Full analysis set: All randomised participants who received at least one dose of investigational product.

Baseline Measures

	Overall study population
Number of Participants [units: Participants]	42
Age Continuous [units: Years] Mean ± Standard Deviation	63.6 ± 6.6
Sex/Gender, Customized [units: Participants]
Female	14
Male	28
Race (NIH/OMB) [units: Participants]
American Indian or Alaska Native	0
Asian	0
Native Hawaiian or Other Pacific Islander	0
Black or African American	0
White	42
More than one race	0
Unknown or Not Reported	0

Outcome Measures

1. Primary Outcome Measure: Change from baseline in trough forced expiratory volume in 1 second (FEV1) [ Time Frame: On Day 15 ]

Measure Type	Primary
Measure Name	Change from baseline in trough forced expiratory volume in 1 second (FEV1)
Measure Description	The efficacy of inhaled AZD8871 in patients with moderate to severe COPD was assessed by measuring the change in trough FEV1 on Day 15
Time Frame	On Day 15
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.
Full analysis set (FAS): all randomised patients who received at least one dose of the IP, irrespective of their protocol adherence and continued participation in the study.

Reporting Groups

	Description
AZD8871 100 µg	The subjects received AZD8871 100 µg once daily by DPI device via single dose DPI that is an adaptation of the multi-dose Genuair™ used in approved inhalation products.
AZD8871 600 µg	The subjects received AZD8871 600 µg once daily by DPI device via single dose DPI that is an adaptation of the multi-dose Genuair™ used in approved inhalation products.
Placebo	The placebo was administered via single dose DPI that is an adaptation of the commercially available Genuair® with a smaller internal volume to enable delivery of single doses. To maintain blinding, each patient received one inhaled dose from placebo DPI provided to him/her on each day of the treatment period.

Measured Values

	AZD8871 100 µg	AZD8871 600 µg	Placebo
Number of Participants Analyzed [units:participants]	34	39	36
Change from baseline in trough forced expiratory volume in 1 second (FEV1) [units: L] Least Squares Mean (Standard Error)	0.168 (0.037)	0.267 (0.035)	0.007 (0.036)

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

Groups^[1]	AZD8871 100 µg, Placebo
Method^[3]	ANCOVA
P-Value^[4]	<0.001

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Comparison of AZD8871 100 µg vs placebo
[3]	Other relevant information, such as adjustments or degrees of freedom:
	Fixed effects: treatment, sequence, period. Random effect for patient nested within sequence. Continuous covariate: baseline.
[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.

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

Groups^[1]	AZD8871 600 µg, Placebo
Method^[3]	ANCOVA
P-Value^[4]	<0.001

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Comparison of AZD8871 600 µg vs placebo
[3]	Other relevant information, such as adjustments or degrees of freedom:
	Fixed effects: treatment, sequence, period. Random effect for patient nested within sequence. Continuous covariate: baseline.
[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.

Statistical Analysis 3 for Change from baseline in trough forced expiratory volume in 1 second (FEV1)

Groups^[1]	AZD8871 100 µg, AZD8871 600 µg
Method^[3]	ANCOVA
P-Value^[4]	0.020

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Comparison of AZD8871 600 µg vs AZD8871 100 µg
[3]	Other relevant information, such as adjustments or degrees of freedom:
	Fixed effects: treatment, sequence, period. Random effect for patient nested within sequence. Continuous covariate: baseline.
[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.

2. Secondary Outcome Measure: Observed maximum plasma (Cmax) of AZD8871 and its metabolites (single dose) [ Time Frame: Pre-dose and 30 min, 1, 2, 4, 6, 8, 12, and 24 hours post-dose on Day 1. ]

Measure Type	Secondary
Measure Name	Observed maximum plasma (Cmax) of AZD8871 and its metabolites (single dose)
Measure Description	Observed maximum concentration, taken directly from the individual concentration-time curve, on Day 1 of each treatment period.
Time Frame	Pre-dose and 30 min, 1, 2, 4, 6, 8, 12, and 24 hours post-dose on Day 1.
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 analysis set: defined as all patients in the safety analysis set who received at least 1 dose of AZD8871 (100 μg or 600 μg), had at least 1 evaluable parameter out of Cmax, AUC or AUClast for AZD8871, and were assumed not to be affected by factors such as protocol deviations.

Reporting Groups

	Description
AZD8871 100 µg	The subjects received AZD8871 100 µg once daily by DPI device via single dose DPI that is an adaptation of the multi-dose Genuair™ used in approved inhalation products.
AZD8871 600 µg	The subjects received AZD8871 600 µg once daily by DPI device via single dose DPI that is an adaptation of the multi-dose Genuair™ used in approved inhalation products.
Placebo	The placebo was administered via single dose DPI that is an adaptation of the commercially available Genuair® with a smaller internal volume to enable delivery of single doses. To maintain blinding, each patient received one inhaled dose from placebo DPI provided to him/her on each day of the treatment period.

Measured Values

	AZD8871 100 µg	AZD8871 600 µg	Placebo
Number of Participants Analyzed [units:participants]	16	18	0
Observed maximum plasma (Cmax) of AZD8871 and its metabolites (single dose) [units: pg/mL] Geometric Mean (Geometric Coefficient of Variation)
AZD8871	61.05 (47.47%)	290.8 (36.30%)
LAS191861	7.796 (38.67%)	33.87 (33.05%)
LAS34850	187.7 (55.41%)	1016 (50.72%)

No statistical analysis provided for Observed maximum plasma (Cmax) of AZD8871 and its metabolites (single dose)

3. Secondary Outcome Measure: Observed maximum plasma (Cmax) of AZD8871 and its metabolites (multiple doses, Day 14) [ Time Frame: Pre-dose and 30 min, 1, 2, 4, 6, 8, 12, and 24 hours post-dose on Day 14. ]

Measure Type	Secondary
Measure Name	Observed maximum plasma (Cmax) of AZD8871 and its metabolites (multiple doses, Day 14)
Measure Description	Observed maximum concentration, taken directly from the individual concentration-time curve, on Day 14 of each treatment period.
Time Frame	Pre-dose and 30 min, 1, 2, 4, 6, 8, 12, and 24 hours post-dose on Day 14.
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 analysis set: defined as all patients in the safety analysis set who received at least 1 dose of AZD8871 (100 μg or 600 μg), had at least 1 evaluable parameter out of Cmax, AUC or AUClast for AZD8871, and were assumed not to be affected by factors such as protocol deviations.

Reporting Groups

	Description
AZD8871 100 µg	The subjects received AZD8871 100 µg once daily by DPI device via single dose DPI that is an adaptation of the multi-dose Genuair™ used in approved inhalation products.
AZD8871 600 µg	The subjects received AZD8871 600 µg once daily by DPI device via single dose DPI that is an adaptation of the multi-dose Genuair™ used in approved inhalation products.
Placebo	The placebo was administered via single dose DPI that is an adaptation of the commercially available Genuair® with a smaller internal volume to enable delivery of single doses. To maintain blinding, each patient received one inhaled dose from placebo DPI provided to him/her on each day of the treatment period.

Measured Values

	AZD8871 100 µg	AZD8871 600 µg	Placebo
Number of Participants Analyzed [units:participants]	16	18	0
Observed maximum plasma (Cmax) of AZD8871 and its metabolites (multiple doses, Day 14) [units: pg/mL] Geometric Mean (Geometric Coefficient of Variation)
AZD8871	72.52 (45.69%)	381.8 (36.09%)
LAS191861	11.89 (39.41%)	63.17 (38.23%)
LAS34850	221.4 (69.96%)	1152 (55.11%)

No statistical analysis provided for Observed maximum plasma (Cmax) of AZD8871 and its metabolites (multiple doses, Day 14)

4. Secondary Outcome Measure: Time to reach maximum plasma concentration (tmax) of AZD8871 and its metabolites (single dose) [ Time Frame: Pre-dose and 30 min, 1, 2, 4, 6, 8, 12, and 24 hours post-dose on Day 1. ]

Measure Type	Secondary
Measure Name	Time to reach maximum plasma concentration (tmax) of AZD8871 and its metabolites (single dose)
Measure Description	Time to reach maximum concentration taken directly from the individual concentration-time curve on Day 1 of each treatment period.
Time Frame	Pre-dose and 30 min, 1, 2, 4, 6, 8, 12, and 24 hours post-dose on Day 1.
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 analysis set: defined as all patients in the safety analysis set who received at least 1 dose of AZD8871 (100 μg or 600 μg), had at least 1 evaluable parameter out of Cmax, AUC or AUClast for AZD8871, and were assumed not to be affected by factors such as protocol deviations.

Reporting Groups

	Description
AZD8871 100 µg	The subjects received AZD8871 100 µg once daily by DPI device via single dose DPI that is an adaptation of the multi-dose Genuair™ used in approved inhalation products.
AZD8871 600 µg	The subjects received AZD8871 600 µg once daily by DPI device via single dose DPI that is an adaptation of the multi-dose Genuair™ used in approved inhalation products.
Placebo	The placebo was administered via single dose DPI that is an adaptation of the commercially available Genuair® with a smaller internal volume to enable delivery of single doses. To maintain blinding, each patient received one inhaled dose from placebo DPI provided to him/her on each day of the treatment period.

Measured Values

	AZD8871 100 µg	AZD8871 600 µg	Placebo
Number of Participants Analyzed [units:participants]	16	18	0
Time to reach maximum plasma concentration (tmax) of AZD8871 and its metabolites (single dose) [units: h] Median (Full Range)
AZD8871	0.93 (0.42 to 2.00)	1.46 (0.48 to 2.03)
LAS191861	1.92 (0.93 to 4.83)	2.02 (1.00 to 4.03)
LAS34850	3.94 (1.92 to 6.00)	3.98 (3.92 to 6.03)

No statistical analysis provided for Time to reach maximum plasma concentration (tmax) of AZD8871 and its metabolites (single dose)

5. Secondary Outcome Measure: Time to reach maximum plasma concentration (tmax) of AZD8871 and its metabolites (multiple doses, Day 14) [ Time Frame: Pre-dose and 30 min, 1, 2, 4, 6, 8, 12, and 24 hours post-dose on Day 14. ]

Measure Type	Secondary
Measure Name	Time to reach maximum plasma concentration (tmax) of AZD8871 and its metabolites (multiple doses, Day 14)
Measure Description	Time to reach maximum concentration taken directly from the individual concentration-time curve on Day 14 of each treatment period.
Time Frame	Pre-dose and 30 min, 1, 2, 4, 6, 8, 12, and 24 hours post-dose on Day 14.
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 analysis set: defined as all patients in the safety analysis set who received at least 1 dose of AZD8871 (100 μg or 600 μg), had at least 1 evaluable parameter out of Cmax, AUC or AUClast for AZD8871, and were assumed not to be affected by factors such as protocol deviations.

Reporting Groups

	Description
AZD8871 100 µg	The subjects received AZD8871 100 µg once daily by DPI device via single dose DPI that is an adaptation of the multi-dose Genuair™ used in approved inhalation products.
AZD8871 600 µg	The subjects received AZD8871 600 µg once daily by DPI device via single dose DPI that is an adaptation of the multi-dose Genuair™ used in approved inhalation products.
Placebo	The placebo was administered via single dose DPI that is an adaptation of the commercially available Genuair® with a smaller internal volume to enable delivery of single doses. To maintain blinding, each patient received one inhaled dose from placebo DPI provided to him/her on each day of the treatment period.

Measured Values

	AZD8871 100 µg	AZD8871 600 µg	Placebo
Number of Participants Analyzed [units:participants]	16	18	0
Time to reach maximum plasma concentration (tmax) of AZD8871 and its metabolites (multiple doses, Day 14) [units: h] Median (Full Range)
AZD8871	0.93 (0.42 to 1.00)	1.00 (0.50 to 2.22)
LAS191861	1.96 (0.98 to 3.95)	2.00 (0.98 to 3.98)
LAS34850	3.92 (0.00 to 4.00)	4.02 (3.90 to 6.05)

No statistical analysis provided for Time to reach maximum plasma concentration (tmax) of AZD8871 and its metabolites (multiple doses, Day 14)

6. Secondary Outcome Measure: AUClast of AZD8871 and its metabolites (single dose) [ Time Frame: Pre-dose and 30 min, 1, 2, 4, 6, 8, 12, and 24 hours post-dose on Day 1. ]

Measure Type	Secondary
Measure Name	AUClast of AZD8871 and its metabolites (single dose)
Measure Description	Area under the plasma concentration-curve from time zero to the last quantifiable time point (24 hours post-dose) calculated on Day 1 of each treatment period.
Time Frame	Pre-dose and 30 min, 1, 2, 4, 6, 8, 12, and 24 hours post-dose on Day 1.
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 analysis set: defined as all patients in the safety analysis set who received at least 1 dose of AZD8871 (100 μg or 600 μg), had at least 1 evaluable parameter out of Cmax, AUC or AUClast for AZD8871, and were assumed not to be affected by factors such as protocol deviations.

Reporting Groups

	Description
AZD8871 100 µg	The subjects received AZD8871 100 µg once daily by DPI device via single dose DPI that is an adaptation of the multi-dose Genuair™ used in approved inhalation products.
AZD8871 600 µg	The subjects received AZD8871 600 µg once daily by DPI device via single dose DPI that is an adaptation of the multi-dose Genuair™ used in approved inhalation products.
Placebo	The placebo was administered via single dose DPI that is an adaptation of the commercially available Genuair® with a smaller internal volume to enable delivery of single doses. To maintain blinding, each patient received one inhaled dose from placebo DPI provided to him/her on each day of the treatment period.

Measured Values

	AZD8871 100 µg	AZD8871 600 µg	Placebo
Number of Participants Analyzed [units:participants]	16	18	0
AUClast of AZD8871 and its metabolites (single dose) [units: pg*h/mL] Geometric Mean (Geometric Coefficient of Variation)
AZD8871	301.0 (54.52%)	1777 (40.93%)
LAS191861	60.06 (94.87%)	358.5 (32.60%)
LAS34850	1414 (69.31%)	9299 (53.88%)

No statistical analysis provided for AUClast of AZD8871 and its metabolites (single dose)

7. Secondary Outcome Measure: AUClast of AZD8871 and its metabolites (multiple doses, Day 14) [ Time Frame: Pre-dose and 30 min, 1, 2, 4, 6, 8, 12, and 24 hours post-dose on Day 14. ]

Measure Type	Secondary
Measure Name	AUClast of AZD8871 and its metabolites (multiple doses, Day 14)
Measure Description	Area under the plasma concentration-curve from time zero to the last quantifiable time point (24 hours post-dose) calculated on Day 14 of each treatment period.
Time Frame	Pre-dose and 30 min, 1, 2, 4, 6, 8, 12, and 24 hours post-dose on Day 14.
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 analysis set: defined as all patients in the safety analysis set who received at least 1 dose of AZD8871 (100 μg or 600 μg), had at least 1 evaluable parameter out of Cmax, AUC or AUClast for AZD8871, and were assumed not to be affected by factors such as protocol deviations.

Reporting Groups

	Description
AZD8871 100 µg	The subjects received AZD8871 100 µg once daily by DPI device via single dose DPI that is an adaptation of the multi-dose Genuair™ used in approved inhalation products.
AZD8871 600 µg	The subjects received AZD8871 600 µg once daily by DPI device via single dose DPI that is an adaptation of the multi-dose Genuair™ used in approved inhalation products.
Placebo	The placebo was administered via single dose DPI that is an adaptation of the commercially available Genuair® with a smaller internal volume to enable delivery of single doses. To maintain blinding, each patient received one inhaled dose from placebo DPI provided to him/her on each day of the treatment period.

Measured Values

	AZD8871 100 µg	AZD8871 600 µg	Placebo
Number of Participants Analyzed [units:participants]	16	18	0
AUClast of AZD8871 and its metabolites (multiple doses, Day 14) [units: pg*h/mL] Geometric Mean (Geometric Coefficient of Variation)
AZD8871	539.2 (51.23%)	3156 (42.51%)
LAS191861	160.2 (64.39%)	935.9 (46.56%)
LAS34850	1964 (93.81%)	13050 (52.49%)

No statistical analysis provided for AUClast of AZD8871 and its metabolites (multiple doses, Day 14)

8. Secondary Outcome Measure: AUC0-24 of AZD8871 and its metabolites (single dose) [ Time Frame: Pre-dose and 30 min, 1, 2, 4, 6, 8, 12, and 24 hours post-dose on Day 1. ]

Measure Type	Secondary
Measure Name	AUC0-24 of AZD8871 and its metabolites (single dose)
Measure Description	Area under the plasma concentration-curve from time zero to 24 hours post-dose calculated on Day 1 of each treatment period.
Time Frame	Pre-dose and 30 min, 1, 2, 4, 6, 8, 12, and 24 hours post-dose on Day 1.
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 analysis set: defined as all patients in the safety analysis set who received at least 1 dose of AZD8871 (100 μg or 600 μg), had at least 1 evaluable parameter out of Cmax, AUC or AUClast for AZD8871, and were assumed not to be affected by factors such as protocol deviations.

Reporting Groups

	Description
AZD8871 100 µg	The subjects received AZD8871 100 µg once daily by DPI device via single dose DPI that is an adaptation of the multi-dose Genuair™ used in approved inhalation products.
AZD8871 600 µg	The subjects received AZD8871 600 µg once daily by DPI device via single dose DPI that is an adaptation of the multi-dose Genuair™ used in approved inhalation products.
Placebo	The placebo was administered via single dose DPI that is an adaptation of the commercially available Genuair® with a smaller internal volume to enable delivery of single doses. To maintain blinding, each patient received one inhaled dose from placebo DPI provided to him/her on each day of the treatment period.

Measured Values

	AZD8871 100 µg	AZD8871 600 µg	Placebo
Number of Participants Analyzed [units:participants]	16	18	0
AUC0-24 of AZD8871 and its metabolites (single dose) [units: pg*h/mL] Geometric Mean (Geometric Coefficient of Variation)
AZD8871	326.1 (49.18%)	1776 (40.95%)
LAS191861	135.6 (25.79%)	358.1 (32.56%)
LAS34850	0 (0%)	10440 (49.47%)

No statistical analysis provided for AUC0-24 of AZD8871 and its metabolites (single dose)

9. Secondary Outcome Measure: AUC0-24 of AZD8871 and its metabolites (multiple doses, Day 14) [ Time Frame: Pre-dose and 30 min, 1, 2, 4, 6, 8, 12, and 24 hours post-dose on Day 14. ]

Measure Type	Secondary
Measure Name	AUC0-24 of AZD8871 and its metabolites (multiple doses, Day 14)
Measure Description	Area under the plasma concentration-curve from time zero to 24 hours post-dose calculated on Day 14 of each treatment period.
Time Frame	Pre-dose and 30 min, 1, 2, 4, 6, 8, 12, and 24 hours post-dose on Day 14.
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 analysis set: defined as all patients in the safety analysis set who received at least 1 dose of AZD8871 (100 μg or 600 μg), had at least 1 evaluable parameter out of Cmax, AUC or AUClast for AZD8871, and were assumed not to be affected by factors such as protocol deviations

Reporting Groups

	Description
AZD8871 100 µg	The subjects received AZD8871 100 µg once daily by DPI device via single dose DPI that is an adaptation of the multi-dose Genuair™ used in approved inhalation products.
AZD8871 600 µg	The subjects received AZD8871 600 µg once daily by DPI device via single dose DPI that is an adaptation of the multi-dose Genuair™ used in approved inhalation products.
Placebo	The placebo was administered via single dose DPI that is an adaptation of the commercially available Genuair® with a smaller internal volume to enable delivery of single doses. To maintain blinding, each patient received one inhaled dose from placebo DPI provided to him/her on each day of the treatment period.

Measured Values

	AZD8871 100 µg	AZD8871 600 µg	Placebo
Number of Participants Analyzed [units:participants]	16	18	0
AUC0-24 of AZD8871 and its metabolites (multiple doses, Day 14) [units: pg*h/mL] Geometric Mean (Geometric Coefficient of Variation)
AZD8871	538.4 (51.16%)	3152 (42.53%)
LAS191861	179.4 (38.81%)	933.8 (46.65%)
LAS34850	3281 (66.13%)	13030 (52.51%)

No statistical analysis provided for AUC0-24 of AZD8871 and its metabolites (multiple doses, Day 14)

10. Secondary Outcome Measure: Accumulation ratio for Cmax (RacCmax) of AZD8871 and its metabolites (Day 14) [ Time Frame: Pre-dose and 30 min, 1, 2, 4, 6, 8, 12, and 24 hours post-dose on Day 1 and Day 14. ]

Measure Type	Secondary
Measure Name	Accumulation ratio for Cmax (RacCmax) of AZD8871 and its metabolites (Day 14)
Measure Description	Accumulation ratio for Cmax estimated as (Cmax on Day 14 / Cmax on Day 1) in each treatment period.
Time Frame	Pre-dose and 30 min, 1, 2, 4, 6, 8, 12, and 24 hours post-dose on Day 1 and Day 14.
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 analysis set: defined as all patients in the safety analysis set who received at least 1 dose of AZD8871 (100 μg or 600 μg), had at least 1 evaluable parameter out of Cmax, AUC or AUClast for AZD8871, and were assumed not to be affected by factors such as protocol deviations.

Reporting Groups

	Description
AZD8871 100 µg	The subjects received AZD8871 100 µg once daily by DPI device via single dose DPI that is an adaptation of the multi-dose Genuair™ used in approved inhalation products.
AZD8871 600 µg	The subjects received AZD8871 600 µg once daily by DPI device via single dose DPI that is an adaptation of the multi-dose Genuair™ used in approved inhalation products.
Placebo	The placebo was administered via single dose DPI that is an adaptation of the commercially available Genuair® with a smaller internal volume to enable delivery of single doses. To maintain blinding, each patient received one inhaled dose from placebo DPI provided to him/her on each day of the treatment period.

Measured Values

	AZD8871 100 µg	AZD8871 600 µg	Placebo
Number of Participants Analyzed [units:participants]	16	18	0
Accumulation ratio for Cmax (RacCmax) of AZD8871 and its metabolites (Day 14) [units: pg/mL] Mean (Full Range)
AZD8871	1.263 (0.765 to 2.30)	1.385 (0.700 to 1.90)
LAS191861	1.594 (0.946 to 2.86)	1.968 (0.929 to 2.74)
LAS34850	1.257 (0.757 to 3.388)	1.133 (0.545 to 1.64)

No statistical analysis provided for Accumulation ratio for Cmax (RacCmax) of AZD8871 and its metabolites (Day 14)

11. Secondary Outcome Measure: Accumulation ratio for AUC0-24 (RacAUC[0-24]) of AZD8871 and its metabolites (Day 14) [ Time Frame: Pre-dose and 30 min, 1, 2, 4, 6, 8, 12, and 24 hours post-dose on Day 1 and Day 14. ]

Measure Type	Secondary
Measure Name	Accumulation ratio for AUC0-24 (RacAUC[0-24]) of AZD8871 and its metabolites (Day 14)
Measure Description	Accumulation ratio for AUC0-24 estimated as AUC0-24 on Day 14 / AUC0-24 on Day 1 in each treatment period.
Time Frame	Pre-dose and 30 min, 1, 2, 4, 6, 8, 12, and 24 hours post-dose on Day 1 and Day 14.
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 analysis set: defined as all patients in the safety analysis set who received at least 1 dose of AZD8871 (100 μg or 600 μg), had at least 1 evaluable parameter out of Cmax, AUC or AUClast for AZD8871, and were assumed not to be affected by factors such as protocol deviations.

Reporting Groups

	Description
AZD8871 100 µg	The subjects received AZD8871 100 µg once daily by DPI device via single dose DPI that is an adaptation of the multi-dose Genuair™ used in approved inhalation products.
AZD8871 600 µg	The subjects received AZD8871 600 µg once daily by DPI device via single dose DPI that is an adaptation of the multi-dose Genuair™ used in approved inhalation products.
Placebo	The placebo was administered via single dose DPI that is an adaptation of the commercially available Genuair® with a smaller internal volume to enable delivery of single doses. To maintain blinding, each patient received one inhaled dose from placebo DPI provided to him/her on each day of the treatment period.

Measured Values

	AZD8871 100 µg	AZD8871 600 µg	Placebo
Number of Participants Analyzed [units:participants]	16	18	0
Accumulation ratio for AUC0-24 (RacAUC[0-24]) of AZD8871 and its metabolites (Day 14) [units: pg*h/mL] Mean (Full Range)
AZD8871	1.893 (1.06 to 3.86)	1.878 (1.09 to 2.87)
LAS191861	1.576 (1.10 to 2.44)	2.721 (1.41 to 3.55)
LAS34850	1.24 (1.24 to 1.24)	1.326 (0.713 to 1.77)

No statistical analysis provided for Accumulation ratio for AUC0-24 (RacAUC[0-24]) of AZD8871 and its metabolites (Day 14)

12. Secondary Outcome Measure: Cavg of AZD8871 and its metabolites during a dosing interval (Day 14) [ Time Frame: Pre-dose and 30 min, 1, 2, 4, 6, 8, 12, and 24 hours post-dose on Day 14. ]

Measure Type	Secondary
Measure Name	Cavg of AZD8871 and its metabolites during a dosing interval (Day 14)
Measure Description	Average plasma concentration during a dosing interval calculated on Day 14 of each treatment period.
Time Frame	Pre-dose and 30 min, 1, 2, 4, 6, 8, 12, and 24 hours post-dose on Day 14.
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 analysis set: defined as all patients in the safety analysis set who received at least 1 dose of AZD8871 (100 μg or 600 μg), had at least 1 evaluable parameter out of Cmax, AUC or AUClast for AZD8871, and were assumed not to be affected by factors such as protocol deviations.

Reporting Groups

	Description
AZD8871 100 µg	The subjects received AZD8871 100 µg once daily by DPI device via single dose DPI that is an adaptation of the multi-dose Genuair™ used in approved inhalation products.
AZD8871 600 µg	The subjects received AZD8871 600 µg once daily by DPI device via single dose DPI that is an adaptation of the multi-dose Genuair™ used in approved inhalation products.
Placebo	The placebo was administered via single dose DPI that is an adaptation of the commercially available Genuair® with a smaller internal volume to enable delivery of single doses. To maintain blinding, each patient received one inhaled dose from placebo DPI provided to him/her on each day of the treatment period.

Measured Values

	AZD8871 100 µg	AZD8871 600 µg	Placebo
Number of Participants Analyzed [units:participants]	16	18	0
Cavg of AZD8871 and its metabolites during a dosing interval (Day 14) [units: pg/mL] Geometric Mean (Geometric Coefficient of Variation)
AZD8871	22.44 (51.13%)	131.4 (42.49%)
LAS191861	7.478 (38.81%)	38.94 (46.62%)
LAS34850	136.7 (66.11%)	543.3 (52.44%)

No statistical analysis provided for Cavg of AZD8871 and its metabolites during a dosing interval (Day 14)

13. Secondary Outcome Measure: Change from baseline in trough FEV1 at Day 1 (single dose) [ Time Frame: on Day 1 ]

Measure Type	Secondary
Measure Name	Change from baseline in trough FEV1 at Day 1 (single dose)
Measure Description	The efficacy of inhaled AZD8871 in patients with moderate to severe COPD was assessed by measuring the change in trough FEV1 on Day 1
Time Frame	on Day 1
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.
Full analysis set (FAS): all randomised patients who received at least one dose of the IP, irrespective of their protocol adherence and continued participation in the study.

Reporting Groups

	Description
AZD8871 100 µg	The subjects received AZD8871 100 µg once daily by DPI device via single dose DPI that is an adaptation of the multi-dose Genuair™ used in approved inhalation products.
AZD8871 600 µg	The subjects received AZD8871 600 µg once daily by DPI device via single dose DPI that is an adaptation of the multi-dose Genuair™ used in approved inhalation products.
Placebo	The placebo was administered via single dose DPI that is an adaptation of the commercially available Genuair® with a smaller internal volume to enable delivery of single doses. To maintain blinding, each patient received one inhaled dose from placebo DPI provided to him/her on each day of the treatment period.

Measured Values

	AZD8871 100 µg	AZD8871 600 µg	Placebo
Number of Participants Analyzed [units:participants]	34	39	36
Change from baseline in trough FEV1 at Day 1 (single dose) [units: L] Least Squares Mean (Standard Error)	0.092 (0.029)	0.161 (0.027)	0.006 (0.028)

Statistical Analysis 1 for Change from baseline in trough FEV1 at Day 1 (single dose)

Groups^[1]	AZD8871 100 µg, Placebo
Method^[3]	ANCOVA
P-Value^[4]	0.002

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Comparison of AZD8871 100 µg vs placebo
[3]	Other relevant information, such as adjustments or degrees of freedom:
	Fixed effects: treatment, sequence, period. Random effect for patient nested within sequence. Continuous covariate: baseline.
[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.

Statistical Analysis 2 for Change from baseline in trough FEV1 at Day 1 (single dose)

Groups^[1]	AZD8871 600 µg, Placebo
Method^[3]	ANCOVA
P-Value^[4]	<0.001

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Comparison of AZD8871 600 µg vs placebo
[3]	Other relevant information, such as adjustments or degrees of freedom:
	Fixed effects: treatment, sequence, period. Random effect for patient nested within sequence. Continuous covariate: baseline.
[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.

Statistical Analysis 3 for Change from baseline in trough FEV1 at Day 1 (single dose)

Groups^[1]	AZD8871 100 µg, AZD8871 600 µg
Method^[3]	ANCOVA
P-Value^[4]	0.011

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Comparison of AZD8871 600 µg vs AZD8871 100 µg
[3]	Other relevant information, such as adjustments or degrees of freedom:
	Fixed effects: treatment, sequence, period. Random effect for patient nested within sequence. Continuous covariate: baseline.
[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.

14. Secondary Outcome Measure: Change from baseline in trough FEV1 at Day 8 (pre-dose) [ Time Frame: on Day 8 (pre-dose) ]

Measure Type	Secondary
Measure Name	Change from baseline in trough FEV1 at Day 8 (pre-dose)
Measure Description	The efficacy of inhaled AZD8871 in patients with moderate to severe COPD was assessed by measuring the change in trough FEV1 on Day 8 (pre-dose)
Time Frame	on Day 8 (pre-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.
Full analysis set (FAS): all randomised patients who received at least one dose of the IP, irrespective of their protocol adherence and continued participation in the study.

Reporting Groups

	Description
AZD8871 100 µg	The subjects received AZD8871 100 µg once daily by DPI device via single dose DPI that is an adaptation of the multi-dose Genuair™ used in approved inhalation products.
AZD8871 600 µg	The subjects received AZD8871 600 µg once daily by DPI device via single dose DPI that is an adaptation of the multi-dose Genuair™ used in approved inhalation products.
Placebo	The placebo was administered via single dose DPI that is an adaptation of the commercially available Genuair® with a smaller internal volume to enable delivery of single doses. To maintain blinding, each patient received one inhaled dose from placebo DPI provided to him/her on each day of the treatment period.

Measured Values

	AZD8871 100 µg	AZD8871 600 µg	Placebo
Number of Participants Analyzed [units:participants]	34	39	36
Change from baseline in trough FEV1 at Day 8 (pre-dose) [units: L] Least Squares Mean (Standard Error)	0.180 (0.033)	0.232 (0.030)	0.032 (0.031)

Statistical Analysis 1 for Change from baseline in trough FEV1 at Day 8 (pre-dose)

Groups^[1]	AZD8871 100 µg, Placebo
Method^[3]	ANCOVA
P-Value^[4]	<0.001

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Comparison of AZD8871 100 µg vs placebo
[3]	Other relevant information, such as adjustments or degrees of freedom:
	Fixed effects: treatment, sequence, period. Random effect for patient nested within sequence. Continuous covariate: baseline.
[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.

Statistical Analysis 2 for Change from baseline in trough FEV1 at Day 8 (pre-dose)

Groups^[1]	AZD8871 600 µg, Placebo
Method^[3]	ANCOVA
P-Value^[4]	<0.001

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Comparison of AZD8871 600 µg vs placebo
[3]	Other relevant information, such as adjustments or degrees of freedom:
	Fixed effects: treatment, sequence, period. Random effect for patient nested within sequence. Continuous covariate: baseline.
[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.

Statistical Analysis 3 for Change from baseline in trough FEV1 at Day 8 (pre-dose)

Groups^[1]	AZD8871 100 µg, AZD8871 600 µg
Method^[3]	ANCOVA
P-Value^[4]	0.201

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Comparison of AZD8871 600 µg vs AZD8871 100 µg
[3]	Other relevant information, such as adjustments or degrees of freedom:
	Fixed effects: treatment, sequence, period. Random effect for patient nested within sequence. Continuous covariate: baseline.
[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.

15. Secondary Outcome Measure: Change from baseline in trough FEV1 over the treatment duration (Days 1-15) [ Time Frame: Days 1-15 ]

Measure Type	Secondary
Measure Name	Change from baseline in trough FEV1 over the treatment duration (Days 1-15)
Measure Description	The efficacy of inhaled AZD8871 in patients with moderate to severe COPD was assessed by measuring the change in trough FEV1 over the treatment duration from Day 1 to Day 15
Time Frame	Days 1-15
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.
Full analysis set (FAS): all randomised patients who received at least one dose of the IP, irrespective of their protocol adherence and continued participation in the study.

Reporting Groups

	Description
AZD8871 100 µg	The subjects received AZD8871 100 µg once daily by DPI device via single dose DPI that is an adaptation of the multi-dose Genuair™ used in approved inhalation products.
AZD8871 600 µg	The subjects received AZD8871 600 µg once daily by DPI device via single dose DPI that is an adaptation of the multi-dose Genuair™ used in approved inhalation products.
Placebo	The placebo was administered via single dose DPI that is an adaptation of the commercially available Genuair® with a smaller internal volume to enable delivery of single doses. To maintain blinding, each patient received one inhaled dose from placebo DPI provided to him/her on each day of the treatment period.

Measured Values

	AZD8871 100 µg	AZD8871 600 µg	Placebo
Number of Participants Analyzed [units:participants]	34	39	36
Change from baseline in trough FEV1 over the treatment duration (Days 1-15) [units: L] Least Squares Mean (Standard Error)	0.146 (0.029)	0.215 (0.027)	0.016 (0.027)

Statistical Analysis 1 for Change from baseline in trough FEV1 over the treatment duration (Days 1-15)

Groups^[1]	AZD8871 100 µg, Placebo
Method^[3]	ANCOVA
P-Value^[4]	<0.001

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Comparison of AZD8871 100 µg vs placebo
[3]	Other relevant information, such as adjustments or degrees of freedom:
	Fixed effect: treatment, sequence, period, treatment*day. Repeat factor: day. Random effect: patient nested in sequence. Continuous covar: baseline.
[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.

Statistical Analysis 2 for Change from baseline in trough FEV1 over the treatment duration (Days 1-15)

Groups^[1]	AZD8871 600 µg, Placebo
Method^[3]	ANCOVA
P-Value^[4]	<0.001

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Comparison of AZD8871 600 µg vs placebo
[3]	Other relevant information, such as adjustments or degrees of freedom:
	Fixed effect: treatment, sequence, period, treatment*day. Repeat factor: day. Random effect: patient nested in sequence. Continuous covar: baseline.
[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.

Statistical Analysis 3 for Change from baseline in trough FEV1 over the treatment duration (Days 1-15)

Groups^[1]	AZD8871 100 µg, AZD8871 600 µg
Method^[3]	ANCOVA
P-Value^[4]	0.020

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Comparison of AZD8871 600 µg vs AZD8871 100 µg
[3]	Other relevant information, such as adjustments or degrees of freedom:
	Fixed effect: treatment, sequence, period, treatment*day. Repeat factor: day. Random effect: patient nested in sequence. Continuous covar: baseline.
[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.

16. Secondary Outcome Measure: Change from baseline in Peak FEV1 at Day 1 (single dose) [ Time Frame: on Day 1 ]

Measure Type	Secondary
Measure Name	Change from baseline in Peak FEV1 at Day 1 (single dose)
Measure Description	The efficacy of inhaled AZD8871 in patients with moderate to severe COPD was assessed by measuring the change in Peak FEV1
Time Frame	on Day 1
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.
Full analysis set (FAS): all randomised patients who received at least one dose of the IP, irrespective of their protocol adherence and continued participation in the study.

Reporting Groups

	Description
AZD8871 100 µg	The subjects received AZD8871 100 µg once daily by DPI device via single dose DPI that is an adaptation of the multi-dose Genuair™ used in approved inhalation products.
AZD8871 600 µg	The subjects received AZD8871 600 µg once daily by DPI device via single dose DPI that is an adaptation of the multi-dose Genuair™ used in approved inhalation products.
Placebo	The placebo was administered via single dose DPI that is an adaptation of the commercially available Genuair® with a smaller internal volume to enable delivery of single doses. To maintain blinding, each patient received one inhaled dose from placebo DPI provided to him/her on each day of the treatment period.

Measured Values

	AZD8871 100 µg	AZD8871 600 µg	Placebo
Number of Participants Analyzed [units:participants]	34	39	36
Change from baseline in Peak FEV1 at Day 1 (single dose) [units: L] Least Squares Mean (Standard Error)	0.376 (0.026)	0.469 (0.025)	0.076 (0.025)

Statistical Analysis 1 for Change from baseline in Peak FEV1 at Day 1 (single dose)

Groups^[1]	AZD8871 100 µg, Placebo
Method^[3]	ANCOVA
P-Value^[4]	<0.001

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Comparison of AZD8871 100 µg vs placebo
[3]	Other relevant information, such as adjustments or degrees of freedom:
	Fixed effects: treatment, sequence, period. Random effect for patient nested within sequence. Continuous covariate: baseline.
[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.

Statistical Analysis 2 for Change from baseline in Peak FEV1 at Day 1 (single dose)

Groups^[1]	AZD8871 600 µg, Placebo
Method^[3]	ANCOVA
P-Value^[4]	<0.001

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Comparison of AZD8871 600 µg vs placebo
[3]	Other relevant information, such as adjustments or degrees of freedom:
	Fixed effects: treatment, sequence, period. Random effect for patient nested within sequence. Continuous covariate: baseline.
[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.

Statistical Analysis 3 for Change from baseline in Peak FEV1 at Day 1 (single dose)

Groups^[1]	AZD8871 100 µg, AZD8871 600 µg
Method^[3]	ANCOVA
P-Value^[4]	<0.001

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Comparison of AZD8871 600 µg vs AZD8871 100 µg
[3]	Other relevant information, such as adjustments or degrees of freedom:
	Fixed effects: treatment, sequence, period. Random effect for patient nested within sequence. Continuous covariate: baseline.
[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.

17. Secondary Outcome Measure: Change from baseline in Peak FEV1 at Day 8 [ Time Frame: on Day 8 ]

Measure Type	Secondary
Measure Name	Change from baseline in Peak FEV1 at Day 8
Measure Description	The efficacy of inhaled AZD8871 in patients with moderate to severe COPD was assessed by measuring the change in Peak FEV1
Time Frame	on Day 8
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.
Full analysis set (FAS): all randomised patients who received at least one dose of the IP, irrespective of their protocol adherence and continued participation in the study.

Reporting Groups

	Description
AZD8871 100 µg	The subjects received AZD8871 100 µg once daily by DPI device via single dose DPI that is an adaptation of the multi-dose Genuair™ used in approved inhalation products.
AZD8871 600 µg	The subjects received AZD8871 600 µg once daily by DPI device via single dose DPI that is an adaptation of the multi-dose Genuair™ used in approved inhalation products.
Placebo	The placebo was administered via single dose DPI that is an adaptation of the commercially available Genuair® with a smaller internal volume to enable delivery of single doses. To maintain blinding, each patient received one inhaled dose from placebo DPI provided to him/her on each day of the treatment period.

Measured Values

	AZD8871 100 µg	AZD8871 600 µg	Placebo
Number of Participants Analyzed [units:participants]	34	39	36
Change from baseline in Peak FEV1 at Day 8 [units: L] Least Squares Mean (Standard Error)	0.486 (0.040)	0.556 (0.037)	0.136 (0.038)

Statistical Analysis 1 for Change from baseline in Peak FEV1 at Day 8

Groups^[1]	AZD8871 100 µg, Placebo
Method^[3]	ANCOVA
P-Value^[4]	<0.001

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Comparison of AZD8871 100 µg vs placebo
[3]	Other relevant information, such as adjustments or degrees of freedom:
	Fixed effects: treatment, sequence, period. Random effect for patient nested within sequence. Continuous covariate: baseline.
[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.

Statistical Analysis 2 for Change from baseline in Peak FEV1 at Day 8

Groups^[1]	AZD8871 600 µg, Placebo
Method^[3]	ANCOVA
P-Value^[4]	<0.001

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Comparison of AZD8871 600 µg vs placebo
[3]	Other relevant information, such as adjustments or degrees of freedom:
	Fixed effects: treatment, sequence, period. Random effect for patient nested within sequence. Continuous covariate: baseline.
[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.

Statistical Analysis 3 for Change from baseline in Peak FEV1 at Day 8

Groups^[1]	AZD8871 100 µg, AZD8871 600 µg
Method^[3]	ANCOVA
P-Value^[4]	0.092

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Comparison of AZD8871 600 µg vs AZD8871 100 µg
[3]	Other relevant information, such as adjustments or degrees of freedom:
	Fixed effects: treatment, sequence, period. Random effect for patient nested within sequence. Continuous covariate: baseline.
[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.

18. Secondary Outcome Measure: Change from baseline in Peak FEV1 at Day 14 [ Time Frame: on Day 14 ]

Measure Type	Secondary
Measure Name	Change from baseline in Peak FEV1 at Day 14
Measure Description	The efficacy of inhaled AZD8871 in patients with moderate to severe COPD was assessed by measuring the change in Peak FEV1
Time Frame	on Day 14
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.
Full analysis set (FAS): all randomised patients who received at least one dose of the IP, irrespective of their protocol adherence and continued participation in the study.

Reporting Groups

	Description
AZD8871 100 µg	The subjects received AZD8871 100 µg once daily by DPI device via single dose DPI that is an adaptation of the multi-dose Genuair™ used in approved inhalation products.
AZD8871 600 µg	The subjects received AZD8871 600 µg once daily by DPI device via single dose DPI that is an adaptation of the multi-dose Genuair™ used in approved inhalation products.
Placebo	The placebo was administered via single dose DPI that is an adaptation of the commercially available Genuair® with a smaller internal volume to enable delivery of single doses. To maintain blinding, each patient received one inhaled dose from placebo DPI provided to him/her on each day of the treatment period.

Measured Values

	AZD8871 100 µg	AZD8871 600 µg	Placebo
Number of Participants Analyzed [units:participants]	34	39	36
Change from baseline in Peak FEV1 at Day 14 [units: L] Least Squares Mean (Standard Error)	0.476 (0.037)	0.522 (0.035)	0.095 (0.036)

Statistical Analysis 1 for Change from baseline in Peak FEV1 at Day 14

Groups^[1]	AZD8871 100 µg, Placebo
Method^[3]	ANCOVA
P-Value^[4]	<0.001

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Comparison of AZD8871 100 µg vs placebo
[3]	Other relevant information, such as adjustments or degrees of freedom:
	Fixed effects: treatment, sequence, period. Random effect for patient nested within sequence. Continuous covariate: baseline.
[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.

Statistical Analysis 2 for Change from baseline in Peak FEV1 at Day 14

Groups^[1]	AZD8871 600 µg, Placebo
Method^[3]	ANCOVA
P-Value^[4]	<0.001

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Comparison of AZD8871 600 µg vs placebo
[3]	Other relevant information, such as adjustments or degrees of freedom:
	Fixed effects: treatment, sequence, period. Random effect for patient nested within sequence. Continuous covariate: baseline.
[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.

Statistical Analysis 3 for Change from baseline in Peak FEV1 at Day 14

Groups^[1]	AZD8871 100 µg, AZD8871 600 µg
Method^[3]	ANCOVA
P-Value^[4]	0.279

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Comparison of AZD8871 600 µg vs AZD8871 100 µg
[3]	Other relevant information, such as adjustments or degrees of freedom:
	Fixed effects: treatment, sequence, period. Random effect for patient nested within sequence. Continuous covariate: baseline.
[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.

19. Secondary Outcome Measure: Change from baseline in Peak FEV1 over the treatment duration (Days 1-15) [ Time Frame: over the treatment duration (Days 1-15) ]

Measure Type	Secondary
Measure Name	Change from baseline in Peak FEV1 over the treatment duration (Days 1-15)
Measure Description	The efficacy of inhaled AZD8871 in patients with moderate to severe COPD was assessed by measuring the change in Peak FEV1
Time Frame	over the treatment duration (Days 1-15)
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.
Full analysis set (FAS): all randomised patients who received at least one dose of the IP, irrespective of their protocol adherence and continued participation in the study.

Reporting Groups

	Description
AZD8871 100 µg	The subjects received AZD8871 100 µg once daily by DPI device via single dose DPI that is an adaptation of the multi-dose Genuair™ used in approved inhalation products.
AZD8871 600 µg	The subjects received AZD8871 600 µg once daily by DPI device via single dose DPI that is an adaptation of the multi-dose Genuair™ used in approved inhalation products.
Placebo	The placebo was administered via single dose DPI that is an adaptation of the commercially available Genuair® with a smaller internal volume to enable delivery of single doses. To maintain blinding, each patient received one inhaled dose from placebo DPI provided to him/her on each day of the treatment period.

Measured Values

	AZD8871 100 µg	AZD8871 600 µg	Placebo
Number of Participants Analyzed [units:participants]	34	39	36
Change from baseline in Peak FEV1 over the treatment duration (Days 1-15) [units: L] Least Squares Mean (Standard Error)	0.438 (0.028)	0.511 (0.027)	0.102 (0.028)

Statistical Analysis 1 for Change from baseline in Peak FEV1 over the treatment duration (Days 1-15)

Groups^[1]	AZD8871 100 µg, Placebo
Method^[3]	ANCOVA
P-Value^[4]	<0.001

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Comparison of AZD8871 100 µg vs placebo
[3]	Other relevant information, such as adjustments or degrees of freedom:
	Fixed effect: treatment, sequence, period, treatment*day. Repeat factor: day. Random effect: patient nested in sequence. Continuous covar: baseline.
[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.

Statistical Analysis 2 for Change from baseline in Peak FEV1 over the treatment duration (Days 1-15)

Groups^[1]	AZD8871 600 µg, Placebo
Method^[3]	ANCOVA
P-Value^[4]	<0.001

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Comparison of AZD8871 600 µg vs placebo
[3]	Other relevant information, such as adjustments or degrees of freedom:
	Fixed effect: treatment, sequence, period, treatment*day. Repeat factor: day. Random effect: patient nested in sequence. Continuous covar: baseline.
[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.

Statistical Analysis 3 for Change from baseline in Peak FEV1 over the treatment duration (Days 1-15)

Groups^[1]	AZD8871 100 µg, AZD8871 600 µg
Method^[3]	ANCOVA
P-Value^[4]	<0.001

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Comparison of AZD8871 600 µg vs AZD8871 100 µg
[3]	Other relevant information, such as adjustments or degrees of freedom:
	Fixed effect: treatment, sequence, period, treatment*day. Repeat factor: day. Random effect: patient nested in sequence. Continuous covar: baseline.
[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.

20. Secondary Outcome Measure: Change from baseline in BCSS questionnaire Total Score from Day 1 to Day 8 post-treatment [ Time Frame: From Day 1 to Day 8 post-treatment ]

Measure Type	Secondary
Measure Name	Change from baseline in BCSS questionnaire Total Score from Day 1 to Day 8 post-treatment
Measure Description	The efficacy of inhaled AZD8871 in patients with moderate to severe COPD was assessed by measuring the change from baseline in Total score of the Breathlessness, Cough Sputum Scale (BCSS) questionnaire. The BCSS questionnaire is a 3-item patient-reported outcome measure. On a daily basis, patients rated 3 symptoms (breathlessness, cough and sputum) on a 5-point Likert scale (range 0-4, high scores indicating higher severity). The BCSS questionnaire Total Score is the sum of the 3 symptom scores, ranging from 0-12 (lowest-highest severity).
Time Frame	From Day 1 to Day 8 post-treatment
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.
Full analysis set (FAS): all randomised patients who received at least one dose of the IP, irrespective of their protocol adherence and continued participation in the study.

Reporting Groups

	Description
AZD8871 100 µg	The subjects received AZD8871 100 µg once daily by DPI device via single dose DPI that is an adaptation of the multi-dose Genuair™ used in approved inhalation products.
AZD8871 600 µg	The subjects received AZD8871 600 µg once daily by DPI device via single dose DPI that is an adaptation of the multi-dose Genuair™ used in approved inhalation products.
Placebo	The placebo was administered via single dose DPI that is an adaptation of the commercially available Genuair® with a smaller internal volume to enable delivery of single doses. To maintain blinding, each patient received one inhaled dose from placebo DPI provided to him/her on each day of the treatment period.

Measured Values

	AZD8871 100 µg	AZD8871 600 µg	Placebo
Number of Participants Analyzed [units:participants]	34	39	36
Change from baseline in BCSS questionnaire Total Score from Day 1 to Day 8 post-treatment [units: Scores on a scale] Least Squares Mean (Standard Error)	-0.416 (0.216)	-0.920 (0.198)	-0.071 (0.205)

Statistical Analysis 1 for Change from baseline in BCSS questionnaire Total Score from Day 1 to Day 8 post-treatment

Groups^[1]	AZD8871 100 µg, Placebo
Method^[3]	ANCOVA
P-Value^[4]	0.205

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Comparison of AZD8871 100 µg vs placebo
[3]	Other relevant information, such as adjustments or degrees of freedom:
	Fixed effects: treatment, sequence, period. Random effect for patient nested within sequence. Continuous covariate: baseline.
[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.

Statistical Analysis 2 for Change from baseline in BCSS questionnaire Total Score from Day 1 to Day 8 post-treatment

Groups^[1]	AZD8871 600 µg, Placebo
Method^[3]	ANCOVA
P-Value^[4]	0.002

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Comparison of AZD8871 600 µg vs placebo
[3]	Other relevant information, such as adjustments or degrees of freedom:
	Fixed effects: treatment, sequence, period. Random effect for patient nested within sequence. Continuous covariate: baseline.
[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.

Statistical Analysis 3 for Change from baseline in BCSS questionnaire Total Score from Day 1 to Day 8 post-treatment

Groups^[1]	AZD8871 100 µg, AZD8871 600 µg
Method^[3]	ANCOVA
P-Value^[4]	0.060

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Comparison of AZD8871 600 µg vs AZD8871 100 µg
[3]	Other relevant information, such as adjustments or degrees of freedom:
	Fixed effects: treatment, sequence, period. Random effect for patient nested within sequence. Continuous covariate: baseline.
[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.

21. Secondary Outcome Measure: Change from baseline in BCSS questionnaire Total Score from Day 9 to Day 14 post-treatment [ Time Frame: From Day 9 to Day 14 post-treatment ]

Measure Type	Secondary
Measure Name	Change from baseline in BCSS questionnaire Total Score from Day 9 to Day 14 post-treatment
Measure Description	The efficacy of inhaled AZD8871 in patients with moderate to severe COPD was assessed by measuring the change from baseline in Total score of the Breathlessness, Cough Sputum Scale (BCSS) questionnaire. The BCSS questionnaire is a 3-item patient-reported outcome measure. On a daily basis, patients rated 3 symptoms (breathlessness, cough and sputum) on a 5-point Likert scale (range 0-4, high scores indicating higher severity). The BCSS questionnaire Total Score is the sum of the 3 symptom scores, ranging from 0-12 (lowest-highest severity).
Time Frame	From Day 9 to Day 14 post-treatment
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.
Full analysis set (FAS): all randomised patients who received at least one dose of the IP, irrespective of their protocol adherence and continued participation in the study.

Reporting Groups

	Description
AZD8871 100 µg	The subjects received AZD8871 100 µg once daily by DPI device via single dose DPI that is an adaptation of the multi-dose Genuair™ used in approved inhalation products.
AZD8871 600 µg	The subjects received AZD8871 600 µg once daily by DPI device via single dose DPI that is an adaptation of the multi-dose Genuair™ used in approved inhalation products.
Placebo	The placebo was administered via single dose DPI that is an adaptation of the commercially available Genuair® with a smaller internal volume to enable delivery of single doses. To maintain blinding, each patient received one inhaled dose from placebo DPI provided to him/her on each day of the treatment period.

Measured Values

	AZD8871 100 µg	AZD8871 600 µg	Placebo
Number of Participants Analyzed [units:participants]	34	39	36
Change from baseline in BCSS questionnaire Total Score from Day 9 to Day 14 post-treatment [units: Scores on a scale] Least Squares Mean (Standard Error)	-0.491 (0.237)	-1.191 (0.219)	-0.030 (0.226)

Statistical Analysis 1 for Change from baseline in BCSS questionnaire Total Score from Day 9 to Day 14 post-treatment

Groups^[1]	AZD8871 100 µg, Placebo
Method^[3]	ANCOVA
P-Value^[4]	0.111

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Comparison of AZD8871 100 µg vs placebo
[3]	Other relevant information, such as adjustments or degrees of freedom:
	Fixed effects: treatment, sequence, period. Random effect for patient nested within sequence. Continuous covariate: baseline.
[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.

Statistical Analysis 2 for Change from baseline in BCSS questionnaire Total Score from Day 9 to Day 14 post-treatment

Groups^[1]	AZD8871 600 µg, Placebo
Method^[3]	ANCOVA
P-Value^[4]	<0.001

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Comparison of AZD8871 600 µg vs placebo
[3]	Other relevant information, such as adjustments or degrees of freedom:
	Fixed effects: treatment, sequence, period. Random effect for patient nested within sequence. Continuous covariate: baseline.
[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.

Statistical Analysis 3 for Change from baseline in BCSS questionnaire Total Score from Day 9 to Day 14 post-treatment

Groups^[1]	AZD8871 100 µg, AZD8871 600 µg
Method^[3]	ANCOVA
P-Value^[4]	0.015

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Comparison of AZD8871 600 µg vs AZD8871 100 µg
[3]	Other relevant information, such as adjustments or degrees of freedom:
	Fixed effects: treatment, sequence, period. Random effect for patient nested within sequence. Continuous covariate: baseline.
[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.

22. Secondary Outcome Measure: Change from baseline in cough individual domain score from Day 1 to Day 8 post-treatment [ Time Frame: From Day 1 to Day 8 post-treatment ]

Measure Type	Secondary
Measure Name	Change from baseline in cough individual domain score from Day 1 to Day 8 post-treatment
Measure Description	The efficacy of inhaled AZD8871 in patients with moderate to severe COPD will be assessed by measuring the change from baseline in Breathlessness, Cough Sputum Scale (BCSS) questionnaire cough individual domain scores. On a daily basis, patients rated cough symptoms on a 5-point Likert scale (range 0-4, high scores indicating higher severity).
Time Frame	From Day 1 to Day 8 post-treatment
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.
Full analysis set (FAS): all randomised patients who received at least one dose of the IP, irrespective of their protocol adherence and continued participation in the study.

Reporting Groups

	Description
AZD8871 100 µg	The subjects received AZD8871 100 µg once daily by DPI device via single dose DPI that is an adaptation of the multi-dose Genuair™ used in approved inhalation products.
AZD8871 600 µg	The subjects received AZD8871 600 µg once daily by DPI device via single dose DPI that is an adaptation of the multi-dose Genuair™ used in approved inhalation products.
Placebo	The placebo was administered via single dose DPI that is an adaptation of the commercially available Genuair® with a smaller internal volume to enable delivery of single doses. To maintain blinding, each patient received one inhaled dose from placebo DPI provided to him/her on each day of the treatment period.

Measured Values

	AZD8871 100 µg	AZD8871 600 µg	Placebo
Number of Participants Analyzed [units:participants]	34	39	36
Change from baseline in cough individual domain score from Day 1 to Day 8 post-treatment [units: Scores on a scale] Least Squares Mean (Standard Error)	-0.186 (0.091)	-0.287 (0.084)	-0.134 (0.087)

Statistical Analysis 1 for Change from baseline in cough individual domain score from Day 1 to Day 8 post-treatment

Groups^[1]	AZD8871 100 µg, Placebo
Method^[3]	ANCOVA
P-Value^[4]	0.621

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Comparison of AZD8871 100 µg vs placebo
[3]	Other relevant information, such as adjustments or degrees of freedom:
	Fixed effects: treatment, sequence, period. Random effect for patient nested within sequence. Continuous covariate: baseline.
[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.

Statistical Analysis 2 for Change from baseline in cough individual domain score from Day 1 to Day 8 post-treatment

Groups^[1]	AZD8871 600 µg, Placebo
Method^[3]	ANCOVA
P-Value^[4]	0.138

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Comparison of AZD8871 600 µg vs placebo
[3]	Other relevant information, such as adjustments or degrees of freedom:
	Fixed effects: treatment, sequence, period. Random effect for patient nested within sequence. Continuous covariate: baseline.
[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.

Statistical Analysis 3 for Change from baseline in cough individual domain score from Day 1 to Day 8 post-treatment

Groups^[1]	AZD8871 100 µg, AZD8871 600 µg
Method^[3]	ANCOVA
P-Value^[4]	0.333

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Comparison of AZD8871 600 µg vs AZD8871 100 µg
[3]	Other relevant information, such as adjustments or degrees of freedom:
	Fixed effects: treatment, sequence, period. Random effect for patient nested within sequence. Continuous covariate: baseline.
[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.

23. Secondary Outcome Measure: Change from baseline in cough individual domain score from Day 9 to Day 14 post-treatment [ Time Frame: From Day 9 to Day 14 post-treatment ]

Measure Type	Secondary
Measure Name	Change from baseline in cough individual domain score from Day 9 to Day 14 post-treatment
Measure Description	The efficacy of inhaled AZD8871 in patients with moderate to severe COPD will be assessed by measuring the change from baseline in Breathlessness, Cough Sputum Scale (BCSS) questionnaire cough individual domain scores. On a daily basis, patients rated cough symptoms on a 5-point Likert scale (range 0-4, high scores indicating higher severity).
Time Frame	From Day 9 to Day 14 post-treatment
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.
Full analysis set (FAS): all randomised patients who received at least one dose of the IP, irrespective of their protocol adherence and continued participation in the study.

Reporting Groups

	Description
AZD8871 100 µg	The subjects received AZD8871 100 µg once daily by DPI device via single dose DPI that is an adaptation of the multi-dose Genuair™ used in approved inhalation products.
AZD8871 600 µg	The subjects received AZD8871 600 µg once daily by DPI device via single dose DPI that is an adaptation of the multi-dose Genuair™ used in approved inhalation products.
Placebo	The placebo was administered via single dose DPI that is an adaptation of the commercially available Genuair® with a smaller internal volume to enable delivery of single doses. To maintain blinding, each patient received one inhaled dose from placebo DPI provided to him/her on each day of the treatment period.

Measured Values

	AZD8871 100 µg	AZD8871 600 µg	Placebo
Number of Participants Analyzed [units:participants]	34	39	36
Change from baseline in cough individual domain score from Day 9 to Day 14 post-treatment [units: Scores on a scale] Least Squares Mean (Standard Error)	-0.160 (0.096)	-0.445 (0.088)	-0.123 (0.091)

Statistical Analysis 1 for Change from baseline in cough individual domain score from Day 9 to Day 14 post-treatment

Groups^[1]	AZD8871 100 µg, Placebo
Method^[3]	ANCOVA
P-Value^[4]	0.748

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Comparison of AZD8871 100 µg vs placebo
[3]	Other relevant information, such as adjustments or degrees of freedom:
	Fixed effects: treatment, sequence, period. Random effect for patient nested within sequence. Continuous covariate: baseline.
[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.

Statistical Analysis 2 for Change from baseline in cough individual domain score from Day 9 to Day 14 post-treatment

Groups^[1]	AZD8871 600 µg, Placebo
Method^[3]	ANCOVA
P-Value^[4]	0.005

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Comparison of AZD8871 600 µg vs placebo
[3]	Other relevant information, such as adjustments or degrees of freedom:
	Fixed effects: treatment, sequence, period. Random effect for patient nested within sequence. Continuous covariate: baseline.
[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.

Statistical Analysis 3 for Change from baseline in cough individual domain score from Day 9 to Day 14 post-treatment

Groups^[1]	AZD8871 100 µg, AZD8871 600 µg
Method^[3]	ANCOVA
P-Value^[4]	0.013

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Comparison of AZD8871 600 µg vs AZD8871 100 µg
[3]	Other relevant information, such as adjustments or degrees of freedom:
	Fixed effects: treatment, sequence, period. Random effect for patient nested within sequence. Continuous covariate: baseline.
[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.

24. Secondary Outcome Measure: Change from baseline in breathlessness individual domain score from Day 1 to Day 8 post-treatment [ Time Frame: From Day 1 to Day 8 post-treatment ]

Measure Type	Secondary
Measure Name	Change from baseline in breathlessness individual domain score from Day 1 to Day 8 post-treatment
Measure Description	The efficacy of inhaled AZD8871 in patients with moderate to severe COPD will be assessed by measuring the change from baseline in Breathlessness, Cough Sputum Scale (BCSS) questionnaire breathlessness individual domain scores. On a daily basis, patients rated breathlessness symptoms on a 5-point Likert scale (range 0-4, high scores indicating higher severity).
Time Frame	From Day 1 to Day 8 post-treatment
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.
Full analysis set (FAS): all randomised patients who received at least one dose of the IP, irrespective of their protocol adherence and continued participation in the study.

Reporting Groups

	Description
AZD8871 100 µg	The subjects received AZD8871 100 µg once daily by DPI device via single dose DPI that is an adaptation of the multi-dose Genuair™ used in approved inhalation products.
AZD8871 600 µg	The subjects received AZD8871 600 µg once daily by DPI device via single dose DPI that is an adaptation of the multi-dose Genuair™ used in approved inhalation products.
Placebo	The placebo was administered via single dose DPI that is an adaptation of the commercially available Genuair® with a smaller internal volume to enable delivery of single doses. To maintain blinding, each patient received one inhaled dose from placebo DPI provided to him/her on each day of the treatment period.

Measured Values

	AZD8871 100 µg	AZD8871 600 µg	Placebo
Number of Participants Analyzed [units:participants]	34	39	36
Change from baseline in breathlessness individual domain score from Day 1 to Day 8 post-treatment [units: Scores on a scale] Least Squares Mean (Standard Error)	-0.122 (0.097)	-0.377 (0.089)	0.099 (0.092)

Statistical Analysis 1 for Change from baseline in breathlessness individual domain score from Day 1 to Day 8 post-treatment

Groups^[1]	AZD8871 100 µg, Placebo
Method^[3]	ANCOVA
P-Value^[4]	0.064

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Comparison of AZD8871 100 µg vs placebo
[3]	Other relevant information, such as adjustments or degrees of freedom:
	Fixed effects: treatment, sequence, period. Random effect for patient nested within sequence. Continuous covariate: baseline.
[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.

Statistical Analysis 2 for Change from baseline in breathlessness individual domain score from Day 1 to Day 8 post-treatment

Groups^[1]	AZD8871 600 µg, Placebo
Method^[3]	ANCOVA
P-Value^[4]	<0.001

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Comparison of AZD8871 600 µg vs placebo
[3]	Other relevant information, such as adjustments or degrees of freedom:
	Fixed effects: treatment, sequence, period. Random effect for patient nested within sequence. Continuous covariate: baseline.
[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.

Statistical Analysis 3 for Change from baseline in breathlessness individual domain score from Day 1 to Day 8 post-treatment

Groups^[1]	AZD8871 100 µg, AZD8871 600 µg
Method^[3]	ANCOVA
P-Value^[4]	0.030

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Comparison of AZD8871 600 µg vs AZD8871 100 µg
[3]	Other relevant information, such as adjustments or degrees of freedom:
	Fixed effects: treatment, sequence, period. Random effect for patient nested within sequence. Continuous covariate: baseline.
[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.

25. Secondary Outcome Measure: Change from baseline in breathlessness individual domain score from Day 9 to Day 14 post-treatment [ Time Frame: From Day 9 to Day 14 post-treatment ]

Measure Type	Secondary
Measure Name	Change from baseline in breathlessness individual domain score from Day 9 to Day 14 post-treatment
Measure Description	The efficacy of inhaled AZD8871 in patients with moderate to severe COPD will be assessed by measuring the change from baseline in Breathlessness, Cough Sputum Scale (BCSS) questionnaire breathlessness individual domain scores. On a daily basis, patients rated breathlessness symptoms on a 5-point Likert scale (range 0-4, high scores indicating higher severity).
Time Frame	From Day 9 to Day 14 post-treatment
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.
Full analysis set (FAS): all randomised patients who received at least one dose of the IP, irrespective of their protocol adherence and continued participation in the study.

Reporting Groups

	Description
AZD8871 100 µg	The subjects received AZD8871 100 µg once daily by DPI device via single dose DPI that is an adaptation of the multi-dose Genuair™ used in approved inhalation products.
AZD8871 600 µg	The subjects received AZD8871 600 µg once daily by DPI device via single dose DPI that is an adaptation of the multi-dose Genuair™ used in approved inhalation products.
Placebo	The placebo was administered via single dose DPI that is an adaptation of the commercially available Genuair® with a smaller internal volume to enable delivery of single doses. To maintain blinding, each patient received one inhaled dose from placebo DPI provided to him/her on each day of the treatment period.

Measured Values

	AZD8871 100 µg	AZD8871 600 µg	Placebo
Number of Participants Analyzed [units:participants]	34	39	36
Change from baseline in breathlessness individual domain score from Day 9 to Day 14 post-treatment [units: Scores on a scale] Least Squares Mean (Standard Error)	-0.202 (0.108)	-0.453 (0.100)	0.106 (0.103)

Statistical Analysis 1 for Change from baseline in breathlessness individual domain score from Day 9 to Day 14 post-treatment

Groups^[1]	AZD8871 100 µg, Placebo
Method^[3]	ANCOVA
P-Value^[4]	0.018

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Comparison of AZD8871 100 µg vs placebo
[3]	Other relevant information, such as adjustments or degrees of freedom:
	Fixed effects: treatment, sequence, period. Random effect for patient nested within sequence. Continuous covariate: baseline.
[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.

Statistical Analysis 2 for Change from baseline in breathlessness individual domain score from Day 9 to Day 14 post-treatment

Groups^[1]	AZD8871 600 µg, Placebo
Method^[3]	ANCOVA
P-Value^[4]	<0.001

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Comparison of AZD8871 600 µg vs placebo
[3]	Other relevant information, such as adjustments or degrees of freedom:
	Fixed effects: treatment, sequence, period. Random effect for patient nested within sequence. Continuous covariate: baseline.
[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.

Statistical Analysis 3 for Change from baseline in breathlessness individual domain score from Day 9 to Day 14 post-treatment

Groups^[1]	AZD8871 100 µg, AZD8871 600 µg
Method^[3]	ANCOVA
P-Value^[4]	0.047

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Comparison of AZD8871 600 µg vs AZD8871 100 µg
[3]	Other relevant information, such as adjustments or degrees of freedom:
	Fixed effects: treatment, sequence, period. Random effect for patient nested within sequence. Continuous covariate: baseline.
[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.

26. Secondary Outcome Measure: Change from baseline in sputum individual domain score from Day 1 to Day 8 post-treatment [ Time Frame: From Day 1 to Day 8 post-treatment ]

Measure Type	Secondary
Measure Name	Change from baseline in sputum individual domain score from Day 1 to Day 8 post-treatment
Measure Description	The efficacy of inhaled AZD8871 in patients with moderate to severe COPD will be assessed by measuring the change from baseline in Breathlessness, Cough Sputum Scale (BCSS) questionnaire sputum individual domain scores. On a daily basis, patients rated sputum symptoms on a 5-point Likert scale (range 0-4, high scores indicating higher severity).
Time Frame	From Day 1 to Day 8 post-treatment
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.
Full analysis set (FAS): all randomised patients who received at least one dose of the IP, irrespective of their protocol adherence and continued participation in the study.

Reporting Groups

	Description
AZD8871 100 µg	The subjects received AZD8871 100 µg once daily by DPI device via single dose DPI that is an adaptation of the multi-dose Genuair™ used in approved inhalation products.
AZD8871 600 µg	The subjects received AZD8871 600 µg once daily by DPI device via single dose DPI that is an adaptation of the multi-dose Genuair™ used in approved inhalation products.
Placebo	The placebo was administered via single dose DPI that is an adaptation of the commercially available Genuair® with a smaller internal volume to enable delivery of single doses. To maintain blinding, each patient received one inhaled dose from placebo DPI provided to him/her on each day of the treatment period.

Measured Values

	AZD8871 100 µg	AZD8871 600 µg	Placebo
Number of Participants Analyzed [units:participants]	34	39	36
Change from baseline in sputum individual domain score from Day 1 to Day 8 post-treatment [units: Scores on a scale] Least Squares Mean (Standard Error)	-0.100 (0.070)	-0.255 (0.064)	-0.035 (0.066)

Statistical Analysis 1 for Change from baseline in sputum individual domain score from Day 1 to Day 8 post-treatment

Groups^[1]	AZD8871 100 µg, Placebo
Method^[3]	ANCOVA
P-Value^[4]	0.477

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Comparison of AZD8871 100 µg vs placebo
[3]	Other relevant information, such as adjustments or degrees of freedom:
	Fixed effects: treatment, sequence, period. Random effect for patient nested within sequence. Continuous covariate: baseline.
[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.

Statistical Analysis 2 for Change from baseline in sputum individual domain score from Day 1 to Day 8 post-treatment

Groups^[1]	AZD8871 600 µg, Placebo
Method^[3]	ANCOVA
P-Value^[4]	0.014

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Comparison of AZD8871 600 µg vs placebo
[3]	Other relevant information, such as adjustments or degrees of freedom:
	Fixed effects: treatment, sequence, period. Random effect for patient nested within sequence. Continuous covariate: baseline.
[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.

Statistical Analysis 3 for Change from baseline in sputum individual domain score from Day 1 to Day 8 post-treatment

Groups^[1]	AZD8871 100 µg, AZD8871 600 µg
Method^[3]	ANCOVA
P-Value^[4]	0.084

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Comparison of AZD8871 600 µg vs AZD8871 100 µg
[3]	Other relevant information, such as adjustments or degrees of freedom:
	Fixed effects: treatment, sequence, period. Random effect for patient nested within sequence. Continuous covariate: baseline.
[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.

27. Secondary Outcome Measure: Change from baseline in sputum individual domain score from Day 9 to Day 14 post-treatment [ Time Frame: From Day 9 to Day 14 post-treatment ]

Measure Type	Secondary
Measure Name	Change from baseline in sputum individual domain score from Day 9 to Day 14 post-treatment
Measure Description	The efficacy of inhaled AZD8871 in patients with moderate to severe COPD will be assessed by measuring the change from baseline in Breathlessness, Cough Sputum Scale (BCSS) questionnaire sputum individual domain scores. On a daily basis, patients rated sputum symptoms on a 5-point Likert scale (range 0-4, high scores indicating higher severity).
Time Frame	From Day 9 to Day 14 post-treatment
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.
Full analysis set (FAS): all randomised patients who received at least one dose of the IP, irrespective of their protocol adherence and continued participation in the study.

Reporting Groups

	Description
AZD8871 100 µg	The subjects received AZD8871 100 µg once daily by DPI device via single dose DPI that is an adaptation of the multi-dose Genuair™ used in approved inhalation products.
AZD8871 600 µg	The subjects received AZD8871 600 µg once daily by DPI device via single dose DPI that is an adaptation of the multi-dose Genuair™ used in approved inhalation products.
Placebo	The placebo was administered via single dose DPI that is an adaptation of the commercially available Genuair® with a smaller internal volume to enable delivery of single doses. To maintain blinding, each patient received one inhaled dose from placebo DPI provided to him/her on each day of the treatment period.

Measured Values

	AZD8871 100 µg	AZD8871 600 µg	Placebo
Number of Participants Analyzed [units:participants]	34	39	36
Change from baseline in sputum individual domain score from Day 9 to Day 14 post-treatment [units: Scores on a scale] Least Squares Mean (Standard Error)	-0.122 (0.078)	-0.297 (0.073)	-0.011 (0.075)

Statistical Analysis 1 for Change from baseline in sputum individual domain score from Day 9 to Day 14 post-treatment

Groups^[1]	AZD8871 100 µg, Placebo
Method^[3]	ANCOVA
P-Value^[4]	0.213

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Comparison of AZD8871 100 µg vs placebo
[3]	Other relevant information, such as adjustments or degrees of freedom:
	Fixed effects: treatment, sequence, period. Random effect for patient nested within sequence. Continuous covariate: baseline.
[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.

Statistical Analysis 2 for Change from baseline in sputum individual domain score from Day 9 to Day 14 post-treatment

Groups^[1]	AZD8871 600 µg, Placebo
Method^[3]	ANCOVA
P-Value^[4]	0.001

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Comparison of AZD8871 600 µg vs placebo
[3]	Other relevant information, such as adjustments or degrees of freedom:
	Fixed effects: treatment, sequence, period. Random effect for patient nested within sequence. Continuous covariate: baseline.
[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.

Statistical Analysis 3 for Change from baseline in sputum individual domain score from Day 9 to Day 14 post-treatment

Groups^[1]	AZD8871 100 µg, AZD8871 600 µg
Method^[3]	ANCOVA
P-Value^[4]	0.046

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Comparison of AZD8871 600 µg vs AZD8871 100 µg
[3]	Other relevant information, such as adjustments or degrees of freedom:
	Fixed effects: treatment, sequence, period. Random effect for patient nested within sequence. Continuous covariate: baseline.
[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.

Serious Adverse Events

Time Frame

From screening to Follow-up/early termination Visit, 28 to 35 days after the last administration of investigational product (IP)

Additional Description

All reported AEs, date of onset, date of resolution, Investigator’s assessment of severity, outcome, action taken with IP, and relationship to the IP were listed. Non-Treatment-emergent adverse event (non-TEAE): any AE occurring before the first dose of IP, or >30 days after the last dose TEAE: event occurring after first dose of IP or present prior to the first dose, but increasing in severity after IP administration.

Reporting Groups

	Description
AZD8871 100 µg	The subjects received AZD8871 100 µg once daily by DPI device via single dose DPI that is an adaptation of the multi-dose Genuair™ used in approved inhalation products.
AZD8871 600 µg	The subjects received AZD8871 600 µg once daily by DPI device via single dose DPI that is an adaptation of the multi-dose Genuair™ used in approved inhalation products.
Placebo	The placebo was administered via single dose DPI that is an adaptation of the commercially available Genuair® with a smaller internal volume to enable delivery of single doses. To maintain blinding, each patient received one inhaled dose from placebo DPI provided to him/her on each day of the treatment period.

Serious Adverse Events

AZD8871 100 µg

AZD8871 600 µg

Placebo

Total, serious adverse events

# participants affected / at risk

0/34 (0.00%)

1/39 (2.56%)

1/36 (2.78%)

Infections and infestations

Abdominal wall abscess¹,^†

# participants affected / at risk

0/34 (0.00%)

0/39 (0.00%)

1/36 (2.78%)

# events

Infections and infestations

Appendicitis¹,^†

# participants affected / at risk

0/34 (0.00%)

0/39 (0.00%)

1/36 (2.78%)

# events

Respiratory, thoracic and mediastinal disorders

Chronic obstructive pulmonary disease exacerbation¹,^†

# participants affected / at risk

0/34 (0.00%)

1/39 (2.56%)

0/36 (0.00%)

# events

†	Events were collected by systematic assessment
1	Term from vocabulary, MedDRA version 20.0

Other Adverse Events

Time Frame

From screening to Follow-up/early termination Visit, 28 to 35 days after the last administration of investigational product (IP)

Additional Description

Frequency Threshold

Threshold above which other adverse events are reported	5%

Reporting Groups

	Description
AZD8871 100 µg	The subjects received AZD8871 100 µg once daily by DPI device via single dose DPI that is an adaptation of the multi-dose Genuair™ used in approved inhalation products.
AZD8871 600 µg	The subjects received AZD8871 600 µg once daily by DPI device via single dose DPI that is an adaptation of the multi-dose Genuair™ used in approved inhalation products.
Placebo	The placebo was administered via single dose DPI that is an adaptation of the commercially available Genuair® with a smaller internal volume to enable delivery of single doses. To maintain blinding, each patient received one inhaled dose from placebo DPI provided to him/her on each day of the treatment period.

Other Adverse Events

AZD8871 100 µg

AZD8871 600 µg

Placebo

Total, other (not including serious) adverse events

# participants affected / at risk

5/34 (14.71%)

7/39 (17.95%)

5/36 (13.89%)

Respiratory, thoracic and mediastinal disorders

Chronic obstructive pulmonary disease¹,^†

# participants affected / at risk

2/34 (5.88%)

2/39 (5.13%)

0/36 (0.00%)

# events

Nervous system disorders

Headache¹,^†

# participants affected / at risk

4/34 (11.76%)

3/39 (7.69%)

4/36 (11.11%)

# events

Musculoskeletal and connective tissue disorders

Back pain¹,^†

# participants affected / at risk

0/34 (0.00%)

2/39 (5.13%)

0/36 (0.00%)

# events

Infections and infestations

Viral upper respiratory tract infections¹,^†

# participants affected / at risk

0/34 (0.00%)

0/39 (0.00%)

2/36 (5.56%)

# events

†	Events were collected by systematic assessment
1	Term from vocabulary, MedDRA version 20.0

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 AstraZeneca

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
No text entered.

Results Point of Contact

Name/Title:	Dr Ioannis Psallidas, MD, PhD
Organization:	AstraZeneca
Phone	1-877-240-9479
E-mail:	[email protected]

Documents available

https://filehosting.pharmacm.com/DownloadService.ashx?client=CTR_MED_7111&studyid=4121&filename=AZD8871%20D6640C00006%20Clinical%20Study%20Protocol%20(CSP)_redacted.pdf
Download
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Download
Trial Results Summaries
Available here

Contacts

Contact

AstraZeneca Clinical Study Information Center

1-877-240-9479

information.center@astrazeneca.com

Investigators

Principal Investigator

Dave Singh

Medicines Evaluation Unit, Manchester, United Kingdom

Sponsors

Collaborators

Inclusion Criteria

Exclusion Criteria

Research Site

Research Site