Multi-centre study to assess the efficacy and safety of AZD5423 in COPD patients on a background therapy of formoterol - -

Study identifier:D2340C00011

ClinicalTrials.gov identifier:NCT01555099

EudraCT identifier:2011-005389-39

CTIS identifier:N/A

Study Complete

Official Title

A phase-II, double-blind, placebo-controlled, randomised, parallel-group,multi-centre study to assess the efficacy and safety of two staggered dose levels of inhaled once daily AZD5423 or twice daily budesonide for 12 weeks in COPD patients on a background therapy of formoterol.

Medical condition

Chronic obstructive pulmonary disease (COPD)

Phase

Phase 2

Healthy volunteers

Study drug

AZD5423, Budesonide, Placebo

Sex

All

Actual Enrollment

482

Study type

Interventional

Age

40 Years - 150 Years

Date

Study Start Date: 01 Apr 2012

Primary Completion Date: 01 Apr 2013

Study Completion Date: 01 Apr 2013

Study design

Allocation: Randomized
Endpoint Classification: Safety Study
Intervention Model: Parallel Assignment
Masking: Double Blind
Primary Purpose: Treatment

Verification:

Verified 01 Mar 2015 by AstraZeneca

Collaborators

Inclusion and exclusion criteria

Inclusion Criteria

- Provision of signed and dated informed consent prior to conducting any study specific procedures
- Men or women aged ≥ 40 years
- Men or post-menopausal or surgically sterile women. Women will be considered
post-menopausal if they have been amenorrheic for at least 12 months, and have a
follicle stimulating hormone (FSH) plasma concentration within the postmenopausal range as defined by the laboratory. Male patients should be willing to use barrier contraception, i.e. condom (with spermicide) from the day of dosing until at least 5 weeks after the last dose with the study drug.
- Clinical diagnosis of COPD for more than 1 year at Visit 1, according to GOLD
guidelines
- Current maintenance therapy with LABA and/or LAMA, ICS/LABA or ICS plus
LAMA combination
- Current or ex-smokers with a smoking history equivalent to at least 10 pack years (1 pack year = 20 cigarettes smoked per day for one year)
- Post-bronchodilator FEV1 ≥40 and ≤ 80% of the predicted normal value
- Post-bronchodilator FEV1/FVC <0,7
- Reversibility of airway obstruction according to reversibility test performed at visit 2, defined as an increase in FEV1 of ≥10% relative baseline after inhalation of in total 400 μg salbutamol or 1 mg terbutaline sulphate
- Chest radiography (not older than 12 months at Visit 2) not showing any
pathological changes that would make the patient unsuitable for inclusion as judged by the Investigator
- Able to read and write and use the electronic devices (eDiary and electronic
spirometry)
- Ability to complete an eDiary correctly. Baseline diary data had to be recorded for at least 8 (any 8) of the last 10 days of the run-in period to accept patients for randomized treatment (Randomisation Criteria at Visit 3).
- Provision of informed consent for genetic sampling and analyses. If a patient
declines to participate in the pharmacogenetic research, there will be no
consequence or loss of benefit to the patient. The patient will not be excluded from other aspects of the study described in the Clinical Study Protocol (CSP), as long as they consent (Inclusion criteria for patients taking part in the pharmacogenetic research)

Exclusion Criteria

- Significant disease or disorder (eg, cardiovascular, pulmonary other than COPD, gastrointestinal, liver, renal, neurological, musculoskeletal, endocrine, metabolic, malignant, psychiatric, major physical impairment) which, in the opinion of the investigator, may either put the patient at risk because of participation in the study, or influence the results of the study, or the patient's ability to participate in the study
- Any clinically relevant abnormal findings in clinical chemistry, haematology,
urinalysis, physical examination, pulse, blood pressure or ECG at Visit 2, which, in the opinion of the investigator, may put the patient at risk because of his/her participation in the study
- Requirement for long term oxygen therapy
- An exacerbation of COPD, defined as use of oral or parenteral glucocorticosteroids or oral/parenteral antibiotics or hospitalisation related to COPD within 6 weeks of Visit 2
- Participation in or scheduled for an intensive COPD rehabilitation program
- Known or suspected hypersensitivity to study therapy or excipients of the study drug
- History of current alcohol or drug abuse or any condition associated with poor
compliance as judged by the investigator
- Plasma donation within one month of screening or any blood donation/blood loss >500 mL during the 3 months prior to screening.
- Participation in any clinical study with an investigational drug or new formulation of a marketed drug in the 3 months prior to Visit 2
- Planned in-patient surgery or hospitalisation during the study
- Previous randomisation of treatment into the present study
- Involvement in the planning and conduct of the study (applies to both AstraZeneca staff or staff at the study site)
- Previous allogeneic bone marrow transplant (Exclusion criteria for patients taking part in the pharmacogenetic research)
- Non-leukocyte depleted whole blood transfusion within 120 days of the date of the genetic sample collection (Exclusion criteria for patients taking part in the pharmacogenetic research)

Location

Research Site

Sofia, Bulgaria

Location

Research Site

Doganovo, Bulgaria

Location

Research Site

Plovdiv, Bulgaria

Location

Research Site

Varna, Bulgaria

Location

Research Site

Montpellier, France

Location

Research Site

Marseille Cedex 20, France

Location

Research Site

Pessac, France

Location

Research Site

Brest Cedex 2, France

Arms	Assigned Interventions
Experimental: AZD5423 New study drug	Drug: AZD5423 oral inhaled Other Name: AZD5423
Active Comparator: Budesonide Comparator to which the new study drug will be compared	Drug: Budesonide oral inhaled Other Name: Budesonide
Placebo Comparator: Placebo No drug to which both other arms will be compared	Drug: Placebo oral inhaled Other Name: Placebo

Participant Flow

Recruitment Details

Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
No text entered.

Pre-Assignment Details

Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
No text entered.

Reporting Groups

	Description
AZD5423 180 ug + AZD5423 800 ug+ Formoterol 9ug bid + SABA prn
Budesonide 640 ug bid + Formoterol 9ug bid + SABA prn
Placebo + formoterol 9ug bid + SABA prn

Participant Flow: Overall Study

	AZD5423 180 ug + AZD5423 800 ug+ Formoterol 9ug bid + SABA prn	Budesonide 640 ug bid + Formoterol 9ug bid + SABA prn	Placebo + formoterol 9ug bid + SABA prn
STARTED	119	117	117
COMPLETED	106	109	107
NOT COMPLETED	13	8	10
Adverse Event	5	2	5
Withdrawal by subject	3	3	3
Eligibility Criteria Not Fulfilled	3	0	2
Severe Non-Compliance To Protocol	1	0	0
Withdrawn Due To Other	1	3	0

Baseline Characteristics

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

Reporting Groups

	Description
AZD5423 180 ug + AZD5423 800 ug+ Formoterol 9ug bid + SABA prn
Budesonide 640 ug bid + Formoterol 9ug bid + SABA prn
Placebo + formoterol 9ug bid + SABA prn

Baseline Measures

	AZD5423 180 ug + AZD5423 800 ug+ Formoterol 9ug bid + SABA prn	Budesonide 640 ug bid + Formoterol 9ug bid + SABA prn	Placebo + formoterol 9ug bid + SABA prn	Total
Number of Participants [units: Participants]	119	117	117	353
Age Continuous [units: Years] Mean ± Standard Deviation	64.0 ± 7.89	63.4 ± 8.41	61.7 ± 8.59	63.0 ± 8.34
Gender, Male/Female [units: Participants]
Female	26	26	30	82
Male	93	91	87	271
Race, Customized [units: Participants]
Asian	1	0	0	1
White	118	117	117	352

Outcome Measures

1. Primary Outcome Measure: To evaluate the efficacy of inhaled AZD5423 800 µg delivered dose od compared with placebo in COPD patients [ Time Frame: Baseline (week 0), and at week 8, 10, and 12 ]

Measure Type	Primary
Measure Name	To evaluate the efficacy of inhaled AZD5423 800 µg delivered dose od compared with placebo in COPD patients
Measure Description	Comparison of absolute change from baseline to mean of week 8 to 12 in pre-dose FEV1 between AZD5423 delivered dose od and placebo.
Time Frame	Baseline (week 0), and at week 8, 10, and 12
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.
On treatment analysis set: will include data from all randomised patients regardless of the treatment actually received. Excluded are patients that did not receive any dose of randomised treatment and discontinued the study.

Reporting Groups

	Description
AZD5423 180 ug + AZD5423 800 ug+ Formoterol 9ug bid + SABA prn
Placebo + formoterol 9ug bid + SABA prn

Measured Values

	AZD5423 180 ug + AZD5423 800 ug+ Formoterol 9ug bid + SABA prn	Placebo + formoterol 9ug bid + SABA prn
Number of Participants Analyzed [units:participants]	109	109
To evaluate the efficacy of inhaled AZD5423 800 µg delivered dose od compared with placebo in COPD patients [units: Litre] Least Squares Mean (Standard Error)	-0.011 (0.023)	-0.008 (0.023)

Statistical Analysis 1 for To evaluate the efficacy of inhaled AZD5423 800 µg delivered dose od compared with placebo in COPD patients

Groups^[1]	All groups
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	ANCOVA
P-Value^[4]	0.928
Mean Difference (Final Values)^[5]	-0.003
95% Confidence Interval	( -0.06 to 0.06 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.
[5]	Other relevant estimation information:
	No text entered.

2. Secondary Outcome Measure: To evaluate the efficacy of inhaled AZD5423 180 µg delivered dose od versus placebo in COPD patients [ Time Frame: Baseline(week 0) and week 2 to 4 ]

Measure Type	Secondary
Measure Name	To evaluate the efficacy of inhaled AZD5423 180 µg delivered dose od versus placebo in COPD patients
Measure Description	Comparison of absolute change from baseline to mean of week 0 to 4 in pre-dose FEV1 between AZD5423 180 µg delivered dose od and placebo.
Time Frame	Baseline(week 0) and week 2 to 4
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.
On treatment analysis set: will include data from all randomised patients regardless of the treatment actually received. Excluded are patients that did not receive any dose of randomised treatment and discontinued the study.

Reporting Groups

	Description
AZD5423 180 ug + AZD5423 800 ug+ Formoterol 9ug bid + SABA prn
Placebo + formoterol 9ug bid + SABA prn

Measured Values

	AZD5423 180 ug + AZD5423 800 ug+ Formoterol 9ug bid + SABA prn	Placebo + formoterol 9ug bid + SABA prn
Number of Participants Analyzed [units:participants]	112	115
To evaluate the efficacy of inhaled AZD5423 180 µg delivered dose od versus placebo in COPD patients [units: Litre] Least Squares Mean (Standard Error)	0.025 (0.022)	0.002 (0.021)

Statistical Analysis 1 for To evaluate the efficacy of inhaled AZD5423 180 µg delivered dose od versus placebo in COPD patients

Groups^[1]	All groups
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	ANCOVA
P-Value^[4]	0.424
Mean Difference (Final Values)^[5]	0.023
95% Confidence Interval	( -0.03 to 0.08 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.
[5]	Other relevant estimation information:
	No text entered.

3. Secondary Outcome Measure: To evaluate the efficacy of inhaled AZD5423 800 µg delivered dose od compared with budesonide [ Time Frame: Baseline(week 0), and at week 8 to 12 ]

Measure Type	Secondary
Measure Name	To evaluate the efficacy of inhaled AZD5423 800 µg delivered dose od compared with budesonide
Measure Description	Comparison of absolute change from baseline to mean of week 8 to 12 in pre-dose FEV1 between AZD5423 800 µg delivered dose od and budesonide 320 μg bid.
Time Frame	Baseline(week 0), and at week 8 to 12
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.
On treatment analysis set: will include data from all randomised patients regardless of the treatment actually received. Excluded are patients that did not receive any dose of randomised treatment and discontinued the study.

Reporting Groups

	Description
AZD5423 180 ug + AZD5423 800 ug+ Formoterol 9ug bid + SABA prn
Budesonide 640 ug bid + Formoterol 9ug bid + SABA prn

Measured Values

	AZD5423 180 ug + AZD5423 800 ug+ Formoterol 9ug bid + SABA prn	Budesonide 640 ug bid + Formoterol 9ug bid + SABA prn
Number of Participants Analyzed [units:participants]	109	109
To evaluate the efficacy of inhaled AZD5423 800 µg delivered dose od compared with budesonide [units: Litre] Least Squares Mean (Standard Error)	-0.011 (0.023)	-0.004 (0.023)

Statistical Analysis 1 for To evaluate the efficacy of inhaled AZD5423 800 µg delivered dose od compared with budesonide

Groups^[1]	All groups
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	ANCOVA
P-Value^[4]	0.820
Mean Difference (Final Values)^[5]	-0.007
95% Confidence Interval	( -0.07 to 0.05 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.
[5]	Other relevant estimation information:
	No text entered.

4. Secondary Outcome Measure: To evaluate the pair-wise comparison between the treatment groups, an absolute change from baseline in post-dose FEV1 [ Time Frame: Baseline (week 0), Week 0 to 4 and Week 8 to 12 ]

Measure Type	Secondary
Measure Name	To evaluate the pair-wise comparison between the treatment groups, an absolute change from baseline in post-dose FEV1
Measure Description	Comparison of absolute change from baseline to mean of week 0 to week 4 and week 8 to 12 in pre-dose FEV1 between AZD5423 180 µg and 800 µg delivered dose od and budesonide 640 ug bid .
Time Frame	Baseline (week 0), Week 0 to 4 and Week 8 to 12
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.
On treatment analysis set: will include data from all randomised patients regardless of the treatment actually received. Excluded are patients that did not receive any dose of randomised treatment and discontinued the study.

Reporting Groups

	Description
AZD5423 180 ug + AZD5423 800 ug+ Formoterol 9ug bid + SABA prn
Placebo + formoterol 9ug bid + SABA prn
Budesonide 640 ug bid + Formoterol 9ug bid + SABA prn

Measured Values

	AZD5423 180 ug + AZD5423 800 ug+ Formoterol 9ug bid + SABA prn	Placebo + formoterol 9ug bid + SABA prn	Budesonide 640 ug bid + Formoterol 9ug bid + SABA prn
Number of Participants Analyzed [units:participants]	117	115	116
To evaluate the pair-wise comparison between the treatment groups, an absolute change from baseline in post-dose FEV1 [units: Liter] Least Squares Mean (Standard Error)
Week 8 to 12	0.13 (0.025)	0.13 (0.025)	0.16 (0.025)
Week 0 to 4	0.163 (0.017)	0.143 (0.017)	0.181 (0.017)
Week 0 to 4	0.163 (0.017)	0.143 (0.017)	0.181 (0.017)

Statistical Analysis 1 for To evaluate the pair-wise comparison between the treatment groups, an absolute change from baseline in post-dose FEV1

Groups^[1]	AZD5423 180 ug + AZD5423 800 ug+ Formoterol 9ug bid + SABA prn, Budesonide 640 ug bid + Formoterol 9ug bid + SABA prn
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	ANCOVA
P-Value^[4]	0.414
Mean Difference (Final Values)^[5]	-0.019
95% Confidence Interval	( -0.06 to 0.03 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Absolute change from baseline in post-dose FEV1 (L) at Week 0 to 4
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 2 for To evaluate the pair-wise comparison between the treatment groups, an absolute change from baseline in post-dose FEV1

Groups^[1]	AZD5423 180 ug + AZD5423 800 ug+ Formoterol 9ug bid + SABA prn, Placebo + formoterol 9ug bid + SABA prn
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	ANCOVA
P-Value^[4]	0.401
Mean Difference (Final Values)^[5]	0.019
95% Confidence Interval	( -0.03 to 0.06 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Absolute change from baseline in post-dose FEV1 (L) at Week 0 to 4
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 3 for To evaluate the pair-wise comparison between the treatment groups, an absolute change from baseline in post-dose FEV1

Groups^[1]	Placebo + formoterol 9ug bid + SABA prn, Budesonide 640 ug bid + Formoterol 9ug bid + SABA prn
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	ANCOVA
P-Value^[4]	0.099
Mean Difference (Final Values)^[5]	0.038
95% Confidence Interval	( -0.01 to 0.08 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Absolute change from baseline in post-dose FEV1 (L) at Week 0 to 4
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 4 for To evaluate the pair-wise comparison between the treatment groups, an absolute change from baseline in post-dose FEV1

Groups^[1]	AZD5423 180 ug + AZD5423 800 ug+ Formoterol 9ug bid + SABA prn, Budesonide 640 ug bid + Formoterol 9ug bid + SABA prn
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	ANCOVA
P-Value^[4]	0.288
Mean Difference (Final Values)^[5]	-0.03
95% Confidence Interval	( -0.10 to 0.03 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Absolute change from baseline in post-dose FEV1 (L) at Week 8 to 12
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 5 for To evaluate the pair-wise comparison between the treatment groups, an absolute change from baseline in post-dose FEV1

Groups^[1]	AZD5423 180 ug + AZD5423 800 ug+ Formoterol 9ug bid + SABA prn, Placebo + formoterol 9ug bid + SABA prn
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	ANCOVA
P-Value^[4]	0.970
Mean Difference (Final Values)^[5]	0.00
95% Confidence Interval	( -0.06 to 0.06 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Absolute change from baseline in post-dose FEV1 (L) at Week 8 to 12
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 6 for To evaluate the pair-wise comparison between the treatment groups, an absolute change from baseline in post-dose FEV1

Groups^[1]	Placebo + formoterol 9ug bid + SABA prn, Budesonide 640 ug bid + Formoterol 9ug bid + SABA prn
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	ANCOVA
P-Value^[4]	0.271
Mean Difference (Final Values)^[5]	0.04
95% Confidence Interval	( -0.03 to 0.10 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Absolute change from baseline in post-dose FEV1 (L) at Week 8 to 12
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.
[5]	Other relevant estimation information:
	No text entered.

