A Phase I, Randomized, Placebo-controlled Study to Assess the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of AZD4831 Following Multiple-ascending Dose Administration in Japanese and Chinese Healthy Volunteers
Overview
- Phase
- Phase 1
- Intervention
- Placebo
- Conditions
- Heart Failure With Preserved Ejection Fraction (HFpEF)
- Sponsor
- AstraZeneca
- Enrollment
- 32
- Locations
- 1
- Primary Endpoint
- Number of subjects with adverse events (AEs)/serious adverse events
- Status
- Completed
- Last Updated
- 5 years ago
Overview
Brief Summary
This study is randomized, single-blind, placebo-controlled Phase 1 study aimed to assess the safety and efficacy, pharmacokinetics and pharmacodynamics of multiple doses of oral AZD4831 in healthy Japanese and Chinese volunteers
Detailed Description
This is a Phase I, randomized, single-blind, placebo-controlled, multiple-ascending dose (MAD), sequential-group study in healthy Japanese (Part 1, Cohorts 1, 2, and 3) and Chinese (Part 2, Cohort 4) male subjects, conducted at a single study center. Four cohorts are planned, but one additional cohort may be enrolled based on a Safety Review Committee (SRC) decision. The 4 multiple dose levels are planned as follows: * Cohort 1: Dose 1 * Cohort 2: Dose 2 * Cohort 3: Dose 3 * Cohort 4: Dose 2 A randomization ratio of 3:1 (AZD4831 versus placebo) will be used. For each cohort the study will comprise: * Screening Period of a maximum of 28 days. * A Treatment Period during which subjects are resident in the study center from the day before first dosing with the Investigational Medicinal Product (Day -1) until at least 48 hours after last dosing on Day 10; subjects will be discharged on Day 12. * Three Follow-up Visits on Day 14, Day 16 (±1 day), and Day 20 (±1 day). * A Final Follow-up Visit on Day 24 (±2 days). Each subject will be involved in the study for 8 to 9 weeks.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Provision of signed and dated, written informed consent prior to any study specific procedures.
- •Healthy male Japanese and Chinese subjects aged 18 - 50 years (inclusive at Screening) with suitable veins for cannulation or repeated venipuncture.
- •A Japanese subject is defined as having both parents and 4 grandparents who are ethnically Japanese. This includes second and third generation Japanese whose parents or grandparents are living in a country other than Japan.
- •A Chinese subject is defined as having both parents and 4 grandparents who are ethnically Chinese. This includes second and third generation Chinese whose parents or grandparents are living in a country other than China.
- •Have a body mass index (BMI) between 18 and 30 kg/m2 inclusive and weigh at least 50 kg and no more than 100 kg inclusive.
- •Provision of signed, written and dated informed consent for optional genetic/biomarker research. If a subject decline 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
- •History of any clinically important 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.
- •History or presence of gastrointestinal, hepatic or renal disease or any other condition known to interfere with absorption, distribution, metabolism or excretion of drugs.
- •Presence of infection(s) (particularly fungal infection), as judged by the Investigator.
- •History of, or current thyroid disease.
- •Any ongoing skin disorder, history of or ongoing clinically significant allergy/hypersensitivity.
- •Any clinically important illness, medical/surgical procedure or trauma within 4 weeks of the first administration of investigational medicinal product (IMP).
- •Any clinically significant abnormalities in clinical chemistry, hematology, or urinalysis results, as judged by the Investigator at Screening and/or Day -
- •Alanine transaminase (ALT) not within normal range
- •Aspartate aminotransferase (AST) not within normal range
- •Creatinine not within normal range
Arms & Interventions
Placebo (Part 2)
Randomized subjects will receive oral suspension of placebo once daily in the morning for a period of 10 days.
Intervention: Placebo
Cohort 1 (Part 1): AZD4831 Dose 1
Randomized subjects will receive oral suspension of AZD4831 Dose 1 once daily in the morning for a period of 10 days
Intervention: AZD4831
Cohort 2 (Part 1): AZD4831 Dose 2
Randomized subjects will receive oral suspension of AZD4831 Dose 2 once daily in the morning for a period of 10 days.
Intervention: AZD4831
Cohort 3 (Part 1): AZD4831 Dose 3
Randomized subjects will receive oral suspension of AZD4831 Dose 3 once daily in the morning for a period of 10 days.
Intervention: AZD4831
Cohort 4 (Part 2): AZD4831 Dose 2
Randomized subjects will receive oral suspension of AZD4831 Dose 2 once daily in the morning for a period of 10 days.
Intervention: AZD4831
Placebo (Part 1)
Randomized subjects will receive oral suspension of placebo once daily in the morning for a period of 10 days.
Intervention: Placebo
Outcomes
Primary Outcomes
Number of subjects with adverse events (AEs)/serious adverse events
Time Frame: Screening through follow-up visit (upto 9 weeks)
To assess AEs as a variable of safety and tolerability of AZD4831 following oral administration of multiple-ascending doses at steady state in healthy Japanese and Chinese subjects.
Number of subjects with abnormal electrocardiogram (ECG)
Time Frame: Screening through follow-up visit (upto 9 weeks)
To assess change ECG as a variable of safety and tolerability of AZD4831 following oral administration of multiple-ascending doses at steady state in healthy Japanese and Chinese subjects.
Number of subjects with abnormal abnormal clinical chemistry/hematology/urinalysis
Time Frame: Screening through follow-up visit (upto 9 weeks)
To assess clinical chemistry/hematology/urinalysis as a variable of safety and tolerability of AZD4831 following oral administration of multiple-ascending doses at steady state in healthy Japanese and Chinese subjects.
Number of subjects with abnormal blood pressure (BP) and pulse
Time Frame: Screening through follow-up visit (upto 9 weeks)
To assess BP and pulse rate as a variable of safety and tolerability of AZD4831 following oral administration of multiple-ascending doses at steady state in healthy Japanese and Chinese subjects.
Number of subjects with abormal physical examination results
Time Frame: Screening through follow-up visit (upto 9 weeks)
To assess physical examination as a variable of safety and tolerability of AZD4831 following oral administration of multiple-ascending doses at steady state in healthy Japanese and Chinese subjects.
Secondary Outcomes
- Plasma Cmax: Maximum observed plasma concentration(Day 1: Pre-dose (pre); 0.25,0.5,1,1.5,2,3,4,6,8,12 h post-dose (post); Day 2-9: Pre; Day 10: Pre and at 0.25,0.5,1,1.5,2,3,4,6,8,12 h post; Day 11:24 and 36 h post; Day 12: 48 h post; Day 16:96,144, and 240 h post; Day 24:336 h post)
- Plasma Ctrough: Observed trough plasma concentration(Day 1: pre; 0.25,0.5,1,1.5,2,3,4,6,8,12 h post; Day 2-9: Pre; Day 10: Pre and at 0.25,0.5,1,1.5,2,3,4,6,8,12 h post; Day 11:24 and 36 h post; Day 12: 48 h post; Day 16:96,144, and 240 h post; Day 24:336 h post)
- Plasma CL/F: Apparent total body clearance of drug from plasma after extravascular administration (Day 10)(Day 1: pre; 0.25,0.5,1,1.5,2,3,4,6,8,12 h post; Day 2-9: Pre; Day 10: Pre and at 0.25,0.5,1,1.5,2,3,4,6,8,12 h post; Day 11:24 and 36 h post; Day 12: 48 h post; Day 16:96,144, and 240 h post; Day 24:336 h post)
- Plasma Vz/F:Apparent volume of distribution for parent drug at terminal phase after extravascular administration(Day 1: pre; 0.25,0.5,1,1.5,2,3,4,6,8,12 h post; Day 2-9: Pre; Day 10: Pre and at 0.25,0.5,1,1.5,2,3,4,6,8,12 h post; Day 11:24 and 36 h post; Day 12: 48 h post; Day 16:96,144, and 240 h post; Day 24:336 h post)
