A Randomized, Single-blind, Placebo-controlled Study to Assess the Safety, Tolerability and Pharmacokinetics of AZD4076 Tetracosasodium Following Single-ascending Dose Administration to Healthy Male Subjects
Overview
- Phase
- Phase 1
- Intervention
- AZD4076
- Conditions
- Non-alcoholic Steatohepatitis (NASH)
- Sponsor
- AstraZeneca
- Enrollment
- 40
- Locations
- 1
- Primary Endpoint
- The safety and tolerability of AZD4076 by assessment of oral temperature
- Status
- Completed
- Last Updated
- 5 months ago
Overview
Brief Summary
This is a first-in-human (FIH) study designed to evaluate the safety, tolerability, and pharmacokinetics (PK) of AZD4076 tetracosasodium in healthy male subjects at increasing single doses
Detailed Description
This is a Phase 1, randomized, first-in-human (FIH) study to assess the safety, tolerability, and pharmacokinetics (PK) of AZD4076 tetracosasodium following subcutaneous (SC) administration in healthy male subjects at increasing single doses
Investigators
Eligibility Criteria
Inclusion Criteria
- •Provision of signed and dated, written informed consent prior to any study specific procedures
- •Healthy male subjects aged 18 - 50 years with suitable veins for cannulation or repeated venipuncture
- •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 research
Exclusion Criteria
- •History or presence 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 hepatic or renal disease, or any other condition known to interfere with distribution, metabolism, or excretion of drugs
- •History or presence of significant neurological or psychiatric disease/mental illness (as judged by the investigator)
- •Suspicion of or known Gilbert's syndrome based on liver function tests
- •Any clinically significant illness, medical/surgical procedure, or trauma within 4 weeks of the administration of IMP
- •Any clinically significant abnormalities in clinical chemistry, hematology, or urinalysis results, as judged by the investigator
- •Any positive result on screening for serum hepatitis B surface antigen (HBsAg), hepatitis C antibody and human immunodeficiency virus (HIV)
- •Serum Creatinine greater than the ULN.
- •Platelet count outside the normal range.
- •AST, ALT, or GGT greater than the ULN.
Arms & Interventions
Cohort 2
Subjects will be fasted for at least 10 hours before dosing and until 4 hours after dosing of a single dose of AZD4076 tetracosasodium or placebo (high doses may be fractionated)
Intervention: AZD4076
Cohort 1
Subjects will be fasted for at least 10 hours before dosing and until 4 hours after dosing of a single dose of AZD4076 tetracosasodium or placebo (high doses may be fractionated)
Intervention: AZD4076
Cohort 1
Subjects will be fasted for at least 10 hours before dosing and until 4 hours after dosing of a single dose of AZD4076 tetracosasodium or placebo (high doses may be fractionated)
Intervention: Placebo
Cohort 2
Subjects will be fasted for at least 10 hours before dosing and until 4 hours after dosing of a single dose of AZD4076 tetracosasodium or placebo (high doses may be fractionated)
Intervention: Placebo
Cohort 3
Subjects will be fasted for at least 10 hours before dosing and until 4 hours after dosing of a single dose of AZD4076 tetracosasodium or placebo (high doses may be fractionated)
Intervention: AZD4076
Cohort 3
Subjects will be fasted for at least 10 hours before dosing and until 4 hours after dosing of a single dose of AZD4076 tetracosasodium or placebo (high doses may be fractionated)
Intervention: Placebo
Cohort 4
Subjects will be fasted for at least 10 hours before dosing and until 4 hours after dosing of a single dose of AZD4076 tetracosasodium or placebo (high doses may be fractionated)
Intervention: AZD4076
Cohort 4
Subjects will be fasted for at least 10 hours before dosing and until 4 hours after dosing of a single dose of AZD4076 tetracosasodium or placebo (high doses may be fractionated)
Intervention: Placebo
Cohort 5
Subjects will be fasted for at least 10 hours before dosing and until 4 hours after dosing of a single dose of AZD4076 tetracosasodium or placebo (high doses may be fractionated)
Intervention: AZD4076
Cohort 5
Subjects will be fasted for at least 10 hours before dosing and until 4 hours after dosing of a single dose of AZD4076 tetracosasodium or placebo (high doses may be fractionated)
Intervention: Placebo
Cohort 6
Subjects will be fasted for at least 10 hours before dosing and until 4 hours after dosing of a single dose of AZD4076 tetracosasodium or placebo (high doses may be fractionated)
Intervention: AZD4076
Cohort 6
Subjects will be fasted for at least 10 hours before dosing and until 4 hours after dosing of a single dose of AZD4076 tetracosasodium or placebo (high doses may be fractionated)
Intervention: Placebo
Outcomes
Primary Outcomes
The safety and tolerability of AZD4076 by assessment of oral temperature
Time Frame: From screening until 72 hours postdose
To assess the safety and tolerability of single doses of AZD4076
The safety and tolerability of AZD4076 by assessment of physical examination
Time Frame: From screening until 16 weeks postdose, up to 5 months
This is a composite of the general appearance, skin, cardiovascular, respiratory, abdomen, head, and neck (including ears, eyes, nose, and throat), lymph nodes, thyroid, musculoskeletal and neurological systems
The safety and tolerability of AZD4076 by assessing the injection site
Time Frame: Postdose until 72 hours
This includes assessment of erythema/redness, swelling, induration, pruritus and pain at injection site
The safety and tolerability of AZD4076 by assessment of pulse
Time Frame: From screening until 16 weeks postdose, up to 5 months
To assess the safety and tolerability of single doses of AZD4076
The safety and tolerability of AZD4076 by assessment of blood pressure
Time Frame: From screening until 16 weeks postdose, up to 5 months
To assess the safety and tolerability of single doses of AZD4076
The safety and tolerability of AZD4076 by assessing hematology
Time Frame: From screening until 16 weeks postdose, up to 5 months
To assess the safety and tolerability of single doses of AZD4076
The safety and tolerability of AZD4076 by assessing urinalysis
Time Frame: From screening until 16 weeks postdose, up to 5 months
To assess the safety and tolerability of single doses of AZD4076
The safety and tolerability of AZD4076 by assessing the number of participants with adverse events
Time Frame: From screening until 16 weeks postdose, up to 5 months
To assess the safety and tolerability of single doses of AZD4076
The safety and tolerability of AZD4076 by assessment of electrocardiogram readings
Time Frame: From screening until 16 weeks postdose, up to 5 months
To assess the safety and tolerability of single doses of AZD4076
The safety and tolerability of AZD4076 by assessment of digital electrocardiogram readings
Time Frame: From predose until 72 hours postdose
To assess the safety and tolerability of single doses of AZD4076
The safety and tolerability of AZD4076 by assessming the number of adverse events
Time Frame: From screening until 16 weeks postdose, up to 5 months
To assess the safety and tolerability of single doses of AZD4076
The safety and tolerability of AZD4076 by assessing clinical chemistry
Time Frame: From screening until 16 weeks postdose, up to 5 months
To assess the safety and tolerability of single doses of AZD4076
The safety and tolerability of AZD4076 by assessment of cardiac telemetry
Time Frame: On Day -1 and predose until 72 hours postdose
To assess the safety and tolerability of single doses of AZD4076 by telemetry monitoring and paper printouts
Secondary Outcomes
- Terminal elimination half-life, estimated as (ln2)/λz [t1/2λz ] assessed for AZD4076 from the plasma data(Predose until 16 weeks postdose)
- Dose normalized area under the plasma concentration-time curve from time zero to time of last quantifiable concentration, calculated by dividing AUC(0-last) by the dose administered [AUC(0 last)/D] assessed for AZD4076 from the plasma data(Predose until 16 weeks postdose)
- Dose normalized area under the plasma concentration-time curve from time zero extrapolated to infinity divided by dose, calculated by dividing AUC by the dose administered [AUC/D] assessed for AZD4076 from the plasma data(Predose until 16 weeks postdose)
- fe(0-t) assessed for AZD4076 metabolites from the urine data(Predose until 72 hours postdose)
- Area under plasma concentration-time curve from time zero extrapolated to infinity [AUC] assessed for AZD4076 from the plasma data(Predose until 16 weeks postdose)
- Apparent total clearance, estimated as dose divided by AUC [CL/F] assessed for AZD4076 from the plasma data(Predose until 16 weeks postdose)
- Dose normalized maximum plasma concentration divided by dose, calculated by dividing Cmax by the dose administered for [Cmax/D] assessed for AZD4076 from the plasma data(Predose until 16 weeks postdose)
- Cumulative amount of analyte excreted in urine from time zero to the last sampling interval (72 hours) [Ae(0-t)] assessed for AZD4076 from the urine data(Predose until 72 hours postdose)
- tmax assessed for AZD4076 metabolites from the plasma data(Predose until 16 weeks postdose)
- AUC/D assessed for AZD4076 metabolites from the plasma data(Predose until 16 weeks postdose)
- Percentage of dose excreted unchanged into the urine from time zero to the last sampling interval (72 hours), estimated by dividing Ae(0-t) by dose [fe(0-t)] assessed for AZD4076 from the urine data(Predose until 72 hours postdose)
- Renal clearance, estimated by dividing Ae(0-t) by AUC(0-72) [CLR] assessed for AZD4076 from the urine data(Predose until 72 hours postdose)
- Cmax assessed for AZD4076 metabolites from the plasma data(Predose until 16 weeks postdose)
- t1/2λz assessed for AZD4076 metabolites from the plasma data(Predose until 16 weeks postdose)
- Observed maximum plasma concentration, taken directly from the individual concentration-time curve [Cmax] assessed for AZD4076 from the plasma data(Predose until 16 weeks postdose)
- Time to reach maximum concentration, taken directly from the individual concentration-time curve [tmax] assessed for AZD4076 from the plasma data(Predose until 16 weeks postdose)
- Area under the plasma concentration-curve from time zero to the time of last quantifiable concentration [AUC(0-last)] assessed for AZD4076 from the plasma data(Predose until 16 weeks postdose)
- Mean Residence Time [MRT] assessed for AZD4076 from the plasma data(Predose until 16 weeks postdose)
- Apparent volume of distribution at terminal phase, estimated by dividing the apparent clearance (CL/F) by λz [Vz/F] assessed for AZD4076 from the plasma data(Predose until 16 weeks postdose)
- Area under the plasma concentration-curve from time zero to 72h after drug administration [AUC(0-72h)] assessed for AZD4076 from the plasma data(Predose until 16 weeks postdose)
- Lag-time, taken directly from the individual concentration-time curve [tlag] assessed for AZD4076 from the plasma data(Predose until 16 weeks postdose)
- AUC(0-last) assessed forAZD4076 metabolites from the plasma data(Predose until 16 weeks postdose)
- AUC(0-72h) assessed for AZD4076 metabolites from the plasma data(Predose until 16 weeks postdose)
- MRT assessed for AZD4076 metabolites from the plasma data(Predose until 16 weeks postdose)
- tlag assessed for AZD4076 metabolites from the plasma data(Predose until 16 weeks postdose)
- Vz/F assessed for AZD4076 metabolites from the plasma data(Predose until 16 weeks postdose)
- Cmax/D assessed for AZD4076 metabolites from the plasma data(Predose until 16 weeks postdose)
- [AUC(0-last)/D assessed for AZD4076 metabolites from the plasma data(Predose until 16 weeks postdose)
- Ae(0-t) assessed for AZD4076 metabolites from the urine data(Predose until 72 hours postdose)
- CLR assessed for AZD4076 metabolites from the urine data(Predose until 72 hours postdose)
- AUC assessed for AZD4076 metabolites from the plasma data(Predose until 16 weeks postdose)
- CL/F assessed for AZD4076 metabolites from the plasma data(Predose until 16 weeks postdose)