Clinical trial NCT02645253: A Study to Assess the Safety, Tolerability and Pharmacokinetics of AZD7594 Inhaled Formulation in Healthy Japanese Men
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Asthma
Chronic Obstructive Pulmonary Disease COPD
Keywords: Safety
Pharmacokinetics
Pharmacodynamics
Glucocorticoid receptor modulator
Healthy male subjects
Lead sponsor: AstraZeneca
Sponsor class: INDUSTRY
First posted: 2016-01-01
Enrollment: 27
Sex: MALE
Minimum age (years): 20
Maximum age (years): 45
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: BASIC_SCIENCE

Brief summary: This is a randomized, single-blind, placebo-controlled, sequential-group study to assess the safety and tolerability as well as how the drug (AZD7594) affects the body (pharmacodynamics \[PD\]) and how the body affects the drug (pharmacokinetics \[PK\]) when AZD7594 is given as single and multiple ascending doses once daily by inhalation to healthy male Japanese subjects, compared with placebo (non-active drug)

Detailed description: This is a phase I, randomized, single-blind, placebo controlled, sequential-group design study to assess the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of AZD7594 after single and multiple ascending doses given once daily by inhalation in healthy male Japanese subjects, compared with placebo

Eligibility 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

Primary outcomes:
measure: Safety and Tolerability of AZD7594 by Assessment of the Number of Participants With Adverse Events
timeFrame: At screening (Day -28, Day -02 and Day -1), Treatment period (Days 1 to 20) and Follow-up (Day 29).
Secondary outcomes:
measure: Rate and Extent of Absorption of AZD7594 (Inhalation/ Administration Via DPI) by Assessment of the Observed Maximum Plasma Concentration (Cmax)
timeFrame: 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: Rate and Extent of Absorption of AZD7594 (Inhalation/ Administration Via DPI) by Assessment of the Time to Reach Maximum Plasma Concentration (Tmax)
timeFrame: 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: 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])
timeFrame: 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: 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]).
timeFrame: 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: Rate and Extent of Absorption of AZD7594 (Inhalation/ Administration Via DPI) by Assessment of the AUC From Time Zero Extrapolated to Infinity (AUC).
timeFrame: 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: 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).
timeFrame: 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: 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).
timeFrame: 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: 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).
timeFrame: 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: 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).
timeFrame: 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: 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)
timeFrame: 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: Rate and Extent of Absorption of AZD7594 by Assessment of the Cmax Divided by the Dose Administered (Cmax/D).
timeFrame: 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: Rate and Extent of Absorption of AZD7594 by Assessment of the AUC Divided by the Dose Administered (AUC/D).
timeFrame: 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: Rate and Extent of Absorption of AZD7594 by Assessment of the AUC(0-24) Divided by the Dose Administered (AUC(0-24)/D)
timeFrame: 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: Rate and Extent of Absorption of AZD7594 by Assessment of the Observed Minimum Plasma Concentration (Cmin)
timeFrame: Days 5 to 15: Pre-dose
measure: Rate and Extent of Absorption of AZD7594 (Inhalation/ Administration Via DPI) by Assessment of the Cmax at Steady State (Css,Max).
timeFrame: 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: Rate and Extent of Absorption of AZD7594 (Inhalation/ Administration Via DPI) by Assessment of the Cmin at Steady State (Cmin, ss)
timeFrame: 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: Rate and Extent of Absorption of AZD7594 (Inhalation/ Administration Via DPI) by Assessment of the Average Concentration Over One Dosing Interval (Cav)
timeFrame: 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: Rate and Extent of Absorption of AZD7594 (Inhalation/ Administration Via DPI) by Assessment of the Tmax at Steady State (Tss,Max).
timeFrame: 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: Rate and Extent of Absorption of AZD7594 by Assessment of the AUC(0-last)
timeFrame: 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: Rate and Extent of Absorption of AZD7594 by Assessment of AUC(0-24)
timeFrame: 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: Rate and Extent of Absorption of AZD7594 by Assessment of the Css,Max Divided by the Dose Administered (Css,Max/D).
timeFrame: 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: Rate and Extent of Absorption of AZD7594 by Assessment AUC(0-24)/D.
timeFrame: 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: Rate and Extent of Absorption of AZD7594 by Assessment of Lamda z (λz)
timeFrame: 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: Rate and Extent of Absorption of AZD7594 by Assessment of t1/2λz.
timeFrame: 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: Rate and Extent of Absorption of AZD7594 by Assessment of the Peak Trough Fluctuation (%Fluctuation).
timeFrame: 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: 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).
timeFrame: 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: Rate and Extent of Absorption of AZD7594 by Assessment of the Temporal Change Parameter (TCP)
timeFrame: 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: 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])
timeFrame: Day 1 predose spot-collection and interval collection up to 96 hours postdose
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])
timeFrame: Day 1 predose spot-collection and interval collection up to 96 hours postdose
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)%)
timeFrame: Day 1 predose spot-collection and interval collection up to 96 hours postdose
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)
timeFrame: Day 1 predose spot-collection and interval collection up to 96 hours postdose
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]).
timeFrame: Day -1 (- 24 hours predose) up to 24 hours postdose; Day 1 and Day 16
measure: Pharmacodynamic Analysis of AZD7594 by Assessment of Plasma Concentration of Dehydroepiandrosterone Sulphate (DHEAS)
timeFrame: Day 1 (predose) and Day 16 (24 hours postdose)
measure: Pharmacodynamic Analysis of AZD7594 by Assessment of Plasma Concentration of Osteocalcin
timeFrame: Day 1 (predose) and Day 16 (24 hours postdose)
Other outcomes:
Locations:
city: Glendale
country: United States
facility: Research Site
state: California
Study officials:
affiliation: California Clinical Trials Medical Group
name: Esther Yoon, M.D
role: PRINCIPAL_INVESTIGATOR
References: