Safety, Tolerability and Pharmacokinetics of Multiple Ascending Doses of AZD8871 in Healthy Male Japanese Subjects


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Primary Outcome Measures:

  • Adverse events. [ Time Frame: From time of ICF to Day 30 (end of follow-up period) ]

    Recording adverse events. An AE is the development of an undesirable medical condition or the deterioration of a preexisting medical condition following or during exposure to a pharmaceutical product, whether or not considered causally related to the product. An undesirable medical condition can be symptoms (e.g., nausea, chest pain), signs (e.g., tachycardia, enlarged liver) or the abnormal results of an investigation (e.g., laboratory findings, ECG). In clinical studies, an AE can include an undesirable medical condition occurring at any time, including run-in or washout periods, even if no study treatment has been administered.

  • Concomitant medication. [ Time Frame: Change from screening up to follow-up period (Day 30 +/- 1) ]

    Recording concomitant medications. Any concomitant medication or therapy given to the subject during the study conduct will be recorded.

  • Physical examination. [ Time Frame: Change from screening up to follow-up period (Day 30 +/- 1) ]

    A full physical examination will include the examination of the following: general appearance, eyes, ears, nose, throat, chest/respiratory, heart/cardiovascular, gastrointestinal/liver, musculoskeletal/extremities, dermatological/skin, thyroid/neck, lymph nodes, neurological/psychiatric.

    A brief physical examination will include assessment of the following: skin, lungs, cardiovascular system and abdomen (liver and spleen).

    A complete physical examination will be performed at the Screening and Follow-up visit.

    Only relevant findings detected will be recorded in the physical examination findings.

  • Vital signs. [ Time Frame: Change from screening up to follow-up period (Day 30 +/- 1) ]

    Recording vital signs. Systolic and diastolic blood pressure (in mmHg) will be measured after at least 10 minutes (can be reduced to 5 minutes at collection time points within the 1st hour after dosing) resting, and also, before taking any blood sample and conducting any spirometry. Measurements will be carried out with subject in the supine position and preferably always on the same arm.

    Subject’s oral body temperature will be measured at each vital signs collection.

  • Number of clinically relevant new findings or worsening of a pre-existing findings as assessed by Hematology. [ Time Frame: Change from screening up to follow-up period (Day 30 +/- 1) ]

    Haematocrit, hemoglobin, erythrocytes (red blood cells), mean corpuscular volume (MCV), mean corpuscular haemoglobin (MCH), mean corpuscular haemoglobin concentration (MCHC), leucocytes (white blood cells), differential blood count (neutrophils, lymphocytes, monocytes, eosinophils and basophils) and thrombocytes (platelets)

  • Number of clinically relevant new findings or worsening of a pre-existing findings as assessed by Clinical chemistry. [ Time Frame: Change from screening up to follow-up period (Day 30 +/- 1) ]

    Electrolytes: sodium, potassium, calcium, chloride and inorganic phosphorus. Enzymes: AST, ALT, ALP, GGT, LDH, creatine kinase. Substrates: glucose (fasting), total cholesterol, triglycerides, creatinine, TBL, total protein, albumin, uric acid, urea and BUN.

    Endocrinology: T4, TSH. Viral serology: HIV I and II antibodies, hepatitis C antibodies, HBsAg, HBc. Coagulation: INR, PT, aPTT.

  • ECG. [ Time Frame: Change from screening up to follow-up period (Day 30 +/- 1) ]

    A 12-lead ECG will be obtained after the subject rested in the supine position for at least 10 minutes (can be reduced to 5 minutes at collection time points within the first hour after dosing; using the sites own ECG machines when not performing dECGs and using the same machine as the dECGs when time points coincide).

  • 2-lead real-time telemetry ECG. [ Time Frame: Change from screening up to follow-up period (Day 30 +/- 1) ]

    Recording telemetry findings. A 2-lead real-time telemetry ECG will be performed for at least 4 hours on Day 1 and then on Days 1, 10 and 16 from 30 minutes predose until 24 hours postdose.

  • Number of clinically relevant new findings or worsening of a pre-existing findings as assessed by urinalysis report. [ Time Frame: Change from screening up to follow-up period (Day 30 +/- 1) ]

    pH, blood, leucocytes, protein, glucose, bilirubin, urobilirubin, ketones and nitrites.

    If clinically relevant abnormalities are detected (positive result in dipstick), microscopy (RBC, WBC and cast [hyaline, granular and cellular]).

Secondary Outcome Measures:

  • Observed maximum concentration, taken directly from the individual concentration-time curve (Cmax) of AZD8871 and its metabollites. [ Time Frame: Day 1 and Day 16 ]

    Observed maximum concentration.

  • Time to reach maximum concentration, taken directly from the individual concentration-time curve (tmax) of AZD8871 and its metabollites. [ Time Frame: Day 1 and Day 16 ]

    Time to reach maximum concentration.

  • Terminal half-life (t½λz) of AZD8871 and its metabollites. [ Time Frame: Day 1 and Day 16 ]

    Terminal half-life, estimated as (ln2)/λz.

  • Area under the plasma concentration-curve from time zero to 24 hours post-dose (AUCτ) of AZD8871 and its metabollites. [ Time Frame: Day 1 and Day 16 ]

    Area under the plasma concentration-curve from time zero to 24 hours post-dose

  • Area under the concentration-time curve from time zero extrapolated to infinity (AUC) of AZD8871 and its metabollites. [ Time Frame: Day 1 ]

    Area under the concentration-time curve from time zero extrapolated to infinity. AUC is estimated by AUC0-last + Clast/λz where Clast is the last observed quantifiable concentration.

  • Apparent clearance for parent drug (CL/F) estimated as dose divided by AUC of AZD8871 and its metabollites. [ Time Frame: Day 1 and Day 16 ]

    Apparent clearance for parent drug estimated as dose divided by AUC.

  • Apparent volume of distribution for parent drug at terminal phase (Vz/F) of AZD8871 and its metabollites. [ Time Frame: Day 1 ]

    Apparent volume of distribution for parent drug at terminal phase (extravascular administration), estimated by dividing the apparent clearance (CL/F) by λz.

  • Accumulation ratio for Cmax (Rac (Cmax)) of AZD8871 and metabollites after repeated administration. [ Time Frame: Day 16 ]

    Accumulation ratio for Cmax estimated as Cmax on Day 16/Cmax on Day 1.

  • Accumulation ratio for AUCτ (RacAUCτ) of AZD8871 and metabollites after repeated administration. [ Time Frame: Day 16 ]

    Accumulation ratio for AUCτ estimated as AUCτ on Day 16/AUCτ on Day 1.

This is a Phase I, single centre, randomised, single blind, placebo-controlled study to investigate the safety, tolerability and pharmacokinetics (PK) of single and multiple ascending doses of inhaled AZD8871 in healthy male Japanese subjects.

All subjects will sign an Informed Consent Form before starting any study-related procedures.

Twenty-four healthy subjects, aged 20 to 55 years, will participate in 3 cohorts. All subjects will be admitted to the unit the day preceding the 1st dose and will be housed in the unit until 96 hours (4 days) post last dose of investigational medicinal product (IMP) (Day 20).

Eight subjects will participate in each cohort and will receive either AZD8871 or placebo, randomised 3:1 (6 subjects to receive AZD8871:2 subjects to receive placebo). Each subject will only be dosed in 1 cohort. The study design allows a gradual escalation of dose (Cohorts 2 and 3) with intensive safety monitoring to ensure the safety of the subjects.

In Cohort 1, subjects will receive only a single dose of AZD8871 300 µg or placebo on Day 1, followed by once daily dosing on Days 5 to 16. The dosing schedule of all cohorts will be single dose of IMP (active or placebo) on Day 1, followed by once daily dosing on Days 5 to 16. Within 5 to 7 days of discharge from the unit, there will be two follow-up visits.

Following each cohort, a maximum dose of 2 times the dose administered in the previous cohort will be considered for the subsequent cohort. However, the planned dose for Cohort 2 is 600 µg and for Cohort 3 is 900 µg. Dosing of Cohorts 2 and 3 will be preceded by a SRC meeting, which will confirm the adequacy of the planned doses. A minimum of 5 subjects on active treatment need to complete dosing per cohort in order to proceed to the next dose level.

The total duration of the study for each subject will be approximately 58 days (from Screening [up to -28 days before randomization] to Final Follow up visit [Day 30]).