A Study to Assess the Effect of Particle Size of AZD7594 on Pharmacokinetics (PK) after a Single Inhaled Dose when Administered using the Dry Powder Inhaler in Healthy Volunteers

Study identifier:D3741C00006

ClinicalTrials.gov identifier:NCT02928354

EudraCT identifier:N/A

CTIS identifier:N/A

Study Complete

Official Title

A Randomized Open Label Three-Way Crossover Study in Healthy Male Volunteers to Investigate the effect of Particle Size on Pharmacokinetics following a Single Inhaled Dose of AZD7594 Via a Dry Powder Inhaler

Medical condition

Asthma, Chronic obstructive pulmonary disease (COPD)

Phase

Phase 1

Healthy volunteers

Yes

Study drug

Treatment A - AZD7594, Treatment B - AZD7594, Treatment C - AZD7594

Sex

Male

Actual Enrollment

Study type

Interventional

Age

18 Years - 55 Years

Date

Study Start Date: 25 Nov 2016

Primary Completion Date: 21 Mar 2017

Study Completion Date: 21 Mar 2017

Study design

Allocation: Randomized
Endpoint Classification: Pharmacokinetics
Intervention Model: Crossover Assignment
Masking: Open Label
Primary Purpose: Treatment

Verification:

Verified 01 Feb 2018 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 subjects aged 18 to 55 years (inclusive) with suitable veins for cannulation or repeated venipuncture.
3. Have a body mass index (BMI) between 18 and 29.9 kg/m2 inclusive and weigh at least 50 kg and no more than 100 kg inclusive.
4. Subjects should be willing to follow reproductive restrictions to prevent pregnancy and drug exposure of a female partner and refrain from donating sperm or fathering a child from the first day of dosing until 3 months after the last dose of IMP.
5. Be able to inhale from the DPI devices according to given instructions.
6. Subjects must read, speak and understand German language.

Exclusion Criteria

1. History of any clinically significant disease or disorder which, in the opinion of the PI, may either put the volunteer at risk because of participation in the study, or influence the results or the volunteer’s ability to participate in the study.
2. History or presence of gastrointestinal, 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 IMP.
4. Any clinically significant abnormalities in clinical chemistry, hematology or urinalysis results, at screening and first admission to the study unit as judged by the PI.
5. Any clinically significant abnormal findings in vital signs at screening and first admission to the study unit, as judged by the PI. Abnormal vital signs, after 10 minutes supine rest, defined as any of the following: − Systolic BP (SBP) < 90 mmHg or > 140 mmHg − Diastolic BP (DBP) < 50 mmHg or > 90 mmHg − Heart rate < 45 or > 90 beats per minute.
6. Any clinically significant abnormalities on 12-lead ECG at screening and first admission to the study unit, as judged by the PI.
7. Any positive result on screening for serum hepatitis surface antigen or antiHBc antibody suggestive of hepatitis B infection, hepatitis C antibody, and human immunodeficiency virus (HIV) antibody.
8. Known or suspected history of drug abuse, as judged by the PI.
9. Has received another new chemical entity (defined as a compound which has not been approved for marketing) within 3 months of the first administration of IMP in this study. The period of exclusion begins 3 months after the final dose or one 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.
10. Plasma donation within 1 month of screening or any blood donation/loss more than 500 mL during the 3 months prior to screening.
11. History of severe allergy/hypersensitivity or ongoing allergy/hypersensitivity, as judged by the PI or history of hypersensitivity to drugs with a similar chemical structure or class to AZD7594.
12. Current smokers or those who have smoked or used nicotine products within the 3 months prior to screening.
13. Subjects who are not able to perform correct spirometry tests at screening.
14. Subjects with forced expiratory volume at one second (FEV1) and forced vital capacity (FVC) <80% predicted (calculated) values and FEV1/FVC ratio <0.7 in pulmonary function test (spirometry) at Screening Visit.
15. Positive screen for drugs of abuse or cotinine at screening or on each admission to the study center or positive screen for alcohol on each admission to the study center.
16. Use of drugs with enzyme-inducing properties such as St John’s Wort within 3 weeks prior to the first administration of IMP.
17. 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 IMP or longer if the medication has a long half-life.
18. Known or suspected history of alcohol or drug abuse or excessive intake of alcohol as judged by the PI.
19. Involvement of any AstraZeneca, PAREXEL or study site employee or their close relatives.
20. Subjects who have previously received AZD7594.
21. Judgment by the PI that the volunteer 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.
22. Vulnerable subjects, e.g., kept in detention, protected adults under guardianship, trusteeship, or committed to an institution by governmental or juridical order.

Location

Research Site

Berlin, Germany, 14050

Arms	Assigned Interventions
Experimental: Treatment A - AZD7594 Treatment A - AZD7594 inhalation powder Particle size Large	Drug: Treatment A - AZD7594 Particle size Large as a single inhaled dose of 440 µg (nominal dose), administered via DPI
Experimental: Treatment B - AZD7594 Treatment B - AZD7594 inhalation powder Particle size Medium	Drug: Treatment B - AZD7594 Particle size Medium as a single inhaled dose of 440 µg (nominal dose), administered via DPI
Experimental: Treatment C - AZD7594 Treatment C - AZD7594 inhalation powder Particle size Small	Drug: Treatment C - AZD7594 Particle size Small as a single inhaled dose of 440 µg (nominal dose), administered via DPI

Participant Flow

Recruitment Details

Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
Subjects who met all the inclusion and none of the exclusion criteria were enrolled at PAREXEL Early Phase Clinical Unit in Berlin.

Pre-Assignment Details

Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
Subjects attended a Screening Visit within 28 days before receiving their first dose of AZD7594. All subjects underwent inclusion exclusion criteria assessment and all eligible subjects signed the informed consent before undergoing any study-related procedures.

Reporting Groups

	Description
Treartment sequence: ABC	All randomized subjects received 440 μg AZD7594 of treatment A: Particle size large, B: Particle size medium and C: Particle size small via DPI.
Treatment sequence BCA	All randomized subjects received 440 μg AZD7594 of treatment B: Particle size medium, C: Particle size small and A: Particle size large via DPI.
Treatment sequence: CAB	All randomized subjects received 440 μg AZD7594 of treatment C: Particle size small, A: Particle size large and B: Particle size medium via DPI.
Treatment sequence: ACB	All randomized subjects received 440 μg AZD7594 of treatment A: Particle size large, C: Particle size small and B: Particle size medium via DPI.
Treatment sequence CBA	All randomized subjects received 440 μg AZD7594 of treatment C: Particle size small and B: Particle size medium and A: Particle size large via DPI.
Treatment sequence: BAC	All randomized subjects received 440 μg AZD7594 of treatment B: Particle size medium and A: Particle size large and C: Particle size small via DPI.

Participant Flow: Overall Study

	Treartment sequence: ABC	Treatment sequence BCA	Treatment sequence: CAB	Treatment sequence: ACB	Treatment sequence CBA	Treatment sequence: BAC
STARTED	3	3	3	3	3	3
COMPLETED	3	3	3	3	2	2
NOT COMPLETED	0	0	0	0	1	1
Protocol Deviation: Drug screen positive	0	0	0	0	1	0
Withdrawal by Subject	0	0	0	0	0	1

Baseline Characteristics

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

Reporting Groups

	Description
Treartment sequence: ABC	All randomized subjects received 440 μg AZD7594 of treatment A: Particle size large, B: Particle size medium and C: Particle size small via DPI.
Treatment sequence BCA	All randomized subjects received 440 μg AZD7594 of treatment B: Particle size medium, C: Particle size small and A: Particle size large via DPI.
Treatment sequence: CAB	All randomized subjects received 440 μg AZD7594 of treatment C: Particle size small, A: Particle size large and B: Particle size medium via DPI.
Treatment sequence: ACB	All randomized subjects received 440 μg AZD7594 of treatment A: Particle size large, C: Particle size small and B: Particle size medium via DPI.
Treatment sequence CBA	All randomized subjects received 440 μg AZD7594 of treatment C: Particle size small and B: Particle size medium and A: Particle size large via DPI.
Treatment sequence: BAC	All randomized subjects received 440 μg AZD7594 of treatment B: Particle size medium and A: Particle size large and C: Particle size small via DPI.

Baseline Measures

	Treartment sequence: ABC	Treatment sequence BCA	Treatment sequence: CAB	Treatment sequence: ACB	Treatment sequence CBA	Treatment sequence: BAC	Total
Number of Participants [units: Participants]	3	3	3	3	3	3	18
Age Continuous [units: Years] Mean ± Standard Deviation	40.3 ± 10.8	30.3 ± 3.8	40.3 ± 12.7	43.0 ± 15.6	44.3 ± 9.5	31.0 ± 4.6	38.2 ± 10.4
Sex: Female, Male [units: Participants]
Female	0	0	0	0	0	0	0
Male	3	3	3	3	3	3	18
Race (NIH/OMB) [units: Participants]
American Indian or Alaska Native	0	0	0	0	0	0	0
Asian	0	0	0	0	0	0	0
Native Hawaiian or Other Pacific Islander	0	0	0	0	0	0	0
Black or African American	0	0	0	0	0	0	0
White	2	3	3	3	3	3	17
More than one race	0	0	0	0	0	0	0
Unknown or Not Reported	1	0	0	0	0	0	1

Outcome Measures

1. Primary Outcome Measure: Area under plasma concentration-time curve from time zero to infinity (AUC) [ Time Frame: At pre-dose and at 15, 30, and 45 minutes, and 1,2, 4, 6, 8, 12, 16, 24, 36 and 48, 72, 96, 144 and 240 hours post dose ]

Measure Type	Primary
Measure Name	Area under plasma concentration-time curve from time zero to infinity (AUC)
Measure Description	To investigate the effect of particle size on the PK (AUC) of AZD7594 following a single inhaled dose of AZD7594 via a DPI.
Time Frame	At pre-dose and at 15, 30, and 45 minutes, and 1,2, 4, 6, 8, 12, 16, 24, 36 and 48, 72, 96, 144 and 240 hours post dose
Safety Issue?

Results not yet posted. Anticipated Posting Date: No text entered. Safety Issue: No text entered.

2. Primary Outcome Measure: Area under the plasma concentration-time curve from time zero to time of last quantifiable concentration (AUClast) [ Time Frame: At pre-dose and at 15, 30, and 45 minutes, and 1,2, 4, 6, 8, 12, 16, 24, 36 and 48, 72, 96, 144 and 240 hours post dose ]

Measure Type	Primary
Measure Name	Area under the plasma concentration-time curve from time zero to time of last quantifiable concentration (AUClast)
Measure Description	To investigate the effect of particle size on the PK (AUClast) of AZD7594 following a single inhaled dose of AZD7594 via a DPI.
Time Frame	At pre-dose and at 15, 30, and 45 minutes, and 1,2, 4, 6, 8, 12, 16, 24, 36 and 48, 72, 96, 144 and 240 hours post dose
Safety Issue?

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The PK analysis set consisted of all subjects who were dosed with the IMP and for whom any safety post-dose data were available and for whom at least one primary PK parameter could be calculated in all 3 treatment periods and with no important protocol deviations that was thought to have impact on the analysis of the PK data.

Reporting Groups

	Description
Treatment A (Particle size: large)	The subjects received 440 μg of large particle size AZD7594 inhalation powder via DPI.
Treatment B (Particle size: medium)	The subjects received 440 μg of medium particle size AZD7594 inhalation powder via DPI.
Treatment C (Particle size: small)	The subjects received 440 μg of small particle size AZD7594 inhalation powder via DPI.

Measured Values

	Treatment A (Particle size: large)	Treatment B (Particle size: medium)	Treatment C (Particle size: small)
Number of Participants Analyzed [units:participants]	16	16	16
Area under the plasma concentration-time curve from time zero to time of last quantifiable concentration (AUClast) [units: h*pmol/L] Geometric Mean (Geometric Coefficient of Variation)	2881 (27.34%)	3738 (39.57%)	3716 (27.45%)

Statistical Analysis 1 for Area under the plasma concentration-time curve from time zero to time of last quantifiable concentration (AUClast)

Groups^[1]	Treatment A (Particle size: large), Treatment C (Particle size: small)
Method^[3]	ANOVA
Other^[5]	128.12
90% Confidence Interval	( 114.88 to 142.90 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Ratio C/A
[3]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 2 for Area under the plasma concentration-time curve from time zero to time of last quantifiable concentration (AUClast)

Groups^[1]	Treatment A (Particle size: large), Treatment B (Particle size: medium)
Method^[3]	ANOVA
Other^[5]	128.33
90% Confidence Interval	( 115.06 to 143.13 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Ratio B/A
[3]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 3 for Area under the plasma concentration-time curve from time zero to time of last quantifiable concentration (AUClast)

Groups^[1]	Treatment B (Particle size: medium), Treatment C (Particle size: small)
Method^[3]	ANOVA
Other^[5]	99.84
90% Confidence Interval	( 89.52 to 111.35 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Ratio C/B
[3]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[5]	Other relevant estimation information:
	No text entered.

3. Primary Outcome Measure: Observed maximum plasma concentration (Cmax) [ Time Frame: At pre-dose and at 15, 30, and 45 minutes, and 1, 2, 4, 6, 8, 12, 16, 24, 36 and 48, 72, 96, 144 and 240 hours post dose ]

Measure Type	Primary
Measure Name	Observed maximum plasma concentration (Cmax)
Measure Description	To investigate the effect of particle size on the PK (Cmax) of AZD7594 following a single inhaled dose of AZD7594 via a DPI.
Time Frame	At pre-dose and at 15, 30, and 45 minutes, and 1, 2, 4, 6, 8, 12, 16, 24, 36 and 48, 72, 96, 144 and 240 hours post dose
Safety Issue?

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The PK analysis set consisted of all subjects who were dosed with the IMP and for whom any safety post-dose data were available and for whom at least one primary PK parameter could be calculated in all 3 treatment periods and with no important protocol deviations that was thought to have impact on the analysis of the PK data.

Reporting Groups

	Description
Treatment A (Particle size: large)	The subjects received 440 μg of large particle size AZD7594 inhalation powder via DPI.
Treatment B (Particle size: medium)	The subjects received 440 μg of medium particle size AZD7594 inhalation powder via DPI.
Treatment C (Particle size: small)	The subjects received 440 μg of small particle size AZD7594 inhalation powder via DPI.

Measured Values

	Treatment A (Particle size: large)	Treatment B (Particle size: medium)	Treatment C (Particle size: small)
Number of Participants Analyzed [units:participants]	16	16	16
Observed maximum plasma concentration (Cmax) [units: pmol/L] Geometric Mean (Geometric Coefficient of Variation)	161.9 (29.44%)	168.0 (28.98%)	198.0 (26.01%)

Statistical Analysis 1 for Observed maximum plasma concentration (Cmax)

Groups^[1]	Treatment A (Particle size: large), Treatment C (Particle size: small)
Method^[3]	ANOVA
Other^[5]	121.62
90% Confidence Interval	( 111.97 to 132.10 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Ratio C/A
[3]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 2 for Observed maximum plasma concentration (Cmax)

Groups^[1]	Treatment A (Particle size: large), Treatment B (Particle size: medium)
Method^[3]	ANOVA
Other^[5]	102.73
90% Confidence Interval	( 94.58 to 111.59 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Ratio B/A
[3]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 3 for Observed maximum plasma concentration (Cmax)

Groups^[1]	Treatment B (Particle size: medium), Treatment C (Particle size: small)
Method^[3]	ANOVA
Other^[5]	118.38
90% Confidence Interval	( 108.99 to 128.58 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Ratio C/B
[3]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[5]	Other relevant estimation information:
	No text entered.

4. Primary Outcome Measure: Time to reach maximum observed plasma concentration (tmax) [ Time Frame: At pre-dose and at 15, 30, and 45 minutes, and 1,2, 4, 6, 8, 12, 16, 24, 36 and 48, 72, 96, 144 and 240 hours post dose ]

Measure Type	Primary
Measure Name	Time to reach maximum observed plasma concentration (tmax)
Measure Description	To investigate the effect of particle size on the PK (tmax) of AZD7594 following a single inhaled dose of AZD7594 via a DPI.
Time Frame	At pre-dose and at 15, 30, and 45 minutes, and 1,2, 4, 6, 8, 12, 16, 24, 36 and 48, 72, 96, 144 and 240 hours post dose
Safety Issue?

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The PK analysis set consisted of all subjects who were dosed with the IMP and for whom any safety post-dose data were available and for whom at least one primary PK parameter could be calculated in all 3 treatment periods and with no important protocol deviations that was thought to have impact on the analysis of the PK data.

Reporting Groups

	Description
Treatment A (Particle size: large)	The subjects received 440 μg of large particle size AZD7594 inhalation powder via DPI.
Treatment B (Particle size: medium)	The subjects received 440 μg of medium particle size AZD7594 inhalation powder via DPI.
Treatment C (Particle size: small)	The subjects received 440 μg of small particle size AZD7594 inhalation powder via DPI.

Measured Values

	Treatment A (Particle size: large)	Treatment B (Particle size: medium)	Treatment C (Particle size: small)
Number of Participants Analyzed [units:participants]	16	16	16
Time to reach maximum observed plasma concentration (tmax) [units: hours] Median (Full Range)	0.25 (0.25 to 1.00)	0.63 (0.25 to 2.00)	0.49 (0.25 to 1.00)

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

5. Primary Outcome Measure: Half-life associated with terminal slope (λz) of a semi-logarithmic concentration-time curve (t½λz) [ Time Frame: At pre-dose and at 15, 30, and 45 minutes, and 1,2, 4, 6, 8, 12, 16, 24, 36 and 48, 72, 96, 144 and 240 hours post dose ]

Measure Type	Primary
Measure Name	Half-life associated with terminal slope (λz) of a semi-logarithmic concentration-time curve (t½λz)
Measure Description	To investigate the effect of particle size on the PK (t½λz) of AZD7594 following a single inhaled dose of AZD7594 via a DPI.
Time Frame	At pre-dose and at 15, 30, and 45 minutes, and 1,2, 4, 6, 8, 12, 16, 24, 36 and 48, 72, 96, 144 and 240 hours post dose
Safety Issue?

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The PK analysis set consisted of all subjects who were dosed with the IMP and for whom any safety post-dose data were available and for whom at least one primary PK parameter could be calculated in all 3 treatment periods and with no important protocol deviations that was thought to have impact on the analysis of the PK data.

Reporting Groups

	Description
Treatment A (Particle size: large)	The subjects received 440 μg of large particle size AZD7594 inhalation powder via DPI.
Treatment B (Particle size: medium)	The subjects received 440 μg of medium particle size AZD7594 inhalation powder via DPI.
Treatment C (Particle size: small)	The subjects received 440 μg of small particle size AZD7594 inhalation powder via DPI.

Measured Values

	Treatment A (Particle size: large)	Treatment B (Particle size: medium)	Treatment C (Particle size: small)
Number of Participants Analyzed [units:participants]	16	16	16
Half-life associated with terminal slope (λz) of a semi-logarithmic concentration-time curve (t½λz) [units: hours] Mean (Standard Deviation)	42.13 (18.20)	37.26 (9.803)	30.69 (5.381)

No statistical analysis provided for Half-life associated with terminal slope (λz) of a semi-logarithmic concentration-time curve (t½λz)

6. Primary Outcome Measure: Mean residence time (MRT) [ Time Frame: At pre-dose and at 15, 30, and 45 minutes, and 1,2, 4, 6, 8, 12, 16, 24, 36 and 48, 72, 96, 144 and 240 hours post dose ]

Measure Type	Primary
Measure Name	Mean residence time (MRT)
Measure Description	To investigate the effect of particle size on the PK (MRT) of AZD7594 following a single inhaled dose of AZD7594 via a DPI.
Time Frame	At pre-dose and at 15, 30, and 45 minutes, and 1,2, 4, 6, 8, 12, 16, 24, 36 and 48, 72, 96, 144 and 240 hours post dose
Safety Issue?

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The PK analysis set consisted of all subjects who were dosed with the IMP and for whom any safety post-dose data were available and for whom at least one primary PK parameter could be calculated in all 3 treatment periods and with no important protocol deviations that was thought to have impact on the analysis of the PK data.

Reporting Groups

	Description
Treatment A (Particle size: large)	The subjects received 440 μg of large particle size AZD7594 inhalation powder via DPI.
Treatment B (Particle size: medium)	The subjects received 440 μg of medium particle size AZD7594 inhalation powder via DPI.
Treatment C (Particle size: small)	The subjects received 440 μg of small particle size AZD7594 inhalation powder via DPI.

Measured Values

	Treatment A (Particle size: large)	Treatment B (Particle size: medium)	Treatment C (Particle size: small)
Number of Participants Analyzed [units:participants]	16	16	16
Mean residence time (MRT) [units: hours] Mean (Standard Deviation)	52.52 (20.62)	51.45 (11.20)	42.90 (6.473)

No statistical analysis provided for Mean residence time (MRT)

7. Primary Outcome Measure: Apparent total body clearance of drug from plasma after extravascular administration, estimated as dose divided by AUC (CL/F) [ Time Frame: At pre-dose and at 15, 30, and 45 minutes, and 1,2, 4, 6, 8, 12, 16, 24, 36 and 48, 72, 96, 144 and 240 hours post dose ]

Measure Type	Primary
Measure Name	Apparent total body clearance of drug from plasma after extravascular administration, estimated as dose divided by AUC (CL/F)
Measure Description	To investigate the effect of particle size on the PK (CL/F) of AZD7594 following a single inhaled dose of AZD7594 via a DPI.
Time Frame	At pre-dose and at 15, 30, and 45 minutes, and 1,2, 4, 6, 8, 12, 16, 24, 36 and 48, 72, 96, 144 and 240 hours post dose
Safety Issue?

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The PK analysis set consisted of all subjects who were dosed with the IMP and for whom any safety post-dose data were available and for whom at least one primary PK parameter could be calculated in all 3 treatment periods and with no important protocol deviations that was thought to have impact on the analysis of the PK data.

Reporting Groups

	Description
Treatment A (Particle size: large)	The subjects received 440 μg of large particle size AZD7594 inhalation powder via DPI.
Treatment B (Particle size: medium)	The subjects received 440 μg of medium particle size AZD7594 inhalation powder via DPI.
Treatment C (Particle size: small)	The subjects received 440 μg of small particle size AZD7594 inhalation powder via DPI.

Measured Values

	Treatment A (Particle size: large)	Treatment B (Particle size: medium)	Treatment C (Particle size: small)
Number of Participants Analyzed [units:participants]	16	16	16
Apparent total body clearance of drug from plasma after extravascular administration, estimated as dose divided by AUC (CL/F) [units: liters/hours] Mean (Standard Deviation)	207.4 (58.59)	163.2 (63.61)	166.1 (37.61)

No statistical analysis provided for Apparent total body clearance of drug from plasma after extravascular administration, estimated as dose divided by AUC (CL/F)

8. Primary Outcome Measure: Apparent volume of distribution during the terminal phase after extravascular administration estimated by dividing CL/F by λz (Vz/F) [ Time Frame: At pre-dose and at 15, 30, and 45 minutes, and 1,2, 4, 6, 8, 12, 16, 24, 36 and 48, 72, 96, 144 and 240 hours post dose ]

Measure Type	Primary
Measure Name	Apparent volume of distribution during the terminal phase after extravascular administration estimated by dividing CL/F by λz (Vz/F)
Measure Description	To investigate the effect of particle size on the PK (Vz/F) of AZD7594 following a single inhaled dose of AZD7594 via a DPI.
Time Frame	At pre-dose and at 15, 30, and 45 minutes, and 1,2, 4, 6, 8, 12, 16, 24, 36 and 48, 72, 96, 144 and 240 hours post dose
Safety Issue?

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The PK analysis set consisted of all subjects who were dosed with the IMP and for whom any safety post-dose data were available and for whom at least one primary PK parameter could be calculated in all 3 treatment periods and with no important protocol deviations that was thought to have impact on the analysis of the PK data.

Reporting Groups

	Description
Treatment A (Particle size: large)	The subjects received 440 μg of large particle size AZD7594 inhalation powder via DPI.
Treatment B (Particle size: medium)	The subjects received 440 μg of medium particle size AZD7594 inhalation powder via DPI.
Treatment C (Particle size: small)	The subjects received 440 μg of small particle size AZD7594 inhalation powder via DPI.

Measured Values

	Treatment A (Particle size: large)	Treatment B (Particle size: medium)	Treatment C (Particle size: small)
Number of Participants Analyzed [units:participants]	16	16	16
Apparent volume of distribution during the terminal phase after extravascular administration estimated by dividing CL/F by λz (Vz/F) [units: liters] Mean (Standard Deviation)	10810 (2002)	8475 (2343)	7292 (1888)

No statistical analysis provided for Apparent volume of distribution during the terminal phase after extravascular administration estimated by dividing CL/F by λz (Vz/F)

9. Secondary Outcome Measure: Adverse Events Overview [ Time Frame: Screening (Day -28) up to follow up visit (10 days after last IMP administration) ]

Measure Type	Secondary
Measure Name	Adverse Events Overview
Measure Description	To evaluate the safety and tolerability of single inhaled doses AZD7594 in healthy subjects
Time Frame	Screening (Day -28) up to follow up visit (10 days after last IMP administration)
Safety Issue?

Population Description

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

Reporting Groups

	Description
Treatment A (Particle size: large)	The subjects received 440 μg of large particle size AZD7594 inhalation powder via DPI.
Treatment B (Particle size: medium)	The subjects received 440 μg of medium particle size AZD7594 inhalation powder via DPI.
Treatment C (Particle size: small)	The subjects received 440 μg of small particle size AZD7594 inhalation powder via DPI.

Measured Values

	Treatment A (Particle size: large)	Treatment B (Particle size: medium)	Treatment C (Particle size: small)
Number of Participants Analyzed [units:participants]	18	18	18
Adverse Events Overview [units: ]
All AEs	3	7	8
All AE causally related to treatment	0	0	0
All AE with outcome death	0	0	0
All AE (death, causally related to treatment)	0	0	0
All SAE (including events with death)	0	0	0
All SAE(death and causally related to treatment)	0	0	0
All AE leading to discontinuation of IMP	0	0	0

No statistical analysis provided for Adverse Events Overview

Serious Adverse Events

Time Frame	Adverse events were collected throughout the study ie. from screening (Day -28) upto follow up visit (10 days after last IMP administration).
Additional Description	No text entered.

Reporting Groups

	Description
Treatment A (Particle size: large)	The subjects received 440 μg of large particle size AZD7594 inhalation powder via DPI.
Treatment B (Particle size: medium)	The subjects received 440 μg of medium particle size AZD7594 inhalation powder via DPI.
Treatment C (Particle size: small)	The subjects received 440 μg of small particle size AZD7594 inhalation powder via DPI.

Serious Adverse Events

	Treatment A (Particle size: large)	Treatment B (Particle size: medium)	Treatment C (Particle size: small)
Total, serious adverse events
# participants affected / at risk	0/18 (0.00%)	0/18 (0.00%)	0/18 (0.00%)

Other Adverse Events

Time Frame	Adverse events were collected throughout the study ie. from screening (Day -28) upto follow up visit (10 days after last IMP administration).
Additional Description	No text entered.

Frequency Threshold

Threshold above which other adverse events are reported	0%

Reporting Groups

	Description
Treatment A (Particle size: large)	The subjects received 440 μg of large particle size AZD7594 inhalation powder via DPI.
Treatment B (Particle size: medium)	The subjects received 440 μg of medium particle size AZD7594 inhalation powder via DPI.
Treatment C (Particle size: small)	The subjects received 440 μg of small particle size AZD7594 inhalation powder via DPI.

Other Adverse Events

Treatment A (Particle size: large)

Treatment B (Particle size: medium)

Treatment C (Particle size: small)

Total, other (not including serious) adverse events