- Plasma Rac(Cmax): Accumulation ratio based upon Cmax(Day 1: pre; 0.25,0.5,1,1.5,2,3,4,6,8,12 h post; Day 2-9: Pre; Day 10: Pre and at 0.25,0.5,1,1.5,2,3,4,6,8,12 h post; Day 11:24 and 36 h post; Day 12: 48 h post; Day 16:96,144, and 240 h post; Day 24:336 h post)
- Plasma tmax: Time to reach peak or maximum observed concentration following drug administration(Day 1: pre; 0.25,0.5,1,1.5,2,3,4,6,8,12 h post; Day 2-9: Pre; Day 10: Pre and at 0.25,0.5,1,1.5,2,3,4,6,8,12 h post; Day 11:24 and 36 h post; Day 12: 48 h post; Day 16:96,144, and 240 h post; Day 24:336 h post)
- Urine CLR: Renal clearance of drug from plasma, estimated by dividing Ae(0-last) by AUC(0-t)(Day1 : Pre; Day 10: 0 to 3, 3 to 6, 6 to 9, 9 to 12, 12 to 24 h post)
- Plasma t1/2λz: Half-life associated with terminal slope (λz) of a semi-logarithmic concentration-time curve(Day 1: pre; 0.25,0.5,1,1.5,2,3,4,6,8,12 h post; Day 2-9: Pre; Day 10: Pre and at 0.25,0.5,1,1.5,2,3,4,6,8,12 h post; Day 11:24 and 36 h post; Day 12: 48 h post; Day 16:96,144, and 240 h post; Day 24:336 h post)
- Plasma AUCτ/D(Day 1: pre; 0.25,0.5,1,1.5,2,3,4,6,8,12 h post; Day 2-9: Pre; Day 10: Pre and at 0.25,0.5,1,1.5,2,3,4,6,8,12 h post; Day 11:24 and 36 h post; Day 12: 48 h post; Day 16:96,144, and 240 h post; Day 24:336 h post)
- Plasma AUCinf/D: Area under the plasma concentration-time curve from time zero extrapolated to infinity divided by dose(Day 1: pre; 0.25,0.5,1,1.5,2,3,4,6,8,12 h post; Day 2-9: Pre; Day 10: Pre and at 0.25,0.5,1,1.5,2,3,4,6,8,12 h post; Day 11:24 and 36 h post; Day 12: 48 h post; Day 16:96,144, and 240 h post; Day 24:336 h post)
- Urine Ae(t1-t2): Amount of analyte excreted into the urine from time t1 to t2(Day1 : Pre; Day 10: 0 to 3, 3 to 6, 6 to 9, 9 to 12, 12 to 24 h post)
- Urine %fe(t1-t2): Fraction of dose (expressed as a percentage) excreted unchanged into the urine from time t1 to t2(Day1 : Pre; Day 10: 0 to 3, 3 to 6, 6 to 9, 9 to 12, 12 to 24 h post)
- Plasma Cmax/D(Day 1: pre; 0.25,0.5,1,1.5,2,3,4,6,8,12 h post; Day 2-9: Pre; Day 10: Pre and at 0.25,0.5,1,1.5,2,3,4,6,8,12 h post; Day 11:24 and 36 h post; Day 12: 48 h post; Day 16:96,144, and 240 h post; Day 24:336 h post)
- Plamsa AUCτ : Area under the plasma concentration-time curve within the dosing interval(Day 1: pre; 0.25,0.5,1,1.5,2,3,4,6,8,12 h post; Day 2-9: Pre; Day 10: Pre and at 0.25,0.5,1,1.5,2,3,4,6,8,12 h post; Day 11:24 and 36 h post; Day 12: 48 h post; Day 16:96,144, and 240 h post; Day 24:336 h post)
- Plasma AUCinf: Area under the concentration-time curve from time zero extrapolated to infinity(Day 1: pre; 0.25,0.5,1,1.5,2,3,4,6,8,12 h post; Day 2-9: Pre; Day 10: Pre and at 0.25,0.5,1,1.5,2,3,4,6,8,12 h post; Day 11:24 and 36 h post; Day 12: 48 h post; Day 16:96,144, and 240 h post; Day 24:336 h post)
- Plasma Rac(AUC): Accumulation ratio based upon AUC(Day 1: pre; 0.25,0.5,1,1.5,2,3,4,6,8,12 h post; Day 2-9: Pre; Day 10: Pre and at 0.25,0.5,1,1.5,2,3,4,6,8,12 h post; Day 11:24 and 36 h post; Day 12: 48 h post; Day 16:96,144, and 240 h post; Day 24:336 h post)
- Urine %fe(0-last): Percentage of dose excreted unchanged into the urine from time zero to the last measured time point for an analyte(Day1 : Pre; Day 10: 0 to 3, 3 to 6, 6 to 9, 9 to 12, 12 to 24 h post)
- Urine Ae(0-last): Cumulative amount of analyte excreted at the last sampling interval(Day1 : Pre; Day 10: 0 to 3, 3 to 6, 6 to 9, 9 to 12, 12 to 24 h post)