A Phase I, Randomised, Single-Blind, Placebo-controlled Study to Assess the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of AZD4831 After Single and Multiple Ascending Dose Administration to Healthy Male Subjects
Overview
- Phase
- Phase 1
- Intervention
- AZD4831
- Conditions
- Cardiovascular Disease
- Sponsor
- AstraZeneca
- Enrollment
- 104
- Primary Endpoint
- Frequencies of adverse events
- Status
- Terminated
- Last Updated
- 9 years ago
Overview
Brief Summary
This is a Phase I, first-in-human (FIH) study to assess the safety, tolerability, pharmacokinetics (PK) and Pharmacodynamics (PD) of AZD4831 after single and multiple ascending doses in healthy male subjects
Detailed Description
This is a Phase I, FIH, randomized, single-blind, placebo-controlled study to assess the safety, tolerability, pharmacokinetics (PK) and Pharmacodynamics (PD) of AZD4831 after single (Part 1) and multiple (Part 2) ascending doses in healthy male subjects. The study will be conducted at a single study center with a planned number of subjects of up to 125 healthy males, aged 18 to 50 years.
Investigators
Eligibility Criteria
Inclusion Criteria
- Not provided
Exclusion Criteria
- •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.
- •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.
- •Presence of infection(s) (particularly fungal infection), as judged by the investigator.
- •History or current thyroid disease.
- •Any clinically significant 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, haematology, or urinalysis results, as judged by the investigator.
- •Any positive result on screening for serum hepatitis B surface antigen (HBsAg), anti-hepatitis B core (anti-HBc) antibodies, hepatitis C antibody and human immunodeficiency virus (HIV).
- •Abnormal vital signs
- •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 LV hypertrophy.
- •Prolonged QTcF \> 450 ms or shortened QTcF \< 340 ms or family history of long QT syndrome.
Arms & Interventions
Part 1, Dose Level 1
Part 1: Part 1A: Single dose administered in the morning on Day 1 under fasted conditions. Part 1B: Single dose administered in the morning of Day 1 under fed conditions.
Intervention: AZD4831
Part 1, Dose Level 2
Part 1: Part 1A: Single dose administered in the morning on Day 1 under fasted conditions. Part 1B: Single dose administered in the morning of Day 1 under fed conditions.
Intervention: AZD4831
Part 1, Dose Level 3
Part 1: Part 1A: Single dose administered in the morning on Day 1 under fasted conditions. Part 1B: Single dose administered in the morning of Day 1 under fed conditions.
Intervention: AZD4831
Part 1, Dose Level 4
Part 1: Part 1A: Single dose administered in the morning on Day 1 under fasted conditions. Part 1B: Single dose administered in the morning of Day 1 under fed conditions.
Intervention: AZD4831
Part 1, Dose Level 5
Part 1: Part 1A: Single dose administered in the morning on Day 1 under fasted conditions. Part 1B: Single dose administered in the morning of Day 1 under fed conditions.
Intervention: AZD4831
Part 1, Dose Level 6
Part 1: Part 1A: Single dose administered in the morning on Day 1 under fasted conditions. Part 1B: Single dose administered in the morning of Day 1 under fed conditions.
Intervention: AZD4831
Part 2, Dose Level 1
Part 2: Single dose administered in the morning on Day 1 and multiple doses administered once daily, in the morning, Days 3 to 12
Intervention: AZD4831
Part 2, Dose Level 2
Part 2: Single dose administered in the morning on Day 1 and multiple doses administered once daily, in the morning, Days 3 to 12
Intervention: AZD4831
Part 2, Dose Level 3
Part 2: Single dose administered in the morning on Day 1 and multiple doses administered once daily, in the morning, Days 3 to 12
Intervention: AZD4831
AZD4831 Placebo
Part 1: Part 1A: Single dose administered in the morning on Day 1 under fasted conditions. Part 1B: Single dose administered in the morning of Day 1 under fed conditions. Part 2: Single dose administered in the morning on Day 1 and multiple doses administered once daily, in the morning, Days 3 to 12
Intervention: AZD4831 placebo
Outcomes
Primary Outcomes
Frequencies of adverse events
Time Frame: From screening up to 10 days post final dose
To assess the safety and tolerability of single and multiple doses of AZD4831
Percentage of adverse events
Time Frame: From screening to 10 days post final dose
To assess the safety and tolerability of single and multiple doses of AZD4831
Supine blood pressure (Part 2)
Time Frame: From screening up to 10 days post final dose
To assess change from baseline in supine blood pressure
To assess the subject through urinalysis laboratory assessment
Time Frame: From screening up to 10 days post final dose
To assess a subject through urinalysis laboratory assessment
Supine blood pressure (Part 1)
Time Frame: From screening up to 48 hours post dose
To assess change from baseline in supine blood pressure
Supine pulse rate (Part 2)
Time Frame: From screening up to 10 days post final dose
To assess change from baseline in supine pulse rate
Supine pulse rate (Part 1)
Time Frame: From screening up to 48 hours post dose
To assess change from baseline in supine pulse rate
Supine body temperature (Part 2)
Time Frame: From screening up to pre-dose Day 12
To assess change from baseline in supine body temperature
12-lead electrocardiogram
Time Frame: From screening up to 10 days post final dose
To assess 12-lead electrocardiogram
12-lead electrocardiogram (cardiac telemetry)
Time Frame: From Day-1 up to 24 hours post final dose
12-lead electrocardiogram (cardiac telemetry)
To assess the subject through hematology laboratory assessment
Time Frame: From screening up to 10 days post final dose
To assess a subject through hematology laboratory assessment
Physical examination
Time Frame: From screening up to 10 days post final dose
To assess subject through a physical examination, including assessment of the general appearance, skin, cardiovascular, respiratory, abdomen, head and neck (including ears, eyes, nose and throat), lymph nodes, thyroid, musculoskeletal and neurological systems.
Chemistry evaluations
Time Frame: From screening up to 10 days post final dose
including high-sensitivity C-reactive protein {hs-CRP} and thyroid panel
Secondary Outcomes
- Terminal rate constant, estimated by log-linear least squares regression of the terminal part of the concentration-time curve (λz)(From pre-dose up to 48 hours post dose)
- Area under the plasma concentration-curve over 24 hours (AUCτ)(From pre-dose up to 48 hours post dose)
- Area under the plasma concentration-curve from time zero to the time of last quantifiable analyte concentration (AUC0-t)(From pre-dose up to 48 hours post dose)
- Area under the plasma concentration-time curve from time zero to time of last quantifiable analyte concentration divided by the dose administered (AUC0-t/D)(From pre-dose up to 48 hours post dose)
- Area under the plasma concentration-time curve from time zero extrapolated to infinity divided by the dose administered (AUC/D)(From pre-dose up to 48 hours post dose)
- Observed maximum plasma concentration divided by the dose administered (Cmax/D)(From pre-dose up to 48 hours post dose)
- Accumulation ratio calculated as AUCτ Day 12/ AUCτ Day 1 (Rac AUC) (Part 2 only)(From pre-dose up to 48 hours post final dose)
- Area under the plasma concentration-curve over the dosing interval divided by the dose administered (AUCτ/D) (Part 2 only)(From pre-dose up to 48 hours post final dose)
- Temporal change parameter in systemic exposure (TCP) (Part 2 only)(From pre-dose up to 48 hours post final dose)
- Observed maximum plasma concentration, taken directly from the individual concentration-time curve (Cmax)(From pre-dose up to 48 hours post dose)
- Time to reach maximum plasma concentration, taken directly from the individual concentration-time curve (tmax)(From pre-dose up to 48 hours post dose)
- Terminal half-life, estimated as (ln2)/λz (t1/2λz)(From pre-dose up to 48 hours post dose)
- Amount of analyte excreted into the urine from time t1 to t2 [Ae(t1-t2)](From pre-dose up to 48 hours post dose)
- Cumulative amount of analyte excreted at time t [Ae(0-t)](From pre-dose up to 48 hours post dose)
- Fraction of dose excreted unchanged into the urine from time t1 to t2, estimated by dividing Ae(t1-t2) by dose [fe(t1-t2)](From pre-dose up to 48 hours post dose)
- Area under the concentration-time curve from time zero extrapolated to infinity (AUC)(From pre-dose up to 48 hours post dose)
- Apparent clearance for parent drug estimated as dose divided by AUC (CL/F)(From pre-dose up to 48 hours post dose)
- Mean Residence Time (MRT)(From pre-dose up to 48 hours post dose)
- Apparent volume of distribution for parent drug at terminal phase (Vz/F)(From pre-dose up to 48 hours post dose)
- Accumulation ratio calculated as Cmax Day 12/ Cmax Day 1 (Rac Cmax) (Part 2 only)(From pre-dose up to 48 hours post final dose)
- Fraction of dose excreted unchanged into the urine from time zero to time t, estimated by dividing Ae(0-t) by dose [fe(0-t)](From pre-dose up to 48 hours post dose)
- Renal clearance, estimated by dividing Ae(0-t) by AUC(0-t) (CLR)(From pre-dose up to 48 hours post dose)