This Phase 1, first-in-human (FiH), single-ascending-dose (SAD) study, will assess the safety and tolerability and characterize the pharmacokinetics (PK) of AZD2693, following subcutaneous (SC) SAD administration of AZD2693 in male and female subjects of non-childbearing potential in overweight but otherwise healthy subjects, and healthy Chinese and Japanese subjects.
This is a single center study, and approximately 64 overweight/mildly obese but otherwise healthy male and female subjects, and up to 16 healthy Japanese subjects and 8 healthy Chinese (all of non-childbearing potential) will be enrolled into this study. Study will consist of following planned cohorts: Eligible healthy subjects will be divided in 6 cohorts, each consisting of 8 subjects, within each cohort, 6 subjects will receive AZD2693 at dose level 1 and 2 subjects will receive placebo. Dosing for each ascending dose cohort will proceed with 2 subjects in a sentinel cohort, such that 1 subject will be randomized to receive placebo and 1 subject will be randomized to receive AZD2693. Eligible healthy Japanese and Chinese subjects will be divided as two cohorts of Japanese subjects, and one cohort of Chinese subjects. Each cohort will consist of 8 subjects. Within each cohort, 6 subjects will receive AZD2693 and 2 subjects will receive placebo. Depending on emerging data, up to 2 additional cohorts may be added to test additional dose levels based on Sponsor's decision. Full study will comprise of following periods: 1. Screening period of maximum 28 days. 2. A Dosing Session during which subjects will be resident at the Clinical Unit from the day before investigational medicinal product (IMP) administration (Day -1) until at least 3 days after IMP administration with discharge on Day 4. 3. A Follow-Up Period of 16 weeks that will consist of 9 Follow-Up Visits, for which the subjects will return to the Clinical Unit at 1, 2, 4, 6, 8, 10, 12, 14, and 16 weeks post dose.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
TRIPLE
Enrollment
73
Research Site
Glendale, California, United States
Number of subjects experiencing adverse events and serious adverse events
To investigate the safety and tolerability of SC administration of SAD of AZD2693
Time frame: From baseline (Day 1) until Day 112 (Week 16, Final follow-up)
Area under the concentration-time curve from time zero extrapolated to infinity (AUC)
To characterize the PK of AZD2693 following SC administration of SAD of AZD2693
Time frame: At Day 1 pre-dose, 0.25 hours [h], 0.5h, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 5h, 6h, 8h, 12h, 24h, 36h, 48h and 72h post-dose and 1, 2, 4, 8, 12 and 16 weeks post-dose
Area under the plasma concentration-time curve from time zero to 48 hours after dosing [AUC(0-48h)]
To characterize the PK of AZD2693 following SC administration of SAD of AZD2693
Time frame: At Day 1 pre-dose, 0.25h, 0.5h, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 5h, 6h, 8h, 12h, 24h, 36h, 48h and 72h post-dose and 1, 2, 4, 8, 12 and 16 weeks post-dose
Area under the plasma concentration-time curve from time zero to time of last quantifiable analyte concentration divided by the dose administered (AUClast/D)
To characterize the PK of AZD2693 following SC administration of SAD of AZD2693
Time frame: At Day 1 pre-dose, 0.25h, 0.5h, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 5h, 6h, 8h, 12h, 24h, 36h, 48h and 72h post-dose and 1, 2, 4, 8, 12 and 16 weeks post-dose
Area under the plasma concentration-curve from time zero to the time of last quantifiable analyte concentration (AUClast)
To characterize the PK of AZD2693 following SC administration of SAD of AZD2693
Time frame: At Day 1 pre-dose, 0.25h, 0.5h, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 5h, 6h, 8h, 12h, 24h, 36h, 48h and 72h post-dose and 1, 2, 4, 8, 12 and 16 weeks post-dose
Area under the plasma concentration-time curve from time zero extrapolated to infinity divided by the dose administered (AUC/D)
To characterize the PK of AZD2693 following SC administration of SAD of AZD2693
Time frame: At Day 1 pre-dose, 0.25h, 0.5h, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 5h, 6h, 8h, 12h, 24h, 36h, 48h and 72h post-dose and 1, 2, 4, 8, 12 and 16 weeks post-dose
Maximum observed plasma drug concentration (Cmax) of AZD2693
To characterize the PK of AZD2693 following SC administration of SAD of AZD2693
Time frame: At Day 1 pre-dose, 0.25h, 0.5h, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 5h, 6h, 8h, 12h, 24h, 36h, 48h and 72h post-dose and 1, 2, 4, 8, 12 and 16 weeks post-dose
Observed maximum plasma concentration divided by the dose administered (Cmax/D)
To characterize the PK of AZD2693 following SC administration of SAD of AZD2693
Time frame: At Day 1 pre-dose, 0.25h, 0.5h, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 5h, 6h, 8h, 12h, 24h, 36h, 48h and 72h post-dose and 1, 2, 4, 8, 12 and 16 weeks post-dose
Time to reach maximum observed concentration following drug administration (tmax)
To characterize the PK of AZD2693 following SC administration of SAD of AZD2693
Time frame: At Day 1 pre-dose, 0.25h, 0.5h, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 5h, 6h, 8h, 12h, 24h, 36h, 48h and 72h post-dose and 1, 2, 4, 8, 12 and 16 weeks post-dose
Apparent terminal elimination half-life associated with the terminal slope (λz) of the semi-logarithmic concentration-time curve, estimated as (ln2)/λz (t½λz)
To characterize the PK of AZD2693 following SC administration of SAD of AZD2693.
Time frame: At Day 1 pre-dose, 0.25h, 0.5h, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 5h, 6h, 8h, 12h, 24h, 36h, 48h and 72h post-dose and 1, 2, 4, 8, 12 and 16 weeks post-dose
Apparent total body clearance of drug from plasma after extravascular administration calculated as Dose/AUC (CL/F)
To characterize the PK of AZD2693 following SC administration of SAD of AZD2693
Time frame: At Day 1 pre-dose, 0.25h, 0.5h, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 5h, 6h, 8h, 12h, 24h, 36h, 48h and 72h post-dose and 1, 2, 4, 8, 12 and 16 weeks post-dose
Apparent volume of distribution for parent drug at terminal phase (extravascular administration), estimated by dividing CL/F by λz (Vz/F)
To characterize the PK of AZD2693 following SC administration of SAD of AZD2693
Time frame: At Day 1 pre-dose, 0.25h, 0.5h, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 5h, 6h, 8h, 12h, 24h, 36h, 48h and 72h post-dose and 1, 2, 4, 8, 12 and 16 weeks post-dose
Mean residence time (MRT)
To characterize the PK of AZD2693 following SC administration of SAD of AZD2693
Time frame: At Day 1 pre-dose, 0.25h, 0.5h, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 5h, 6h, 8h, 12h, 24h, 36h, 48h and 72h post-dose and 1, 2, 4, 8, 12 and 16 weeks post-dose
Terminal elimination rate constant, estimated by log-linear least-squares regression of the terminal part of the concentration-time curve (λz)
To characterize the PK of AZD2693 following SC administration of SAD of AZD2693
Time frame: At Day 1 pre-dose, 0.25h, 0.5h, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 5h, 6h, 8h, 12h, 24h, 36h, 48h and 72h post-dose and 1, 2, 4, 8, 12 and 16 weeks post-dose
Time delay between drug administration and the first observed concentration in plasma (tlag)
To characterize the PK of AZD2693 following SC administration of SAD of AZD2693
Time frame: At Day 1 pre-dose, 0.25h, 0.5h, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 5h, 6h, 8h, 12h, 24h, 36h, 48h and 72h post-dose and 1, 2, 4, 8, 12 and 16 weeks post-dose
Time of the last quantifiable concentration (tlast)
To characterize the PK of AZD2693 following SC administration of SAD of AZD2693
Time frame: At Day 1 pre-dose, 0.25h, 0.5h, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 5h, 6h, 8h, 12h, 24h, 36h, 48h and 72h post-dose and 1, 2, 4, 8, 12 and 16 weeks post-dose
Cumulative fraction (%) of dose excreted unchanged into the urine from time zero to the last measured time point [fe(0-last)]
To characterize the PK of AZD2693 following SC administration of SAD of AZD2693
Time frame: At Day 1 pre-dose, 0-6h, 6-12h and then 0-12h intervals up to 72h post-dose
Cumulative amount of analyte excreted into the urine from time zero through the last sampling interval [Ae(0-last)]
To characterize the PK of AZD2693 following SC administration of SAD of AZD2693
Time frame: At Day 1 pre-dose, 0-6h, 6-12h and then 0-12h intervals up to 72h post-dose
Renal clearance of drug from plasma, estimated by dividing Ae(0-t) by AUC(0-t) where the 0-t interval is the same for both Ae and AUC [CLR]
To characterize the PK of AZD2693 following SC administration of SAD of AZD2693
Time frame: At Day 1 pre-dose, 0-6h, 6-12h and then 0-12h intervals up to 72h post-dose
Amount of analyte excreted into the urine from time t1 to t2 [Ae(t1-t2)]
To characterize the PK of AZD2693 following SC administration of SAD of AZD2693
Time frame: At Day 1 pre-dose, 0-6h, 6-12h and then 0-12h intervals up to 72h post-dose
Fraction of dose excreted unchanged into the urine from time t1 to t2 [fe(t1-t2)]
To characterize the PK of AZD2693 following SC administration of SAD of AZD2693
Time frame: At Day 1 pre-dose, 0-6h, 6-12h and then 0-12h intervals up to 72h post-dose
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