A Study to Assess the Safety and Tolerability of Single Doses of AZD4076 in Healthy Male Subjects

AstraZeneca40 enrolled

Overview

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

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

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

BASIC_SCIENCE

Masking

SINGLE

Enrollment

Conditions

Non-alcoholic Steatohepatitis (NASH)

Interventions

AZD4076DRUG

Subcutaneous (SC) administration of single ascending doses; there will be no more than 2 mL per syringe/injection

PlaceboDRUG

Subcutaneous (SC) administration of single ascending doses; there will be no more than 2 mL per syringe/injection

Eligibility

Sex: MALEMin age: 18 YearsMax age: 50 YearsHealthy volunteers:

Medical Language ↔ Plain English

Inclusion Criteria: 1. Provision of signed and dated, written informed consent prior to any study specific procedures 2. Healthy male subjects aged 18 - 50 years with suitable veins for cannulation or repeated venipuncture 3. 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 4. Provision of signed, written and dated informed consent for optional genetic research Exclusion Criteria: 1. 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 2. History or presence of hepatic or renal disease, or any other condition known to interfere with distribution, metabolism, or excretion of drugs 3. History or presence of significant neurological or psychiatric disease/mental illness (as judged by the investigator) 4. Suspicion of or known Gilbert's syndrome based on liver function tests 5. Any clinically significant illness, medical/surgical procedure, or trauma within 4 weeks of the administration of IMP 6. Any clinically significant abnormalities in clinical chemistry, hematology, or urinalysis results, as judged by the investigator 7. Any positive result on screening for serum hepatitis B surface antigen (HBsAg), hepatitis C antibody and human immunodeficiency virus (HIV) 8. Serum Creatinine greater than the ULN. 9. Platelet count outside the normal range. 10. AST, ALT, or GGT greater than the ULN. 11. Abnormal vital signs, after 10 minutes supine rest, defined as any of the following: * Systolic BP (SBP) \< 90mmHg or ≥ 140 mmHg * Diastolic BP (DBP) \< 50mmHg or ≥ 90 mmHg * Pulse \< 45 or \> 85 beats per minute (bpm) 12. 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 left ventricular hypertrophy 13. Prolonged QTcF \> 450 ms or shortened QTcF \< 340 ms or family history of long QT syndrome 14. PR(PQ) interval shortening \< 120 ms (PR \> 110 ms but \< 120 ms is acceptable if there is no evidence of ventricular pre-excitation) 15. PR (PQ) interval prolongation (\> 240 ms) intermittent second (Wenckebach block while asleep is not exclusive) or third degree AV block, or AV dissociation 16. Persistent or intermittent complete bundle branch block (BBB), incomplete bundle branch block (IBBB), or intraventricular conduction delay (IVCD) with QRS \> 110 ms. Subjects with QRS \> 110 ms but \< 115 ms are acceptable if there is no evidence of, for example, ventricular hypertrophy or pre-excitation 17. Known or suspected history of drug abuse, as judged by the investigator 18. Current smokers or those who have smoked or used nicotine products within the 3 months prior to screening 19. History of alcohol abuse or excessive intake of alcohol, as judged by the investigator 20. Positive screen for drugs of abuse or cotinine (nicotine) at screening or admission to the unit or positive screen for alcohol on admission to the unit prior to the administration of IMP 21. History of severe allergy/hypersensitivity or ongoing clinically significant allergy/hypersensitivity, as judged by the investigator or history of hypersensitivity to drugs with a similar chemical structure or class to AZD4076 tetracosasodium 22. Excessive intake of caffeine containing drinks or food (e.g., coffee, tea), as judged by the investigator 23. Use of drugs with enzyme inducing properties such as St John's Wort within 3 weeks prior to the administration of IMP 24. Use of any prescribed or non-prescribed medication including antacids, analgesics (other than paracetamol/acetaminophen), herbal remedies, megadose vitamins (intake of 20 to 600 times the recommended daily dose) and minerals during the two weeks prior to the administration of IMP or longer if the medication has a long half-life 25. Plasma donation within one month of screening or any blood donation/blood loss \> 500 mL during the 3 months prior to screening 26. Has received another new chemical entity (defined as a compound which has not been approved for marketing) within 3 months of the administration of IMP in this study. The period of exclusion begins three months after the final dose or one month after the last visit whichever is the longest. Note: Subjects consented and screened, but not randomized in this study or a previous phase I study, are not excluded. 27. Vulnerable subjects, e.g., kept in detention, protected adults under guardianship, trusteeship, or committed to an institution by governmental or juridical order 28. Involvement of any Astra Zeneca, PAREXEL or study site employee or their close relatives 29. Judgment by the investigator that the subject should not participate in the study if they have any ongoing or recent (i.e., during the screening period) minor medical complaints that may interfere with the interpretation of study data or are considered unlikely to comply with study procedures, restrictions and requirements 30. Subjects who are vegans or have medical dietary restrictions 31. Subjects who cannot communicate reliably with the investigator In addition, any of the following is regarded as a criterion for exclusion from the genetic research: 32. Previous bone marrow transplant 33. Non-leukocyte depleted whole blood transfusion within 120 days of the date of the genetic sample collection

Locations (1)

Research Site

Brooklyn, Maryland, United States

Outcomes

Primary Outcomes

The safety and tolerability of AZD4076 by assessment of blood pressure

To assess the safety and tolerability of single doses of AZD4076

Time frame: From screening until 16 weeks postdose, up to 5 months

The safety and tolerability of AZD4076 by assessment of pulse

To assess the safety and tolerability of single doses of AZD4076

Time frame: From screening until 16 weeks postdose, up to 5 months

The safety and tolerability of AZD4076 by assessment of oral temperature

To assess the safety and tolerability of single doses of AZD4076

Time frame: From screening until 72 hours postdose

The safety and tolerability of AZD4076 by assessment of electrocardiogram readings

To assess the safety and tolerability of single doses of AZD4076

Time frame: From screening until 16 weeks postdose, up to 5 months

The safety and tolerability of AZD4076 by assessment of digital electrocardiogram readings

To assess the safety and tolerability of single doses of AZD4076

Time frame: From predose until 72 hours postdose

The safety and tolerability of AZD4076 by assessment of cardiac telemetry

To assess the safety and tolerability of single doses of AZD4076 by telemetry monitoring and paper printouts

Time frame: On Day -1 and predose until 72 hours postdose

The safety and tolerability of AZD4076 by assessment of physical examination

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

Data from ClinicalTrials.gov

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Secondary Outcomes

Observed maximum plasma concentration, taken directly from the individual concentration-time curve [Cmax] assessed for AZD4076 from the plasma data

To characterize the plasma pharmacokinetics of AZD4076

Time frame: 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

To characterize the plasma pharmacokinetics of AZD4076

Time frame: Predose until 16 weeks postdose

Terminal elimination half-life, estimated as (ln2)/λz [t1/2λz ] assessed for AZD4076 from the plasma data

To characterize the plasma pharmacokinetics of AZD4076

Time frame: 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

To characterize the plasma pharmacokinetics of AZD4076

Time frame: 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

To characterize the plasma pharmacokinetics of AZD4076

Time frame: Predose until 16 weeks postdose

Area under plasma concentration-time curve from time zero extrapolated to infinity [AUC] assessed for AZD4076 from the plasma data

To characterize the plasma pharmacokinetics of AZD4076

Time frame: Predose until 16 weeks postdose

Apparent total clearance, estimated as dose divided by AUC [CL/F] assessed for AZD4076 from the plasma data

To characterize the plasma pharmacokinetics of AZD4076

Time frame: Predose until 16 weeks postdose

Mean Residence Time [MRT] assessed for AZD4076 from the plasma data

To characterize the plasma pharmacokinetics of AZD4076

Time frame: 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

To characterize the plasma pharmacokinetics of AZD4076

Time frame: 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

To characterize the plasma pharmacokinetics of AZD4076

Time frame: 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

To characterize the plasma pharmacokinetics of AZD4076

Time frame: 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

To characterize the plasma pharmacokinetics of AZD4076

Time frame: Predose until 16 weeks postdose

Lag-time, taken directly from the individual concentration-time curve [tlag] assessed for AZD4076 from the plasma data

To characterize the plasma pharmacokinetics of AZD4076

Time frame: 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

To characterize the pharmacokinetics of AZD4076 in urine

Time frame: Predose until 72 hours 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

To characterize the pharmacokinetics of AZD4076 in urine

Time frame: 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

To characterize the pharmacokinetics of AZD4076 in urine

Time frame: Predose until 72 hours postdose

Cmax assessed for AZD4076 metabolites from the plasma data

To characterize the plasma pharmacokinetics of AZD4076 metabolites (longmers, shortmers, sum of longmers and shortmers and sum of AZD4076, longmers and shortmers)

Time frame: Predose until 16 weeks postdose

tmax assessed for AZD4076 metabolites from the plasma data

To characterize the plasma pharmacokinetics of AZD4076 metabolites (longmers, shortmers, sum of longmers and shortmers and sum of AZD4076, longmers and shortmers)

Time frame: Predose until 16 weeks postdose

t1/2λz assessed for AZD4076 metabolites from the plasma data

To characterize the plasma pharmacokinetics of AZD4076 metabolites (longmers, shortmers, sum of longmers and shortmers and sum of AZD4076, longmers and shortmers)

Time frame: Predose until 16 weeks postdose

AUC(0-last) assessed forAZD4076 metabolites from the plasma data

To characterize the plasma pharmacokinetics of AZD4076 metabolites (longmers, shortmers, sum of longmers and shortmers and sum of AZD4076, longmers and shortmers)

Time frame: Predose until 16 weeks postdose

AUC(0-72h) assessed for AZD4076 metabolites from the plasma data

To characterize the plasma pharmacokinetics of AZD4076 metabolites (longmers, shortmers, sum of longmers and shortmers and sum of AZD4076, longmers and shortmers)

Time frame: Predose until 16 weeks postdose

MRT assessed for AZD4076 metabolites from the plasma data

To characterize the plasma pharmacokinetics of AZD4076 metabolites (longmers, shortmers, sum of longmers and shortmers and sum of AZD4076, longmers and shortmers)

Time frame: Predose until 16 weeks postdose

tlag assessed for AZD4076 metabolites from the plasma data

To characterize the plasma pharmacokinetics of AZD4076 metabolites (longmers, shortmers, sum of longmers and shortmers and sum of AZD4076, longmers and shortmers)

Time frame: Predose until 16 weeks postdose

Vz/F assessed for AZD4076 metabolites from the plasma data

To characterize the plasma pharmacokinetics of AZD4076 metabolites (longmers, shortmers, sum of longmers and shortmers and sum of AZD4076, longmers and shortmers)

Time frame: Predose until 16 weeks postdose

Cmax/D assessed for AZD4076 metabolites from the plasma data

To characterize the plasma pharmacokinetics of AZD4076 metabolites (longmers, shortmers, sum of longmers and shortmers and sum of AZD4076, longmers and shortmers)

Time frame: Predose until 16 weeks postdose

[AUC(0-last)/D assessed for AZD4076 metabolites from the plasma data

To characterize the plasma pharmacokinetics of AZD4076 metabolites (longmers, shortmers, sum of longmers and shortmers and sum of AZD4076, longmers and shortmers)

Time frame: Predose until 16 weeks postdose

AUC/D assessed for AZD4076 metabolites from the plasma data

To characterize the plasma pharmacokinetics of AZD4076 metabolites (longmers, shortmers, sum of longmers and shortmers and sum of AZD4076, longmers and shortmers)

Time frame: Predose until 16 weeks postdose

Ae(0-t) assessed for AZD4076 metabolites from the urine data

To characterize the pharmacokinetics of AZD4076 metabolites (longmers, shortmers, sum of longmers and shortmers and sum of AZD4076, longmers and shortmers)

Time frame: Predose until 72 hours postdose

fe(0-t) assessed for AZD4076 metabolites from the urine data

To characterize the pharmacokinetics of AZD4076 metabolites (longmers, shortmers, sum of longmers and shortmers and sum of AZD4076, longmers and shortmers)

Time frame: Predose until 72 hours postdose

CLR assessed for AZD4076 metabolites from the urine data

To characterize the pharmacokinetics of AZD4076 metabolites (longmers, shortmers, sum of longmers and shortmers and sum of AZD4076, longmers and shortmers)

Time frame: Predose until 72 hours postdose

AUC assessed for AZD4076 metabolites from the plasma data

To characterize the plasma pharmacokinetics of AZD4076 metabolites (longmers, shortmers, sum of longmers and shortmers and sum of AZD4076, longmers and shortmers)

Time frame: Predose until 16 weeks postdose

CL/F assessed for AZD4076 metabolites from the plasma data

To characterize the plasma pharmacokinetics of AZD4076 metabolites (longmers, shortmers, sum of longmers and shortmers and sum of AZD4076, longmers and shortmers)

Time frame: Predose until 16 weeks postdose