5. Secondary Outcome Measure: To evaluate the pair-wise comparison between the treatment groups, an absolute change from baseline in pre-dose FVC [ Time Frame: Baseline (week 0), Week 2 to 4 and Week 8 to 12 ]

Measure Type	Secondary
Measure Name	To evaluate the pair-wise comparison between the treatment groups, an absolute change from baseline in pre-dose FVC
Measure Description	Comparison of absolute change from baseline to mean of week 0 to week 4 and week 8 to 12 in in pre-dose FVC between AZD5423 180 μg and AZD5423 800 μg delivered dose od and placebo.
Time Frame	Baseline (week 0), Week 2 to 4 and Week 8 to 12
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.
On treatment analysis set: will include data from all randomised patients regardless of the treatment actually received. Excluded are patients that did not receive any dose of randomised treatment and discontinued the study.

Reporting Groups

	Description
AZD5423 180 ug + AZD5423 800 ug+ Formoterol 9ug bid + SABA prn
Placebo + formoterol 9ug bid + SABA prn
Budesonide 640 ug bid + Formoterol 9ug bid + SABA prn

Measured Values

	AZD5423 180 ug + AZD5423 800 ug+ Formoterol 9ug bid + SABA prn	Placebo + formoterol 9ug bid + SABA prn	Budesonide 640 ug bid + Formoterol 9ug bid + SABA prn
Number of Participants Analyzed [units:participants]	112	115	116
To evaluate the pair-wise comparison between the treatment groups, an absolute change from baseline in pre-dose FVC [units: Liter] Least Squares Mean (Standard Error)
Week 2 to 4	-0.00 (0.037)	0.03 (0.037)	0.06 (0.036)
Week 8 to 12	-0.04 (0.038)	-0.01 (0.039)	0.00 (0.038)

Statistical Analysis 1 for To evaluate the pair-wise comparison between the treatment groups, an absolute change from baseline in pre-dose FVC

Groups^[1]	AZD5423 180 ug + AZD5423 800 ug+ Formoterol 9ug bid + SABA prn, Budesonide 640 ug bid + Formoterol 9ug bid + SABA prn
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	ANCOVA
P-Value^[4]	0.175
Mean Difference (Final Values)^[5]	-0.07
95% Confidence Interval	( -0.16 to 0.03 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Absolute change from baseline in pre-dose FVC (L) at Week 2 to 4
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 2 for To evaluate the pair-wise comparison between the treatment groups, an absolute change from baseline in pre-dose FVC

Groups^[1]	AZD5423 180 ug + AZD5423 800 ug+ Formoterol 9ug bid + SABA prn, Placebo + formoterol 9ug bid + SABA prn
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	ANCOVA
P-Value^[4]	0.511
Mean Difference (Final Values)^[5]	-0.03
95% Confidence Interval	( -0.13 to 0.06 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Absolute change from baseline in pre-dose FVC (L) at Week 2 to 4
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 3 for To evaluate the pair-wise comparison between the treatment groups, an absolute change from baseline in pre-dose FVC

Groups^[1]	Placebo + formoterol 9ug bid + SABA prn, Budesonide 640 ug bid + Formoterol 9ug bid + SABA prn
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	ANCOVA
P-Value^[4]	0.483
Mean Difference (Final Values)^[5]	0.03
95% Confidence Interval	( -0.06 to 0.13 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Absolute change from baseline in pre-dose FVC (L) at Week 2 to 4
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 4 for To evaluate the pair-wise comparison between the treatment groups, an absolute change from baseline in pre-dose FVC

Groups^[1]	AZD5423 180 ug + AZD5423 800 ug+ Formoterol 9ug bid + SABA prn, Budesonide 640 ug bid + Formoterol 9ug bid + SABA prn
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	ANCOVA
P-Value^[4]	0.405
Mean Difference (Final Values)^[5]	-0.04
95% Confidence Interval	( -0.14 to 0.06 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Absolute change from baseline in pre-dose FVC (L) at Week 8 to 12
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 5 for To evaluate the pair-wise comparison between the treatment groups, an absolute change from baseline in pre-dose FVC

Groups^[1]	AZD5423 180 ug + AZD5423 800 ug+ Formoterol 9ug bid + SABA prn, Placebo + formoterol 9ug bid + SABA prn
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	ANCOVA
P-Value^[4]	0.571
Mean Difference (Final Values)^[5]	-0.03
95% Confidence Interval	( -0.13 to 0.07 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Absolute change from baseline in pre-dose FVC (L) at Week 8 to 12
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 6 for To evaluate the pair-wise comparison between the treatment groups, an absolute change from baseline in pre-dose FVC

Groups^[1]	Placebo + formoterol 9ug bid + SABA prn, Budesonide 640 ug bid + Formoterol 9ug bid + SABA prn
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	ANCOVA
P-Value^[4]	0.791
Mean Difference (Final Values)^[5]	0.01
95% Confidence Interval	( -0.09 to 0.11 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Absolute change from baseline in pre-dose FVC (L) at Week 8 to 12
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.
[5]	Other relevant estimation information:
	No text entered.

6. Secondary Outcome Measure: To evaluate the pair-wise comparison between the treatment groups, an absolute change from baseline in post-dose FVC [ Time Frame: Baseline (week 0), Week 0 to 4 and Week 8 to 12 ]

Measure Type	Secondary
Measure Name	To evaluate the pair-wise comparison between the treatment groups, an absolute change from baseline in post-dose FVC
Measure Description	Comparison of absolute change from baseline to mean of week 0 to week 4 and week 8 to 12 in post-dose FVC between AZD5423 180 μg and AZD5423 800 μg delivered dose od and placebo.
Time Frame	Baseline (week 0), Week 0 to 4 and Week 8 to 12
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.
On treatment analysis set: will include data from all randomised patients regardless of the treatment actually received. Excluded are patients that did not receive any dose of randomised treatment and discontinued the study.

Reporting Groups

	Description
AZD5423 180 ug + AZD5423 800 ug+ Formoterol 9ug bid + SABA prn
Placebo + formoterol 9ug bid + SABA prn
Budesonide 640 ug bid + Formoterol 9ug bid + SABA prn

Measured Values

	AZD5423 180 ug + AZD5423 800 ug+ Formoterol 9ug bid + SABA prn	Placebo + formoterol 9ug bid + SABA prn	Budesonide 640 ug bid + Formoterol 9ug bid + SABA prn
Number of Participants Analyzed [units:participants]	117	115	116
To evaluate the pair-wise comparison between the treatment groups, an absolute change from baseline in post-dose FVC [units: Liter] Least Squares Mean (Standard Error)
Week 0 to 4	0.25 (0.031)	0.22 (0.032)	0.29 (0.032)
Week 8 to 12	0.21 (0.042)	0.20 (0.042)	0.25 (0.041)

Statistical Analysis 1 for To evaluate the pair-wise comparison between the treatment groups, an absolute change from baseline in post-dose FVC

Groups^[1]	AZD5423 180 ug + AZD5423 800 ug+ Formoterol 9ug bid + SABA prn, Budesonide 640 ug bid + Formoterol 9ug bid + SABA prn
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	ANCOVA
P-Value^[4]	0.334
Mean Difference (Final Values)^[5]	-0.04
95% Confidence Interval	( -0.12 to 0.04 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Absolute change from baseline in post-dose FVC (L) at Week 0 to 4
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 2 for To evaluate the pair-wise comparison between the treatment groups, an absolute change from baseline in post-dose FVC

Groups^[1]	AZD5423 180 ug + AZD5423 800 ug+ Formoterol 9ug bid + SABA prn, Placebo + formoterol 9ug bid + SABA prn
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	ANCOVA
P-Value^[4]	0.475
Mean Difference (Final Values)^[5]	0.03
95% Confidence Interval	( -0.05 to 0.11 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Absolute change from baseline in post-dose FVC (L) at Week 0 to 4
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 3 for To evaluate the pair-wise comparison between the treatment groups, an absolute change from baseline in post-dose FVC

Groups^[1]	Placebo + formoterol 9ug bid + SABA prn, Budesonide 640 ug bid + Formoterol 9ug bid + SABA prn
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	ANCOVA
P-Value^[4]	0.094
Mean Difference (Final Values)^[5]	0.07
95% Confidence Interval	( -0.01 to 0.15 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Absolute change from baseline in post-dose FVC (L) at Week 0 to 4
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 4 for To evaluate the pair-wise comparison between the treatment groups, an absolute change from baseline in post-dose FVC

Groups^[1]	AZD5423 180 ug + AZD5423 800 ug+ Formoterol 9ug bid + SABA prn, Budesonide 640 ug bid + Formoterol 9ug bid + SABA prn
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	ANCOVA
P-Value^[4]	0.565
Mean Difference (Final Values)^[5]	-0.03
95% Confidence Interval	( -0.14 to 0.08 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Absolute change from baseline in post-dose FVC (L) at Week 8 to 12
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 5 for To evaluate the pair-wise comparison between the treatment groups, an absolute change from baseline in post-dose FVC

Groups^[1]	AZD5423 180 ug + AZD5423 800 ug+ Formoterol 9ug bid + SABA prn, Placebo + formoterol 9ug bid + SABA prn
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	ANCOVA
P-Value^[4]	0.838
Mean Difference (Final Values)^[5]	0.01
95% Confidence Interval	( -0.10 to 0.12 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Absolute change from baseline in post-dose FVC (L) at Week 8 to 12
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 6 for To evaluate the pair-wise comparison between the treatment groups, an absolute change from baseline in post-dose FVC

Groups^[1]	Placebo + formoterol 9ug bid + SABA prn, Budesonide 640 ug bid + Formoterol 9ug bid + SABA prn
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	ANCOVA
P-Value^[4]	0.437
Mean Difference (Final Values)^[5]	0.04
95% Confidence Interval	( -0.06 to 0.15 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Absolute change from baseline in post-dose FVC (L) at Week 8 to 12
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.
[5]	Other relevant estimation information:
	No text entered.

7. Secondary Outcome Measure: Pharmacokinetics (PK) Profile of AZD5423 [ Time Frame: Week 4 and 12 ]

Measure Type	Secondary
Measure Name	Pharmacokinetics (PK) Profile of AZD5423
Measure Description	Summary of AUC(0-24h) of AZD5423 180 µg and 800 µg delivered dose od in subset of patients
Time Frame	Week 4 and 12
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.
PK analysis set: All patients with extended 24h PK blood sampling performed and with data sufficient to calculate pharmacokinetic parameters.

Reporting Groups

	Description
AZD5423 180 ug + AZD5423 800 ug+ Formoterol 9ug bid + SABA prn

Measured Values

	AZD5423 180 ug + AZD5423 800 ug+ Formoterol 9ug bid + SABA prn
Number of Participants Analyzed [units:participants]	54
Pharmacokinetics (PK) Profile of AZD5423 [units: nmol.h/L] Geometric Mean (Geometric Coefficient of Variation)
AZD5423 180ug OD (n=34)	4.26 (122.2%)
AZD5423 800ug OD (n=46)	12.09 (79.1%)

No statistical analysis provided for Pharmacokinetics (PK) Profile of AZD5423

8. Secondary Outcome Measure: Number of St George's Respiratory Questionnaire (SGRQ-C) responders [ Time Frame: Baseline(week 0), at week 4 and week 12 ]

Measure Type	Secondary
Measure Name	Number of St George's Respiratory Questionnaire (SGRQ-C) responders
Measure Description	Primary comparison will be the St George's Respiratory Questionnaire (SGRQ-C) responders at week 12
Time Frame	Baseline(week 0), at week 4 and week 12
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.
On treatment analysis set: will include data from all randomised patients regardless of the treatment actually received. Excluded are patients that did not receive any dose of randomised treatment and discontinued the study.

Reporting Groups

	Description
AZD5423 180 ug + AZD5423 800 ug+ Formoterol 9ug bid + SABA prn
Budesonide 640 ug bid + Formoterol 9ug bid + SABA prn
Placebo + formoterol 9ug bid + SABA prn

Measured Values

	AZD5423 180 ug + AZD5423 800 ug+ Formoterol 9ug bid + SABA prn	Budesonide 640 ug bid + Formoterol 9ug bid + SABA prn	Placebo + formoterol 9ug bid + SABA prn
Number of Participants Analyzed [units:participants]	117	116	115
Number of St George's Respiratory Questionnaire (SGRQ-C) responders [units: Score on a scale]
Improvement (change < -4 units)	45	56	50
No Change (> -4 to < 4)	42	34	31
Deterioration (>= 4 units)	19	19	26

No statistical analysis provided for Number of St George's Respiratory Questionnaire (SGRQ-C) responders

9. Secondary Outcome Measure: Assessment of Baseline/Transitional Dyspnea Index (BDI/TDI) Score [ Time Frame: Baseline(week 0), and at week 4 and 12 ]

Measure Type	Secondary
Measure Name	Assessment of Baseline/Transitional Dyspnea Index (BDI/TDI) Score
Measure Description	Descriptive Statistics for Baseline /Transitional Dyspnea Index (BDI/TDI) Score
Time Frame	Baseline(week 0), and at week 4 and 12
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.
On treatment analysis set: will include data from all randomised patients regardless of the treatment actually received. Excluded are patients that did not receive any dose of randomised treatment and discontinued the study

Reporting Groups

	Description
AZD5423 180 ug + AZD5423 800 ug+ Formoterol 9ug bid + SABA prn
Budesonide 640 ug bid + Formoterol 9ug bid + SABA prn
Placebo + formoterol 9ug bid + SABA prn

Measured Values

	AZD5423 180 ug + AZD5423 800 ug+ Formoterol 9ug bid + SABA prn	Budesonide 640 ug bid + Formoterol 9ug bid + SABA prn	Placebo + formoterol 9ug bid + SABA prn
Number of Participants Analyzed [units:participants]	117	116	115
Assessment of Baseline/Transitional Dyspnea Index (BDI/TDI) Score [units: Score on a scale] Mean (Standard Deviation)
Baseline	6.56 (1.632)	6.40 (1.667)	6.30 (1.696)
Week 4	0.41 (2.928)	1.10 (2.304)	0.64 (2.860)
Week 12	1.16 (2.954)	1.54 (2.665)	0.69 (2.679)

No statistical analysis provided for Assessment of Baseline/Transitional Dyspnea Index (BDI/TDI) Score

10. Secondary Outcome Measure: Assessment of Breathlessness, Cough and Sputum Scale (Total BCSS) Score [ Time Frame: week 0 to week 12; Daily by eDairy ]

Measure Type	Secondary
Measure Name	Assessment of Breathlessness, Cough and Sputum Scale (Total BCSS) Score
Measure Description	Summary of Treatment comparison for eDiary mean total BCSS scale (Breathlessness, Cough and Sputum Scale) variable at Week 0 to 4 and Week 5 to 12
Time Frame	week 0 to week 12; Daily by eDairy
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.
On treatment analysis set: will include data from all randomised patients regardless of the treatment actually received. Excluded are patients that did not receive any dose of randomised treatment and discontinued the study

Reporting Groups

	Description
AZD5423 180 ug + AZD5423 800 ug+ Formoterol 9ug bid + SABA prn
Budesonide 640 ug bid + Formoterol 9ug bid + SABA prn
Placebo + formoterol 9ug bid + SABA prn

Measured Values

	AZD5423 180 ug + AZD5423 800 ug+ Formoterol 9ug bid + SABA prn	Budesonide 640 ug bid + Formoterol 9ug bid + SABA prn	Placebo + formoterol 9ug bid + SABA prn
Number of Participants Analyzed [units:participants]	117	116	115
Assessment of Breathlessness, Cough and Sputum Scale (Total BCSS) Score [units: Score on a scale] Mean (Standard Deviation)
Baseline	4.03 (2.027)	3.64 (1.948)	3.96 (1.727)
Mean(week 5-12)	3.76 (1.999)	3.45 (2.004)	3.79 (1.841)
Mean(week 0-4)	3.78 (1.899)	3.44 (1.982)	3.73 (1.697)

Statistical Analysis 1 for Assessment of Breathlessness, Cough and Sputum Scale (Total BCSS) Score

Groups^[1]	AZD5423 180 ug + AZD5423 800 ug+ Formoterol 9ug bid + SABA prn, Budesonide 640 ug bid + Formoterol 9ug bid + SABA prn
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	ANCOVA
P-Value^[4]	0.777
Mean Difference (Final Values)^[5]	0.04
95% Confidence Interval	( -0.23 to 0.31 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Summary of Treatment comparison for eDiary variable: mean Total BCSS Score at week 0 to week 4
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 2 for Assessment of Breathlessness, Cough and Sputum Scale (Total BCSS) Score

Groups^[1]	AZD5423 180 ug + AZD5423 800 ug+ Formoterol 9ug bid + SABA prn, Placebo + formoterol 9ug bid + SABA prn
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	ANCOVA
P-Value^[4]	0.943
Mean Difference (Final Values)^[5]	0.01
95% Confidence Interval	( -0.26 to 0.28 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Summary of Treatment comparison for eDiary variable: mean Total BCSS Score at week 0 to week 4
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 3 for Assessment of Breathlessness, Cough and Sputum Scale (Total BCSS) Score

Groups^[1]	Budesonide 640 ug bid + Formoterol 9ug bid + SABA prn, Placebo + formoterol 9ug bid + SABA prn
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	ANCOVA
P-Value^[4]	0.832
Mean Difference (Final Values)^[5]	-0.03
95% Confidence Interval	( -0.30 to 0.24 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Summary of Treatment comparison for eDiary variable: mean Total BCSS Score at week 0 to week 4
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 4 for Assessment of Breathlessness, Cough and Sputum Scale (Total BCSS) Score

Groups^[1]	AZD5423 180 ug + AZD5423 800 ug+ Formoterol 9ug bid + SABA prn, Budesonide 640 ug bid + Formoterol 9ug bid + SABA prn
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	ANCOVA
P-Value^[4]	0.672
Mean Difference (Final Values)^[5]	0.08
95% Confidence Interval	( -0.28 to 0.43 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Summary of Treatment comparison for eDiary variable: mean Total BCSS Score at week 5 to week 12
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 5 for Assessment of Breathlessness, Cough and Sputum Scale (Total BCSS) Score

Groups^[1]	AZD5423 180 ug + AZD5423 800 ug+ Formoterol 9ug bid + SABA prn, Placebo + formoterol 9ug bid + SABA prn
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	ANCOVA
P-Value^[4]	0.836
Mean Difference (Final Values)^[5]	0.04
95% Confidence Interval	( -0.32 to 0.39 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Summary of Treatment comparison for eDiary variable: mean Total BCSS Score at week 5 to week 12
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 6 for Assessment of Breathlessness, Cough and Sputum Scale (Total BCSS) Score

Groups^[1]	Budesonide 640 ug bid + Formoterol 9ug bid + SABA prn, Placebo + formoterol 9ug bid + SABA prn
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	ANCOVA
P-Value^[4]	0.827
Mean Difference (Final Values)^[5]	-0.04
95% Confidence Interval	( -0.39 to 0.31 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Summary of Treatment comparison for eDiary variable: mean Total BCSS Score at week 5 to week 12
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.
[5]	Other relevant estimation information:
	No text entered.

11. Secondary Outcome Measure: Time to exacerbation [ Time Frame: Randomisation to Follow-up ]

Measure Type	Secondary
Measure Name	Time to exacerbation
Measure Description
Time Frame	Randomisation to Follow-up
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.
On treatment analysis set: will include data from all randomised patients regardless of the treatment actually received. Excluded are patients that did not receive any dose of randomised treatment and discontinued the study.

Reporting Groups

	Description
AZD5423 180 ug + AZD5423 800 ug+ Formoterol 9ug bid + SABA prn
Placebo + formoterol 9ug bid + SABA prn
Budesonide 640 ug bid + Formoterol 9ug bid + SABA prn

Measured Values

	AZD5423 180 ug + AZD5423 800 ug+ Formoterol 9ug bid + SABA prn	Placebo + formoterol 9ug bid + SABA prn	Budesonide 640 ug bid + Formoterol 9ug bid + SABA prn
Number of Participants Analyzed [units:participants]	117	115	116
Time to exacerbation [units: Participants]
Patients with at least one exacerbation	5	6	6
Total of exacerbations	5	8	7
1 exacerbation	5	5	5
2 exacerbations	0	0	1
3 exacerbations	0	1	0

No statistical analysis provided for Time to exacerbation

12. Secondary Outcome Measure: Pharmacokinetics (PK) Profile of AZD5423 [ Time Frame: Week 4 and 12 ]

Measure Type	Secondary
Measure Name	Pharmacokinetics (PK) Profile of AZD5423
Measure Description	Summary of Cmax of AZD5423 180 µg and 800 µg delivered dose od in subset of patients
Time Frame	Week 4 and 12
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.
PK analysis set: All patients with extended 24h PK blood sampling performed and with data sufficient to calculate pharmacokinetic parameters.

Reporting Groups

	Description
AZD5423 180 ug + AZD5423 800 ug+ Formoterol 9ug bid + SABA prn

Measured Values

	AZD5423 180 ug + AZD5423 800 ug+ Formoterol 9ug bid + SABA prn
Number of Participants Analyzed [units:participants]	54
Pharmacokinetics (PK) Profile of AZD5423 [units: nmol.h/L] Geometric Mean (Geometric Coefficient of Variation)
AZD5423 180ug OD (n=44)	0.76 (193.7%)
AZD5423 800ug OD (n=50)	2.37 (98.1%)

No statistical analysis provided for Pharmacokinetics (PK) Profile of AZD5423

Serious Adverse Events

Time Frame	Adverse Events (AEs) will be collected from time of signature of informed consent throughout the treatment periods and including the follow-up period
Additional Description	No text entered.

Reporting Groups

	Description
AZD5423 180 ug + AZD5423 800 ug+ Formoterol 9ug bid + SABA prn	No text entered.
Budesonide 640 ug bid + Formoterol 9ug bid + SABA prn	No text entered.
Placebo + formoterol 9ug bid + SABA prn	No text entered.

Serious Adverse Events

AZD5423 180 ug + AZD5423 800 ug+ Formoterol 9ug bid + SABA prn

Budesonide 640 ug bid + Formoterol 9ug bid + SABA prn

Placebo + formoterol 9ug bid + SABA prn

Total, serious adverse events

# participants affected / at risk

3/117 (2.56%)

3/116 (2.59%)

4/115 (3.48%)

Cardiac disorders

Atrial fibrillation¹,^†

# participants affected / at risk

0/117 (0.00%)

0/116 (0.00%)

1/115 (0.87%)

# events

Cardiac disorders

Atrial flutter¹,^†

# participants affected / at risk

0/117 (0.00%)

1/116 (0.86%)

1/115 (0.87%)

# events

Cardiac disorders

Cardiac failure acute¹,^†

# participants affected / at risk

1/117 (0.85%)

0/116 (0.00%)

0/115 (0.00%)

# events

Cardiac disorders

Coronary artery stenosis¹,^†

# participants affected / at risk

0/117 (0.00%)

0/116 (0.00%)

1/115 (0.87%)

# events

Gastrointestinal disorders

Pancreatitis acute¹,^†

# participants affected / at risk

0/117 (0.00%)

1/116 (0.86%)

0/115 (0.00%)

# events

Hepatobiliary disorders

Drug-induced liver injury¹,^†

# participants affected / at risk

0/117 (0.00%)

0/116 (0.00%)

1/115 (0.87%)

# events

Infections and infestations

Lower respiratory tract infection¹,^†

# participants affected / at risk

1/117 (0.85%)

0/116 (0.00%)

0/115 (0.00%)

# events

Infections and infestations

Pneumonia¹,^†

# participants affected / at risk

1/117 (0.85%)

0/116 (0.00%)

0/115 (0.00%)

# events

Investigations

Alanine aminotransferase increased¹,^†

# participants affected / at risk

0/117 (0.00%)

0/116 (0.00%)

1/115 (0.87%)

# events

Investigations

Aspartate aminotransferase increased¹,^†

# participants affected / at risk

0/117 (0.00%)

0/116 (0.00%)

1/115 (0.87%)

# events

Investigations

Electrocardiogram T wave inversion¹,^†

# participants affected / at risk

0/117 (0.00%)

1/116 (0.86%)

0/115 (0.00%)

# events

Investigations

Hepatic enzyme increased¹,^†

# participants affected / at risk

0/117 (0.00%)

0/116 (0.00%)

1/115 (0.87%)

# events

Musculoskeletal and connective tissue disorders

Arthralgia¹,^†

# participants affected / at risk

1/117 (0.85%)

0/116 (0.00%)

0/115 (0.00%)

# events

Musculoskeletal and connective tissue disorders

Musculoskeletal chest pain¹,^†

# participants affected / at risk

1/117 (0.85%)

0/116 (0.00%)

0/115 (0.00%)

# events

Nervous system disorders

Ischaemic stroke¹,^†

# participants affected / at risk

0/117 (0.00%)

0/116 (0.00%)

1/115 (0.87%)

# events

Respiratory, thoracic and mediastinal disorders

Laryngeal oedema¹,^†

# participants affected / at risk

1/117 (0.85%)

0/116 (0.00%)

0/115 (0.00%)

# events

†	Events were collected by systematic assessment
1	Term from vocabulary, MedDRA 15.1

Other Adverse Events

Time Frame	Adverse Events (AEs) will be collected from time of signature of informed consent throughout the treatment periods and including the follow-up period
Additional Description	No text entered.

Frequency Threshold

Threshold above which other adverse events are reported	5%

Reporting Groups

	Description
AZD5423 180 ug + AZD5423 800 ug+ Formoterol 9ug bid + SABA prn	No text entered.
Budesonide 640 ug bid + Formoterol 9ug bid + SABA prn	No text entered.
Placebo + formoterol 9ug bid + SABA prn	No text entered.

Other Adverse Events

AZD5423 180 ug + AZD5423 800 ug+ Formoterol 9ug bid + SABA prn

Budesonide 640 ug bid + Formoterol 9ug bid + SABA prn

Placebo + formoterol 9ug bid + SABA prn

Total, other (not including serious) adverse events

# participants affected / at risk

10/117 (8.55%)

12/116 (10.34%)

11/115 (9.57%)

Nervous system disorders

Headache¹,^†

# participants affected / at risk

5/117 (4.27%)

7/116 (6.03%)

6/115 (5.22%)

# events

Respiratory, thoracic and mediastinal disorders

Chronic obstructive pulmonary disease¹,^†

# participants affected / at risk

5/117 (4.27%)

6/116 (5.17%)

5/115 (4.35%)

# events

†	Events were collected by systematic assessment
1	Term from vocabulary, MedDRA 15.1

Certain Agreements

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

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

The agreement is:

	The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
	The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days . The sponsor cannot require changes to the communication and cannot extend the embargo.
	Other disclosure agreement that restricts the right of the PI to discuss or publish trial results after the trial is completed. Restriction Description: Study results may be used only for internal research, educational or patient care purposes and can’t be publish before the first Study results publication by AstraZeneca or end of 18 month after Study completion. Any material should be provided for AstraZeneca review. AstraZeneca can withhold material from any use for an additional ninety (90) days to allow for the patent application filing or preserving its proprietary rights in the information.

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:	Carin Jorup, Medical Science Director
Organization:	AstraZeneca
Phone	+46 31 7761000
E-mail:	[email protected]

Documents available

CSR synopsis
Download
Trial Results Summaries
Available here

Contacts

Contact

AstraZeneca Clinical Study Information

800-236-9933

ClinicalTrialTransparency@astrazeneca.com

Investigators

Principal Investigator

Piotr Kuna

Uniwersytecki Szpital Kliniczny nr 1 im. N. Barlickiego w Łodzi, ul. Kopcińskiego 22, 90-153, Łódź, Poland

Sponsors

Collaborators

Inclusion Criteria

Exclusion Criteria

Research Site

Research Site

Research Site

Research Site

Research Site

Research Site

Research Site

Research Site

CSR synopsis

Trial Results Summaries