Clinical trial NCT02648438: A Study to Assess the Bioavailability and to Compare the Pharmacokinetics of AZD7594 Inhaled Via Monodose Inhaler and Multiple-dose Dry Powder Inhalers (DPI) or Pressurized Metered-dose Inhaler (pMDI) in Healthy Male Subjects
Official title: An Open Label, Partially Randomized, Four-period Study in Healthy Male Subjects to Investigate the Bioavailability and Pharmacokinetics of a Single Dose of AZD7594 When Administered Intravenously, Orally and Inhaled Via Two Different Dry Powder Inhalers (DPI) and a Pressurized Metered-dose Inhaler (pMDI)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Asthma
Chronic Obstructive Pulmonary Disease (COPD)
Keywords: AZD7594
Bioavailability
Healthy male subjects
Safety
Tolerability
Pharmacokinetics
Monodose inhaler
Multiple-dose dry powder inhaler
Lead sponsor: AstraZeneca
Sponsor class: INDUSTRY
First posted: 2016-01-07
Enrollment: 30
Sex: MALE
Minimum age (years): 18
Maximum age (years): 45
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: BASIC_SCIENCE

Brief summary: This is an open-label,partially randomized, four-period study in healthy male subjects to assess the bioavailability and pharmacokinetics of a single dose of AZD7594 when administered intravenously, orally and inhaled via two different dry powder inhalers (DPIs) and a pressurized meter-dose inhaler (pMDI)

Detailed description: This study is an open-label, partially randomized, 4-period, 5-treatment study in healthy male subjects, performed at a single study center. All subjects will receive the 4 of the 5 treatments. The IV infusion will be fixed as the first treatment (Period 1), the Monodose inhaler will be fixed as the second treatment (Period 2) and the oral formulation will be fixed as the fourth treatment (Period 4). During Period 3, subjects are split into 2 equal cohorts, multiple-dose DPI and pMDI.

Eligibility criteria: Inclusion Criteria:

1. Provision of signed and dated, written informed consent prior to any study specific procedures.
2. Healthy male subjects aged 18 - 45 years with suitable veins for cannulation or repeated venipuncture.
3. Have a body mass index (BMI) between 18 and 30 kg/m2, inclusive, and weigh at least 50 kg.
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 investigational product.
5. Be able to inhale from the dry powder inhaler (DPI) devices and the pressurized metered-dose inhaler (pMDI) device according to given instructions.

Exclusion Criteria:

1. History of any clinically significant disease or disorder which, in the opinion of the Investigator, 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 (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, major medical/surgical procedure, or trauma within 4 weeks of the first administration of Investigational medicinal product (IMP).
4. Any clinically significant abnormalities in clinical chemistry, hematology, or urinalysis results at screening and check-in, as judged by the investigator.
5. Any clinically significant abnormal findings in vital signs after a 5 minute rest at screening and check-in, as judged by the investigator, defined as any of the following:

   * Systolic blood pressure (BP) \> 140 mm Hg;
   * Systolic BP \< 90 mm Hg;
   * Diastolic BP \> 90 mm Hg;
   * Diastolic BP \< 60 mm Hg; or
   * Heart rate \< 40 or \> 85 beats per minute (bpm).
6. Any clinically significant abnormities in physical examination or lung function, as judged by the investigator.
7. Any clinically significant abnormalities on 12-lead electrocardiogram (ECG) at screening and check-in, as judged by the investigator.
8. Any clinically important abnormalities in rhythm, conduction or morphology of resting ECG that may interfere with the interpretation of QTc (QT interval corrected) interval changes. This includes subjects with any of the following:

   * Clinically significant PR (PQ) (ECG interval measured from the onset of the P wave to the onset of the QRS complex) interval prolongation;
   * Intermittent or persistent second or third degree AV block;
   * Persistent or intermittent complete bundle branch block (BBB), incomplete bundle branch block (IBBB), or intraventricular conduction delay (IVCD) with QRS (ECG interval measured from the onset of the QRS complex to the J point) \> 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; or
   * Abnormal T wave morphology, particularly in the protocol defined primary lead.
9. Prolonged QTcF (QT interval corrected for heart rate using Fridericia's formula) \> 450 msec or family history of long QT (ECG interval measured from the onset of the QRS complex to the end of the T wave) syndrome.
10. Known or suspected history of drug abuse, as judged by the investigator
11. Current smokers or those who have smoked or used nicotine products within the previous 3 months.
12. History of alcohol abuse or excessive intake of alcohol as judged by the investigator.
13. Positive screen for drugs of abuse, alcohol, and cotinine at screening or on each admission to the study center.
14. History of severe allergy/hypersensitivity or ongoing allergy/hypersensitivity, as judged by the investigator or history of hypersensitivity to drugs with a similar chemical structure or class to AZD7594 or to excipients.
15. Excessive intake of caffeine containing drinks e.g., coffee, tea, caffeine containing energy drinks and cola (in total no more than 3 cups per day).
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 vaccines, antacids, analgesics (other than paracetamol/acetaminophen), herbal remedies, vitamins and minerals during the 2 weeks prior to the first administration of IMP or longer if the medication has a long half-life. Occasional use of paracetamol/acetaminophen is allowed for minor pains and headaches (no more than 3000 mg/day).
18. Plasma donation within 1 month of screening or any blood donation/loss more than 500 mL during the 3 months prior to screening.
19. Has participated in a clinical study investigating clinical evaluation methods 1 month (or at least 5 half-lives) prior to the administration of investigational product.
20. Known Gilbert's syndrome, family history of Gilbert's syndrome or suspicion of Gilbert's syndrome based on liver function tests.
21. Any contraindication against the use of vagolytic or sympaticomimetic drugs, as judged by the investigator.
22. Involvement of any AstraZeneca, PAREXEL or study site employee or their close relatives.
23. Any positive result on screening for serum hepatitis B surface antigen (HBsAg), hepatitis C antibody and human immunodeficiency virus (HIV) antibody.
24. 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.
25. Vulnerable subjects, e.g., kept in detention, protected adults under guardianship, trusteeship, or committed to an institution by governmental or juridical order.

Primary outcomes:
measure: Pharmacokinetics (PK) of AZD7594 Delivered by Monodose Inhaler and Multiple-dose DPI or pMDI in Terms of Pulmonary Bioavailability After Inhalation (Fpulmonary)
timeFrame: 0-96 hours
Secondary outcomes:
measure: PK of AZD7594 Following Oral Administration by Assessment of the Absolute Systemic Bioavailability After Oral Administration (Fpo)
timeFrame: 0-96 hours
measure: Observed Maximum Plasma Concentration (Cmax)
timeFrame: 0-96 hours
measure: Area Under the Plasma Concentration-curve From Time Zero to Time of Last Quantifiable Concentration (AUC0-t)
timeFrame: 0-96 hours
measure: Absolute Systemic Bioavailability After Inhalation (F Inhalation, Total)
timeFrame: 0-96 hours
measure: Oral Bioavailability After Inhaled Treatment (F Oral)
timeFrame: 0-96 hours
measure: Area Under Plasma Concentration-time Curve From Time Zero Extrapolated to Infinity (AUC)
timeFrame: 0-96 hours
Other outcomes:
Locations:
city: Baltimore
country: United States
facility: Research Site
state: Maryland
Study officials:
affiliation: Parexel
name: Ronald Goldwater, M.D
role: PRINCIPAL_INVESTIGATOR
References: