A Phase I, Randomized, Single-blind, Placebo-controlled Study to Assess the Safety, Tolerability and Pharmacokinetics of AZD3974 After Single and Multiple Ascending Dosing to Healthy Participants
Overview
- Phase
- Phase 1
- Status
- Recruiting
- Sponsor
- AstraZeneca
- Enrollment
- 176
- Locations
- 3
- Primary Endpoint
- Number of participants with adverse events (AEs) and serious adverse events (SAEs)
Overview
Brief Summary
The purpose of this study is to assess the safety and tolerability of AZD3974 and characterize the pharmacokinetics (PK) of AZD3974 following oral administration to healthy participants, including participants of Japanese and Chinese descent.
Detailed Description
This is a first in human, randomized, single-blind, placebo-controlled study. It consists of two parts.
Part A (single ascending dose - SAD): This study part will enroll six cohorts (plus two optional additional cohorts) of healthy participants (Part A1), three cohorts (plus one optional additional cohort) of healthy Japanese participants (Part A2) and one cohort (plus one optional additional cohort) of healthy Chinese participants (Part A3). Cohort 3 of Part A1 will be extended to evaluate the effect of food intake on the PK of AZD3974. In Part A (all cohorts), participants will receive a single dose of AZD3974 or placebo.
Part B (Multiple Ascending Dose - MAD): This study part will consist of four cohorts (plus two optional additional cohorts) of healthy participants (Part B1) and one cohort (plus one optional additional cohort) of healthy Japanese participants (Part B2). In all Part B cohorts, participants will receive multiple doses of AZD3974 or placebo.
Both Part A and Part B will comprise of:
- A Screening Period of maximum 28 days
- A Dosing session during which participants will receive the study intervention at study specific time points.
- Follow-up Period of 7 days post last-dose.
Study Design
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Sequential
- Primary Purpose
- Treatment
- Masking
- Single (Participant)
Eligibility Criteria
- Ages
- 18 Years to 55 Years (Adult)
- Sex
- All
- Accepts Healthy Volunteers
- Yes
Inclusion Criteria
- •Healthy male and female (of non-childbearing potential) participants with suitable veins for cannulation or repeated venipuncture at the Screening Visit.
- •All females must have a negative pregnancy test. Females of non-childbearing potential must be confirmed via post-menopausal status or documentation of irreversible surgical sterilization at the Screening Visit.
- •Sexually active fertile male participants with partners of childbearing potential must adhere to the contraception methods.
- •Have a body mass index between 18 and 32 kg/m2 inclusive and weigh at least 50 kg at Screening.
- •For healthy Japanese cohorts (Part A2 and Part B2): healthy male and female participants are to be Japanese (eg, natives of Japan or Japan Americans), defined as having both parents and 4 grandparents who are Japanese. This includes second and third generation participants of Japanese descent whose parents or grandparents are living in a country other than Japan.
- •For healthy Chinese cohort (Part A3): healthy male and female Chinese participants for whom both parents and 4 grandparents are Chinese. This includes second and third generation participants of Chinese descent whose parents or grandparents are living in a country other than China.
Exclusion Criteria
- •History of any clinically important disease or disorder which, may either put the participant at risk because of participation in the study, or influence the results or the participant's ability to participate in the study.
- •History or presence of gastrointestinal, hepatic, or renal disease or any other condition known to interfere with absorption, distribution, metabolism, or excretion of drugs.
- •Any clinically important illness, medical/surgical procedure, or trauma within 4 weeks of the first administration of study intervention.
- •Any abnormal laboratory values, vital signs, or any clinically important abnormalities in clinical chemistry, hematology, or urinalysis results.
- •Any positive result on Screening for serum hepatitis B and C viruses and human immunodeficiency virus.
- •Any clinically important abnormalities in rhythm, conduction, or morphology of the resting 12 lead electrocardiography at Screening and/or admission to the Clinical Unit .
- •Known or suspected history of alcohol or drug abuse or excessive intake of alcohol.
- •Positive screen for drugs of abuse, or alcohol, or cotinine.
- •History of severe allergy/hypersensitivity or ongoing clinically important allergy/hypersensitivity.
- •Participants who have previously received AZD3974.
Arms & Interventions
Part A1 (SAD) Cohort 3: Placebo (Food Effect Cohort)
Healthy participants will receive two single doses of matching placebo to AZD3974
Intervention: Placebo (Other)
Part A2 (SAD) Japanese Cohort 1: AZD3974
Healthy Japanese participants will receive a single dose of AZD3974
Intervention: AZD3974 (Drug)
Part A2 (SAD) Japanese Cohort 2: AZD3974
Healthy Japanese participants will receive a single dose of AZD3974
Intervention: AZD3974 (Drug)
Part A2 (SAD) Japanese Cohort 3: AZD3974
Healthy Japanese participants will receive a single dose of AZD3974
Intervention: AZD3974 (Drug)
Part A1 (SAD) Cohort 1: AZD3974 (Dose 1)
Healthy participants will receive a single dose of AZD3974 - Dose 1
Intervention: AZD3974 (Drug)
Part A1 (SAD) Cohort 2: AZD3974 (Dose 2)
Healthy participants will receive a single dose of AZD3974 - Dose 2
Intervention: AZD3974 (Drug)
Part A1 (SAD) Cohort 3: AZD3974 (Dose 3) (Food Effect Cohort)
Healthy participants will receive two single doses of AZD3974 - Dose 3
Intervention: AZD3974 (Drug)
Part A1 (SAD) Cohort 4: AZD3974 (Dose 4)
Healthy participants will receive a single dose of AZD3974 - Dose 4
Intervention: AZD3974 (Drug)
Part A1 (SAD) Cohort 5: AZD3974 (Dose 5)
Healthy participants will receive a single dose of AZD3974 - Dose 5
Intervention: AZD3974 (Drug)
Part A1 (SAD) Cohort 6: AZD3974 (Dose 6)
Healthy participants will receive a single dose of AZD3974 - Dose 6
Intervention: AZD3974 (Drug)
Part A1 (SAD) optional additional Cohort 7: AZD3974
Healthy participants will receive a single dose of AZD3974
Intervention: AZD3974 (Drug)
Part A1 (SAD) optional additional Cohort 8: AZD3974
Healthy participants will receive a single dose of AZD3974
Intervention: AZD3974 (Drug)
Part A1 (SAD) Cohort: Placebo
Healthy participants will receive a single dose of matching placebo to AZD3974
Intervention: Placebo (Other)
Part A2 (SAD) optional additional Japanese Cohort 4: AZD3974
Healthy Japanese participants will receive a single dose of AZD3974
Intervention: AZD3974 (Drug)
Part A2 (SAD) Japanese Cohort: Placebo
Healthy Japanese participants will receive a single dose of matching placebo to AZD3974
Intervention: Placebo (Other)
Part A3 (SAD) Chinese Cohort 1: AZD3974
Healthy Chinese participants will receive a single dose of AZD3974
Intervention: AZD3974 (Drug)
Part A3 (SAD) optional additional Chinese Cohort 2: AZD3974
Healthy Chinese participants will receive a single dose of AZD3974
Intervention: AZD3974 (Drug)
Part A3 (SAD) Chinese Cohort: Placebo
Healthy Chinese participants will receive a single dose of matching placebo to AZD3974
Intervention: Placebo (Other)
Part B1 (MAD) Cohort 1: AZD3974
Healthy participants will receive multiple doses of AZD3974
Intervention: AZD3974 (Drug)
Part B1 (MAD) Cohort 2: AZD3974
Healthy participants will receive multiple doses of AZD3974
Intervention: AZD3974 (Drug)
Part B1 (MAD) Cohort 3: AZD3974
Healthy participants will receive multiple doses of AZD3974
Intervention: AZD3974 (Drug)
Part B1 (MAD) Cohort 4: AZD3974
Healthy participants will receive multiple doses of AZD3974
Intervention: AZD3974 (Drug)
Part B1 (MAD) optional additional Cohort 5: AZD3974
Healthy participants will receive multiple doses of AZD3974
Intervention: AZD3974 (Drug)
Part B1 (MAD) optional additional Cohort 6: AZD3974
Healthy participants will receive multiple doses of AZD3974
Intervention: AZD3974 (Drug)
Part Bl (MAD) Cohort: Placebo
Healthy participants will receive multiple doses of matching placebo to AZD3974
Intervention: Placebo (Other)
Part B2 (MAD) Japanese Cohort 1: AZD3974
Healthy Japanese participants will receive multiple doses of AZD397
Intervention: AZD3974 (Drug)
Part B2 (MAD) optional additional Japanese Cohort 2: AZD3974
Healthy Japanese participants will receive multiple doses of matching placebo to AZD3974
Intervention: AZD3974 (Drug)
Part B2 (MAD) Japanese Cohort: Placebo
Healthy Japanese participants will receive multiple doses of matching placebo to AZD3974
Intervention: Placebo (Other)
Outcomes
Primary Outcomes
Number of participants with adverse events (AEs) and serious adverse events (SAEs)
Time Frame: Part A: Upto Day 7; Part A1 Cohort 3: Upto Day 10; Part B: Upto Day 14
To assess the safety and tolerability of AZD3974 following oral administration of single and multiple ascending doses in healthy participants, including Chinese and Japanese participants
Secondary Outcomes
- Part A and Part B: Plasma concentrations of AZD3974(Part A: Day 1 to Day 2; Part B: Day 1 to Day 9)
- Part A1-Cohort 3: Plasma concentrations of AZD3974(Day 1 to Day 4)
- Part A and Part B: Urine concentrations of AZD3974(Part A: Day 1; Part B: Day 1 and Day 7)
- Part A1-Cohort 3: Urine concentrations of AZD3974(Day 1 and Day 3)
- Part A and Part B: Area under concentration-curve from time 0 to the last quantifiable concentration (AUClast)(Part A: Day 1 to Day 2; Part B: Day 1 to Day 9)
- Part A1-Cohort 3: Area under concentration-curve from time 0 to the last quantifiable concentration (AUClast)(Day 1 to Day 4)
- Part A: Area under concentration-time curve from time 0 to infinity (AUCinf)(Day 1 to Day 2)
- Part A1-Cohort 3: Area under concentration-time curve from time 0 to infinity (AUCinf)(Day 1 to Day 4)
- Part A and Part B: Maximum observed drug concentration (Cmax)(Part A: Day 1 to Day 2; Part B: Day 1 to Day 9)
- Part A1-Cohort 3: Maximum observed drug concentration (Cmax)(Day 1 to Day 4)
- Part A and Part B: Time to reach maximum observed concentration (tmax)(Part A: Day 1 to Day 2; Part B: Day 1 to Day 9)
- Part A1-Cohort 3: Time to reach maximum observed concentration (tmax)(Day 1 to Day 4)
- Part A and Part B: Terminal elimination half-life (t½λz)(Part A: Day 1 to Day 2; Part B: Day 1 to Day 9)
- Part A1-Cohort 3: Terminal elimination half-life (t½λz)(Day 1 to Day 4)
- Part A and Part B: Apparent total body clearance (CL/F)(Part A: Day 1 to Day 2; Part B: Day 1 to Day 9)
- Part A1-Cohort 3: Apparent total body clearance (CL/F)(Day 1 to Day 4)
- Part A and Part B: Apparent volume of distribution based on the terminal phase (Vz/F)(Part A: Day 1 to Day 2; Part B: Day 1 to Day 9)
- Part A1-Cohort 3: Apparent volume of distribution based on the terminal phase (Vz/F)(Day 1 to Day 4)
- Part A and Part B: Individual and cumulative amount of unchanged drug excreted into urine from time t0 to time tlast [Ae(0-last)](Part A: Day 1; Part B: Day 1 and Day 7)
- Part A1-Cohort 3: Individual and cumulative amount of unchanged drug excreted into urine from time t0 to time tlast [Ae(0-last)](Day 1 and Day 3)
- Part A and Part B: Individual and cumulative percentage of dose excreted unchanged in urine from time t0 to tlast [fe(0-last)](Part A: Day 1; Part B: Day 1 and Day 7)
- Part A1-Cohort 3: Individual and cumulative percentage of dose excreted unchanged in urine from time t0 to tlast [fe(0-last)](Day 1 and Day 3)
- Part A and Part B: Renal clearance (CLR)(Part A: Day 1; Part B: Day 1 and Day 7)
- Part A1-Cohort 3: Renal clearance (CLR)(Day 1 and Day 3)
- Part A and Part B: Mean Residence Time (MRT)(Part A: Day 1 to Day 2; Part B: Day 1 to Day 9)
- Part A1-Cohort 3: Mean Residence Time (MRT)(Day 1 to Day 4)
- Part A and Part B: Time delay between drug administration and the first observed concentration (tlag)(Part A: Day 1 to Day 2; Part B: Day 1 to Day 9)
- Part A1-Cohort 3: Time delay between drug administration and the first observed concentration (tlag)(Day 1 to Day 4)
- Part A and Part B: Time of last quantifiable concentration (tlast)(Part A: Day 1 to Day 2; Part B: Day 1 to Day 9)
- Part A1-Cohort 3: Time of last quantifiable concentration (tlast)(Day 1 to Day 4)
- Part A and Part B: Individual and cumulative amount of unchanged drug excreted into urine from time t1 to time t2 [Ae(t1 t2)](Part A: Day 1; Part B: Day 1 and Day 7)
- Part A1-Cohort 3: Individual and cumulative amount of unchanged drug excreted into urine from time t1 to time t2 [Ae(t1 t2)](Day 1 and Day 3)
- Part A and Part B: Individual and cumulative percentage of dose excreted unchanged in urine from time t1 to time t2 - [fe(t1-t2)](Part A: Day 1; Part B: Day 1 and Day 7)
- Part A1-Cohort 3: Individual and cumulative percentage of dose excreted unchanged in urine from time t1 to time t2 - [fe(t1-t2)](Day 1 and Day 3)
- Part A and Part B: Cumulative amount of unchanged drug excreted into urine (Aeinf)(Part A: Day 1; Part B : Day 1 and Day 7)
- Part A1-Cohort 3: Cumulative amount of unchanged drug excreted into urine (Aeinf)(Day 1 and Day 3)
- Part B: Area under concentration time curve in the dosing interval (AUCtau)(Day 1 to Day 9)
- Part B: Observed lowest concentration before the next dose is administered: (Ctrough)(Day 1 to Day 9)
- Part B: Accumulation ratio for AUC calculated as steady State AUCτ/First Dose AUCτ (Rac AUC)(Day 1 to Day 9)
- Part B: Accumulation ratio for Cmax calculated as steady State Cmax/First Dose Cmax (Rac Cmax)(Day 1 to Day 9)
- Part B: Temporal change parameter calculated as steady State AUCτ/First Dose AUCinf (TCP)(Day 1 to Day 9)