Clinical trial NCT02712372: A Study to Assess the Safety and Tolerability of Single and Multiple Doses of AZD4831 in Healthy Male Subjects
Official title: A Phase I, Randomised, Single-Blind, Placebo-controlled Study to Assess the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of AZD4831 After Single and Multiple Ascending Dose Administration to Healthy Male Subjects
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
Conditions: Cardiovascular Disease
Keywords: AZD4831 oral suspension
Healthy male subjects
Safety
Tolerability
Pharmacokinetics
Pharmacodynamics
Lead sponsor: AstraZeneca
Sponsor class: INDUSTRY
First posted: 2016-03-18
Enrollment: 104
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 Phase I, first-in-human (FIH) study to assess the safety, tolerability, pharmacokinetics (PK) and Pharmacodynamics (PD) of AZD4831 after single and multiple ascending doses in healthy male subjects

Detailed description: This is a Phase I, FIH, randomized, single-blind, placebo-controlled study to assess the safety, tolerability, pharmacokinetics (PK) and Pharmacodynamics (PD) of AZD4831 after single (Part 1) and multiple (Part 2) ascending doses in healthy male subjects. The study will be conducted at a single study center with a planned number of subjects of up to 125 healthy males, aged 18 to 50 years.

Eligibility criteria: Inclusion Criteria

* Provision of signed and dated, written informed consent before any study specific procedures.
* Healthy male subjects aged 18 - 50 years, inclusive, with suitable veins for cannulation or repeated venipuncture.
* Have a body mass index (BMI) between 18 and 29.9 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/biomarker research.
* Subjects must be able to read, speak and understand the German language.

Exclusion Criteria:

* History 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 gastrointestinal (GI), hepatic or renal disease, or any other condition known to interfere with absorption, distribution, metabolism, or excretion of drugs.
* Presence of infection(s) (particularly fungal infection), as judged by the investigator.
* History or current thyroid disease.
* Any clinically significant illness, medical/surgical procedure, or trauma within 4 weeks of the first administration of investigational medicinal product (IMP).
* Any clinically significant abnormalities in clinical chemistry, haematology, or urinalysis results, as judged by the investigator.
* Any positive result on screening for serum hepatitis B surface antigen (HBsAg), anti-hepatitis B core (anti-HBc) antibodies, hepatitis C antibody and human immunodeficiency virus (HIV).
* Abnormal vital signs
* 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 LV hypertrophy.
* Prolonged QTcF \> 450 ms or shortened QTcF \< 340 ms or family history of long QT syndrome.
* PR(PQ) interval shortening \< 120 ms (PR \> 110 ms but \< 120 ms is acceptable if there is no evidence of ventricular pre-excitation)
* PR (PQ) interval prolongation (\> 200 ms) intermittent second (Wenckebach block while asleep is not exclusive) or third degree AV block, or AV dissociation
* Persistent or intermittent complete bundle branch block, incomplete bundle branch block, or intraventricular conduction delay 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.
* ECG findings suggesting a metabolic or other non-cardiac condition that may confound interpretation of serial changes (such as hypokalemia).
* Known or suspected history of drug abuse, as judged by the investigator.
* Current smokers or those who have smoked or used nicotine products within the previous 3 months.
* History of alcohol abuse or excessive intake of alcohol, as judged by the investigator.
* Positive screen for drugs of abuse, cotinine (nicotine) or alcohol at screening or admission to the unit before the first administration of IMP.
* 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 AZD4831.
* Excessive intake of caffeine containing drinks or food (e.g., coffee, tea, chocolate), as judged by the investigator.
* Use of drugs with enzyme inducing properties such as St John's Wort within 3 weeks before the first administration of IMP.
* 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 2 weeks before the first administration of IMP or longer if the medication has a long half-life.
* Plasma donation within 1 month of screening or any blood donation/blood loss \> 500 mL during the 3 months before screening.
* Has received another new chemical entity (defined as a compound which has not been approved for marketing) within 3 months of the first administration of IMP in this study. The period of exclusion begins 3 months after the final dose or 1 month after the last visit whichever is the longest.
* Vulnerable subjects, e.g., kept in detention, protected adults under guardianship, trusteeship, or committed to an institution by governmental or juridical order.
* Involvement of any Astra Zeneca, PAREXEL or study site employee or their close relatives.
* 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.
* Subjects who are vegans or have medical dietary restrictions.
* Subjects who cannot communicate reliably with the investigator.

Exclusion from the genetic research:

* Previous bone marrow transplant.
* Non-leukocyte depleted whole blood transfusion within 120 days of the date of the genetic sample collection.

