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

AstraZeneca

Status and phase: Active, not recruiting; Phase 1

Conditions: Non-alcoholic Steatohepatitis (NASH)

Treatments: Drug: Placebo; Drug: AZD4076

Study type: Interventional

Funder types: Industry

Identifiers

NCT02612662

D5590C00001

Details and patient eligibility

About

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

Full 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

Enrollment: 40 patients

Sex: Male

Ages: 18 to 50 years old

Volunteers: Accepts Healthy Volunteers

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

Trial design

Primary purpose: Basic Science

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Single Blind

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40 participants in 6 patient groups

Cohort 1

Experimental group

Description:

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)

Treatment:

Drug: AZD4076

Drug: Placebo

Cohort 2

Experimental group

Description:

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)

Treatment:

Drug: AZD4076

Drug: Placebo

Cohort 3

Experimental group

Description:

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)

Treatment:

Drug: AZD4076

Drug: Placebo

Cohort 4

Experimental group

Description:

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)

Treatment:

Drug: AZD4076

Drug: Placebo

Cohort 5

Experimental group

Description:

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)

Treatment:

Drug: AZD4076

Drug: Placebo

Cohort 6

Experimental group

Description:

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)

Treatment:

Drug: AZD4076

Drug: Placebo