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

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ClinicalTrials.gov Identifier: NCT02612662
Recruitment Status : Active, not recruiting
First Posted : November 24, 2015
Last Update Posted : August 6, 2019
Sponsor:
Information provided by (Responsible Party):
AstraZeneca

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.

Condition or disease Intervention/treatment Phase
Non-alcoholic Steatohepatitis (NASH) Drug: AZD4076 Drug: Placebo Phase 1

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

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 40 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single (Participant)
Primary Purpose: Basic Science
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
Actual Study Start Date : November 25, 2015
Actual Primary Completion Date : November 4, 2017
Estimated Study Completion Date : December 28, 2020


Arm Intervention/treatment
Experimental: 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)
Drug: AZD4076
Subcutaneous (SC) administration of single ascending doses; there will be no more than 2 mL per syringe/injection

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

Experimental: 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)
Drug: AZD4076
Subcutaneous (SC) administration of single ascending doses; there will be no more than 2 mL per syringe/injection

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

Experimental: 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)
Drug: AZD4076
Subcutaneous (SC) administration of single ascending doses; there will be no more than 2 mL per syringe/injection

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

Experimental: 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)
Drug: AZD4076
Subcutaneous (SC) administration of single ascending doses; there will be no more than 2 mL per syringe/injection

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

Experimental: 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)
Drug: AZD4076
Subcutaneous (SC) administration of single ascending doses; there will be no more than 2 mL per syringe/injection

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

Experimental: 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)
Drug: AZD4076
Subcutaneous (SC) administration of single ascending doses; there will be no more than 2 mL per syringe/injection

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




Primary Outcome Measures :
  1. 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

  2. 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

  3. 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

  4. 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

  5. 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

  6. 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

  7. 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

  8. 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

  9. 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

  10. 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

  11. 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

  12. 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

  13. 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


Secondary Outcome Measures :
  1. Observed maximum plasma concentration, taken directly from the individual concentration-time curve [Cmax] assessed for AZD4076 from the plasma data [ Time Frame: Predose until 16 weeks postdose ]
    To characterize the plasma pharmacokinetics of AZD4076

  2. Time to reach maximum concentration, taken directly from the individual concentration-time curve [tmax] assessed for AZD4076 from the plasma data [ Time Frame: Predose until 16 weeks postdose ]
    To characterize the plasma pharmacokinetics of AZD4076

  3. Terminal elimination half-life, estimated as (ln2)/λz [t1/2λz ] assessed for AZD4076 from the plasma data [ Time Frame: Predose until 16 weeks postdose ]
    To characterize the plasma pharmacokinetics of AZD4076

  4. Area under the plasma concentration-curve from time zero to 72h after drug administration [AUC(0-72h)] assessed for AZD4076 from the plasma data [ Time Frame: Predose until 16 weeks postdose ]
    To characterize the plasma pharmacokinetics of AZD4076

  5. 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 [ Time Frame: Predose until 16 weeks postdose ]
    To characterize the plasma pharmacokinetics of AZD4076

  6. Area under plasma concentration-time curve from time zero extrapolated to infinity [AUC] assessed for AZD4076 from the plasma data [ Time Frame: Predose until 16 weeks postdose ]
    To characterize the plasma pharmacokinetics of AZD4076

  7. Apparent total clearance, estimated as dose divided by AUC [CL/F] assessed for AZD4076 from the plasma data [ Time Frame: Predose until 16 weeks postdose ]
    To characterize the plasma pharmacokinetics of AZD4076

  8. Mean Residence Time [MRT] assessed for AZD4076 from the plasma data [ Time Frame: Predose until 16 weeks postdose ]
    To characterize the plasma pharmacokinetics of AZD4076

  9. 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 [ Time Frame: Predose until 16 weeks postdose ]
    To characterize the plasma pharmacokinetics of AZD4076

  10. 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 [ Time Frame: Predose until 16 weeks postdose ]
    To characterize the plasma pharmacokinetics of AZD4076

  11. 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 [ Time Frame: Predose until 16 weeks postdose ]
    To characterize the plasma pharmacokinetics of AZD4076

  12. 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 [ Time Frame: Predose until 16 weeks postdose ]
    To characterize the plasma pharmacokinetics of AZD4076

  13. Lag-time, taken directly from the individual concentration-time curve [tlag] assessed for AZD4076 from the plasma data [ Time Frame: Predose until 16 weeks postdose ]
    To characterize the plasma pharmacokinetics of AZD4076

  14. 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 [ Time Frame: Predose until 72 hours postdose ]
    To characterize the pharmacokinetics of AZD4076 in urine

  15. 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 [ Time Frame: Predose until 72 hours postdose ]
    To characterize the pharmacokinetics of AZD4076 in urine

  16. Renal clearance, estimated by dividing Ae(0-t) by AUC(0-72) [CLR] assessed for AZD4076 from the urine data [ Time Frame: Predose until 72 hours postdose ]
    To characterize the pharmacokinetics of AZD4076 in urine

  17. Cmax assessed for AZD4076 metabolites from the plasma data [ Time Frame: Predose until 16 weeks postdose ]
    To characterize the plasma pharmacokinetics of AZD4076 metabolites (longmers, shortmers, sum of longmers and shortmers and sum of AZD4076, longmers and shortmers)

  18. tmax assessed for AZD4076 metabolites from the plasma data [ Time Frame: Predose until 16 weeks postdose ]
    To characterize the plasma pharmacokinetics of AZD4076 metabolites (longmers, shortmers, sum of longmers and shortmers and sum of AZD4076, longmers and shortmers)

  19. t1/2λz assessed for AZD4076 metabolites from the plasma data [ Time Frame: Predose until 16 weeks postdose ]
    To characterize the plasma pharmacokinetics of AZD4076 metabolites (longmers, shortmers, sum of longmers and shortmers and sum of AZD4076, longmers and shortmers)

  20. AUC(0-last) assessed forAZD4076 metabolites from the plasma data [ Time Frame: Predose until 16 weeks postdose ]
    To characterize the plasma pharmacokinetics of AZD4076 metabolites (longmers, shortmers, sum of longmers and shortmers and sum of AZD4076, longmers and shortmers)

  21. AUC(0-72h) assessed for AZD4076 metabolites from the plasma data [ Time Frame: Predose until 16 weeks postdose ]
    To characterize the plasma pharmacokinetics of AZD4076 metabolites (longmers, shortmers, sum of longmers and shortmers and sum of AZD4076, longmers and shortmers)

  22. MRT assessed for AZD4076 metabolites from the plasma data [ Time Frame: Predose until 16 weeks postdose ]
    To characterize the plasma pharmacokinetics of AZD4076 metabolites (longmers, shortmers, sum of longmers and shortmers and sum of AZD4076, longmers and shortmers)

  23. tlag assessed for AZD4076 metabolites from the plasma data [ Time Frame: Predose until 16 weeks postdose ]
    To characterize the plasma pharmacokinetics of AZD4076 metabolites (longmers, shortmers, sum of longmers and shortmers and sum of AZD4076, longmers and shortmers)

  24. Vz/F assessed for AZD4076 metabolites from the plasma data [ Time Frame: Predose until 16 weeks postdose ]
    To characterize the plasma pharmacokinetics of AZD4076 metabolites (longmers, shortmers, sum of longmers and shortmers and sum of AZD4076, longmers and shortmers)

  25. Cmax/D assessed for AZD4076 metabolites from the plasma data [ Time Frame: Predose until 16 weeks postdose ]
    To characterize the plasma pharmacokinetics of AZD4076 metabolites (longmers, shortmers, sum of longmers and shortmers and sum of AZD4076, longmers and shortmers)

  26. [AUC(0-last)/D assessed for AZD4076 metabolites from the plasma data [ Time Frame: Predose until 16 weeks postdose ]
    To characterize the plasma pharmacokinetics of AZD4076 metabolites (longmers, shortmers, sum of longmers and shortmers and sum of AZD4076, longmers and shortmers)

  27. AUC/D assessed for AZD4076 metabolites from the plasma data [ Time Frame: Predose until 16 weeks postdose ]
    To characterize the plasma pharmacokinetics of AZD4076 metabolites (longmers, shortmers, sum of longmers and shortmers and sum of AZD4076, longmers and shortmers)

  28. Ae(0-t) assessed for AZD4076 metabolites from the urine data [ Time Frame: Predose until 72 hours postdose ]
    To characterize the pharmacokinetics of AZD4076 metabolites (longmers, shortmers, sum of longmers and shortmers and sum of AZD4076, longmers and shortmers)

  29. fe(0-t) assessed for AZD4076 metabolites from the urine data [ Time Frame: Predose until 72 hours postdose ]
    To characterize the pharmacokinetics of AZD4076 metabolites (longmers, shortmers, sum of longmers and shortmers and sum of AZD4076, longmers and shortmers)

  30. CLR assessed for AZD4076 metabolites from the urine data [ Time Frame: Predose until 72 hours postdose ]
    To characterize the pharmacokinetics of AZD4076 metabolites (longmers, shortmers, sum of longmers and shortmers and sum of AZD4076, longmers and shortmers)

  31. AUC assessed for AZD4076 metabolites from the plasma data [ Time Frame: Predose until 16 weeks postdose ]
    To characterize the plasma pharmacokinetics of AZD4076 metabolites (longmers, shortmers, sum of longmers and shortmers and sum of AZD4076, longmers and shortmers)

  32. CL/F assessed for AZD4076 metabolites from the plasma data [ Time Frame: Predose until 16 weeks postdose ]
    To characterize the plasma pharmacokinetics of AZD4076 metabolites (longmers, shortmers, sum of longmers and shortmers and sum of AZD4076, longmers and shortmers)



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 50 Years   (Adult)
Sexes Eligible for Study:   Male
Accepts Healthy Volunteers:   Yes
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02612662


Locations
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United States, Maryland
Research Site
Baltimore, Maryland, United States, 21225
Sponsors and Collaborators
AstraZeneca
Investigators
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Principal Investigator: Ronald Goldwater, MDCM, M.Sc, CPI PAREXEL Early Phase Clinical Unit Baltimore

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Responsible Party: AstraZeneca
ClinicalTrials.gov Identifier: NCT02612662     History of Changes
Other Study ID Numbers: D5590C00001
First Posted: November 24, 2015    Key Record Dates
Last Update Posted: August 6, 2019
Last Verified: August 2019
Keywords provided by AstraZeneca:
AZD4076
Healthy male subjects
Safety
Subcutaneous
Tolerability
Additional relevant MeSH terms:
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Fatty Liver
Non-alcoholic Fatty Liver Disease
Liver Diseases
Digestive System Diseases