Primary outcomes:
measure: Frequencies of adverse events
timeFrame: From screening up to 10 days post final dose
measure: Supine blood pressure (Part 1)
timeFrame: From screening up to 48 hours post dose
measure: Supine pulse rate (Part 1)
timeFrame: From screening up to 48 hours post dose
measure: Supine body temperature (Part 2)
timeFrame: From screening up to pre-dose Day 12
measure: 12-lead electrocardiogram
timeFrame: From screening up to 10 days post final dose
measure: 12-lead electrocardiogram (cardiac telemetry)
timeFrame: From Day-1 up to 24 hours post final dose
measure: Physical examination
timeFrame: From screening up to 10 days post final dose
measure: To assess the subject through hematology laboratory assessment
timeFrame: From screening up to 10 days post final dose
measure: Percentage of adverse events
timeFrame: From screening to 10 days post final dose
measure: Supine blood pressure (Part 2)
timeFrame: From screening up to 10 days post final dose
measure: Supine pulse rate (Part 2)
timeFrame: From screening up to 10 days post final dose
measure: Chemistry evaluations
timeFrame: From screening up to 10 days post final dose
measure: To assess the subject through urinalysis laboratory assessment
timeFrame: From screening up to 10 days post final dose
Secondary outcomes:
measure: Observed maximum plasma concentration, taken directly from the individual concentration-time curve (Cmax)
timeFrame: From pre-dose up to 48 hours post dose
measure: Time to reach maximum plasma concentration, taken directly from the individual concentration-time curve (tmax)
timeFrame: From pre-dose up to 48 hours post dose
measure: Terminal rate constant, estimated by log-linear least squares regression of the terminal part of the concentration-time curve (λz)
timeFrame: From pre-dose up to 48 hours post dose
measure: Terminal half-life, estimated as (ln2)/λz (t1/2λz)
timeFrame: From pre-dose up to 48 hours post dose
measure: Area under the plasma concentration-curve over 24 hours (AUCτ)
timeFrame: From pre-dose up to 48 hours post dose
measure: Area under the plasma concentration-curve from time zero to the time of last quantifiable analyte concentration (AUC0-t)
timeFrame: From pre-dose up to 48 hours post dose
measure: Area under the concentration-time curve from time zero extrapolated to infinity (AUC)
timeFrame: From pre-dose up to 48 hours post dose
measure: Apparent clearance for parent drug estimated as dose divided by AUC (CL/F)
timeFrame: From pre-dose up to 48 hours post dose
measure: Mean Residence Time (MRT)
timeFrame: From pre-dose up to 48 hours post dose
measure: Apparent volume of distribution for parent drug at terminal phase (Vz/F)
timeFrame: From pre-dose up to 48 hours post dose
measure: Area under the plasma concentration-time curve from time zero to time of last quantifiable analyte concentration divided by the dose administered (AUC0-t/D)
timeFrame: From pre-dose up to 48 hours post dose
measure: Area under the plasma concentration-time curve from time zero extrapolated to infinity divided by the dose administered (AUC/D)
timeFrame: From pre-dose up to 48 hours post dose
measure: Observed maximum plasma concentration divided by the dose administered (Cmax/D)
timeFrame: From pre-dose up to 48 hours post dose
measure: Area under the plasma concentration-curve over the dosing interval divided by the dose administered (AUCτ/D) (Part 2 only)
timeFrame: From pre-dose up to 48 hours post final dose
measure: Accumulation ratio calculated as AUCτ Day 12/ AUCτ Day 1 (Rac AUC) (Part 2 only)
timeFrame: From pre-dose up to 48 hours post final dose
measure: Accumulation ratio calculated as Cmax Day 12/ Cmax Day 1 (Rac Cmax) (Part 2 only)
timeFrame: From pre-dose up to 48 hours post final dose
measure: Temporal change parameter in systemic exposure (TCP) (Part 2 only)
timeFrame: From pre-dose up to 48 hours post final dose
measure: Amount of analyte excreted into the urine from time t1 to t2 [Ae(t1-t2)]
timeFrame: From pre-dose up to 48 hours post dose
measure: Cumulative amount of analyte excreted at time t [Ae(0-t)]
timeFrame: From pre-dose up to 48 hours post dose
measure: Fraction of dose excreted unchanged into the urine from time t1 to t2, estimated by dividing Ae(t1-t2) by dose [fe(t1-t2)]
timeFrame: From pre-dose up to 48 hours post dose
measure: Fraction of dose excreted unchanged into the urine from time zero to time t, estimated by dividing Ae(0-t) by dose [fe(0-t)]
timeFrame: From pre-dose up to 48 hours post dose
measure: Renal clearance, estimated by dividing Ae(0-t) by AUC(0-t) (CLR)
timeFrame: From pre-dose up to 48 hours post dose
Other outcomes:
Locations:
Study officials:
affiliation: PAREXEL Early Phase Clinical Unit Berlin, On the premises of Klinikum Westend, Haus 31, Spandauer Damm 130, 14050 Berlin, Germany
name: Rainard Fuhr, Dr. med.
role: PRINCIPAL_INVESTIGATOR
References: