Clinical trial NCT04072562: 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.
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Asthma
Keywords: Bioavailability
Pharmacokinetics
Safety
Selective glucocorticoid receptor modulator
Lead sponsor: AstraZeneca
Sponsor class: INDUSTRY
Collaborators: name: Parexel
First posted: 2019-08-28
Enrollment: 24
Sex: ALL
Minimum age (years): 18
Maximum age (years): 55
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

Brief summary: 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.

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Maximum observed plasma concentration (Cmax)
timeFrame: 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)
measure: Area under plasma concentration-time curve from zero to infinity (AUC)
timeFrame: 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)
measure: Area under the plasma concentration-time curve from time zero to time of last quantifiable concentration (AUC0-t)
timeFrame: 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)
measure: Individual ratios of test versus reference for AUC
timeFrame: 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)
measure: Individual ratios of test versus reference for AUC0-t
timeFrame: 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)
measure: Individual ratios of test versus reference for Cmax
timeFrame: 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 outcomes:
measure: Time to reach maximum observed plasma concentration (tmax)
timeFrame: 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)
measure: Terminal elimination rate constant (λz)
timeFrame: 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)
measure: Half-life associated with terminal slope (λz) of a semilogarithmic concentration-time curve (t1/2λz)
timeFrame: 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)
measure: Mean residence time of the unchanged drug in the systemic circulation from zero to infinity (MRT)
timeFrame: 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)
measure: Apparent total body clearance of drug from plasma after extravascular administration (CL/F)
timeFrame: 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)
measure: Apparent volume of distribution during the terminal phase after extravascular administration (Vz/F)
timeFrame: 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)
measure: Number of participants with adverse events
timeFrame: From Screening (Day -28) up to the Follow-up visit (10 to 14 days after last dose)
measure: Number of participants with abnormal findings in systolic BP
timeFrame: From Screening (Day -28) up to the Follow-up visit (10 to 14 days after last dose)
measure: Number of participants with abnormal findings in diastolic BP
timeFrame: From Screening (Day -28) up to the Follow-up visit (10 to 14 days after last dose)
measure: Number of participants with abnormal findings in pulse rate
timeFrame: From Screening (Day -28) up to the Follow-up visit (10 to 14 days after last dose)
measure: Number of participants with abnormal findings in body temperature
timeFrame: From Screening (Day -28) up to the Follow-up visit (10 to 14 days after last dose)
measure: Number of participants with abnormal findings in ECG
timeFrame: From Screening (Day -28) up to the Follow-up visit (10 to 14 days after last dose)
measure: Number of participants with abnormal findings in physical examination
timeFrame: From Screening (Day -28) up to the Follow-up visit (10 to 14 days after last dose)
measure: Number of participants with abnormal findings in spirometry
timeFrame: From Screening (Day -28) up to the Follow-up visit (10 to 14 days after last dose)
measure: Number of participants with abnormal findings in haemoglobin
timeFrame: From Screening (Day -28) up to the Follow-up visit (10 to 14 days after last dose)
measure: Number of participants with abnormal findings in haematocrit
timeFrame: From Screening (Day -28) up to the Follow-up visit (10 to 14 days after last dose)
measure: Number of participants with abnormal findings in white blood cell count
timeFrame: From Screening (Day -28) up to the Follow-up visit (10 to 14 days after last dose)
measure: Number of participants with abnormal findings in red blood cell count
timeFrame: From Screening (Day -28) up to the Follow-up visit (10 to 14 days after last dose)
measure: Number of participants with abnormal findings in mean corpuscular volume (MCV)
timeFrame: From Screening (Day -28) up to the Follow-up visit (10 to 14 days after last dose)
measure: Number of participants with abnormal findings in mean corpuscular haemoglobin (MCH)
timeFrame: From Screening (Day -28) up to the Follow-up visit (10 to 14 days after last dose)
measure: Number of participants with abnormal findings in mean corpuscular hemoglobin concentration (MCHC)
timeFrame: From Screening (Day -28) up to the Follow-up visit (10 to 14 days after last dose)
measure: Number of participants with abnormal findings in neutrophils absolute count
timeFrame: From Screening (Day -28) up to the Follow-up visit (10 to 14 days after last dose)
measure: Number of participants with abnormal findings in lymphocytes absolute count
timeFrame: From Screening (Day -28) up to the Follow-up visit (10 to 14 days after last dose)
measure: Number of participants with abnormal findings in monocytes absolute count
timeFrame: From Screening (Day -28) up to the Follow-up visit (10 to 14 days after last dose)
measure: Number of participants with abnormal findings in eosinophils absolute count
timeFrame: From Screening (Day -28) up to the Follow-up visit (10 to 14 days after last dose)
measure: Number of participants with abnormal findings in basophils absolute count
timeFrame: From Screening (Day -28) up to the Follow-up visit (10 to 14 days after last dose)
measure: Number of participants with abnormal findings in platelets
timeFrame: From Screening (Day -28) up to the Follow-up visit (10 to 14 days after last dose)
measure: Number of participants with abnormal findings in reticulocytes absolute count
timeFrame: From Screening (Day -28) up to the Follow-up visit (10 to 14 days after last dose)
measure: Number of participants with abnormal findings in sodium
timeFrame: From Screening (Day -28) up to the Follow-up visit (10 to 14 days after last dose)
measure: Number of participants with abnormal findings in potassium
timeFrame: From Screening (Day -28) up to the Follow-up visit (10 to 14 days after last dose)
measure: Number of participants with abnormal findings in urea
timeFrame: From Screening (Day -28) up to the Follow-up visit (10 to 14 days after last dose)
measure: Number of participants with abnormal findings in creatinine
timeFrame: From Screening (Day -28) up to the Follow-up visit (10 to 14 days after last dose)
measure: Number of participants with abnormal findings in albumin
timeFrame: From Screening (Day -28) up to the Follow-up visit (10 to 14 days after last dose)
measure: Number of participants with abnormal findings in calcium
timeFrame: From Screening (Day -28) up to the Follow-up visit (10 to 14 days after last dose)
measure: Number of participants with abnormal findings in phosphate
timeFrame: From Screening (Day -28) up to the Follow-up visit (10 to 14 days after last dose)
measure: Number of participants with abnormal findings in glucose (fasting)
timeFrame: From Screening (Day -28) up to the Follow-up visit (10 to 14 days after last dose)
measure: Number of participants with abnormal findings in C-reactive protein
timeFrame: From Screening (Day -28) up to the Follow-up visit (10 to 14 days after last dose)
measure: Number of participants with abnormal findings in T4 hormone
timeFrame: From Screening (Day -28) up to the Follow-up visit (10 to 14 days after last dose)
measure: Number of participants with abnormal findings in thyroid-stimulating hormone
timeFrame: From Screening (Day -28) up to the Follow-up visit (10 to 14 days after last dose)
measure: Number of participants with abnormal findings in liver enzymes
timeFrame: From Screening (Day -28) up to the Follow-up visit (10 to 14 days after last dose)
measure: Number of participants with abnormal findings in total bilirubin (TBL)
timeFrame: From Screening (Day -28) up to the Follow-up visit (10 to 14 days after last dose)
measure: Number of participants with abnormal findings in unconjugated bilirubin
timeFrame: From Screening (Day -28) up to the Follow-up visit (10 to 14 days after last dose)
measure: Number of participants with abnormal findings in follicle stimulating hormone (FSH)
timeFrame: From Screening (Day -28) up to the Follow-up visit (10 to 14 days after last dose)
measure: Number of participants with abnormal findings in lutenizing hormone (LH)
timeFrame: From Screening (Day -28) up to the Follow-up visit (10 to 14 days after last dose)
measure: Number of participants with abnormal findings in coagulation
timeFrame: From Screening (Day -28) up to the Follow-up visit (10 to 14 days after last dose)
measure: Number of participants with abnormal findings in urinalysis
timeFrame: From Screening (Day -28) up to the Follow-up visit (10 to 14 days after last dose)
Other outcomes:
measure: AZD7594 concentrations in dried blood PK sample
timeFrame: Days 1, 2 and 3 (2, 6, 12, 24 and 48 h post dose)
Locations:
city: Berlin
country: Germany
facility: Research Site
Study officials:
affiliation: Parexel
name: Rainard Fuhr
role: PRINCIPAL_INVESTIGATOR
References: