A Study to Evaluate the Amount of Drug That Becomes Available to the Blood Circulation When Inhaled by a Nebulizer and Dry Powder Inhaler in Healthy Subjects.

An Open-label, Single-centre, Randomised, 3-period, 3-treatment, Single-dose, Crossover Study to Assess the Relative Bioavailability of AZD7594 Inhaled Via a Nebulizer and Via a Dry Powder Inhaler in Healthy Subjects

The purpose of this study is to assess the relative bioavailability of the AZD7594 nebulized formulations (test) and the dry powder formulation (reference).

The study results will provide information on the pharmacokinetic (PK) profile following use of the 2 devices to be used in further clinical development.

Study Overview

• Status: Completed
• Conditions: Asthma
• Intervention / Treatment: Drug: AZD7594

Detailed Description

This study will be an open-label, randomised, 3 period, 3-treatment, crossover study in healthy subjects (males and females), performed at a single clinical unit.

The study will comprise:

• A screening period of maximum 28 days;
• Three treatment periods during which subjects will be resident from the morning (fasting conditions) of the day before dosing with AZD7594 (Day -1) until at least 48 hours after dosing; discharged on the morning of Day 3;
• Two ambulatory visits (Day 4 and Day 5) within each treatment period; and
• A final visit 10 to 14 days after the last administration of AZD7594.
• There will be a minimum washout period of 10 days between each dose administration.

A total of 24 subjects will be randomised to receive single doses of AZD7594 on 3 occasions, under fasted conditions (overnight fast of at least 10 hours):

• Treatment A: 0.7 mg (delivered dose) AZD7594 via nebulizer, test
• Treatment B: 1.6 mg (delivered dose) AZD7594 via nebulizer, test
• Treatment C: 720 μg (delivered dose) AZD7594 via dry powder inhaler (DPI), reference

Each subject will be involved in the study for approximately 10 to 12 weeks.

• Study Type: Interventional
• Enrollment (Actual): 24
• Phase: Phase 1

Contacts and Locations

Study Locations

• Germany
  • Berlin, Germany, 14050
    • Research Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 55 years (Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Provision of signed and dated, written informed consent prior to any study specific procedures.
2. Healthy male and female subjects aged 18 - 55 years (inclusive) at Screening with suitable veins for cannulation or repeated venepuncture.
3. Females must have a negative pregnancy test at screening and on admission to the unit for each treatment period, and must not be lactating. Women of child-bearing potential (WOCBP) must be stable on their chosen method of highly effective birth control for a minimum of 3 months prior to Visit 1, and willing to use that for the entire duration of the study (from the time they sign the informed consent), and for 14 days after the last dose of IMP. They must agree not to become pregnant or donate ova throughout the study and for 14 days after the last dose of IMP. Male subjects must be surgically sterile or be willing to use a condom during the study.
4. 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).
5. Subject is able to understand and communicate in German.

Exclusion Criteria:

1. History of any clinically significant disease or disorder which, in the opinion of the PI, 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, hepatic or renal disease, or any other condition known to interfere with absorption, distribution, metabolism, or excretion of drugs.
3. History of Gilbert's syndrome, history of cholecystectomy or gall stone.
4. History of tuberculosis, any other significant lung diseases like surgeries, asthma, chronic obstructive pulmonary disease.
5. Upper respiratory tract infections (excluding otitis media) within 14 days of the first study day, or lower respiratory tract infection within 3 months prior to Screening.
6. Any clinically significant illness, medical/surgical procedure, or trauma within 4 weeks of the first administration of IMP.
7. Any clinically significant abnormalities in clinical chemistry, haematology, or urinalysis results, at screening and first admission to the study unit (first treatment period) as judged by the PI.

8. Any clinically significant abnormal findings in vital signs at screening and first admission to the study unit (first treatment period), as judged by the PI, and defined as:

   • Systolic BP <90 mmHg or ≥140 mmHg and diastolic BP <50 mmHg or ≥90 mmHg
   • Heart rate <50 bpm or >90 bpm

9. Any clinically significant abnormalities on 12-lead ECG at screening and first admission to the study unit (first treatment period), as judged by the PI, and defined as:

   • Sick sinus syndrome
   • Arrhythmia
   • Prolonged QT interval corrected using Fridericia's formula > 450 ms
10. Any positive result at screening for serum hepatitis B surface antigen (HBsAg), hepatitis C virus (HCV) antibody or human immunodeficiency virus (HIV) results.
11. 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 1 month after the last visit whichever is the longest. Note: subjects consented and screened, but not randomised in this study or other clinical studies, are not excluded.
12. Plasma donation within 1 month of screening or any blood donation/loss more than 500 mL during the 3 months prior to screening.

13. History of severe allergy/hypersensitivity or ongoing allergy/hypersensitivity to AZD7594 or formulation excipients, as judged by the PI or history of hypersensitivity to drugs with a similar chemical structure or class to AZD7594.

    Note: subjects with hay fever are allowed to participate, unless hay fever is active

14. Current smokers or those who have smoked or used nicotine products (including e-cigarettes; >10 pack-year) within the 6 months prior to screening.
15. Known or suspected history of alcohol or drug abuse or excessive intake of alcohol as judged by the PI or positive screen for drugs of abuse, cotinine, and/or alcohol at screening or on each admission to the clinical unit.
16. Use of drugs with enzyme-inducing properties within 3 weeks prior to the first administration of IMP or herbal preparations/medications including, but not limited to, St. John's wort, kava, ephedra (ma huang), gingko biloba, dehydroepiandrosterone, yohimbe, saw palmetto, and ginseng. Subjects should stop using these herbal medications 14 days 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.

    Note: Hormonal replacement therapy (HRT) and systemic contraceptives are allowed for females.

18. Subjects not able to perform a technically acceptable spirometry and/or not able to use the DPI correctly or not able to tolerate the pre-defined inhalation/nebulization.
19. Subjects with a pregnant partner.
20. Involvement of any AstraZeneca, PAREXEL or study site employee or their close relatives.
21. Subjects who have previously received AZD7594.
22. Vulnerable subjects, eg, kept in detention, protected adults under guardianship, trusteeship, or committed to an institution by governmental or juridical order.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: AZD7594 0.7 mg; The study subjects will receive AZD7594 via nebulizer, during 8 minutes: 0.7 mg, delivered dose 1 inhalation	Drug: AZD7594; Treatment A: The study drug is a nebulizer suspension with strength 2.8 mg/mL using 2 mL in the device. The study drug is administered via oral inhalation. Treatment B: The study drug is a nebulizer suspension with strength 6.3 mg/mL using 2 mL in the device. The study drug was administered via oral inhalation. Treatment C: The study drug is an inhalation powder. The study drug was administered via oral inhalation.
Experimental: AZD7594 1.6 mg; The study subjects will receive AZD7594 via nebulizer, during 8 minutes: 1.6 mg, delivered dose 1 inhalation	Drug: AZD7594; Treatment A: The study drug is a nebulizer suspension with strength 2.8 mg/mL using 2 mL in the device. The study drug is administered via oral inhalation. Treatment B: The study drug is a nebulizer suspension with strength 6.3 mg/mL using 2 mL in the device. The study drug was administered via oral inhalation. Treatment C: The study drug is an inhalation powder. The study drug was administered via oral inhalation.
Active Comparator: AZD7594 720 μg; The study subjects will receive AZD7594 via DPI: 0.72 mg, delivered dose (792 µg nominal dose) 1 inhalation	Drug: AZD7594; Treatment A: The study drug is a nebulizer suspension with strength 2.8 mg/mL using 2 mL in the device. The study drug is administered via oral inhalation. Treatment B: The study drug is a nebulizer suspension with strength 6.3 mg/mL using 2 mL in the device. The study drug was administered via oral inhalation. Treatment C: The study drug is an inhalation powder. The study drug was administered via oral inhalation.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maximum observed plasma concentration (Cmax)	To estimate the relative bioavailability of AZD7594 following inhalation via nebulizer Omron NE C900-E (2 dose levels) and via DPI SD3FL	At pre-dose, at 15, 30, and 45 minutes, and at 1, 2, 4, 6, 8, 12, 16, 24, 36, 48, 72, and 96 hours post dose (Days 1, 2, 3, 4 and 5)
Area under plasma concentration-time curve from zero to infinity (AUC)	To estimate the relative bioavailability of AZD7594 following inhalation via nebulizer Omron NE C900-E (2 dose levels) and via DPI SD3FL	At pre-dose, at 15, 30, and 45 minutes, and at 1, 2, 4, 6, 8, 12, 16, 24, 36, 48, 72, and 96 hours post dose (Days 1, 2, 3, 4 and 5)
Area under the plasma concentration-time curve from time zero to time of last quantifiable concentration (AUC0-t)	To estimate the relative bioavailability of AZD7594 following inhalation via nebulizer Omron NE C900-E (2 dose levels) and via DPI SD3FL	At pre-dose, at 15, 30, and 45 minutes, and at 1, 2, 4, 6, 8, 12, 16, 24, 36, 48, 72, and 96 hours post dose (Days 1, 2, 3, 4 and 5)
Individual ratios of test versus reference for AUC	To estimate the relative bioavailability of AZD7594 following inhalation via nebulizer Omron NE C900-E (2 dose levels) and via DPI SD3FL	At pre-dose, at 15, 30, and 45 minutes, and at 1, 2, 4, 6, 8, 12, 16, 24, 36, 48, 72, and 96 hours post dose (Days 1, 2, 3, 4 and 5)
Individual ratios of test versus reference for AUC0-t	To estimate the relative bioavailability of AZD7594 following inhalation via nebulizer Omron NE C900-E (2 dose levels) and via DPI SD3FL	At pre-dose, at 15, 30, and 45 minutes, and at 1, 2, 4, 6, 8, 12, 16, 24, 36, 48, 72, and 96 hours post dose (Days 1, 2, 3, 4 and 5)
Individual ratios of test versus reference for Cmax	To estimate the relative bioavailability of AZD7594 following inhalation via nebulizer Omron NE C900-E (2 dose levels) and via DPI SD3FL	At pre-dose, at 15, 30, and 45 minutes, and at 1, 2, 4, 6, 8, 12, 16, 24, 36, 48, 72, and 96 hours post dose (Days 1, 2, 3, 4 and 5)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to reach maximum observed plasma concentration (tmax)	To evaluate the PK profiles of AZD7594 when administered as the two formulations	At pre-dose, at 15, 30, and 45 minutes, and at 1, 2, 4, 6, 8, 12, 16, 24, 36, 48, 72, and 96 hours post dose (Days 1, 2, 3, 4 and 5)
Terminal elimination rate constant (λz)	To evaluate the PK profiles of AZD7594 when administered as the two formulations	At pre-dose, at 15, 30, and 45 minutes, and at 1, 2, 4, 6, 8, 12, 16, 24, 36, 48, 72, and 96 hours post dose (Days 1, 2, 3, 4 and 5)
Half-life associated with terminal slope (λz) of a semilogarithmic concentration-time curve (t1/2λz)	To evaluate the PK profiles of AZD7594 when administered as the two formulations	At pre-dose, at 15, 30, and 45 minutes, and at 1, 2, 4, 6, 8, 12, 16, 24, 36, 48, 72, and 96 hours post dose (Days 1, 2, 3, 4 and 5)
Mean residence time of the unchanged drug in the systemic circulation from zero to infinity (MRT)	To evaluate the PK profiles of AZD7594 when administered as the two formulations	At pre-dose, at 15, 30, and 45 minutes, and at 1, 2, 4, 6, 8, 12, 16, 24, 36, 48, 72, and 96 hours post dose (Days 1, 2, 3, 4 and 5)
Apparent total body clearance of drug from plasma after extravascular administration (CL/F)	To evaluate the PK profiles of AZD7594 when administered as the two formulations	At pre-dose, at 15, 30, and 45 minutes, and at 1, 2, 4, 6, 8, 12, 16, 24, 36, 48, 72, and 96 hours post dose (Days 1, 2, 3, 4 and 5)
Apparent volume of distribution during the terminal phase after extravascular administration (Vz/F)	To evaluate the PK profiles of AZD7594 when administered as the two formulations	At pre-dose, at 15, 30, and 45 minutes, and at 1, 2, 4, 6, 8, 12, 16, 24, 36, 48, 72, and 96 hours post dose (Days 1, 2, 3, 4 and 5)
Number of participants with adverse events	To further assess the safety of single doses of AZD7594 in healthy volunteers	From Screening (Day -28) up to the Follow-up visit (10 to 14 days after last dose)
Number of participants with abnormal findings in systolic BP	To further assess the safety of single doses of AZD7594 in healthy volunteers	From Screening (Day -28) up to the Follow-up visit (10 to 14 days after last dose)
Number of participants with abnormal findings in diastolic BP	To further assess the safety of single doses of AZD7594 in healthy volunteers	From Screening (Day -28) up to the Follow-up visit (10 to 14 days after last dose)
Number of participants with abnormal findings in pulse rate	To further assess the safety of single doses of AZD7594 in healthy volunteers	From Screening (Day -28) up to the Follow-up visit (10 to 14 days after last dose)
Number of participants with abnormal findings in body temperature	To further assess the safety of single doses of AZD7594 in healthy volunteers	From Screening (Day -28) up to the Follow-up visit (10 to 14 days after last dose)
Number of participants with abnormal findings in ECG	To further assess the safety of single doses of AZD7594 in healthy volunteers	From Screening (Day -28) up to the Follow-up visit (10 to 14 days after last dose)
Number of participants with abnormal findings in physical examination	To further assess the safety of single doses of AZD7594 in healthy volunteers. The complete physical examinations will include an assessment of the general appearance, respiratory, cardiovascular, abdomen, skin, head, and neck (including ears, eyes, nose, and throat), lymph nodes, thyroid, musculoskeletal and neurological systems.	From Screening (Day -28) up to the Follow-up visit (10 to 14 days after last dose)
Number of participants with abnormal findings in spirometry	To further assess the safety of single doses of AZD7594 in healthy volunteers. All spirometry measurements will be performed using the Jaeger Masterscope for which calibration will be performed daily using a 3 L calibration syringe. Spirometry measurements with the Jaeger Masterscope will be performed according to European Respiratory Society/American Thoracic Society guidelines. Global Lung Function Initiative 2012 reference values will be used.	From Screening (Day -28) up to the Follow-up visit (10 to 14 days after last dose)
Number of participants with abnormal findings in haemoglobin	To further assess the safety of single doses of AZD7594 in healthy volunteers	From Screening (Day -28) up to the Follow-up visit (10 to 14 days after last dose)
Number of participants with abnormal findings in haematocrit	To further assess the safety of single doses of AZD7594 in healthy volunteers	From Screening (Day -28) up to the Follow-up visit (10 to 14 days after last dose)
Number of participants with abnormal findings in white blood cell count	To further assess the safety of single doses of AZD7594 in healthy volunteers	From Screening (Day -28) up to the Follow-up visit (10 to 14 days after last dose)
Number of participants with abnormal findings in red blood cell count	To further assess the safety of single doses of AZD7594 in healthy volunteers	From Screening (Day -28) up to the Follow-up visit (10 to 14 days after last dose)
Number of participants with abnormal findings in mean corpuscular volume (MCV)	To further assess the safety of single doses of AZD7594 in healthy volunteers	From Screening (Day -28) up to the Follow-up visit (10 to 14 days after last dose)
Number of participants with abnormal findings in mean corpuscular haemoglobin (MCH)	To further assess the safety of single doses of AZD7594 in healthy volunteers	From Screening (Day -28) up to the Follow-up visit (10 to 14 days after last dose)
Number of participants with abnormal findings in mean corpuscular hemoglobin concentration (MCHC)	To further assess the safety of single doses of AZD7594 in healthy volunteers	From Screening (Day -28) up to the Follow-up visit (10 to 14 days after last dose)
Number of participants with abnormal findings in neutrophils absolute count	To further assess the safety of single doses of AZD7594 in healthy volunteers	From Screening (Day -28) up to the Follow-up visit (10 to 14 days after last dose)
Number of participants with abnormal findings in lymphocytes absolute count	To further assess the safety of single doses of AZD7594 in healthy volunteers	From Screening (Day -28) up to the Follow-up visit (10 to 14 days after last dose)
Number of participants with abnormal findings in monocytes absolute count	To further assess the safety of single doses of AZD7594 in healthy volunteers	From Screening (Day -28) up to the Follow-up visit (10 to 14 days after last dose)
Number of participants with abnormal findings in eosinophils absolute count	To further assess the safety of single doses of AZD7594 in healthy volunteers	From Screening (Day -28) up to the Follow-up visit (10 to 14 days after last dose)
Number of participants with abnormal findings in basophils absolute count	To further assess the safety of single doses of AZD7594 in healthy volunteers	From Screening (Day -28) up to the Follow-up visit (10 to 14 days after last dose)
Number of participants with abnormal findings in platelets	To further assess the safety of single doses of AZD7594 in healthy volunteers	From Screening (Day -28) up to the Follow-up visit (10 to 14 days after last dose)
Number of participants with abnormal findings in reticulocytes absolute count	To further assess the safety of single doses of AZD7594 in healthy volunteers	From Screening (Day -28) up to the Follow-up visit (10 to 14 days after last dose)
Number of participants with abnormal findings in sodium	To further assess the safety of single doses of AZD7594 in healthy volunteers.	From Screening (Day -28) up to the Follow-up visit (10 to 14 days after last dose)
Number of participants with abnormal findings in potassium	To further assess the safety of single doses of AZD7594 in healthy volunteers.	From Screening (Day -28) up to the Follow-up visit (10 to 14 days after last dose)
Number of participants with abnormal findings in urea	To further assess the safety of single doses of AZD7594 in healthy volunteers.	From Screening (Day -28) up to the Follow-up visit (10 to 14 days after last dose)
Number of participants with abnormal findings in creatinine	To further assess the safety of single doses of AZD7594 in healthy volunteers.	From Screening (Day -28) up to the Follow-up visit (10 to 14 days after last dose)
Number of participants with abnormal findings in albumin	To further assess the safety of single doses of AZD7594 in healthy volunteers.	From Screening (Day -28) up to the Follow-up visit (10 to 14 days after last dose)
Number of participants with abnormal findings in calcium	To further assess the safety of single doses of AZD7594 in healthy volunteers.	From Screening (Day -28) up to the Follow-up visit (10 to 14 days after last dose)
Number of participants with abnormal findings in phosphate	To further assess the safety of single doses of AZD7594 in healthy volunteers.	From Screening (Day -28) up to the Follow-up visit (10 to 14 days after last dose)
Number of participants with abnormal findings in glucose (fasting)	To further assess the safety of single doses of AZD7594 in healthy volunteers.	From Screening (Day -28) up to the Follow-up visit (10 to 14 days after last dose)
Number of participants with abnormal findings in C-reactive protein	To further assess the safety of single doses of AZD7594 in healthy volunteers.	From Screening (Day -28) up to the Follow-up visit (10 to 14 days after last dose)
Number of participants with abnormal findings in T4 hormone	To further assess the safety of single doses of AZD7594 in healthy volunteers.	From Screening (Day -28) up to the Follow-up visit (10 to 14 days after last dose)
Number of participants with abnormal findings in thyroid-stimulating hormone	To further assess the safety of single doses of AZD7594 in healthy volunteers.	From Screening (Day -28) up to the Follow-up visit (10 to 14 days after last dose)
Number of participants with abnormal findings in liver enzymes	To further assess the safety of single doses of AZD7594 in healthy volunteers. The laboratory variables to be measured are: Alkaline phosphatase (ALP), Alanine aminotransferase (ALT), Aspartate aminotransferase (AST), Gamma glutamyl transpeptidase (GGT)	From Screening (Day -28) up to the Follow-up visit (10 to 14 days after last dose)
Number of participants with abnormal findings in total bilirubin (TBL)	To further assess the safety of single doses of AZD7594 in healthy volunteers.	From Screening (Day -28) up to the Follow-up visit (10 to 14 days after last dose)
Number of participants with abnormal findings in unconjugated bilirubin	To further assess the safety of single doses of AZD7594 in healthy volunteers.	From Screening (Day -28) up to the Follow-up visit (10 to 14 days after last dose)
Number of participants with abnormal findings in follicle stimulating hormone (FSH)	To further assess the safety of single doses of AZD7594 in healthy volunteers.	From Screening (Day -28) up to the Follow-up visit (10 to 14 days after last dose)
Number of participants with abnormal findings in lutenizing hormone (LH)	To further assess the safety of single doses of AZD7594 in healthy volunteers.	From Screening (Day -28) up to the Follow-up visit (10 to 14 days after last dose)
Number of participants with abnormal findings in coagulation	To further assess the safety of single doses of AZD7594 in healthy volunteers. The laboratory variables to be measured are: international normalized ratio and activated partial thrombin time	From Screening (Day -28) up to the Follow-up visit (10 to 14 days after last dose)
Number of participants with abnormal findings in urinalysis	To further assess the safety of single doses of AZD7594 in healthy volunteers. The laboratory variables to be measured are: protein, glucose, and blood.	From Screening (Day -28) up to the Follow-up visit (10 to 14 days after last dose)

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
AZD7594 concentrations in dried blood PK sample	To assess AZD7594 concentrations in dried blood PK samples (collected via both venepuncture and finger prick) and compare with wet blood and plasma PK samples.	Days 1, 2 and 3 (2, 6, 12, 24 and 48 h post dose)

Collaborators and Investigators

• Sponsor: AstraZeneca
• Collaborators: Parexel

Study record dates

Study Major Dates

• Study Start (Actual): September 19, 2019
• Primary Completion (Actual): November 28, 2019
• Study Completion (Actual): November 28, 2019

Study Registration Dates

• First Submitted: July 19, 2019
• First Submitted That Met QC Criteria: August 27, 2019
• First Posted (Actual): August 28, 2019

Study Record Updates

• Last Update Posted (Actual): December 16, 2019
• Last Update Submitted That Met QC Criteria: December 13, 2019
• Last Verified: December 1, 2019

More Information

Terms related to this study

• Keywords: Safety; Pharmacokinetics; Bioavailability; Selective glucocorticoid receptor modulator
• Other Study ID Numbers: D3742C00001

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No