A study to assess the safety, tolerability and pharmacokinetics of AZD7594 inhaled formulation in healthy Japanese men

Study identifier:D3741C00005

ClinicalTrials.gov identifier:NCT02645253

EudraCT identifier:N/A

CTIS identifier:N/A

Study Complete

Official Title

A phase I, randomized, single-blind, placebo-controlled, sequential-group, single-center study to investigate the safety, tolerability, pharmacokinetics and pharmacodynamics of single and multiple ascending doses of AZD7594 given once daily as inhaled formulation in healthy Japanese men

Medical condition

asthma

Phase

Phase 1

Healthy volunteers

Yes

Study drug

AZD7594 inhalation powder (200 μg), AZD7594 inhalation powder (400 μg), AZD7594 pressurized inhalation suspension (200 μg), AZD7594 placebo inhalation powder, AZD7594 placebo pressurized inhalation suspension

Sex

Male

Actual Enrollment

Study type

Interventional

Age

20 Years - 45 Years

Date

Study Start Date: 12 Jan 2016

Primary Completion Date: 17 Apr 2016

Study Completion Date: 17 Apr 2016

Study design

Allocation: Randomized
Endpoint Classification: Safety
Intervention Model: Parallel Assignment
Masking: Single Blind
Primary Purpose: Basic Science

Verification:

Verified 01 Aug 2017 by AstraZeneca

Collaborators

Inclusion and exclusion criteria

Inclusion Criteria

1. Provision of signed and dated, written informed consent prior to any study specific procedures.
2. Healthy male Japanese subjects aged 20 to 45 years with suitable veins for cannulation or repeated venipuncture.
A Japanese male subject is defined as being born in Japan, having both parents and four grandparents who are Japanese. The subject must not have lived outside of Japan for more than 5 years.
3. Have a body mass index (BMI) between 18 and 30 kg/m2 inclusive and weigh at least 45 kg and no more than 100 kg inclusive.
4. Provision of signed, written and dated informed consent for optional genetic research
Note: If a subject declines to participate in the genetic component of the study, there will be no penalty or loss of benefit to the subject. The subject will not be excluded from other aspects of the study described in this protocol.

Exclusion Criteria

1. History of any clinically significant disease or disorder which, in the opinion of the investigator, may either put the subject at risk because of participation in the study, or influence the results or the subject’s ability to participate in the study.
2. History or presence of gastrointestinal (GI), hepatic or renal disease, or any other condition known to interfere with absorption, distribution, metabolism, or excretion of drugs.
3. Any clinically significant illness, medical/surgical procedure, or trauma within 4 weeks of the first administration of investigational drug administration.
4. Any contraindication against the use of vagolytic or sympaticomimetic drugs, as judged by the investigator.
5. Any clinically significant abnormalities in clinical chemistry, hematology, urinalysis, physical examination, vital signs, electrocardiogram (ECG) or lung function results at baseline, as judged by the investigator.
6. Known Gilbert’s syndrome, family history of Gilbert’s syndrome or suspicion of Gilbert’s syndrome based on liver function tests.
7. Use of systemic glucocorticosteroids within 6 weeks of enrollment.
8. Any positive result on screening for serum hepatitis B surface antigen (HBsAg), hepatitis C antibody and human immunodeficiency virus (HIV).
9. Known or suspected hypersensitivity to investigational product or excipients.
10. Plasma donation within one month of screening or any blood donation/blood loss > 500 mL during the 3 months prior to screening.
11. Abnormal vital signs, after 10 minutes supine rest, defined as any of the following:
• Systolic blood pressure (BP) < 90mmHg or > 140 mmHg
• Diastolic BP < 60mmHg or > 90 mmHg
• Pulse rate < 40 or > 85 beats per minute (bpm)
12. Any clinically significant abnormalities in rhythm, conduction or morphology of the resting ECG and any clinically significant abnormalities in the 12-lead ECG, as considered by the investigator that may interfere with the interpretation of QTc interval changes, including abnormal ST-T-wave morphology, particularly in the protocol defined primary lead or left ventricular hypertrophy.
13. Prolonged QT interval corrected for heart rate (HR) using Fridericia's formula (QTcF) > 450 ms or family history of long QT syndrome.
14. PR(PQ) interval shortening < 120 ms (PR > 110 ms but < 120 ms is acceptable if there is no evidence of ventricular pre-excitation).
15. PR (PQ) interval prolongation (> 240 ms) intermittent second (Wenckebach block while asleep is not exclusive) or third degree AV block, or AV dissociation.
16. Persistent or intermittent complete bundle branch block (BBB), incomplete bundle branch block (IBBB), or intraventricular conduction delay (IVCD) with QRS > 110 ms. Subjects with QRS > 110 ms but < 115 ms are acceptable if there is no evidence of, for example, ventricular hypertrophy or pre-excitation.
17. Known or suspected history of drug abuse, as judged by the investigator.
18. Current smokers or those who have smoked or used nicotine products within the previous 3 months.
19. History of alcohol abuse or excessive intake of alcohol, as judged by the investigator.
20. Positive screen for drugs of abuse or cotinine (nicotine) at screening or admission to the unit.
21. History of severe allergy/hypersensitivity or ongoing clinically significant allergy/hypersensitivity, as judged by the investigator or history of hypersensitivity to drugs with a similar chemical structure or class to ADZ7594.
22. Excessive intake of caffeine containing drinks or food (e.g., coffee, tea, chocolate), as judged by the investigator.
23. Use of drugs with enzyme inducing properties such as St John’s Wort within 3 weeks prior to the first administration of investigational drug.
24. Use of any prescribed or non-prescribed medication including antacids, analgesics (other than paracetamol/acetaminophen), herbal remedies, megadose vitamins (intake of 20 to 600 times the recommended daily dose) and minerals during the 2 weeks prior to the first administration of investigational drug or longer if the medication has a long half-life.
25. Has received another new chemical entity (defined as a compound which has not been approved for marketing in the US) within 30 days or at least 5 half-lives (whichever is longer) of the first administration of investigational drug in this study. The period of exclusion begins 3 months after the final dose or 1 month after the last visit whichever is the longest.
Note: Subjects consented and screened, but not randomized in this study or a previous phase I study, are not excluded.
26. Vulnerable subjects, e.g., kept in detention, protected adults under guardianship, trusteeship, or committed to an institution by governmental or juridical order.
27. Subjects who have previously received AZD7594.
28. Involvement of any Astra Zeneca or study site employee or their close relatives.
29. Judgment by the investigator that the subject should not participate in the study if they have any ongoing or recent (i.e., during the screening period) minor medical complaints that may interfere with the interpretation of study data or are considered unlikely to comply with study procedures, restrictions and requirements.
30. Subjects who are vegans or have medical dietary restrictions.
31. Subjects who cannot communicate reliably with the investigator. It is acceptable to make use of an interpreter. The informed consent document (ICD) must be available in the Japanese language.
In addition, any of the following is regarded as a criterion for exclusion from the genetic research:
32. Previous bone marrow transplant.
33. Non-leukocyte depleted whole blood transfusion within 120 days of the date of the genetic sample collection

Location

Research Site

Glendale, CA, United States, 91206

Arms	Assigned Interventions
Experimental: Cohort 1 AZD7594 inhalation powder (200 μg) or AZD7594 placebo inhalation powder via multi-dose dry powder inhaler (DPI)	Drug: AZD7594 inhalation powder (200 μg) 200 μg AZD7594 inhalation powder via multi-dose dry powder inhaler (DPI) Drug: AZD7594 placebo inhalation powder AZD7594 placebo inhalation powder via multi-dose DPI
Experimental: Cohort 2 AZD7594 inhalation powder (400 μg) or AZD7594 placebo inhalation powder via multi-dose dry powder inhaler (DPI)	Drug: AZD7594 inhalation powder (400 μg) Cohort 2: 400 μg AZD7594 inhalation powder via multi-dose DPI Cohort 3: 1600 μg (4 x 400 μg inhalations) AZD7594 inhalation powder via multi-dose DPI Drug: AZD7594 placebo inhalation powder AZD7594 placebo inhalation powder via multi-dose DPI
Experimental: Cohort 3 1600 μg AZD7594 inhalation powder (4 x 400 μg) or AZD7594 placebo inhalation powder via multi-dose dry powder inhaler (DPI)	Drug: AZD7594 inhalation powder (400 μg) Cohort 2: 400 μg AZD7594 inhalation powder via multi-dose DPI Cohort 3: 1600 μg (4 x 400 μg inhalations) AZD7594 inhalation powder via multi-dose DPI Drug: AZD7594 placebo inhalation powder AZD7594 placebo inhalation powder via multi-dose DPI
Experimental: Cohort 4 400 μg AZD7594 pressurized inhalation suspension (2 x 200 μg inhalations) or placebo pressurized inhalation suspension via pressurized metered dose inhaler (pMDI)	Drug: AZD7594 pressurized inhalation suspension (200 μg) 400 μg (2 x 200 μg inhalations) AZD7594 pressurized inhalation suspension via pressurized metered dose inhaler (pMDI) Drug: AZD7594 placebo pressurized inhalation suspension AZD7594 placebo pressurized inhalation suspension via pressurized metered dose inhaler (pMDI)

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 PAREXEL Early Phase Clinical Unit – Los Angeles

Pre-Assignment Details

Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
Twenty-seven participants were randomized in 3 sequential cohorts. Each cohort consisted of nine participants in it. Within each cohort, 7 participants were randomly assigned to receive AZD7594 (different doses) and 2 subjects were randomly assigned to receive placebo.

Reporting Groups

	Description
AZD7594 200 μg	Participants received 200 μg inhaled AZD7594 via multi-dose dry powder inhaler (DPI) (1 x 200 μg inhalation)
AZD7594 400 μg	Participants received 400 μg inhaled AZD7594 via multi-dose DPI (1 x 400 μg inhalation)
AZD7594 1600 μg	Participants received 1600 μg inhaled AZD7594 via multi-dose DPI (4 x 400 μg inhalations).
Palcebo	Participants received placebo

Participant Flow: Overall Study

	AZD7594 200 μg	AZD7594 400 μg	AZD7594 1600 μg	Palcebo
STARTED	7	7	7	6
COMPLETED	7	7	7	6
NOT COMPLETED	0	0	0	0

Baseline Characteristics

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

Twenty-seven subjects in total were randomized to this study, 6 subjects received placebo and 21 subjects received AZD7594. All randomized subjects received treatment and completed the study.

Reporting Groups

	Description
AZD7594 200 μg	Participants received 200 μg inhaled AZD7594 via multi-dose dry powder inhaler (DPI) (1 x 200 μg inhalation)
AZD7594 400 μg	Participants received 400 μg inhaled AZD7594 via multi-dose DPI (1 x 400 μg inhalation)
AZD7594 1600 μg	Participants received 1600 μg inhaled AZD7594 via multi-dose DPI (4 x 400 μg inhalations).
Palcebo	Participants received placebo

Baseline Measures

	AZD7594 200 μg	AZD7594 400 μg	AZD7594 1600 μg	Palcebo	Total
Number of Participants [units: Participants]	7	7	7	6	27
Gender, Male/Female [units: Participants]
Female	0	0	0	0	0
Male	7	7	7	6	27
Age Continuous [units: Years] Mean ± Standard Deviation	32.7 ± 5.41	34.1 ± 6.41	33.6 ± 6.43	35.7 ± 5.54	34.0 ± 5.73

Outcome Measures

1. Primary Outcome Measure: Safety and tolerability of AZD7594 by assessment of the number of participants with adverse events [ Time Frame: At screening (Day -28, Day -02 and Day -1), Treatment period (Days 1 to 20) and Follow-up (Day 29). ]

Measure Type	Primary
Measure Name	Safety and tolerability of AZD7594 by assessment of the number of participants with adverse events
Measure Description	To assess the safety and tolerability of single and multiple doses of AZD7594
Time Frame	At screening (Day -28, Day -02 and Day -1), Treatment period (Days 1 to 20) and Follow-up (Day 29).
Safety Issue?	Yes

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
All subjects who received at least one dose of IMP and for whom any post-dose data were available were included in the safety analysis set.

Reporting Groups

	Description
AZD7594 200 μg	Participants received 200 μg inhaled AZD7594 via multi-dose dry powder inhaler (DPI) (1 x 200 μg inhalation)
AZD7594 400 μg	Participants received 400 μg inhaled AZD7594 via multi-dose DPI (1 x 400 μg inhalation)
AZD7594 1600 μg	Participants received 1600 μg inhaled AZD7594 via multi-dose DPI (4 x 400 μg inhalations).
Total AZD7594	Overall number of participants who received treatment with AZD7594.
Placebo	Participants who received placebo.
All subjects	Total number of participants in the study.

Measured Values

	AZD7594 200 μg	AZD7594 400 μg	AZD7594 1600 μg	Total AZD7594	Placebo	All subjects
Number of Participants Analyzed [units:participants]	7	7	7	21	6	27
Safety and tolerability of AZD7594 by assessment of the number of participants with adverse events [units: Pariticpants]
Any AE	3	1	1	5	1	6
Any AE with outcome = death	0	0	0	0	0	0
Any SAE including events with outcome =death	0	0	0	0	0	0
Any AE leading to discontinuation of IP	0	0	0	0	0	0

No statistical analysis provided for Safety and tolerability of AZD7594 by assessment of the number of participants with adverse events

2. Secondary Outcome Measure: Rate and extent of absorption of AZD7594 (Inhalation/ administration via DPI) by assessment of the observed maximum plasma concentration (Cmax) [ Time Frame: Day 1: pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72 and 96 hours post-dose. ]

Measure Type	Secondary
Measure Name	Rate and extent of absorption of AZD7594 (Inhalation/ administration via DPI) by assessment of the observed maximum plasma concentration (Cmax)
Measure Description	Assessment of the plasma PK following a single dose of AZD7594. Cmax was defined as observed maximum plasma concentration, taken directly from the individual concentration-time curve.
Time Frame	Day 1: pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72 and 96 hours post-dose.
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The pharmacokinetic (PK) analysis set consisted of all subjects in the safety analysis set who received AZD7594 and had at least 1 measured AZD7594 plasma concentration at a scheduled PK time point post-dose, with no major protocol deviations thought to impact on the analysis of the PK data.

Reporting Groups

	Description
AZD7594 200 μg	Participants received 200 μg inhaled AZD7594 via multi-dose dry powder inhaler (DPI) (1 x 200 μg inhalation)
AZD7594 400 μg	Participants received 400 μg inhaled AZD7594 via multi-dose DPI (1 x 400 μg inhalation)
AZD7594 1600 μg	Participants received 1600 μg inhaled AZD7594 via multi-dose DPI (4 x 400 μg inhalations).

Measured Values

	AZD7594 200 μg	AZD7594 400 μg	AZD7594 1600 μg
Number of Participants Analyzed [units:participants]	7	7	7
Rate and extent of absorption of AZD7594 (Inhalation/ administration via DPI) by assessment of the observed maximum plasma concentration (Cmax) [units: pmol/L] Geometric Mean (Geometric Coefficient of Variation)	56.05 (22.0%)	76.93 (34.4%)	430.8 (22.4%)

Statistical Analysis 1 for Rate and extent of absorption of AZD7594 (Inhalation/ administration via DPI) by assessment of the observed maximum plasma concentration (Cmax)

Groups^[1]	All groups
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	Other [Linear Model]
Slope^[5]	1.02
Standard Error of the mean	± 0.0785
90% Confidence Interval	( 0.882 to 1.15 )

[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.
[5]	Other relevant estimation information:
	No text entered.

3. Secondary Outcome Measure: Rate and extent of absorption of AZD7594 (Inhalation/ administration via DPI) by assessment of the time to reach maximum plasma concentration (tmax) [ Time Frame: Day 1: pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72 and 96 hours post-dose. ]

Measure Type	Secondary
Measure Name	Rate and extent of absorption of AZD7594 (Inhalation/ administration via DPI) by assessment of the time to reach maximum plasma concentration (tmax)
Measure Description	Assessment of the plasma PK following a single dose of AZD7594. tmax was defined as time to reach maximum plasma concentration, taken directly from the individual concentration-time curve.
Time Frame	Day 1: pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72 and 96 hours post-dose.
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The PK analysis set consisted of all subjects in the safety analysis set who received AZD7594 and had at least 1 measured AZD7594 plasma concentration at a scheduled PK time point post-dose, with no major protocol deviations thought to impact on the analysis of the PK data.

Reporting Groups

	Description
AZD7594 200 μg	Participants received 200 μg inhaled AZD7594 via multi-dose dry powder inhaler (DPI) (1 x 200 μg inhalation)
AZD7594 400 μg	Participants received 400 μg inhaled AZD7594 via multi-dose DPI (1 x 400 μg inhalation)
AZD7594 1600 μg	Participants received 1600 μg inhaled AZD7594 via multi-dose DPI (4 x 400 μg inhalations).

Measured Values

	AZD7594 200 μg	AZD7594 400 μg	AZD7594 1600 μg
Number of Participants Analyzed [units:participants]	7	7	7
Rate and extent of absorption of AZD7594 (Inhalation/ administration via DPI) by assessment of the time to reach maximum plasma concentration (tmax) [units: Hours] Median (Full Range)	0.25 (0.25 to 0.98)	0.52 (0.25 to 3.00)	0.50 (0.25 to 4.00)

No statistical analysis provided for Rate and extent of absorption of AZD7594 (Inhalation/ administration via DPI) by assessment of the time to reach maximum plasma concentration (tmax)

4. Secondary Outcome Measure: Rate and extent of absorption of AZD7594 (Inhalation/ administration via DPI) by assessment of the area under the plasma concentration-time curve (AUC) from time zero to the time of last quantifiable analyte concentration (AUC [0-last]) [ Time Frame: Day 1: pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72 and 96 hours post-dose ]

Measure Type	Secondary
Measure Name	Rate and extent of absorption of AZD7594 (Inhalation/ administration via DPI) by assessment of the area under the plasma concentration-time curve (AUC) from time zero to the time of last quantifiable analyte concentration (AUC [0-last])
Measure Description	Assessment of the plasma PK following a single dose of AZD7594. AUC (0-last) was defined as the area under the plasma concentration-time curve from time zero to the time of last quantifiable analyte concentration.
Time Frame	Day 1: pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72 and 96 hours post-dose
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The PK analysis set consisted of all subjects in the safety analysis set who received AZD7594 and had at least 1 measured AZD7594 plasma concentration at a scheduled PK time point post-dose, with no major protocol deviations thought to impact on the analysis of the PK data.

Reporting Groups

	Description
AZD7594 200 μg	Participants received 200 μg inhaled AZD7594 via multi-dose dry powder inhaler (DPI) (1 x 200 μg inhalation)
AZD7594 400 μg	Participants received 400 μg inhaled AZD7594 via multi-dose DPI (1 x 400 μg inhalation)
AZD7594 1600 μg	Participants received 1600 μg inhaled AZD7594 via multi-dose DPI (4 x 400 μg inhalations).

Measured Values

	AZD7594 200 μg	AZD7594 400 μg	AZD7594 1600 μg
Number of Participants Analyzed [units:participants]	7	7	7
Rate and extent of absorption of AZD7594 (Inhalation/ administration via DPI) by assessment of the area under the plasma concentration-time curve (AUC) from time zero to the time of last quantifiable analyte concentration (AUC [0-last]) [units: h*pmol/L] Geometric Mean (Geometric Coefficient of Variation)	1314 (28.2%)	2736 (12.2%)	13960 (18.2%)

Statistical Analysis 1 for Rate and extent of absorption of AZD7594 (Inhalation/ administration via DPI) by assessment of the area under the plasma concentration-time curve (AUC) from time zero to the time of last quantifiable analyte concentration (AUC [0-last])

Groups^[1]	All groups
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	Other [Linear Model]
Slope^[5]	1.14
Standard Error of the mean	± 0.0503
90% Confidence Interval	( 1.06 to 1.23 )

[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.
[5]	Other relevant estimation information:
	No text entered.

5. Secondary Outcome Measure: Rate and extent of absorption of AZD7594 (Inhalation/ administration via DPI) by assessment of the AUC from time zero to 24 hours after dosing (AUC [0-24]). [ Time Frame: Day 1: pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72 and 96 hours post-dose ]

Measure Type	Secondary
Measure Name	Rate and extent of absorption of AZD7594 (Inhalation/ administration via DPI) by assessment of the AUC from time zero to 24 hours after dosing (AUC [0-24]).
Measure Description	Assessment of the plasma PK following a single dose of AZD7594. AUC (0-24) was defined as area under the plasma concentration-time curve from time zero to 24 hours after dosing.
Time Frame	Day 1: pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72 and 96 hours post-dose
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The PK analysis set consisted of all subjects in the safety analysis set who received AZD7594 and had at least 1 measured AZD7594 plasma concentration at a scheduled PK time point post-dose, with no major protocol deviations thought to impact on the analysis of the PK data.

Reporting Groups

	Description
AZD7594 200 μg	Participants received 200 μg inhaled AZD7594 via multi-dose dry powder inhaler (DPI) (1 x 200 μg inhalation)
AZD7594 400 μg	Participants received 400 μg inhaled AZD7594 via multi-dose DPI (1 x 400 μg inhalation)
AZD7594 1600 μg	Participants received 1600 μg inhaled AZD7594 via multi-dose DPI (4 x 400 μg inhalations).

Measured Values

	AZD7594 200 μg	AZD7594 400 μg	AZD7594 1600 μg
Number of Participants Analyzed [units:participants]	7	7	7
Rate and extent of absorption of AZD7594 (Inhalation/ administration via DPI) by assessment of the AUC from time zero to 24 hours after dosing (AUC [0-24]). [units: h*pmol/L] Geometric Mean (Geometric Coefficient of Variation)	681.1 (11.5%)	1084 (19.4%)	6060 (18.4%)

No statistical analysis provided for Rate and extent of absorption of AZD7594 (Inhalation/ administration via DPI) by assessment of the AUC from time zero to 24 hours after dosing (AUC [0-24]).

6. Secondary Outcome Measure: Rate and extent of absorption of AZD7594 (Inhalation/ administration via DPI) by assessment of the AUC from time zero extrapolated to infinity (AUC). [ Time Frame: Day 1: pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72 and 96 hours post-dose ]

Measure Type	Secondary
Measure Name	Rate and extent of absorption of AZD7594 (Inhalation/ administration via DPI) by assessment of the AUC from time zero extrapolated to infinity (AUC).
Measure Description	Assessment of the plasma PK following a single dose of AZD7594. AUC was defined as area under the plasma concentration-time curve from time zero extrapolated to infinity. AUC is estimated by AUC(0-last) + Clast/λz where Clast is the last observed quantifiable concentration. NOTE: No results were available for participants belonging to AZD7594 2ug and AZD7594 400ug groups.
Time Frame	Day 1: pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72 and 96 hours post-dose
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The PK analysis set consisted of all subjects in the safety analysis set who received AZD7594 and had at least 1 measured AZD7594 plasma concentration at a scheduled PK time point post-dose, with no major protocol deviations thought to impact on the analysis of the PK data.

Reporting Groups

	Description
AZD7594 200 μg	Participants received 200 μg inhaled AZD7594 via multi-dose dry powder inhaler (DPI) (1 x 200 μg inhalation)
AZD7594 400 μg	Participants received 400 μg inhaled AZD7594 via multi-dose DPI (1 x 400 μg inhalation)
AZD7594 1600 μg	Participants received 1600 μg inhaled AZD7594 via multi-dose DPI (4 x 400 μg inhalations).

Measured Values

	AZD7594 200 μg	AZD7594 400 μg	AZD7594 1600 μg
Number of Participants Analyzed [units:participants]	7	7	7
Rate and extent of absorption of AZD7594 (Inhalation/ administration via DPI) by assessment of the AUC from time zero extrapolated to infinity (AUC). [units: h*pmol/L] Geometric Mean (Geometric Coefficient of Variation)	NA (NA%)^[1]	NA (NA%)^[2]	18260 (22.9%)

[1]	NA: Not applicable due to greater than 30% extrapolated area AUC values for most subjects were determined with >30% extrapolated area, thus were excluded from statistical analysis.
[2]	NA: Not applicable due to greater than 30% extrapolated area AUC values for most subjects were determined with >30% extrapolated area, thus were excluded from statistical analysis.

Statistical Analysis 1 for Rate and extent of absorption of AZD7594 (Inhalation/ administration via DPI) by assessment of the AUC from time zero extrapolated to infinity (AUC).

Groups^[1]	All groups
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	Other [Linear Model]
Slope^[5]	1.05
Standard Error of the mean	± 0.119
90% Confidence Interval	( 0.801 to 1.31 )

[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.
[5]	Other relevant estimation information:
	No text entered.

7. Secondary Outcome Measure: Rate and extent of absorption of AZD7594 by assessment of the terminal elimination rate constant, estimated by log-linear least squares regression of the terminal part of the concentration-time curve(lamda z or λz). [ Time Frame: Day 1: pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72 and 96 hours post-dose ]

Measure Type	Secondary
Measure Name	Rate and extent of absorption of AZD7594 by assessment of the terminal elimination rate constant, estimated by log-linear least squares regression of the terminal part of the concentration-time curve(lamda z or λz).
Measure Description	Assessment of the plasma PK following a single dose of AZD7594. λz was defined as terminal elimination rate constant, estimated by log-linear least squares regression of the terminal part of the concentration-time curve.
Time Frame	Day 1: pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72 and 96 hours post-dose
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The PK analysis set consisted of all subjects in the safety analysis set who received AZD7594 and had at least 1 measured AZD7594 plasma concentration at a scheduled PK time point post-dose, with no major protocol deviations thought to impact on the analysis of the PK data.

Reporting Groups

	Description
AZD7594 200 μg	Participants received 200 μg inhaled AZD7594 via multi-dose dry powder inhaler (DPI) (1 x 200 μg inhalation)
AZD7594 400 μg	Participants received 400 μg inhaled AZD7594 via multi-dose DPI (1 x 400 μg inhalation)
AZD7594 1600 μg	Participants received 1600 μg inhaled AZD7594 via multi-dose DPI (4 x 400 μg inhalations).

Measured Values

	AZD7594 200 μg	AZD7594 400 μg	AZD7594 1600 μg
Number of Participants Analyzed [units:participants]	7	7	7
Rate and extent of absorption of AZD7594 by assessment of the terminal elimination rate constant, estimated by log-linear least squares regression of the terminal part of the concentration-time curve(lamda z or λz). [units: l/h] Geometric Mean (Geometric Coefficient of Variation)	0.015573 (24.5%)	0.011058 (18.3%)	0.013862 (21.4%)

No statistical analysis provided for Rate and extent of absorption of AZD7594 by assessment of the terminal elimination rate constant, estimated by log-linear least squares regression of the terminal part of the concentration-time curve(lamda z or λz).

8. Secondary Outcome Measure: Rate and extent of absorption of AZD7594 (Inhalation/ administration via DPI) by assessment of the half-life associated with the terminal slope of a semi-logarithmic concentration-time curve (t1/2λz). [ Time Frame: Day 1: pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72 and 96 hours post-dose ]

Measure Type	Secondary
Measure Name	Rate and extent of absorption of AZD7594 (Inhalation/ administration via DPI) by assessment of the half-life associated with the terminal slope of a semi-logarithmic concentration-time curve (t1/2λz).
Measure Description	Assessment of the plasma PK following a single dose of AZD7594. t1/2λz was defined as half-life associated with terminal slope (λz) of a semi-logarithmic concentration-time curve. NOTE: No results were available for participants belonging to AZD7594 400ug group.
Time Frame	Day 1: pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72 and 96 hours post-dose
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The PK analysis set consisted of all subjects in the safety analysis set who received AZD7594 and had at least 1 measured AZD7594 plasma concentration at a scheduled PK time point post-dose, with no major protocol deviations thought to impact on the analysis of the PK data.

Reporting Groups

	Description
AZD7594 200 μg	Participants received 200 μg inhaled AZD7594 via multi-dose dry powder inhaler (DPI) (1 x 200 μg inhalation)
AZD7594 400 μg	Participants received 400 μg inhaled AZD7594 via multi-dose DPI (1 x 400 μg inhalation)
AZD7594 1600 μg	Participants received 1600 μg inhaled AZD7594 via multi-dose DPI (4 x 400 μg inhalations).

Measured Values

	AZD7594 200 μg	AZD7594 400 μg	AZD7594 1600 μg
Number of Participants Analyzed [units:participants]	7	7	7
Rate and extent of absorption of AZD7594 (Inhalation/ administration via DPI) by assessment of the half-life associated with the terminal slope of a semi-logarithmic concentration-time curve (t1/2λz). [units: Hours] Mean (Standard Deviation)	39.88 (5.441)	NA (NA)^[1]	43.57 (3.815)

[1]	NA - Not applicable. When t½λz was greater than half of total sampling interval (48 hours) or percentage of AUC obtained by extrapolating area under plasma concentration-time curve (%AUCextr) was > 30%, t½λz was excluded from descriptive statistics

No statistical analysis provided for Rate and extent of absorption of AZD7594 (Inhalation/ administration via DPI) by assessment of the half-life associated with the terminal slope of a semi-logarithmic concentration-time curve (t1/2λz).

9. Secondary Outcome Measure: Rate and extent of absorption of AZD7594 (Inhalation/ administration via DPI) by assessment of the mean residence time from time zero extrapolated to infinity (MRT). [ Time Frame: Day 1: pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72 and 96 hours post-dose ]

Measure Type	Secondary
Measure Name	Rate and extent of absorption of AZD7594 (Inhalation/ administration via DPI) by assessment of the mean residence time from time zero extrapolated to infinity (MRT).
Measure Description	Assessment of the plasma PK following a single dose of AZD7594. MRT was defined as Mean residence time from time zero extrapolated to infinity. NOTE: No results were available for participants belonging to AZD7594 200ug and AZD7594 400ug groups.
Time Frame	Day 1: pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72 and 96 hours post-dose
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The PK analysis set consisted of all subjects in the safety analysis set who received AZD7594 and had at least 1 measured AZD7594 plasma concentration at a scheduled PK time point post-dose, with no major protocol deviations thought to impact on the analysis of the PK data.

Reporting Groups

	Description
AZD7594 200 μg	Participants received 200 μg inhaled AZD7594 via multi-dose dry powder inhaler (DPI) (1 x 200 μg inhalation)
AZD7594 400 μg	Participants received 400 μg inhaled AZD7594 via multi-dose DPI (1 x 400 μg inhalation)
AZD7594 1600 μg	Participants received 1600 μg inhaled AZD7594 via multi-dose DPI (4 x 400 μg inhalations).

Measured Values

	AZD7594 200 μg	AZD7594 400 μg	AZD7594 1600 μg
Number of Participants Analyzed [units:participants]	7	7	7
Rate and extent of absorption of AZD7594 (Inhalation/ administration via DPI) by assessment of the mean residence time from time zero extrapolated to infinity (MRT). [units: Hours] Geometric Mean (Geometric Coefficient of Variation)	NA (NA%)^[1]	NA (NA%)^[2]	65.03 (4.7%)

[1]	NA - Not applicable. When t½λz was greater than half of the total sampling interval (48 hours) or %AUCextr was > 30%, the terminal elimination phase dependent parameter (MRT) was excluded from descriptive statistics.
[2]	NA - Not applicable. When t½λz was greater than half of the total sampling interval (48 hours) or %AUCextr was > 30%, the terminal elimination phase dependent parameter (MRT) was excluded from descriptive statistics.

No statistical analysis provided for Rate and extent of absorption of AZD7594 (Inhalation/ administration via DPI) by assessment of the mean residence time from time zero extrapolated to infinity (MRT).

10. Secondary Outcome Measure: Rate and extent of absorption of AZD7594 by assessment of the apparent total body clearance after extravascular administration estimated as dose divided by AUC (AZD7594) (CL/F). [ Time Frame: Day 1: pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72 and 96 hours post-dose. ]

Measure Type	Secondary
Measure Name	Rate and extent of absorption of AZD7594 by assessment of the apparent total body clearance after extravascular administration estimated as dose divided by AUC (AZD7594) (CL/F).
Measure Description	Assessment of the plasma PK following a single dose of AZD7594. CL/F was defined as apparent total body clearance after extravascular administration estimated as dose divided by AUC (AZD7594). NOTE: No results were available for participants belonging to AZD7594 200ug and AZD7594 400ug groups.
Time Frame	Day 1: pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72 and 96 hours post-dose.
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The PK analysis set consisted of all subjects in the safety analysis set who received AZD7594 and had at least 1 measured AZD7594 plasma concentration at a scheduled PK time point post-dose, with no major protocol deviations thought to impact on the analysis of the PK data.

Reporting Groups

	Description
AZD7594 200 μg	Participants received 200 μg inhaled AZD7594 via multi-dose dry powder inhaler (DPI) (1 x 200 μg inhalation)
AZD7594 400 μg	Participants received 400 μg inhaled AZD7594 via multi-dose DPI (1 x 400 μg inhalation)
AZD7594 1600 μg	Participants received 1600 μg inhaled AZD7594 via multi-dose DPI (4 x 400 μg inhalations).

Measured Values

	AZD7594 200 μg	AZD7594 400 μg	AZD7594 1600 μg
Number of Participants Analyzed [units:participants]	7	7	7
Rate and extent of absorption of AZD7594 by assessment of the apparent total body clearance after extravascular administration estimated as dose divided by AUC (AZD7594) (CL/F). [units: L/h] Geometric Mean (Geometric Coefficient of Variation)	NA (NA%)^[1]	NA (NA%)^[2]	144.5 (22.9%)

[1]	NA - Not applicable. When t½λz was greater than half of the total sampling interval (48 hours) or %AUCextr was > 30%, the terminal elimination phase dependent parameter (CL/F) was excluded from descriptive statistics
[2]	NA - Not applicable. When t½λz was greater than half of the total sampling interval (48 hours) or %AUCextr was > 30%, the terminal elimination phase dependent parameter (CL/F) was excluded from descriptive statistics

No statistical analysis provided for Rate and extent of absorption of AZD7594 by assessment of the apparent total body clearance after extravascular administration estimated as dose divided by AUC (AZD7594) (CL/F).

11. Secondary Outcome Measure: Rate and extent of absorption of AZD7594 by assessment of the apparent volume of distribution during the terminal phase after extravascular administration, estimated by dividing CL/F by lamda z (Vz/F) [ Time Frame: Day 1: pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72 and 96 hours post-dose. ]

Measure Type	Secondary
Measure Name	Rate and extent of absorption of AZD7594 by assessment of the apparent volume of distribution during the terminal phase after extravascular administration, estimated by dividing CL/F by lamda z (Vz/F)
Measure Description	Assessment of the plasma PK following a single dose of AZD7594. Vz/F was defined as apparent volume of distribution during the terminal phase after extravascular administration, estimated by dividing the apparent clearance (CL/F) by λz. NOTE: No results were available for participants belonging to AZD7594 200ug and AZD7594 400ug groups.
Time Frame	Day 1: pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72 and 96 hours post-dose.
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The PK analysis set consisted of all subjects in the safety analysis set who received AZD7594 and had at least 1 measured AZD7594 plasma concentration at a scheduled PK time point post-dose, with no major protocol deviations thought to impact on the analysis of the PK data.

Reporting Groups

	Description
AZD7594 200 μg	Participants received 200 μg inhaled AZD7594 via multi-dose dry powder inhaler (DPI) (1 x 200 μg inhalation)
AZD7594 400 μg	Participants received 400 μg inhaled AZD7594 via multi-dose DPI (1 x 400 μg inhalation)
AZD7594 1600 μg	Participants received 1600 μg inhaled AZD7594 via multi-dose DPI (4 x 400 μg inhalations).

Measured Values

	AZD7594 200 μg	AZD7594 400 μg	AZD7594 1600 μg
Number of Participants Analyzed [units:participants]	7	7	7
Rate and extent of absorption of AZD7594 by assessment of the apparent volume of distribution during the terminal phase after extravascular administration, estimated by dividing CL/F by lamda z (Vz/F) [units: Litres] Geometric Mean (Geometric Coefficient of Variation)	NA (NA%)^[1]	NA (NA%)^[2]	9297 (24.1%)

[1]	NA - Not applicable. When t½λz was greater than half of the total sampling interval (48 hours) or %AUCextr was > 30%, the terminal elimination phase dependent parameter (Vz/F) was excluded from descriptive statistics
[2]	NA - Not applicable. When t½λz was greater than half of the total sampling interval (48 hours) or %AUCextr was > 30%, the terminal elimination phase dependent parameter (Vz/F) was excluded from descriptive statistics

No statistical analysis provided for Rate and extent of absorption of AZD7594 by assessment of the apparent volume of distribution during the terminal phase after extravascular administration, estimated by dividing CL/F by lamda z (Vz/F)

12. Secondary Outcome Measure: Rate and extent of absorption of AZD7594 by assessment of the Cmax divided by the dose administered (Cmax/D). [ Time Frame: Day 1: pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72 and 96 hours post-dose ]

Measure Type	Secondary
Measure Name	Rate and extent of absorption of AZD7594 by assessment of the Cmax divided by the dose administered (Cmax/D).
Measure Description	Assessment of the plasma PK following a single dose of AZD7594. Cmax/D was defined as observed maximum plasma concentration divided by the dose administered.
Time Frame	Day 1: pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72 and 96 hours post-dose
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The PK analysis set consisted of all subjects in the safety analysis set who received AZD7594 and had at least 1 measured AZD7594 plasma concentration at a scheduled PK time point post-dose, with no major protocol deviations thought to impact on the analysis of the PK data.

Reporting Groups

	Description
AZD7594 200 μg	Participants received 200 μg inhaled AZD7594 via multi-dose dry powder inhaler (DPI) (1 x 200 μg inhalation)
AZD7594 400 μg	Participants received 400 μg inhaled AZD7594 via multi-dose DPI (1 x 400 μg inhalation)
AZD7594 1600 μg	Participants received 1600 μg inhaled AZD7594 via multi-dose DPI (4 x 400 μg inhalations).

Measured Values

	AZD7594 200 μg	AZD7594 400 μg	AZD7594 1600 μg
Number of Participants Analyzed [units:participants]	7	7	7
Rate and extent of absorption of AZD7594 by assessment of the Cmax divided by the dose administered (Cmax/D). [units: (pmol/L)/umol] Geometric Mean (Geometric Coefficient of Variation)	169.9 (22.0%)	116.7 (34.4%)	163.2 (22.4%)

No statistical analysis provided for Rate and extent of absorption of AZD7594 by assessment of the Cmax divided by the dose administered (Cmax/D).

13. Secondary Outcome Measure: Rate and extent of absorption of AZD7594 by assessment of the AUC divided by the dose administered (AUC/D). [ Time Frame: Day 1: pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72 and 96 hours post-dose. ]

Measure Type	Secondary
Measure Name	Rate and extent of absorption of AZD7594 by assessment of the AUC divided by the dose administered (AUC/D).
Measure Description	Assessment of the plasma PK following a single dose of AZD7594. AUC/D was defined as Area under the plasma concentration-time curve from time zero extrapolated to infinity divided by the dose administered. NOTE: No results were available for participants belonging to AZD7594 200ug and AZD7594 400ug groups.
Time Frame	Day 1: pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72 and 96 hours post-dose.
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The PK analysis set consisted of all subjects in the safety analysis set who received AZD7594 and had at least 1 measured AZD7594 plasma concentration at a scheduled PK time point post-dose, with no major protocol deviations thought to impact on the analysis of the PK data.

Reporting Groups

	Description
AZD7594 200 μg	Participants received 200 μg inhaled AZD7594 via multi-dose dry powder inhaler (DPI) (1 x 200 μg inhalation)
AZD7594 400 μg	Participants received 400 μg inhaled AZD7594 via multi-dose DPI (1 x 400 μg inhalation)
AZD7594 1600 μg	Participants received 1600 μg inhaled AZD7594 via multi-dose DPI (4 x 400 μg inhalations).

Measured Values

	AZD7594 200 μg	AZD7594 400 μg	AZD7594 1600 μg
Number of Participants Analyzed [units:participants]	7	7	7
Rate and extent of absorption of AZD7594 by assessment of the AUC divided by the dose administered (AUC/D). [units: (pmol*h/L)/umol] Geometric Mean (Geometric Coefficient of Variation)	NA (NA%)^[1]	NA (NA%)^[2]	6918 (22.9%)

[1]	NA - Not available For 6 participants, %AUCextr was > 30%. Hence, values were excluded from descriptive statistics.
[2]	NA - Not available NA - Not available For all participants, %AUCextr was > 30%. Hence, values were excluded from descriptive statistics.

No statistical analysis provided for Rate and extent of absorption of AZD7594 by assessment of the AUC divided by the dose administered (AUC/D).

14. Secondary Outcome Measure: Rate and extent of absorption of AZD7594 by assessment of the AUC(0-24) divided by the dose administered (AUC(0-24)/D) [ Time Frame: Day 1: pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72 and 96 hours post-dose. ]

Measure Type	Secondary
Measure Name	Rate and extent of absorption of AZD7594 by assessment of the AUC(0-24) divided by the dose administered (AUC(0-24)/D)
Measure Description	Assessment of the plasma PK following a single dose of AZD7594. AUC(0-24)/D was defined as area under the plasma concentration-time curve from time zero to 24 hours after dosing divided by the dose administered.
Time Frame	Day 1: pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72 and 96 hours post-dose.
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The PK analysis set consisted of all subjects in the safety analysis set who received AZD7594 and had at least 1 measured AZD7594 plasma concentration at a scheduled PK time point post-dose, with no major protocol deviations thought to impact on the analysis of the PK data.

Reporting Groups

	Description
AZD7594 200 μg	Participants received 200 μg inhaled AZD7594 via multi-dose dry powder inhaler (DPI) (1 x 200 μg inhalation)
AZD7594 400 μg	Participants received 400 μg inhaled AZD7594 via multi-dose DPI (1 x 400 μg inhalation)
AZD7594 1600 μg	Participants received 1600 μg inhaled AZD7594 via multi-dose DPI (4 x 400 μg inhalations).

Measured Values

	AZD7594 200 μg	AZD7594 400 μg	AZD7594 1600 μg
Number of Participants Analyzed [units:participants]	7	7	7
Rate and extent of absorption of AZD7594 by assessment of the AUC(0-24) divided by the dose administered (AUC(0-24)/D) [units: (pmol*h/L)/umol] Geometric Mean (Geometric Coefficient of Variation)	2064 (11.5%)	1645 (19.4%)	2295 (18.4%)

No statistical analysis provided for Rate and extent of absorption of AZD7594 by assessment of the AUC(0-24) divided by the dose administered (AUC(0-24)/D)

15. Secondary Outcome Measure: Rate and extent of absorption of AZD7594 by assessment of the observed minimum plasma concentration (Cmin) [ Time Frame: Days 5 to 15: Pre-dose ]

Measure Type	Secondary
Measure Name	Rate and extent of absorption of AZD7594 by assessment of the observed minimum plasma concentration (Cmin)
Measure Description	Cmin was defined as observed minimum plasma concentration, taken directly from the individual concentration-time curve
Time Frame	Days 5 to 15: 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.
The pharmacokinetic (PK) analysis set consisted of all subjects in the safety analysis set who received AZD7594 and had at least 1 measured AZD7594 plasma concentration at a scheduled PK time point post-dose, with no major protocol deviations thought to impact on the analysis of the PK data.

Reporting Groups

	Description
AZD7594 200 μg	Participants received 200 μg inhaled AZD7594 via multi-dose dry powder inhaler (DPI) (1 x 200 μg inhalation)
AZD7594 400 μg	Participants received 400 μg inhaled AZD7594 via multi-dose DPI (1 x 400 μg inhalation)
AZD7594 1600 μg	Participants received 1600 μg inhaled AZD7594 via multi-dose DPI (4 x 400 μg inhalations).

Measured Values

	AZD7594 200 μg	AZD7594 400 μg	AZD7594 1600 μg
Number of Participants Analyzed [units:participants]	7	7	7
Rate and extent of absorption of AZD7594 by assessment of the observed minimum plasma concentration (Cmin) [units: pmol/L] Geometric Mean (Geometric Coefficient of Variation)
Day 5 - Pre-dose	NA (NA%)^[1]	16.27 (13.13%)	68.91 (21.55%)
Day 5 - 1 hour	59.81 (27.60%)	77.10 (26.92%)	404.2 (22.74%)
Day 6 - Pre-dose	29.35 (17.83%)	47.75 (20.76%)	252.2 (24.53%)
Day 7 - Pre-dose	41.59 (10.33%)	76.91 (16.27%)	369.0 (20.88%)
Day 8 - Pre-dose	51.99 (12.29%)	92.18 (18.17%)	458.4 (22.39%)
Day 8 - 1 hour	106.4 (19.69%)	162.3 (20.93%)	793.0 (26.60%)
Day 9 - Pre-dose	60.37 (16.48%)	108.2 (25.11%)	548.3 (25.72%)
Day 10 - Pre-dose	61.88 (21.52%)	119.3 (31.01%)	554.2 (23.65%)
Day 11 - Pre-dose	68.39 (19.83%)	136.3 (26.20%)	623.5 (21.10%)
Day 12 - Pre-dose	78.39 (9.019%)	142.6 (30.88%)	603.8 (16.84%)
Day 12 - 1 hour	139.5 (8.216%)	219.8 (26.21%)	925.8 (16.61%)
Day 13 - Pre-dose	79.31 (12.92%)	145.5 (38.15%)	698.3 (19.89%)
Day 14 - Pre-dose	77.04 (7.165%)	147.0 (34.87%)	718.4 (23.65%)
Day 15 - Pre-dose	82.40 (13.30%)	151.9 (35.42%)	694.9 (11.67%)

[1]	NA: Not applicable 6 participants were in below lower limit of quantification (10 pmol/L) category

No statistical analysis provided for Rate and extent of absorption of AZD7594 by assessment of the observed minimum plasma concentration (Cmin)

16. Secondary Outcome Measure: Rate and extent of absorption of AZD7594 (Inhalation/ administration via DPI) by assessment of the Cmax at steady state (Css,max). [ Time Frame: Day 16: pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72 and 96 hours post-dose ]

Measure Type	Secondary
Measure Name	Rate and extent of absorption of AZD7594 (Inhalation/ administration via DPI) by assessment of the Cmax at steady state (Css,max).
Measure Description	Assessment of the plasma PK following a single dose of AZD7594. Css,max was defined as observed maximum plasma concentration at steady state, taken directly from the individual concentration-time curve.
Time Frame	Day 16: pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72 and 96 hours post-dose
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The PK analysis set consisted of all subjects in the safety analysis set who received AZD7594 and had at least 1 measured AZD7594 plasma concentration at a scheduled PK time point post-dose, with no major protocol deviations thought to impact on the analysis of the PK data.

Reporting Groups

	Description
AZD7594 200 μg	Participants received 200 μg inhaled AZD7594 via multi-dose dry powder inhaler (DPI) (1 x 200 μg inhalation)
AZD7594 400 μg	Participants received 400 μg inhaled AZD7594 via multi-dose DPI (1 x 400 μg inhalation)
AZD7594 1600 μg	Participants received 1600 μg inhaled AZD7594 via multi-dose DPI (4 x 400 μg inhalations).

Measured Values

	AZD7594 200 μg	AZD7594 400 μg	AZD7594 1600 μg
Number of Participants Analyzed [units:participants]	7	7	7
Rate and extent of absorption of AZD7594 (Inhalation/ administration via DPI) by assessment of the Cmax at steady state (Css,max). [units: pmol/L] Geometric Mean (Geometric Coefficient of Variation)	164.3 (14.0%)	261.2 (37.0%)	1206 (14.7%)

Statistical Analysis 1 for Rate and extent of absorption of AZD7594 (Inhalation/ administration via DPI) by assessment of the Cmax at steady state (Css,max).

Groups^[1]	All groups
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	Other [Linear Model]
Slope^[5]	0.979
Standard Error of the mean	± 0.0633
90% Confidence Interval	( 0.870 to 1.09 )

[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.
[5]	Other relevant estimation information:
	No text entered.

17. Secondary Outcome Measure: Rate and extent of absorption of AZD7594 (Inhalation/ administration via DPI) by assessment of the Cmin at steady state (Cmin, ss) [ Time Frame: Day 16: pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72 and 96 hours post-dose. ]

Measure Type	Secondary
Measure Name	Rate and extent of absorption of AZD7594 (Inhalation/ administration via DPI) by assessment of the Cmin at steady state (Cmin, ss)
Measure Description	Assessment of the plasma PK following a single dose of AZD7594. Cmin, ss was defined as observed minimum concentration, taken directly from the individual concentration-time curve.
Time Frame	Day 16: pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72 and 96 hours post-dose.
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The PK analysis set consisted of all subjects in the safety analysis set who received AZD7594 and had at least 1 measured AZD7594 plasma concentration at a scheduled PK time point post-dose, with no major protocol deviations thought to impact on the analysis of the PK data.

Reporting Groups

	Description
AZD7594 200 μg	Participants received 200 μg inhaled AZD7594 via multi-dose dry powder inhaler (DPI) (1 x 200 μg inhalation)
AZD7594 400 μg	Participants received 400 μg inhaled AZD7594 via multi-dose DPI (1 x 400 μg inhalation)
AZD7594 1600 μg	Participants received 1600 μg inhaled AZD7594 via multi-dose DPI (4 x 400 μg inhalations).

Measured Values

	AZD7594 200 μg	AZD7594 400 μg	AZD7594 1600 μg
Number of Participants Analyzed [units:participants]	7	7	7
Rate and extent of absorption of AZD7594 (Inhalation/ administration via DPI) by assessment of the Cmin at steady state (Cmin, ss) [units: pmol/L] Geometric Mean (Geometric Coefficient of Variation)	82.15 (12.8%)	140.6 (38.5%)	600.0 (27.0%)

No statistical analysis provided for Rate and extent of absorption of AZD7594 (Inhalation/ administration via DPI) by assessment of the Cmin at steady state (Cmin, ss)

18. Secondary Outcome Measure: Rate and extent of absorption of AZD7594 (Inhalation/ administration via DPI) by assessment of the average concentration over one dosing interval (Cav) [ Time Frame: Day 16: pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72 and 96 hours post-dose. ]

Measure Type	Secondary
Measure Name	Rate and extent of absorption of AZD7594 (Inhalation/ administration via DPI) by assessment of the average concentration over one dosing interval (Cav)
Measure Description	Assessment of the plasma PK following a single dose of AZD7594. Cav was defined as average concentration over one dosing interval.
Time Frame	Day 16: pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72 and 96 hours post-dose.
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The PK analysis set consisted of all subjects in the safety analysis set who received AZD7594 and had at least 1 measured AZD7594 plasma concentration at a scheduled PK time point post-dose, with no major protocol deviations thought to impact on the analysis of the PK data.

Reporting Groups

	Description
AZD7594 200 μg	Participants received 200 μg inhaled AZD7594 via multi-dose dry powder inhaler (DPI) (1 x 200 μg inhalation)
AZD7594 400 μg	Participants received 400 μg inhaled AZD7594 via multi-dose DPI (1 x 400 μg inhalation)
AZD7594 1600 μg	Participants received 1600 μg inhaled AZD7594 via multi-dose DPI (4 x 400 μg inhalations).

Measured Values

	AZD7594 200 μg	AZD7594 400 μg	AZD7594 1600 μg
Number of Participants Analyzed [units:participants]	7	7	7
Rate and extent of absorption of AZD7594 (Inhalation/ administration via DPI) by assessment of the average concentration over one dosing interval (Cav) [units: pmol/L] Geometric Mean (Geometric Coefficient of Variation)	101.1 (13.4%)	183.7 (33.4%)	867.8 (13.2%)

No statistical analysis provided for Rate and extent of absorption of AZD7594 (Inhalation/ administration via DPI) by assessment of the average concentration over one dosing interval (Cav)

19. Secondary Outcome Measure: Rate and extent of absorption of AZD7594 (Inhalation/ administration via DPI) by assessment of the tmax at steady state (tss,max). [ Time Frame: Day 16: pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72 and 96 hours post-dose. ]

Measure Type	Secondary
Measure Name	Rate and extent of absorption of AZD7594 (Inhalation/ administration via DPI) by assessment of the tmax at steady state (tss,max).
Measure Description	Assessment of the plasma PK following a single dose of AZD7594. tss,max was defined as Time to reach maximum concentration, taken directly from the individual concentration-time curve.
Time Frame	Day 16: pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72 and 96 hours post-dose.
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The PK analysis set consisted of all subjects in the safety analysis set who received AZD7594 and had at least 1 measured AZD7594 plasma concentration at a scheduled PK time point post-dose, with no major protocol deviations thought to impact on the analysis of the PK data.

Reporting Groups

	Description
AZD7594 200 μg	Participants received 200 μg inhaled AZD7594 via multi-dose dry powder inhaler (DPI) (1 x 200 μg inhalation)
AZD7594 400 μg	Participants received 400 μg inhaled AZD7594 via multi-dose DPI (1 x 400 μg inhalation)
AZD7594 1600 μg	Participants received 1600 μg inhaled AZD7594 via multi-dose DPI (4 x 400 μg inhalations).

Measured Values

	AZD7594 200 μg	AZD7594 400 μg	AZD7594 1600 μg
Number of Participants Analyzed [units:participants]	7	7	7
Rate and extent of absorption of AZD7594 (Inhalation/ administration via DPI) by assessment of the tmax at steady state (tss,max). [units: Hours] Median (Full Range)	0.25 (0.25 to 4.02)	1.50 (0.25 to 8.00)	1.50 (0.25 to 4.00)

No statistical analysis provided for Rate and extent of absorption of AZD7594 (Inhalation/ administration via DPI) by assessment of the tmax at steady state (tss,max).

20. Secondary Outcome Measure: Rate and extent of absorption of AZD7594 by assessment of the AUC(0-last) [ Time Frame: Day 16: pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72 and 96 hours post-dose. ]

Measure Type	Secondary
Measure Name	Rate and extent of absorption of AZD7594 by assessment of the AUC(0-last)
Measure Description	Assessment of the plasma PK following a single dose of AZD7594. AUC(0-last) was defined as Area under the plasma concentration-time curve from time zero to the time of the last quantifiable analyte concentration.
Time Frame	Day 16: pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72 and 96 hours post-dose.
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The PK analysis set consisted of all subjects in the safety analysis set who received AZD7594 and had at least 1 measured AZD7594 plasma concentration at a scheduled PK time point post-dose, with no major protocol deviations thought to impact on the analysis of the PK data.

Reporting Groups

	Description
AZD7594 200 μg	Participants received 200 μg inhaled AZD7594 via multi-dose dry powder inhaler (DPI) (1 x 200 μg inhalation)
AZD7594 400 μg	Participants received 400 μg inhaled AZD7594 via multi-dose DPI (1 x 400 μg inhalation)
AZD7594 1600 μg	Participants received 1600 μg inhaled AZD7594 via multi-dose DPI (4 x 400 μg inhalations).

Measured Values

	AZD7594 200 μg	AZD7594 400 μg	AZD7594 1600 μg
Number of Participants Analyzed [units:participants]	7	7	7
Rate and extent of absorption of AZD7594 by assessment of the AUC(0-last) [units: pmol*h/L] Geometric Mean (Geometric Coefficient of Variation)	6136 (16.2%)	11490 (36.9%)	54120 (11.5%)

No statistical analysis provided for Rate and extent of absorption of AZD7594 by assessment of the AUC(0-last)

21. Secondary Outcome Measure: Rate and extent of absorption of AZD7594 by assessment of AUC(0-24) [ Time Frame: Day 16: pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72 and 96 hours post-dose. ]

Measure Type	Secondary
Measure Name	Rate and extent of absorption of AZD7594 by assessment of AUC(0-24)
Measure Description	Assessment of the plasma PK following a single dose of AZD7594. AUC(0-24) was defined as area under the plasma concentration-time curve from time zero to 24 hours after dosing
Time Frame	Day 16: pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72 and 96 hours post-dose.
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The PK analysis set consisted of all subjects in the safety analysis set who received AZD7594 and had at least 1 measured AZD7594 plasma concentration at a scheduled PK time point post-dose, with no major protocol deviations thought to impact on the analysis of the PK data

Reporting Groups

	Description
AZD7594 200 μg	Participants received 200 μg inhaled AZD7594 via multi-dose dry powder inhaler (DPI) (1 x 200 μg inhalation)
AZD7594 400 μg	Participants received 400 μg inhaled AZD7594 via multi-dose DPI (1 x 400 μg inhalation)
AZD7594 1600 μg	Participants received 1600 μg inhaled AZD7594 via multi-dose DPI (4 x 400 μg inhalations).

Measured Values

	AZD7594 200 μg	AZD7594 400 μg	AZD7594 1600 μg
Number of Participants Analyzed [units:participants]	7	7	7
Rate and extent of absorption of AZD7594 by assessment of AUC(0-24) [units: pmol*h/L] Geometric Mean (Geometric Coefficient of Variation)	2426 (13.4%)	4409 (33.4%)	20830 (13.2%)

Statistical Analysis 1 for Rate and extent of absorption of AZD7594 by assessment of AUC(0-24)

Groups^[1]	All groups
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	Other [Linear Model]
Slope^[5]	1.05
Standard Error of the mean	± 0.0552
90% Confidence Interval	( 0.951 to 1.14 )

[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.
[5]	Other relevant estimation information:
	No text entered.

22. Secondary Outcome Measure: Rate and extent of absorption of AZD7594 by assessment of the Css,max divided by the dose administered (Css,max/D). [ Time Frame: Day 16: pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72 and 96 hours post-dose. ]

Measure Type	Secondary
Measure Name	Rate and extent of absorption of AZD7594 by assessment of the Css,max divided by the dose administered (Css,max/D).
Measure Description	Assessment of the plasma PK following a single dose of AZD7594. Css,max/D was defined as observed maximum plasma concentration divided by the dose administered.
Time Frame	Day 16: pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72 and 96 hours post-dose.
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The PK analysis set consisted of all subjects in the safety analysis set who received AZD7594 and had at least 1 measured AZD7594 plasma concentration at a scheduled PK time point post-dose, with no major protocol deviations thought to impact on the analysis of the PK data.

Reporting Groups

	Description
AZD7594 200 μg	Participants received 200 μg inhaled AZD7594 via multi-dose dry powder inhaler (DPI) (1 x 200 μg inhalation)
AZD7594 400 μg	Participants received 400 μg inhaled AZD7594 via multi-dose DPI (1 x 400 μg inhalation)
AZD7594 1600 μg	Participants received 1600 μg inhaled AZD7594 via multi-dose DPI (4 x 400 μg inhalations).

Measured Values

	AZD7594 200 μg	AZD7594 400 μg	AZD7594 1600 μg
Number of Participants Analyzed [units:participants]	7	7	7
Rate and extent of absorption of AZD7594 by assessment of the Css,max divided by the dose administered (Css,max/D). [units: (pmol/L)/umol] Geometric Mean (Geometric Coefficient of Variation)	498.0 (14.0%)	396.4 (37.0%)	456.9 (14.7%)

No statistical analysis provided for Rate and extent of absorption of AZD7594 by assessment of the Css,max divided by the dose administered (Css,max/D).

23. Secondary Outcome Measure: Rate and extent of absorption of AZD7594 by assessment AUC(0-24)/D. [ Time Frame: Day 16: pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72 and 96 hours post-dose. ]

Measure Type	Secondary
Measure Name	Rate and extent of absorption of AZD7594 by assessment AUC(0-24)/D.
Measure Description	Assessment of the plasma PK following a single dose of AZD7594. AUC(0-24)/D was defined as the area under the plasma concentration-time curve from time zero to 24 hours after dosing divided by the dose administered.
Time Frame	Day 16: pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72 and 96 hours post-dose.
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The PK analysis set consisted of all subjects in the safety analysis set who received AZD7594 and had at least 1 measured AZD7594 plasma concentration at a scheduled PK time point post-dose, with no major protocol deviations thought to impact on the analysis of the PK data.

Reporting Groups

	Description
AZD7594 200 μg	Participants received 200 μg inhaled AZD7594 via multi-dose dry powder inhaler (DPI) (1 x 200 μg inhalation)
AZD7594 400 μg	Participants received 400 μg inhaled AZD7594 via multi-dose DPI (1 x 400 μg inhalation)
AZD7594 1600 μg	Participants received 1600 μg inhaled AZD7594 via multi-dose DPI (4 x 400 μg inhalations).

Measured Values

	AZD7594 200 μg	AZD7594 400 μg	AZD7594 1600 μg
Number of Participants Analyzed [units:participants]	7	7	7
Rate and extent of absorption of AZD7594 by assessment AUC(0-24)/D. [units: (pmol*h/L)/umol] Geometric Mean (Geometric Coefficient of Variation)	7351 (13.4%)	6691 (33.4%)	7889 (13.2%)

No statistical analysis provided for Rate and extent of absorption of AZD7594 by assessment AUC(0-24)/D.

24. Secondary Outcome Measure: Rate and extent of absorption of AZD7594 by assessment of lamda z (λz) [ Time Frame: Day 16: pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72 and 96 hours post-dose. ]

Measure Type	Secondary
Measure Name	Rate and extent of absorption of AZD7594 by assessment of lamda z (λz)
Measure Description	Assessment of the plasma PK following a single dose of AZD7594. λz was defined as terminal elimination rate constant, estimated by log-linear least.
Time Frame	Day 16: pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72 and 96 hours post-dose.
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The PK analysis set consisted of all subjects in the safety analysis set who received AZD7594 and had at least 1 measured AZD7594 plasma concentration at a scheduled PK time point post-dose, with no major protocol deviations thought to impact on the analysis of the PK data.

Reporting Groups

	Description
AZD7594 200 μg	Participants received 200 μg inhaled AZD7594 via multi-dose dry powder inhaler (DPI) (1 x 200 μg inhalation)
AZD7594 400 μg	Participants received 400 μg inhaled AZD7594 via multi-dose DPI (1 x 400 μg inhalation)
AZD7594 1600 μg	Participants received 1600 μg inhaled AZD7594 via multi-dose DPI (4 x 400 μg inhalations).

Measured Values

	AZD7594 200 μg	AZD7594 400 μg	AZD7594 1600 μg
Number of Participants Analyzed [units:participants]	7	7	7
Rate and extent of absorption of AZD7594 by assessment of lamda z (λz) [units: l/hour] Geometric Mean (Geometric Coefficient of Variation)	0.013393 (19.8%)	0.011465 (38.8%)	0.010660 (27.4%)

No statistical analysis provided for Rate and extent of absorption of AZD7594 by assessment of lamda z (λz)

25. Secondary Outcome Measure: Rate and extent of absorption of AZD7594 by assessment of t1/2λz. [ Time Frame: Day 16: pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72 and 96 hours post-dose ]

Measure Type	Secondary
Measure Name	Rate and extent of absorption of AZD7594 by assessment of t1/2λz.
Measure Description	Assessment of the plasma PK following a single dose of AZD7594. t1/2λz was defined as half-life associated with terminal slope (λz) of a semi-logarithmic concentration-time curve. Participant count analyzed = 1
Time Frame	Day 16: pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72 and 96 hours post-dose
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The PK analysis set consisted of all subjects in the safety analysis set who received AZD7594 and had at least 1 measured AZD7594 plasma concentration at a scheduled PK time point post-dose, with no major protocol deviations thought to impact on the analysis of the PK data.

Reporting Groups

	Description
AZD7594 200 μg	Participants received 200 μg inhaled AZD7594 via multi-dose dry powder inhaler (DPI) (1 x 200 μg inhalation)
AZD7594 400 μg	Participants received 400 μg inhaled AZD7594 via multi-dose DPI (1 x 400 μg inhalation)
AZD7594 1600 μg	Participants received 1600 μg inhaled AZD7594 via multi-dose DPI (4 x 400 μg inhalations).

Measured Values

	AZD7594 200 μg	AZD7594 400 μg	AZD7594 1600 μg
Number of Participants Analyzed [units:participants]	7	7	7
Rate and extent of absorption of AZD7594 by assessment of t1/2λz. [units: Hours] Geometric Mean (Geometric Coefficient of Variation)	NA (NA%)^[1]	NA (NA%)^[2]	NA (NA%)^[3]

[1]	NA - Not applicable When Rsq_adj (regression co-efficient adjusted for λz) was < 0.7 or estimated t1/2λz was greater than half of the total sampling interval (48 hours), t½λz was excluded from descriptive statistics
[2]	NA - Not applicable When Rsq_adj (regression co-efficient adjusted for λz) was < 0.7 or estimated t1/2λz was greater than half of the total sampling interval (48 hours), t½λz was excluded from descriptive statistics
[3]	NA - Not applicable When Rsq_adj (regression co-efficient adjusted for λz) was < 0.7 or estimated t1/2λz was greater than half of the total sampling interval (48 hours), t½λz was excluded from descriptive statistics

No statistical analysis provided for Rate and extent of absorption of AZD7594 by assessment of t1/2λz.

26. Secondary Outcome Measure: Rate and extent of absorption of AZD7594 by assessment of the peak trough fluctuation (%fluctuation). [ Time Frame: Day 16: pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72 and 96 hours post-dose. ]

Measure Type	Secondary
Measure Name	Rate and extent of absorption of AZD7594 by assessment of the peak trough fluctuation (%fluctuation).
Measure Description	Assessment of the plasma PK following a single dose of AZD7594. Peak trough fluctuation calculated as [100*(Css,max– Css,min)/Cav].
Time Frame	Day 16: pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72 and 96 hours post-dose.
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The pharmacodynamics analysis set will include all subjects who receive at least 1 dose of IMP and for whom it is possible to calculate the cortisol AUEC on Day -1, Day 1 and/or Day 16 and with no major protocol deviations considered to impact on the analysis of the PD (cortisol, plasma DHEAS and osteocalcin) data.

Reporting Groups

	Description
AZD7594 200 μg	Participants received 200 μg inhaled AZD7594 via multi-dose dry powder inhaler (DPI) (1 x 200 μg inhalation)
AZD7594 400 μg	Participants received 400 μg inhaled AZD7594 via multi-dose DPI (1 x 400 μg inhalation)
AZD7594 1600 μg	Participants received 1600 μg inhaled AZD7594 via multi-dose DPI (4 x 400 μg inhalations).

Measured Values

	AZD7594 200 μg	AZD7594 400 μg	AZD7594 1600 μg
Number of Participants Analyzed [units:participants]	7	7	7
Rate and extent of absorption of AZD7594 by assessment of the peak trough fluctuation (%fluctuation). [units: Percentage of fluctuation] Geometric Mean (Geometric Coefficient of Variation)	80.12 (23.8%)	64.61 (21.8%)	68.08 (21.0%)

No statistical analysis provided for Rate and extent of absorption of AZD7594 by assessment of the peak trough fluctuation (%fluctuation).

27. Secondary Outcome Measure: Rate and extent of absorption of AZD7594 by assessment of the accumulation ratio calculated as AUC(0-24) on Day 16/AUC (0-24) on Day 1 (RAC). [ Time Frame: Day 16: pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72 and 96 hours post-dose. ]

Measure Type	Secondary
Measure Name	Rate and extent of absorption of AZD7594 by assessment of the accumulation ratio calculated as AUC(0-24) on Day 16/AUC (0-24) on Day 1 (RAC).
Measure Description	Assessment of the plasma PK following a single dose of AZD7594. Accumulation ratio calculated as AUC(0-24) on Day 16/AUC(0-24) on Day 1.
Time Frame	Day 16: pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72 and 96 hours post-dose.
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The PK analysis set consisted of all subjects in the safety analysis set who received AZD7594 and had at least 1 measured AZD7594 plasma concentration at a scheduled PK time point post-dose, with no major protocol deviations thought to impact on the analysis of the PK data.

Reporting Groups

	Description
AZD7594 200 μg	Participants received 200 μg inhaled AZD7594 via multi-dose dry powder inhaler (DPI) (1 x 200 μg inhalation)
AZD7594 400 μg	Participants received 400 μg inhaled AZD7594 via multi-dose DPI (1 x 400 μg inhalation)
AZD7594 1600 μg	Participants received 1600 μg inhaled AZD7594 via multi-dose DPI (4 x 400 μg inhalations).

Measured Values

	AZD7594 200 μg	AZD7594 400 μg	AZD7594 1600 μg
Number of Participants Analyzed [units:participants]	7	7	7
Rate and extent of absorption of AZD7594 by assessment of the accumulation ratio calculated as AUC(0-24) on Day 16/AUC (0-24) on Day 1 (RAC). [units: Ratio] Geometric Mean (Geometric Coefficient of Variation)	3.562 (15.7%)	4.067 (43.7%)	3.437 (7.3%)

No statistical analysis provided for Rate and extent of absorption of AZD7594 by assessment of the accumulation ratio calculated as AUC(0-24) on Day 16/AUC (0-24) on Day 1 (RAC).

28. Secondary Outcome Measure: Rate and extent of absorption of AZD7594 by assessment of the temporal change parameter (TCP) [ Time Frame: Day 16: pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72 and 96 hours post-dose. ]

Measure Type	Secondary
Measure Name	Rate and extent of absorption of AZD7594 by assessment of the temporal change parameter (TCP)
Measure Description	Assessment of the plasma PK following a single dose of AZD7594. Temporal change parameter, calculated as AUC(0-24) [Day 16]/AUC [Day 1]. NOTE: No results were available for participants belonging to AZD7594 200ug and AZD7594 400ug groups.
Time Frame	Day 16: pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72 and 96 hours post-dose.
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The PK analysis set consisted of all subjects in the safety analysis set who received AZD7594 and had at least 1 measured AZD7594 plasma concentration at a scheduled PK time point post-dose, with no major protocol deviations thought to impact on the analysis of the PK data.

Reporting Groups

	Description
AZD7594 200 μg	Participants received 200 μg inhaled AZD7594 via multi-dose dry powder inhaler (DPI) (1 x 200 μg inhalation)
AZD7594 400 μg	Participants received 400 μg inhaled AZD7594 via multi-dose DPI (1 x 400 μg inhalation)
AZD7594 1600 μg	Participants received 1600 μg inhaled AZD7594 via multi-dose DPI (4 x 400 μg inhalations).

Measured Values

	AZD7594 200 μg	AZD7594 400 μg	AZD7594 1600 μg
Number of Participants Analyzed [units:participants]	7	7	7
Rate and extent of absorption of AZD7594 by assessment of the temporal change parameter (TCP) [units: Ratio] Geometric Mean (Geometric Coefficient of Variation)	NA (NA%)^[1]	NA (NA%)^[2]	1.147 (7.7%)

[1]	NA - Not available For all participants, AUC value on Day 1 could not be reliably determined. Hence, values were excluded from descriptive statistics
[2]	NA - Not available For all participants, AUC value on Day 1 could not be reliably determined. Hence, values were excluded from descriptive statistics

No statistical analysis provided for Rate and extent of absorption of AZD7594 by assessment of the temporal change parameter (TCP)

29. Secondary Outcome Measure: Rate and extent of absorption of AZD7594 by assessment of the amount of AZD7594 excreted into the urine from time t1 to t2 (Ae [t1-t2]) [ Time Frame: Day 1 predose spot-collection and interval collection up to 96 hours postdose ]

Measure Type	Secondary
Measure Name	Rate and extent of absorption of AZD7594 by assessment of the amount of AZD7594 excreted into the urine from time t1 to t2 (Ae [t1-t2])
Measure Description	Assessment of the urine PK following a single dose of AZD7594. Ae (t1-t2) was defined as the amount of AZD7594 excreted into the urine from time t1 to t2.
Time Frame	Day 1 predose spot-collection and interval collection up to 96 hours postdose
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The PK analysis set consisted of all subjects in the safety analysis set who received AZD7594 and had at least 1 measured AZD7594 plasma concentration at a scheduled PK time point post-dose, with no major protocol deviations thought to impact on the analysis of the PK data.

Reporting Groups

	Description
AZD7594 200 μg	Participants received 200 μg inhaled AZD7594 via multi-dose dry powder inhaler (DPI) (1 x 200 μg inhalation)
AZD7594 400 μg	Participants received 400 μg inhaled AZD7594 via multi-dose DPI (1 x 400 μg inhalation)
AZD7594 1600 μg	Participants received 1600 μg inhaled AZD7594 via multi-dose DPI (4 x 400 μg inhalations).

Measured Values

	AZD7594 200 μg	AZD7594 400 μg	AZD7594 1600 μg
Number of Participants Analyzed [units:participants]	7	7	7
Rate and extent of absorption of AZD7594 by assessment of the amount of AZD7594 excreted into the urine from time t1 to t2 (Ae [t1-t2]) [units: pmol] Mean (Standard Deviation)
0-6h	1.856 (4.910)	6.738 (9.751)	55.64 (58.01)
6-12h	1.434 (3.795)	5.031 (6.645)	73.15 (53.23)
12-24h	1.893 (5.008)	1.907 (5.046)	73.13 (50.96)
24-48h	NA (NA)^[1]	NA (NA)^[2]	107.9 (76.97)
48-72h	NA (NA)^[3]	NA (NA)^[4]	72.43 (58.77)
72-96h	NA (NA)^[5]	NA (NA)^[6]	48.95 (48.49)

[1]	NA - Not available Participants concentration values were below lower limit of quantitation (10 pmol/L) category
[2]	NA - Not available Participants concentration values were below lower limit of quantitation (10 pmol/L) category
[3]	NA - Not available Participants concentration values were below lower limit of quantitation (10 pmol/L) category
[4]	NA - Not available Participants concentration values were below lower limit of quantitation (10 pmol/L) category
[5]	NA - Not available Participants concentration values were below lower limit of quantitation (10 pmol/L) category
[6]	NA - Not available Participants concentration values were below lower limit of quantitation (10 pmol/L) category

No statistical analysis provided for Rate and extent of absorption of AZD7594 by assessment of the amount of AZD7594 excreted into the urine from time t1 to t2 (Ae [t1-t2])

30. Secondary Outcome Measure: Rate and extent of absorption of AZD7594 by assessment of the cumulative amount of AZD7594 excreted from time zero to the last sampling interval (Ae [0-last]) [ Time Frame: Day 1 predose spot-collection and interval collection up to 96 hours postdose ]

Measure Type	Secondary
Measure Name	Rate and extent of absorption of AZD7594 by assessment of the cumulative amount of AZD7594 excreted from time zero to the last sampling interval (Ae [0-last])
Measure Description	Assessment of the urine PK following a single dose of AZD7594. Ae(0-last) was defined as Cumulative amount of AZD7594 excreted from time zero to the last sampling interval.
Time Frame	Day 1 predose spot-collection and interval collection up to 96 hours postdose
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The PK analysis set consisted of all subjects in the safety analysis set who received AZD7594 and had at least 1 measured AZD7594 plasma concentration at a scheduled PK time point post-dose, with no major protocol deviations thought to impact on the analysis of the PK data.

Reporting Groups

	Description
AZD7594 200 μg	Participants received 200 μg inhaled AZD7594 via multi-dose dry powder inhaler (DPI) (1 x 200 μg inhalation)
AZD7594 400 μg	Participants received 400 μg inhaled AZD7594 via multi-dose DPI (1 x 400 μg inhalation)
AZD7594 1600 μg	Participants received 1600 μg inhaled AZD7594 via multi-dose DPI (4 x 400 μg inhalations).

Measured Values

	AZD7594 200 μg	AZD7594 400 μg	AZD7594 1600 μg
Number of Participants Analyzed [units:participants]	7	7	7
Rate and extent of absorption of AZD7594 by assessment of the cumulative amount of AZD7594 excreted from time zero to the last sampling interval (Ae [0-last]) [units: pmol] Mean (Standard Deviation)
0-6h	1.856 (4.910)	6.738 (9.751)	55.64 (58.01)
0-12h	3.290 (8.705)	11.77 (15.25)	128.8 (83.03)
0-24h	5.183 (13.71)	13.68 (17.07)	201.9 (117.9)
0-48h	5.183 (13.71)	13.68 (17.07)	309.9 (175.6)
0-72h	5.183 (13.71)	13.68 (17.07)	382.3 (219.7)
0-96h	5.183 (13.71)	13.68 (17.07)	431.2 (262.2)

No statistical analysis provided for Rate and extent of absorption of AZD7594 by assessment of the cumulative amount of AZD7594 excreted from time zero to the last sampling interval (Ae [0-last])

31. Secondary Outcome Measure: Rate and extent of absorption of AZD7594 by assessment of the percentage of dose excreted unchanged into the urine from time zero to the last measured time point for an AZD7594, estimated by dividing Ae(0-last) by dose (fe(0-last)%) [ Time Frame: Day 1 predose spot-collection and interval collection up to 96 hours postdose ]

Measure Type	Secondary
Measure Name	Rate and extent of absorption of AZD7594 by assessment of the percentage of dose excreted unchanged into the urine from time zero to the last measured time point for an AZD7594, estimated by dividing Ae(0-last) by dose (fe(0-last)%)
Measure Description	Assessment of the urine PK following a single dose of AZD7594. fe(0-last)% was defined as Percentage of dose excreted unchanged into the urine from time zero to the last measured time point for an AZD7594, estimated by dividing Ae(0-last) by dose.
Time Frame	Day 1 predose spot-collection and interval collection up to 96 hours postdose
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The PK analysis set consisted of all subjects in the safety analysis set who received AZD7594 and had at least 1 measured AZD7594 plasma concentration at a scheduled PK time point post-dose, with no major protocol deviations thought to impact on the analysis of the PK data.

Reporting Groups

	Description
AZD7594 200 μg	Participants received 200 μg inhaled AZD7594 via multi-dose dry powder inhaler (DPI) (1 x 200 μg inhalation)
AZD7594 400 μg	Participants received 400 μg inhaled AZD7594 via multi-dose DPI (1 x 400 μg inhalation)
AZD7594 1600 μg	Participants received 1600 μg inhaled AZD7594 via multi-dose DPI (4 x 400 μg inhalations).

Measured Values

	AZD7594 200 μg	AZD7594 400 μg	AZD7594 1600 μg
Number of Participants Analyzed [units:participants]	7	7	7
Rate and extent of absorption of AZD7594 by assessment of the percentage of dose excreted unchanged into the urine from time zero to the last measured time point for an AZD7594, estimated by dividing Ae(0-last) by dose (fe(0-last)%) [units: Percentage of dose excreted unchanged] Mean (Standard Deviation)
0-6h	0.0005623 (0.001488)	0.001022 (0.001480)	0.002108 (0.002197)
6-12h	0.0004346 (0.001150)	0.0007634 (0.001008)	0.002771 (0.002016)
12-24h	0.0005736 (0.001518)	0.0002894 (0.0007657)	0.002770 (0.001930)
24-48h	NA (NA)^[1]	NA (NA)^[2]	0.004088 (0.002915)
48-72h	NA (NA)^[3]	NA (NA)^[4]	0.002743 (0.002226)
72-96h	NA (NA)^[5]	NA (NA)^[6]	0.001854 (0.001837)

[1]	NA - Not available Participants concentration values were below lower limit of quantitation (10 pmol/L) category
[2]	NA - Not available Participants concentration values were below lower limit of quantitation (10 pmol/L) category
[3]	NA - Not available Participants concentration values were below lower limit of quantitation (10 pmol/L) category
[4]	NA - Not available Participants concentration values were below lower limit of quantitation (10 pmol/L) category
[5]	NA - Not available Participants concentration values were below lower limit of quantitation (10 pmol/L) category
[6]	NA - Not available Participants concentration values were below lower limit of quantitation (10 pmol/L) category

No statistical analysis provided for Rate and extent of absorption of AZD7594 by assessment of the percentage of dose excreted unchanged into the urine from time zero to the last measured time point for an AZD7594, estimated by dividing Ae(0-last) by dose (fe(0-last)%)

32. Secondary Outcome Measure: Rate and extent of absorption of AZD7594 by assessment of the renal clearance, estimated by dividing Ae(0-96) by AUC(0-96) (CLR) [ Time Frame: Day 1 predose spot-collection and interval collection up to 96 hours postdose ]

Measure Type	Secondary
Measure Name	Rate and extent of absorption of AZD7594 by assessment of the renal clearance, estimated by dividing Ae(0-96) by AUC(0-96) (CLR)
Measure Description	Assessment of the urine PK following a single dose of AZD7594. CLR was defined as the renal clearance, estimated by dividing Ae(0-96) by AUC(0-96).
Time Frame	Day 1 predose spot-collection and interval collection up to 96 hours postdose
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The PK analysis set consisted of all subjects in the safety analysis set who received AZD7594 and had at least 1 measured AZD7594 plasma concentration at a scheduled PK time point post-dose, with no major protocol deviations thought to impact on the analysis of the PK data.

Reporting Groups

	Description
AZD7594 200 μg	Participants received 200 μg inhaled AZD7594 via multi-dose dry powder inhaler (DPI) (1 x 200 μg inhalation)
AZD7594 400 μg	Participants received 400 μg inhaled AZD7594 via multi-dose DPI (1 x 400 μg inhalation)
AZD7594 1600 μg	Participants received 1600 μg inhaled AZD7594 via multi-dose DPI (4 x 400 μg inhalations).

Measured Values

	AZD7594 200 μg	AZD7594 400 μg	AZD7594 1600 μg
Number of Participants Analyzed [units:participants]	7	7	7
Rate and extent of absorption of AZD7594 by assessment of the renal clearance, estimated by dividing Ae(0-96) by AUC(0-96) (CLR) [units: L/h] Geometric Mean (Geometric Coefficient of Variation)	NA (NA%)^[1]	NA (NA%)^[2]	0.02329 (98.8%)

[1]	NA - Not available Since, %AUCextr was > 30%, values were excluded from descriptive statistics
[2]	NA - Not available Since, %AUCextr was > 30%, values were excluded from descriptive statistics

No statistical analysis provided for Rate and extent of absorption of AZD7594 by assessment of the renal clearance, estimated by dividing Ae(0-96) by AUC(0-96) (CLR)

33. Secondary Outcome Measure: Pharmacodynamic analysis of AZD7594 by assessment of the area under the effect curve for plasma cortisol from time zero to 24 hours after dosing (AUEC [0-24]). [ Time Frame: Day -1 (- 24 hours predose) up to 24 hours postdose; Day 1 and Day 16 ]

Measure Type	Secondary
Measure Name	Pharmacodynamic analysis of AZD7594 by assessment of the area under the effect curve for plasma cortisol from time zero to 24 hours after dosing (AUEC [0-24]).
Measure Description	Assessment of the plasma pharmacodynamics (PD) effects of AZD7594 after single and multiple ascending inhaled doses. AUEC(0-24) was defined as area under the effect curve for plasma cortisol from time zero to 24 hours after dosing.
Time Frame	Day -1 (- 24 hours predose) up to 24 hours postdose; Day 1 and Day 16
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The pharmacodynamics analysis set will include all subjects who receive at least 1 dose of IMP and for whom it is possible to calculate the cortisol AUEC on Day -1, Day 1 and/or Day 16 and with no major protocol deviations considered to impact on the analysis of the PD (cortisol, plasma DHEAS and osteocalcin) data.

Reporting Groups

	Description
AZD7594 200 μg	Participants received 200 μg inhaled AZD7594 via multi-dose dry powder inhaler (DPI) (1 x 200 μg inhalation)
AZD7594 400 μg	Participants received 400 μg inhaled AZD7594 via multi-dose DPI (1 x 400 μg inhalation)
AZD7594 1600 μg	Participants received 1600 μg inhaled AZD7594 via multi-dose DPI (4 x 400 μg inhalations).
Placebo	Participants received placebo.

Measured Values

	AZD7594 200 μg	AZD7594 400 μg	AZD7594 1600 μg	Placebo
Number of Participants Analyzed [units:participants]	7	7	7	6
Pharmacodynamic analysis of AZD7594 by assessment of the area under the effect curve for plasma cortisol from time zero to 24 hours after dosing (AUEC [0-24]). [units: min*nmol/L] Mean (Standard Deviation)
Day -1	294273.817 (66921.717)	286677.610 (41429.744)	298827.031 (57082.835)	275402.666 (42811.506)
Day 1	268228.553 (34086.352)	274458.997 (36894.669)	264104.101 (47619.269)	256226.560 (48755.915)
Day 16	253767.846 (11407.064)	249097.459 (46925.914)	213505.523 (40857.201)	273268.869 (57797.995)

Statistical Analysis 1 for Pharmacodynamic analysis of AZD7594 by assessment of the area under the effect curve for plasma cortisol from time zero to 24 hours after dosing (AUEC [0-24]).

Groups^[1]	AZD7594 200 μg, Placebo
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	ANCOVA
Other^[5]	102.99
95% Confidence Interval	( 86.88 to 122.09 )

[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.
[5]	Other relevant estimation information:
	Day 1/ Day -1

Statistical Analysis 2 for Pharmacodynamic analysis of AZD7594 by assessment of the area under the effect curve for plasma cortisol from time zero to 24 hours after dosing (AUEC [0-24]).

Groups^[1]	AZD7594 200 μg, Placebo
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	ANCOVA
Other^[5]	91.82
95% Confidence Interval	( 77.32 to 109.04 )

[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.
[5]	Other relevant estimation information:
	Day 16 / Day -1

Statistical Analysis 3 for Pharmacodynamic analysis of AZD7594 by assessment of the area under the effect curve for plasma cortisol from time zero to 24 hours after dosing (AUEC [0-24]).

Groups^[1]	AZD7594 400 μg, Placebo
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	ANCOVA
Other^[5]	105.92
95% Confidence Interval	( 89.40 to 125.49 )

[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.
[5]	Other relevant estimation information:
	Day 1 / Day -1

Statistical Analysis 4 for Pharmacodynamic analysis of AZD7594 by assessment of the area under the effect curve for plasma cortisol from time zero to 24 hours after dosing (AUEC [0-24]).

Groups^[1]	AZD7594 400 μg, Placebo
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	ANCOVA
Other^[5]	89.44
95% Confidence Interval	( 75.35 to 106.16 )

[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.
[5]	Other relevant estimation information:
	Day 16 / Day -1

Statistical Analysis 5 for Pharmacodynamic analysis of AZD7594 by assessment of the area under the effect curve for plasma cortisol from time zero to 24 hours after dosing (AUEC [0-24]).

Groups^[1]	AZD7594 1600 μg, Placebo
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	ANCOVA
Other^[5]	99.82
95% Confidence Interval	( 84.12 to 118.46 )

[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.
[5]	Other relevant estimation information:
	Day 1 / Day -1

Statistical Analysis 6 for Pharmacodynamic analysis of AZD7594 by assessment of the area under the effect curve for plasma cortisol from time zero to 24 hours after dosing (AUEC [0-24]).

Groups^[1]	AZD7594 1600 μg, Placebo
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	ANCOVA
Other^[5]	75.38
95% Confidence Interval	( 63.40 to 89.61 )

[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.
[5]	Other relevant estimation information:
	Day 16 / Day -1

34. Secondary Outcome Measure: Pharmacodynamic analysis of AZD7594 by assessment of plasma concentration of dehydroepiandrosterone sulphate (DHEAS) [ Time Frame: Day 1 (predose) and Day 16 (24 hours postdose) ]

Measure Type	Secondary
Measure Name	Pharmacodynamic analysis of AZD7594 by assessment of plasma concentration of dehydroepiandrosterone sulphate (DHEAS)
Measure Description	Assessment of the plasma PD following a single dose of AZD7594
Time Frame	Day 1 (predose) and Day 16 (24 hours postdose)
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The pharmacodynamics analysis set will include all subjects who receive at least 1 dose of IMP and for whom it is possible to calculate the cortisol AUEC on Day -1, Day 1 and/or Day 16 and with no major protocol deviations considered to impact on the analysis of the PD (cortisol, plasma DHEAS and osteocalcin) data.

Reporting Groups

	Description
AZD7594 200 μg	Participants received 200 μg inhaled AZD7594 via multi-dose dry powder inhaler (DPI) (1 x 200 μg inhalation)
AZD7594 400 μg	Participants received 400 μg inhaled AZD7594 via multi-dose DPI (1 x 400 μg inhalation)
AZD7594 1600 μg	Participants received 1600 μg inhaled AZD7594 via multi-dose DPI (4 x 400 μg inhalations).
Placebo	Participants received placebo.

Measured Values

	AZD7594 200 μg	AZD7594 400 μg	AZD7594 1600 μg	Placebo
Number of Participants Analyzed [units:participants]	7	7	7	6
Pharmacodynamic analysis of AZD7594 by assessment of plasma concentration of dehydroepiandrosterone sulphate (DHEAS) [units: μmol/L] Mean (Standard Deviation)
Result: Day 1 / pre-dose	6.716 (1.405)	7.380 (2.429)	6.747 (2.936)	6.280 (1.829)
Result: Day 17 / 24 h	6.104 (0.862)	6.250 (1.005)	7.125 (2.708)	6.392 (2.179)

No statistical analysis provided for Pharmacodynamic analysis of AZD7594 by assessment of plasma concentration of dehydroepiandrosterone sulphate (DHEAS)

35. Secondary Outcome Measure: Pharmacodynamic analysis of AZD7594 by assessment of plasma concentration of osteocalcin [ Time Frame: Day 1 (predose) and Day 16 (24 hours postdose) ]

Measure Type	Secondary
Measure Name	Pharmacodynamic analysis of AZD7594 by assessment of plasma concentration of osteocalcin
Measure Description	Assessment of the plasma PD following a single dose of AZD7594
Time Frame	Day 1 (predose) and Day 16 (24 hours postdose)
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The pharmacodynamics analysis set will include all subjects who receive at least 1 dose of IMP and for whom it is possible to calculate the cortisol AUEC on Day -1, Day 1 and/or Day 16 and with no major protocol deviations considered to impact on the analysis of the PD (cortisol, plasma DHEAS and osteocalcin) data.

Reporting Groups

	Description
AZD7594 200 μg	Participants received 200 μg inhaled AZD7594 via multi-dose dry powder inhaler (DPI) (1 x 200 μg inhalation)
AZD7594 400 μg	Participants received 400 μg inhaled AZD7594 via multi-dose DPI (1 x 400 μg inhalation)
AZD7594 1600 μg	Participants received 1600 μg inhaled AZD7594 via multi-dose DPI (4 x 400 μg inhalations).
Placebo	Participants received placebo.

Measured Values

	AZD7594 200 μg	AZD7594 400 μg	AZD7594 1600 μg	Placebo
Number of Participants Analyzed [units:participants]	7	7	7	6
Pharmacodynamic analysis of AZD7594 by assessment of plasma concentration of osteocalcin [units: μg/L] Mean (Standard Deviation)
Day 1 / pre-dose	21.31 (17.22)	23.13 (10.02)	20.01 (5.77)	22.92 (20.13)
Day 17 / 24 h	17.81 (8.55)	19.66 (11.56)	13.37 (8.26)	17.03 (5.60)

No statistical analysis provided for Pharmacodynamic analysis of AZD7594 by assessment of plasma concentration of osteocalcin

Serious Adverse Events

Time Frame	Serious adverse events (SAEs) were recorded from the signing of informed consent and adverse events (AEs) were recorded from randomization until the final follow-up visit.
Additional Description	An AE is an undesirable medical condition or the deterioration of a pre-existing medical condition following or during exposure to a pharmaceutical product, whether or not considered causally related to the product. AEs which met the "Definitions of Serious Adverse Event" defined in the clinical study protocol were regarded as SAEs.

Reporting Groups

	Description
AZD7594 200 μg	Participants received 200 μg inhaled AZD7594 via multi-dose dry powder inhaler (DPI) (1 x 200 μg inhalation)
AZD7594 400 μg	Participants received 400 μg inhaled AZD7594 via multi-dose DPI (1 x 400 μg inhalation)
AZD7594 1600 μg	Participants received 1600 μg inhaled AZD7594 via multi-dose DPI (4 x 400 μg inhalations).
Palcebo	Participants received placebo
Total AZD7594	Overall number of subjects who received AZD7594 therapy.
All subjects	Overall number of subjects who participated in the study.

Serious Adverse Events

	AZD7594 200 μg	AZD7594 400 μg	AZD7594 1600 μg	Palcebo	Total AZD7594	All subjects
Total, serious adverse events
# participants affected / at risk	0/7 (0.00%)	0/7 (0.00%)	0/7 (0.00%)	0/6 (0.00%)	0/21 (0.00%)	0/27 (0.00%)

Other Adverse Events

Time Frame	Serious adverse events (SAEs) were recorded from the signing of informed consent and adverse events (AEs) were recorded from randomization until the final follow-up visit.
Additional Description	An AE is an undesirable medical condition or the deterioration of a pre-existing medical condition following or during exposure to a pharmaceutical product, whether or not considered causally related to the product. AEs which met the "Definitions of Serious Adverse Event" defined in the clinical study protocol were regarded as SAEs.

Frequency Threshold

Threshold above which other adverse events are reported	0%

Reporting Groups

	Description
AZD7594 200 μg	Participants received 200 μg inhaled AZD7594 via multi-dose dry powder inhaler (DPI) (1 x 200 μg inhalation)
AZD7594 400 μg	Participants received 400 μg inhaled AZD7594 via multi-dose DPI (1 x 400 μg inhalation)
AZD7594 1600 μg	Participants received 1600 μg inhaled AZD7594 via multi-dose DPI (4 x 400 μg inhalations).
Palcebo	Participants received placebo
Total AZD7594	Overall number of subjects who received AZD7594 therapy.
All subjects	Overall number of subjects who participated in the study.

Other Adverse Events

AZD7594 200 μg

AZD7594 400 μg

AZD7594 1600 μg

Palcebo

Total AZD7594

All subjects

Total, other (not including serious) adverse events

# participants affected / at risk

3/7 (42.86%)

1/7 (14.29%)

1/6 (16.67%)

5/21 (23.81%)

6/27 (22.22%)

Respiratory, thoracic and mediastinal disorders

Dry throat¹

# participants affected / at risk

1/7 (14.29%)

0/7 (0.00%)

0/6 (0.00%)

1/21 (4.76%)

1/27 (3.70%)

# events

Respiratory, thoracic and mediastinal disorders

Nasal congestion¹

# participants affected / at risk

1/7 (14.29%)

0/7 (0.00%)

0/6 (0.00%)

1/21 (4.76%)

1/27 (3.70%)

# events

Respiratory, thoracic and mediastinal disorders

Oropharyngeal pain¹

# participants affected / at risk

1/7 (14.29%)

0/7 (0.00%)

0/6 (0.00%)

1/21 (4.76%)

1/27 (3.70%)

# events

Infections and infestations

Folliculitis¹

# participants affected / at risk

0/7 (0.00%)

1/7 (14.29%)

0/7 (0.00%)

0/6 (0.00%)

1/21 (4.76%)

1/27 (3.70%)

# events

Metabolism and nutrition disorders

Gout¹

# participants affected / at risk

0/7 (0.00%)

1/6 (16.67%)

0/21 (0.00%)

1/27 (3.70%)

# events

Nervous system disorders

Presyncope¹

# participants affected / at risk

0/7 (0.00%)

1/7 (14.29%)

0/6 (0.00%)

1/21 (4.76%)

1/27 (3.70%)

# events

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

Certain Agreements

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

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

The agreement is:

	The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
	The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days . The sponsor cannot require changes to the communication and cannot extend the embargo.
	Other disclosure agreement that restricts the right of the PI to discuss or publish trial results after the trial is completed. Restriction Description: All clinical study findings and documents will be regarded as confidential. The investigator and members of his/her research team must not disclose such information without prior written approval from the sponsor.

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:	AZD7594 Global Clinical Leader
Organization:	AstraZeneca AB
Phone	+46317761000
E-mail:	[email protected]

Documents available

Trial Results Summaries
Available here

Contacts

Contact

AstraZeneca Clinical Study Information Center

1-877-240-9479

information.center@astrazeneca.com

Investigators

Principal Investigator

Esther Yoon

California Clinical Trials Medical Group

Sponsors

Collaborators

Inclusion Criteria

Exclusion Criteria

Research Site