Clinical trial NCT02612662: A Study to Assess the Safety and Tolerability of Single Doses of AZD4076 in Healthy Male Subjects
Official title: 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
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE1
Conditions: Non-alcoholic Steatohepatitis (NASH)
Keywords: AZD4076
Healthy male subjects
Safety
Subcutaneous
Tolerability
Lead sponsor: AstraZeneca
Sponsor class: INDUSTRY
First posted: 2015-11-24
Enrollment: 40
Sex: MALE
Minimum age (years): 18
Maximum age (years): 50
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: BASIC_SCIENCE

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

Eligibility criteria: 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

Primary outcomes:
measure: The safety and tolerability of AZD4076 by assessment of blood pressure
timeFrame: From screening until 16 weeks postdose, up to 5 months
measure: The safety and tolerability of AZD4076 by assessment of pulse
timeFrame: From screening until 16 weeks postdose, up to 5 months
measure: The safety and tolerability of AZD4076 by assessment of oral temperature
timeFrame: From screening until 72 hours postdose
measure: The safety and tolerability of AZD4076 by assessment of electrocardiogram readings
timeFrame: From screening until 16 weeks postdose, up to 5 months
measure: The safety and tolerability of AZD4076 by assessment of digital electrocardiogram readings
timeFrame: From predose until 72 hours postdose
measure: The safety and tolerability of AZD4076 by assessment of cardiac telemetry
timeFrame: On Day -1 and predose until 72 hours postdose
measure: The safety and tolerability of AZD4076 by assessment of physical examination
timeFrame: From screening until 16 weeks postdose, up to 5 months
measure: The safety and tolerability of AZD4076 by assessing hematology
timeFrame: From screening until 16 weeks postdose, up to 5 months
measure: The safety and tolerability of AZD4076 by assessing the injection site
timeFrame: Postdose until 72 hours
measure: The safety and tolerability of AZD4076 by assessming the number of adverse events
timeFrame: From screening until 16 weeks postdose, up to 5 months
measure: The safety and tolerability of AZD4076 by assessing clinical chemistry
timeFrame: From screening until 16 weeks postdose, up to 5 months
measure: The safety and tolerability of AZD4076 by assessing urinalysis
timeFrame: From screening until 16 weeks postdose, up to 5 months
measure: The safety and tolerability of AZD4076 by assessing the number of participants with adverse events
timeFrame: From screening until 16 weeks postdose, up to 5 months
Secondary outcomes:
measure: Observed maximum plasma concentration, taken directly from the individual concentration-time curve [Cmax] assessed for AZD4076 from the plasma data
timeFrame: Predose until 16 weeks postdose
measure: Time to reach maximum concentration, taken directly from the individual concentration-time curve [tmax] assessed for AZD4076 from the plasma data
timeFrame: Predose until 16 weeks postdose
measure: Terminal elimination half-life, estimated as (ln2)/λz [t1/2λz ] assessed for AZD4076 from the plasma data
timeFrame: Predose until 16 weeks postdose
measure: Area under the plasma concentration-curve from time zero to 72h after drug administration [AUC(0-72h)] assessed for AZD4076 from the plasma data
timeFrame: Predose until 16 weeks postdose
measure: 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
timeFrame: Predose until 16 weeks postdose
measure: Area under plasma concentration-time curve from time zero extrapolated to infinity [AUC] assessed for AZD4076 from the plasma data
timeFrame: Predose until 16 weeks postdose
measure: Apparent total clearance, estimated as dose divided by AUC [CL/F] assessed for AZD4076 from the plasma data
timeFrame: Predose until 16 weeks postdose
measure: Mean Residence Time [MRT] assessed for AZD4076 from the plasma data
timeFrame: Predose until 16 weeks postdose
measure: 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
timeFrame: Predose until 16 weeks postdose
measure: 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
timeFrame: Predose until 16 weeks postdose
measure: 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
timeFrame: Predose until 16 weeks postdose
measure: 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
timeFrame: Predose until 16 weeks postdose
measure: Lag-time, taken directly from the individual concentration-time curve [tlag] assessed for AZD4076 from the plasma data
timeFrame: Predose until 16 weeks postdose
measure: 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
timeFrame: Predose until 72 hours postdose
measure: 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
timeFrame: Predose until 72 hours postdose
measure: Renal clearance, estimated by dividing Ae(0-t) by AUC(0-72) [CLR] assessed for AZD4076 from the urine data
timeFrame: Predose until 72 hours postdose
measure: Cmax assessed for AZD4076 metabolites from the plasma data
timeFrame: Predose until 16 weeks postdose
measure: tmax assessed for AZD4076 metabolites from the plasma data
timeFrame: Predose until 16 weeks postdose
measure: t1/2λz assessed for AZD4076 metabolites from the plasma data
timeFrame: Predose until 16 weeks postdose
measure: AUC(0-last) assessed forAZD4076 metabolites from the plasma data
timeFrame: Predose until 16 weeks postdose
measure: AUC(0-72h) assessed for AZD4076 metabolites from the plasma data
timeFrame: Predose until 16 weeks postdose
measure: MRT assessed for AZD4076 metabolites from the plasma data
timeFrame: Predose until 16 weeks postdose
measure: tlag assessed for AZD4076 metabolites from the plasma data
timeFrame: Predose until 16 weeks postdose
measure: Vz/F assessed for AZD4076 metabolites from the plasma data
timeFrame: Predose until 16 weeks postdose
measure: Cmax/D assessed for AZD4076 metabolites from the plasma data
timeFrame: Predose until 16 weeks postdose
measure: [AUC(0-last)/D assessed for AZD4076 metabolites from the plasma data
timeFrame: Predose until 16 weeks postdose
measure: AUC/D assessed for AZD4076 metabolites from the plasma data
timeFrame: Predose until 16 weeks postdose
measure: Ae(0-t) assessed for AZD4076 metabolites from the urine data
timeFrame: Predose until 72 hours postdose
measure: fe(0-t) assessed for AZD4076 metabolites from the urine data
timeFrame: Predose until 72 hours postdose
measure: CLR assessed for AZD4076 metabolites from the urine data
timeFrame: Predose until 72 hours postdose
measure: AUC assessed for AZD4076 metabolites from the plasma data
timeFrame: Predose until 16 weeks postdose
measure: CL/F assessed for AZD4076 metabolites from the plasma data
timeFrame: Predose until 16 weeks postdose
Other outcomes:
Locations:
city: Brooklyn
country: United States
facility: Research Site
state: Maryland
Study officials:
affiliation: PAREXEL Early Phase Clinical Unit Baltimore
name: Ronald Goldwater, MDCM, M.Sc, CPI
role: PRINCIPAL_INVESTIGATOR
References: