A Study to Assess the Safety and Tolerability of Single and Multiple Doses of AZD4831 in Healthy Male Subjects

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

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

Study Overview

• Status: Terminated
• Conditions: Cardiovascular Disease
• Intervention / Treatment: Drug: AZD4831; Drug: AZD4831 placebo

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.

• Study Type: Interventional
• Enrollment (Actual): 104
• Phase: Phase 1

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 50 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Male

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

10

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Part 1, Dose Level 1; Part 1: Part 1A: Single dose administered in the morning on Day 1 under fasted conditions. Part 1B: Single dose administered in the morning of Day 1 under fed conditions.	Drug: AZD4831; AZD4831 1-50 mg/g oral suspension
Experimental: Part 1, Dose Level 2; Part 1: Part 1A: Single dose administered in the morning on Day 1 under fasted conditions. Part 1B: Single dose administered in the morning of Day 1 under fed conditions.	Drug: AZD4831; AZD4831 1-50 mg/g oral suspension
Experimental: Part 1, Dose Level 3; Part 1: Part 1A: Single dose administered in the morning on Day 1 under fasted conditions. Part 1B: Single dose administered in the morning of Day 1 under fed conditions.	Drug: AZD4831; AZD4831 1-50 mg/g oral suspension
Experimental: Part 1, Dose Level 4; Part 1: Part 1A: Single dose administered in the morning on Day 1 under fasted conditions. Part 1B: Single dose administered in the morning of Day 1 under fed conditions.	Drug: AZD4831; AZD4831 1-50 mg/g oral suspension
Experimental: Part 1, Dose Level 5; Part 1: Part 1A: Single dose administered in the morning on Day 1 under fasted conditions. Part 1B: Single dose administered in the morning of Day 1 under fed conditions.	Drug: AZD4831; AZD4831 1-50 mg/g oral suspension
Experimental: Part 1, Dose Level 6; Part 1: Part 1A: Single dose administered in the morning on Day 1 under fasted conditions. Part 1B: Single dose administered in the morning of Day 1 under fed conditions.	Drug: AZD4831; AZD4831 1-50 mg/g oral suspension
Experimental: Part 2, Dose Level 1; Part 2: Single dose administered in the morning on Day 1 and multiple doses administered once daily, in the morning, Days 3 to 12	Drug: AZD4831; AZD4831 1-50 mg/g oral suspension
Experimental: Part 2, Dose Level 2; Part 2: Single dose administered in the morning on Day 1 and multiple doses administered once daily, in the morning, Days 3 to 12	Drug: AZD4831; AZD4831 1-50 mg/g oral suspension
Experimental: Part 2, Dose Level 3; Part 2: Single dose administered in the morning on Day 1 and multiple doses administered once daily, in the morning, Days 3 to 12	Drug: AZD4831; AZD4831 1-50 mg/g oral suspension
Placebo Comparator: AZD4831 Placebo; Part 1: Part 1A: Single dose administered in the morning on Day 1 under fasted conditions. Part 1B: Single dose administered in the morning of Day 1 under fed conditions. Part 2: Single dose administered in the morning on Day 1 and multiple doses administered once daily, in the morning, Days 3 to 12	Drug: AZD4831 placebo; AZD4831 placebo oral suspension

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Frequencies of adverse events	To assess the safety and tolerability of single and multiple doses of AZD4831	From screening up to 10 days post final dose
Supine blood pressure (Part 1)	To assess change from baseline in supine blood pressure	From screening up to 48 hours post dose
Supine pulse rate (Part 1)	To assess change from baseline in supine pulse rate	From screening up to 48 hours post dose
Supine body temperature (Part 2)	To assess change from baseline in supine body temperature	From screening up to pre-dose Day 12
12-lead electrocardiogram	To assess 12-lead electrocardiogram	From screening up to 10 days post final dose
12-lead electrocardiogram (cardiac telemetry)	12-lead electrocardiogram (cardiac telemetry)	From Day-1 up to 24 hours post final dose
Physical examination	To assess subject through a physical examination, including assessment of the general appearance, skin, cardiovascular, respiratory, abdomen, head and neck (including ears, eyes, nose and throat), lymph nodes, thyroid, musculoskeletal and neurological systems.	From screening up to 10 days post final dose
To assess the subject through hematology laboratory assessment	To assess a subject through hematology laboratory assessment	From screening up to 10 days post final dose
Percentage of adverse events	To assess the safety and tolerability of single and multiple doses of AZD4831	From screening to 10 days post final dose
Supine blood pressure (Part 2)	To assess change from baseline in supine blood pressure	From screening up to 10 days post final dose
Supine pulse rate (Part 2)	To assess change from baseline in supine pulse rate	From screening up to 10 days post final dose
Chemistry evaluations	including high-sensitivity C-reactive protein {hs-CRP} and thyroid panel	From screening up to 10 days post final dose
To assess the subject through urinalysis laboratory assessment	To assess a subject through urinalysis laboratory assessment	From screening up to 10 days post final dose

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Observed maximum plasma concentration, taken directly from the individual concentration-time curve (Cmax)	To characterize the plasma pharmacokinetics of AZD4831	From pre-dose up to 48 hours post dose
Time to reach maximum plasma concentration, taken directly from the individual concentration-time curve (tmax)	To characterize the plasma pharmacokinetics of AZD4831	From pre-dose up to 48 hours post dose
Terminal rate constant, estimated by log-linear least squares regression of the terminal part of the concentration-time curve (λz)	To characterize the plasma pharmacokinetics of AZD4831	From pre-dose up to 48 hours post dose
Terminal half-life, estimated as (ln2)/λz (t1/2λz)	To characterize the plasma pharmacokinetics of AZD4831	From pre-dose up to 48 hours post dose
Area under the plasma concentration-curve over 24 hours (AUCτ)	To characterize the plasma pharmacokinetics of AZD4831	From pre-dose up to 48 hours post dose
Area under the plasma concentration-curve from time zero to the time of last quantifiable analyte concentration (AUC0-t)	To characterize the plasma pharmacokinetics of AZD4831	From pre-dose up to 48 hours post dose
Area under the concentration-time curve from time zero extrapolated to infinity (AUC)	To characterize the plasma pharmacokinetics of AZD4831	From pre-dose up to 48 hours post dose
Apparent clearance for parent drug estimated as dose divided by AUC (CL/F)	To characterize the plasma pharmacokinetics of AZD4831	From pre-dose up to 48 hours post dose
Mean Residence Time (MRT)	To characterize the plasma pharmacokinetics of AZD4831	From pre-dose up to 48 hours post dose
Apparent volume of distribution for parent drug at terminal phase (Vz/F)	To characterize the plasma pharmacokinetics of AZD4831	From pre-dose up to 48 hours post dose
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)	To characterize the plasma pharmacokinetics of AZD4831	From pre-dose up to 48 hours post dose
Area under the plasma concentration-time curve from time zero extrapolated to infinity divided by the dose administered (AUC/D)	To characterize the plasma pharmacokinetics of AZD4831	From pre-dose up to 48 hours post dose
Observed maximum plasma concentration divided by the dose administered (Cmax/D)	To characterize the plasma pharmacokinetics of AZD4831	From pre-dose up to 48 hours post dose
Area under the plasma concentration-curve over the dosing interval divided by the dose administered (AUCτ/D) (Part 2 only)	To characterize the plasma pharmacokinetics of AZD4831	From pre-dose up to 48 hours post final dose
Accumulation ratio calculated as AUCτ Day 12/ AUCτ Day 1 (Rac AUC) (Part 2 only)	To characterize the plasma pharmacokinetics of AZD4831	From pre-dose up to 48 hours post final dose
Accumulation ratio calculated as Cmax Day 12/ Cmax Day 1 (Rac Cmax) (Part 2 only)	To characterize the plasma pharmacokinetics of AZD4831	From pre-dose up to 48 hours post final dose
Temporal change parameter in systemic exposure (TCP) (Part 2 only)	To characterize the plasma pharmacokinetics of AZD4831	From pre-dose up to 48 hours post final dose
Amount of analyte excreted into the urine from time t1 to t2 [Ae(t1-t2)]	Assessment of the urine PK following single and multiple doses of pharmacokinetics of AZD4831	From pre-dose up to 48 hours post dose
Cumulative amount of analyte excreted at time t [Ae(0-t)]	Assessment of the urine PK following single and multiple doses of pharmacokinetics of AZD4831	From pre-dose up to 48 hours post dose
Fraction of dose excreted unchanged into the urine from time t1 to t2, estimated by dividing Ae(t1-t2) by dose [fe(t1-t2)]	Assessment of the urine PK following single and multiple doses of pharmacokinetics of AZD4831	From pre-dose up to 48 hours post dose
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)]	Assessment of the urine PK following single and multiple doses of pharmacokinetics of AZD4831	From pre-dose up to 48 hours post dose
Renal clearance, estimated by dividing Ae(0-t) by AUC(0-t) (CLR)	Assessment of the urine PK following single and multiple doses of pharmacokinetics of AZD4831	From pre-dose up to 48 hours post dose

Collaborators and Investigators

• Sponsor: AstraZeneca
• Investigators: Principal Investigator: Rainard Fuhr, Dr. med., PAREXEL Early Phase Clinical Unit Berlin, On the premises of Klinikum Westend, Haus 31, Spandauer Damm 130, 14050 Berlin, Germany

Study record dates

Study Major Dates

• Study Start: June 1, 2016
• Primary Completion (Actual): October 1, 2016
• Study Completion (Actual): October 1, 2016

Study Registration Dates

• First Submitted: March 15, 2016
• First Submitted That Met QC Criteria: March 15, 2016
• First Posted (Estimate): March 18, 2016

Study Record Updates

• Last Update Posted (Estimate): January 6, 2017
• Last Update Submitted That Met QC Criteria: January 5, 2017
• Last Verified: January 1, 2017

More Information

Terms related to this study

• Keywords: Safety; Pharmacokinetics; Tolerability; Pharmacodynamics; Healthy male subjects; AZD4831 oral suspension
• Additional Relevant MeSH Terms: Cardiovascular Diseases
• Other Study ID Numbers: D6580C00001