Clinical trial NCT03136991: A Phase I, Safety Tolerability and Pharmacokinetics of AZD4831 to Treat Cardiovascular Disease
Official title: A Phase I, Randomized, Single-blind, Placebo-controlled Study to Assess the Safety, Tolerability and Pharmacokinetics of AZD4831 After Multiple Ascending Dose Administration to Healthy Male Subjects
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Cardiovascular Disease
Keywords: Oral myeloperoxidase inhibitor
Lead sponsor: AstraZeneca
Sponsor class: INDUSTRY
Collaborators: name: Parexel
First posted: 2017-05-02
Enrollment: 38
Sex: MALE
Minimum age (years): 18
Maximum age (years): 50
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: This study will be a randomized, single-blind (site personnel to remain blinded until SRC meeting), placebo-controlled, MAD, sequential group design study in healthy male subjects, performed at a single study center. Up to 60 healthy male subjects aged 18 to 50 years (inclusive) are planned to be investigated in 4 cohorts, but up to 6 cohorts may be included if the SRC considers it necessary to repeat a dose level or if additional dose levels are required.

Up to 10 subjects will participate in each cohort. Within each cohort 8 subjects will be randomly assigned to receive AZD4831 and 2 subjects to receive placebo. AZD4831 or placebo will be administered once daily for a period of 10 days. It is anticipated this will be sufficient to achieve and maintain steady state PK profiles for several days, permitting evaluation of the safety and tolerability of multiple dose administrations at steady state. The subjects will stay at the study center during the whole dosing period and until 48h
Primary purpose: TREATMENT

Brief summary: This is a Phase I study to investigate the safety and tolerability of AZD4831 in healthy male participants, conducted at a single center. The results from this study will form the basis for decisions on future studies. Another purpose of this dose escalation study is to find out the right dose of the experimental drug to be given to study participants in future studies. Even though there were no harmful effects seen in the animals tested, investigator does not know what side effects the experimental drug might cause in humans. However, site personnel managing the study participants will be blinded to the extent possible and as long as possible to minimize any impact on data collection. Study participants will be blinded to treatment allocation.

The study will be conducted in healthy participants to avoid interference from disease processes or other drugs.

The participants will stay at the study center during the whole dosing period and until 48 hours post final dose.

Detailed description: This is a Phase I study to investigate the safety and tolerability of AZD4831 in healthy male participants, conducted at a single center.The results from this study will form the basis for decisions on future studies. Another purpose of this dose escalation study is to find out the right dose of the experimental drug to be given to study participants in future studies. The study will be conducted in healthy participants to avoid interference from disease processes or other drugs. The participants will stay at the study center during the whole dosing period and until 48 hours post final dose.

Eligibility criteria: Inclusion Criteria:

* Healthy male participants aged 18 to 50 years (inclusive at Screening) with suitable veins for cannulation or repeated venipuncture.
* Have a BMI between 18 and 30 kg/m2 inclusive and weigh at least 50 kg and no more than 100 kg inclusive.

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 IMP.
* Any clinically significant abnormalities in biochemistry, hematology, or urinalysis results, as judged by the Investigator at Screening and/or Day 1, including

  1. Alanine aminotransferase (ALT) not within normal range;
  2. Aspartate aminotransferase (AST) not within normal range;
  3. Creatinine not within normal range;
  4. White blood cell (WBC) not within normal range;
  5. Hemoglobin not within normal range; and
  6. Estimated Glomerular Filtration Rate (eGFR) not within normal range.
* Any positive result on screening for serum hepatitis B surface antigen (HBsAg), hepatitis C antibody and human immunodeficiency virus (HIV) type 1 and 2.
* Abnormal vital signs, after 10 minutes supine rest, at Screening and/or Day 1, defined as any of the following:

  1. Systolic BP (SBP) \< 90 mmHg or ≥ 140 mmHg
  2. Diastolic BP (DBP) \< 50 mmHg or ≥ 90 mmHg
  3. Pulse \< 45 or \> 85 beats per minute (bpm)
* Persistent or intermittent complete bundle branch block, incomplete bundle branch block, or interventricular conduction delay with QRS \> 110 ms. Participants with QRS \> 110 ms but \< 115 ms are acceptable if there is no evidence of, for example, ventricular hypertrophy or pre-excitation at Screening and/or Day 1.
* Electrocardiogram findings suggesting a metabolic or other non-cardiac condition that may confound interpretation of serial changes (such as hypokalemia) at Screening and/or Day 1.
* Use of any prescribed or non-prescribed medication (other than paracetamol/acetaminophen), including antacids, analgesics, 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 participants, e.g., kept in detention, protected adults under guardianship, trusteeship, or committed to an institution by governmental or juridical order.

Primary outcomes:
measure: Number of participants with adverse events (AEs)
timeFrame: From screening (Day -28 to Day -2) until final follow-up (Day 24)
measure: Systolic Blood pressure
timeFrame: At screening (Day-28 to Day-2), Day -1, treatment period (Day 1, Day 10 and Day 12) and final follow-up (Day 24)
measure: Twelve lead safety electrocardiography (ECG)
timeFrame: At screening (Day-28 to Day-2), treatment period (Day 1 to Day 12), and final follow-up period (Day 24)
measure: Twelve lead digital electrocardiography (dECG)
timeFrame: Treatment Period (Day 1 to Day 12)
measure: Telemetry
timeFrame: At Day -1 and treatment period (Day 1 and Day 10)
measure: Hematology
timeFrame: At screening (Day -28 to Day -2), Day -1, treatment period (Day 1, Day 10 and Day 12), final follow-up (Day 24)
measure: Physical examination
timeFrame: At screening (Day-28 to Day-2), Day -1, treatment period (Day 2 and Day 12), and final follow-up period (Day 24)
measure: Diastolic blood pressure
timeFrame: At screening (Day-28 to Day-2), Day -1, treatment period (Day 1, Day 10 and Day 12) and final follow-up (Day 24)
measure: Pulse rate
timeFrame: At screening (Day-28 to Day-2), Day -1, treatment period (Day 1, Day 10 and Day 12) and final follow-up (Day 24)
measure: Oral body temperature
timeFrame: At screening (Day-28 to Day-2), Day-1, treatment period (Day 1 and Day 10 pre-dose)
measure: Biochemistry
timeFrame: At screening (Day -28 to Day -2), Day -1, treatment period (Day 1 pre-dose, Day 10 pre-dose and Day 12 - 48 hours post final dose before check-out) and final follow-up (Day 24)
measure: Urinalysis
timeFrame: At Day -1, treatment period (pre-dose - Day 1, day 5 and Day 10), follow-up (Day 14, day 16 and Day 20) and final follow-up (Day 24)
measure: Microscopy
timeFrame: At Day -1, treatment period (pre-dose - Day 1, day 5 and Day 10), follow-up (Day 14, day 16 and Day 20) and final follow-up (Day 24)
measure: Immunology
timeFrame: At Day -1, treatment period (Day 1 to Day 12), follow-up visits
Secondary outcomes:
measure: Observed maximum concentration, taken directly from the individual concentration-time curve(Cmax) of AZD4831 and its metabolites
timeFrame: Day 1 and Day 10
measure: Time to reach maximum concentration, taken directly from the individual concentration-time curve (tmax) of AZD4831
timeFrame: Day 1 to Day 10
measure: Observed trough plasma concentration [measured concentration at the end of the dosing interval taken just prior to the next administration] (Ctrough) of AZD4831
timeFrame: Day 2 to Day 10
measure: Terminal half-life (t1/2λz), estimated as (ln2)/λz) of AZD4831
timeFrame: Day 10
measure: Area under the plasma concentration-curve over 24 hours (AUCτ) of AZD4831
timeFrame: Day 1 and Day 10
measure: Area under the plasma concentration-time curve over the dosing interval divided by the dose administered (AUCτ/D) of AZD4831
timeFrame: Day 1 and Day 10
measure: Observed maximum plasma concentration divided by the dose administered (Cmax/D) of AZD4831.
timeFrame: Day 1 and Day 10
measure: Apparent clearance for parent drug (CL/F) estimated as dose divided by AUCτ of AZD4831.
timeFrame: Day 10
measure: Mean Residence Time (MRT)
timeFrame: Day 10
measure: Apparent volume of distribution for parent drug at terminal phase(Vz/F)(extravascular administration), estimated by dividing the apparent clearance (CL/F) by λz of AZD4831.
timeFrame: Day 10
measure: Accumulation ratio calculated as AUCτ Day 10/ AUCτ Day 1 (RacAUC) of AZD4831.
timeFrame: Day 10
measure: Accumulation ratio calculated as Cmax Day 10/ Cmax Day 1 (Rac Cmax) of AZD4831.
timeFrame: Day 10
measure: Amount of analyte excreted into the urine from time t1 to t2 (Ae(t1-t2)) of AZD4831.
timeFrame: Day 1 and Day 10
measure: Cumulative amount of analyte excreted at time t (Ae(0-t)) of AZD4831.
timeFrame: Day 1 and Day 10
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)) of AZD4831.
timeFrame: Day 1 and Day 10
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)) of AZD4831
timeFrame: Day 1 and Day 10
measure: Renal clearance, estimated by dividing Ae(0-t) by AUC(0-t), using appropriate matching time t (CLR) of AZD4831.
timeFrame: Day 1 and Day 10
measure: Terminal rate constant, estimated by log-linear least-squares regression rate constant, estiamteed by log-linear least-squares (λz)
timeFrame: Day 10
Other outcomes:
Locations:
city: Glendale
country: United States
facility: Research Site
state: California
Study officials:
affiliation: California Clinical Trials Medical Group 1560 East Chevy Chase Dr., Suite 140 Glendale, CA 91206
name: David Han, MD
role: PRINCIPAL_INVESTIGATOR
References: