A Study to Assess the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of AZD5718 After Single and Multiple Ascending Dose Administration to Healthy Japanese Men

NCT03400488 | Completed Phase 1 FDA Drug

• 1 other identifier: D7550C00004
• Study Type: interventional
• Target: 32
• Locations: 1 country
• Sites: 1

Brief Summary

This is a Phase I study to investigate the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of the novel compound, AZD5718 in healthy Japanese men. The results from this study will form the basis for decisions on future studies.

Conditions

Coronary Artery Disease

Keywords

Coronary Artery Disease,; Cardiovascular disease (CAD),; 5-lipoxygenase activating protein (FLAP) inhibitor,; Leukotrienes.

Outcome Measures

Primary Outcomes (42)

• Number of patients with Adverse Events (AEs) due to AZD5817

  To assess the adverse events as a variable of safety and tolerability of AZD5718 following oral administration of single and multiple ascending doses. Adverse Events will be collected from the start of randomization throughout the treatment period up to and including the follow-up visit. Serious adverse events (SAEs) will be recorded from the time of informed consent.

  Change from baseline up to follow-up (7 to 10 days post-(final) dose)

• Supine vital sign (Systolic Blood pressure [BP])

  To assess the vital sign as a variable of safety and tolerability variable of AZD5718 following oral administration of single and multiple ascending doses.

  Change from baseline up to follow-up (7 to 10 days post-(final) dose)

• Supine vital sign (pulse rate)

  To assess the vital sign as a variable of safety and tolerability of AZD5718 following oral administration of single and multiple ascending doses.

  Change from baseline up to follow-up (7 to 10 days post-(final) dose)

• Number of participants with abnormal findings in electrocardiograms (ECGs) (safety ECGs, digital ECGs [dECG])

  To assess any clinically important abnormalities in the cardiovascular system functioning as a variable of safety and tolerability of AZD5718 following oral administration of single and multiple ascending doses. A 12-lead 10-second safety ECG will be performed with the Schiller Cardiovit CS-200 recorder immediately following all scheduled dECGs. 12-lead continuous dECG will be recorded over at least 5 minutes with the Schiller Cardiovit CS-200 recorder and transmitted to the AstraZeneca central dECG repository, according to AstraZeneca ECG Center´s standard procedures for settings, recording, and transmission of dECGs. For dECG, QTcF (QT interval corrected for heart rate using Fridericia's formula) will be calculated as QTcF =(QT\*(RR/1000)\^(-1/3)), where RR (the time between corresponding points on 2 consecutive R waves on ECG) is presented in milliseconds. Heart rate (HR) will also be calculated, based on the RR interval.

  From baseline up to follow-up (7 to 10 days post-(final) dose). For dECG: Days 1 to 12

• Number of participants with abnormal cardiac telemetry

  To assess any clinically important abnormalities in the cardiovascular system functioning (heart beat/rythm) using 2-lead real-time telemetry ECG as a variable of safety and tolerability of AZD5718 following oral administration of single and multiple ascending doses. The telemetry monitoring system will be reviewed by the Investigator or research nurse and paper printouts of any clinically important events will be stored as source data.

  From baseline up to Day 10

• Number of participants with abnormal findings in physical examinations

  To assess any clinically important abnormal findings in physical conditions as a variable of safety and tolerability of AZD5718 following oral administration of single and multiple ascending doses. The complete physical examinations include an 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. The brief physical examinations include an assessment of the general appearance, skin, cardiovascular system, respiratory and abdomen. Any new or aggravated clinically relevant abnormal medical finding at a physical examination as compared with the baseline assessment will be reported as an adverse event.

  From baseline up to follow-up (7 to 10 days post-(final) dose)

• Laboratory assessment: Hematology (leukocyte count)

  To assess the leukocyte count as a variable of safety and tolerability of AZD5718 following oral administration of single and multiple ascending doses.

  Change from baseline up to follow-up (7 to 10 days post-(final) dose)

• Supine vital sign (diastolic BP)

  To assess the vital sign as a variable of safety and tolerability of AZD5718 following oral administration of single and multiple ascending doses.

  Change from baseline up to follow-up (7 to 10 days post-(final) dose)

• Laboratory assessment: Clinical chemistry (sodium)

  To assess the clinical chemistry value (sodium) as a variable of safety and tolerability of AZD5718, following oral administration of single and multiple ascending doses.

  Change from baseline up to follow-up (7 to 10 days post-(final) dose)

• Laboratory assessment: Urinalysis (glucose)

  To assess urinalysis (glucose) as a variable of safety and tolerability of AZD5718, following oral administration of single and multiple ascending doses.

  Change from baseline up to follow-up (7 to 10 days post-(final) dose)

• Laboratory assessment: Hematology (Red blood cell [RBC] count)

  To assess the RBC count as a variable of safety and tolerability of AZD5718 following oral administration of single and multiple ascending doses.

  Change from baseline up to follow-up (7 to 10 days post-(final) dose)

• Laboratory assessment: Hematology (Hemoglobin [Hb])

  To assess the Hb as a criterion of safety and tolerability variable of AZD5718 following oral administration of single and multiple ascending doses.

  Change from baseline up to follow-up (7 to 10 days post-(final) dose)

• Laboratory assessment: Hematology (Hematocrit [HCT])

  To assess the HCT as a variable of safety and tolerability of AZD5718 following oral administration of single and multiple ascending doses.

  Change from baseline up to follow-up (7 to 10 days post-(final) dose)

• Laboratory assessment: Hematology (Mean corpuscular volume [MCV])

  To assess the MCV as a variable of safety and tolerability of AZD5718 following oral administration of single and multiple ascending doses.

  Change from baseline up to follow-up (7 to 10 days post-(final) dose)

• Laboratory assessment: Hematology (Mean corpuscular hemoglobin [MCH])

  To assess the MCH as a variable of safety and tolerability of AZD5718 following oral administration of single and multiple ascending doses.

  Change from baseline up to follow-up (7 to 10 days post-(final) dose)

• Laboratory assessment: Hematology (Mean corpuscular hemoglobin concentration [MCHC])

  To assess the MCHC as a variable of safety and tolerability variable of AZD5718 following oral administration of single and multiple ascending doses.

  Change from baseline up to follow-up (7 to 10 days post-(final) dose)

• Laboratory assessment: Clinical chemistry (potassium)

  To assess the clinical chemistry value (potassium) as a variable of safety and tolerability of AZD5718, following oral administration of single and multiple ascending doses.

  Change from baseline up to follow-up (7 to 10 days post-(final) dose)

• Laboratory assessment: Clinical chemistry (urea)

  To assess the clinical chemistry value (urea) as a variable of safety and tolerability of AZD5718, following oral administration of single and multiple ascending doses.

  Change from baseline up to follow-up (7 to 10 days post-(final) dose)

• Laboratory assessment: Clinical chemistry (creatinine)

  To assess the clinical chemistry value (creatinine) as a variable of safety and tolerability of AZD5718, following oral administration of single and multiple ascending doses.

  Change from baseline up to follow-up (7 to 10 days post-(final) dose)

• Laboratory assessment: Clinical chemistry (albumin)

  To assess the clinical chemistry value (albumin) as a variable of safety and tolerability of AZD5718, following oral administration of single and multiple ascending doses.

  Change from baseline up to follow-up (7 to 10 days post-(final) dose)

• Laboratory assessment: Clinical chemistry (calcium)

  To assess the clinical chemistry value (calcium) as a variable of safety and tolerability of AZD5718, following oral administration of single and multiple ascending doses.

  Change from baseline up to follow-up (7 to 10 days post-(final) dose)

• Laboratory assessment: Clinical chemistry (phosphate)

  To assess the clinical chemistry value (phosphate) as a variable of safety and tolerability of AZD5718, following oral administration of single and multiple ascending doses.

  Change from baseline up to follow-up (7 to 10 days post-(final) dose)

• Laboratory assessment: Clinical chemistry (glucose (fasting))

  To assess the clinical chemistry value (glucose (fasting)) as a variable of safety and tolerability of AZD5718, following oral administration of single and multiple ascending doses.

  Change from baseline up to follow-up (7 to 10 days post-(final) dose)

• Laboratory assessment: Clinical chemistry (insulin)

  To assess the clinical chemistry value (insulin) as a variable of safety and tolerability of AZD5718, following oral administration of single and multiple ascending doses.

  Change from baseline up to follow-up (7 to 10 days post-(final) dose)

• Laboratory assessment: Clinical chemistry (fibrinogen)

  To assess the clinical chemistry value (fibrinogen) as a variable of safety and tolerability of AZD5718, following oral administration of single and multiple ascending doses.

  Change from baseline up to follow-up (7 to 10 days post-(final) dose)

• Laboratory assessment: Clinical chemistry (thyroid-stimulating hormone)

  To assess the clinical chemistry value (thyroid-stimulating hormone) as a variable of safety and tolerability of AZD5718, following oral administration of single and multiple ascending doses.

  Change from baseline up to follow-up (7 to 10 days post-(final) dose)

• Laboratory assessment: Urinalysis (blood)

  To assess urinalysis (blood) as a variable of safety and tolerability of AZD5718, following oral administration of single and multiple ascending doses. If urinalysis is positive for blood, a microscopy test will be performed to assess RBC, white blood cell \[WBC\], casts \[cellular, granular, hyaline\]).

  Change from baseline up to follow-up (7 to 10 days post-(final) dose)

• Laboratory assessment: Urinalysis (protein)

  To assess urinalysis (protein) as a variable of safety and tolerability of AZD5718, following oral administration of single and multiple ascending doses. If urinalysis is positive for protein, a microscopy test will be performed to assess RBC, WBC, casts \[cellular, granular, hyaline\]).

  Change from baseline up to follow-up (7 to 10 days post-(final) dose)

• Laboratory assessment: Urinalysis (urine creatinine)

  To assess urinalysis (urine creatinine) as a variable of safety and tolerability of AZD5718, following oral administration of single and multiple ascending doses.

  Change from baseline up to follow-up (7 to 10 days post-(final) dose)

• Laboratory assessment: Hematology (Differential Count)

  To assess the differential count as a variable of safety and tolerability of AZD5718 following oral administration of single and multiple ascending doses.

  Change from baseline up to follow-up (7 to 10 days post-(final) dose)

• Laboratory assessment: Hematology (Platelets)

  To assess the platelets as a variable of safety and tolerability of AZD5718 following oral administration of single and multiple ascending doses.

  Change from baseline up to follow-up (7 to 10 days post-(final) dose)

• Laboratory assessment: Hematology (Reticulocytes absolute count)

  To assess the reticulocytes absolute count as a variable of safety and tolerability of AZD5718 following oral administration of single and multiple ascending doses.

  Change from baseline up to follow-up (7 to 10 days post-(final) dose)

• Laboratory assessment: Clinical chemistry (High sensitivity-C-reactive protein [CRP])

  To assess the clinical chemistry value (CRP) as a variable of safety and tolerability of AZD5718, following oral administration of single and multiple ascending doses.

  Change from baseline up to follow-up (7 to 10 days post-(final) dose)

• Laboratory assessment: Clinical chemistry (Free T4)

  To assess the clinical chemistry value (Free T4) as a variable of safety and tolerability of AZD5718, following oral administration of single and multiple ascending doses.

  Change from baseline up to follow-up (7 to 10 days post-(final) dose)

• Laboratory assessment: Clinical chemistry (Alkaline phosphatase [ALP])

  To assess the clinical chemistry value (ALP) as a variable of safety and tolerability of AZD5718, following oral administration of single and multiple ascending doses.

  Change from baseline up to follow-up (7 to 10 days post-(final) dose)

• Laboratory assessment: Clinical chemistry (Alanine aminotransferase [ALT])

  To assess the clinical chemistry value (ALT) as a variable of safety and tolerability of AZD5718, following oral administration of single and multiple ascending doses.

  Change from baseline up to follow-up (7 to 10 days post-(final) dose)

• Laboratory assessment: Clinical chemistry (Aspartate aminotransferase [AST])

  To assess the clinical chemistry value (AST) as a variable of safety and tolerability of AZD5718, following oral administration of single and multiple ascending doses.

  Change from baseline up to follow-up (7 to 10 days post-(final) dose)

• Laboratory assessment: Clinical chemistry (Gamma glutamyl transpeptidase [GGT])

  To assess the clinical chemistry value (GGT) as a variable of safety and tolerability of AZD5718, following oral administration of single and multiple ascending doses.

  Change from baseline up to follow-up (7 to 10 days post-(final) dose)

• Laboratory assessment: Clinical chemistry (Total Bilirubin)

  To assess the clinical chemistry value (total bilirubin) as a variable of safety and tolerability of AZD5718, following oral administration of single and multiple ascending doses.

  Change from baseline up to follow-up (7 to 10 days post-(final) dose)

• Laboratory assessment: Clinical chemistry (Unconjugated bilirubin)

  To assess the clinical chemistry value (unconjugated bilirubin) as a variable of safety and tolerability of AZD5718, following oral administration of single and multiple ascending doses.

  Change from baseline up to follow-up (7 to 10 days post-(final) dose)

• Laboratory assessment: Clinical chemistry (Glutamate dehydrogenase)

  To assess the clinical chemistry value (glutamate dehydrogenase) as a variable of safety and tolerability of AZD5718, following oral administration of single and multiple ascending doses.

  Change from baseline up to follow-up (7 to 10 days post-(final) dose)

• Laboratory assessment: Clinical chemistry (Lactate dehydrogenase [LDH])

  To assess the clinical chemistry value (LDH) as a variable of safety and tolerability of AZD5718, following oral administration of single and multiple ascending doses.

  Change from baseline up to follow-up (7 to 10 days post-(final) dose)

Secondary Outcomes (20)

• Plasma PK assessment: Observed maximum plasma concentration (Cmax) assessment for AZD5817 after single and repeated oral dosing

  Day 1 and Day 10: pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24, 32 and 48 hours (Day 3 pre-dose) post-dose, Day 4-9 pre morning dose

• Plasma PK assessment: Time to reach peak or maximum observed concentration following drug administration (tmax) assessment for AZD5817 after single and repeated oral dosing

  Day 1 and Day 10: pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24, 32 and 48 hours (Day 3 pre-dose) post-dose, Day 4-9 pre morning dose

• Plasma PK assessment: Terminal rate constant (λZ) assessment for AZD5817 after single and repeated oral dosing

  Day 1 and Day 10: pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24, 32 and 48 hours (Day 3 pre-dose) post-dose, Day 4-9 pre morning dose

• Plasma PK assessment: Terminal half-life (t½λz) assessment for AZD5817 after single and repeated oral dosing

  Day 1 and Day 10: pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24, 32 and 48 hours (Day 3 pre-dose) post-dose, Day 4-9 pre morning dose

• Plasma PK assessment: Area under the plasma concentration-time curve from time zero to 24 hours after dosing (AUC(0-24)) assessment for AZD5817 after single and repeated oral dosing

  Day 1 and Day 10: pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24, 32 and 48 hours (Day 3 pre-dose) post-dose, Day 4-9 pre morning dose

Study Arms (2)

AZD5718

EXPERIMENTAL

Randomized subjects will receive orally once daily dose of AZD5718 oral suspension on Day 1 (SAD) and MAD from Days 3 to 10. On Day 2, no dose will be given. These procedures will be repeated in all cohorts.

Drug: AZD5718 oral suspension

Placebo

PLACEBO COMPARATOR

Randomized subjects will receive orally once daily dose of placebo matching AZD5718 oral suspension on Day 1 (SAD) and MAD form Days 3 to 10. On Day 2, no dose will be given. These procedures will be repeated in all cohorts.

Other: Placebo matching AZD5817 oral suspension

Interventions

AZD5718 oral suspension DRUG

In all cohorts, randomized subjects will receive orally AZD5718 oral suspension SAD (60 mg) on Day 1 and MAD (180 mg, 360 mg and 600 mg) from Days 3 to 10. On Day 2, no dose will be given. In total each subject will receive 9 doses of AZD5718.

AZD5718

Placebo matching AZD5817 oral suspension OTHER

In all cohorts, randomized subjects will receive orally placebo matching AZD5718 oral suspension on Day 1 and from Days 3 to 10. On Day 2, no dose will be given.

Placebo

Eligibility Criteria

• Age: 18 Years - 50 Years
• Sex: male
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Provision of signed and dated, written informed consent prior to any study specific procedures
• Healthy male Japanese subjects aged 18-50 years with suitable veins for cannulation or repeated venipuncture. A subject will be considered as Japanese if:
• both of his parents and all grandparents are Japanese,
• he was born in Japan and have a Japanese passport, and
• he has not lived outside Japan for more than 10 years.
• 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.
• Provision of signed, written and dated informed consent for optional genetic/biomarker research. If a subject declines to participate in the genetic component of the study, there will be no penalty or loss of benefit to the subject. The subject will not be excluded from other aspects of the study described in this protocol.

You may not qualify if:

• History of any clinically important 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, hepatic or renal disease or any other condition known to interfere with absorption, distribution, metabolism or excretion of drugs.
• Any clinically important illness, medical/surgical procedure or trauma within 4 weeks of the first administration of investigational medicinal product (IMP).
• Any clinically important abnormalities in clinical chemistry, hematology or urinalysis results as judged by the Investigator.
• Any positive result on Screening for serum hepatitis B surface antigen, hepatitis C antibody and human immunodeficiency virus (HIV).
• Suspicion or known Gilbert's syndrome.
• Abnormal vital signs, after 10 minutes supine rest, at screening and check-in, defined as any of the following (repeat evaluations may be done once if the values for a subject are outside the designated range at screening and on Day -1):
• Systolic blood pressure \< 90 mmHg or \> 140 mmHg Diastolic blood pressure \< 50 mmHg or \> 90 mmHg Heart rate \< 45 or \> 90 beats per minute (bpm)
• Any clinically important abnormalities in rhythm, conduction or morphology of the resting ECG and any clinically important abnormalities at screening and check-in 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. If deemed necessary, an ECG may be repeated once for each ECG measurement.
• Prolonged QTcF \> 450 ms or shortened QTcF \< 340 ms or family history of long QT syndrome at screening and check-in. If deemed necessary, an ECG may be repeated once for each ECG measurement.
• PR(PQ) interval shortening \< 120 ms (PR \> 110 ms but \< 120 ms is acceptable if there is no evidence of ventricular pre-excitation) at screening and check-in. If deemed necessary, an ECG may be repeated once for each ECG measurement.
• PR (PQ) interval prolongation (\> 240 ms) intermittent second (Wenckebach block while asleep is not exclusive) or third degree atrioventricular (AV) block, or AV dissociation at screening and check-in. If deemed necessary, an ECG may be repeated once for each ECG measurement.
• 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 e.g., ventricular hypertrophy or pre-excitation, at screening and check-in. If deemed necessary, an ECG may be repeated once for each ECG measurement.
• Known or suspected history of drug abuse as judged by the Investigator.
• Current smokers or those who have smoked or used nicotine products (including e-cigarettes within the previous 3 months).

Sponsors & Collaborators

• AstraZeneca: lead

Study Sites (1)

Research Site

Glendale, California, 91206, United States

Location

MeSH Terms

Conditions

Coronary Artery Disease; Cardiovascular Diseases

Condition Hierarchy (Ancestors)

Coronary Disease; Myocardial Ischemia; Heart Diseases; Arteriosclerosis; Arterial Occlusive Diseases; Vascular Diseases

Study Officials

• David Han, Dr

  PAREXEL Early Phase Clinical Unit-Los Angeles

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: PARTICIPANT
• Masking Details: This study is single-blind (in which the study centre staff will remain blinded during the clinical conduct of a given cohort) with regard to treatment (AZD5718 or placebo) at each dose level. In the event of a medical emergency when management of a subject's condition requires knowledge of the trial medication, the treatment received may be revealed by personnel authorized by the Principal Investigator (PI).
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 12, 2017
• First Posted: January 17, 2018
• Study Start: January 16, 2018
• Primary Completion: June 12, 2018
• Study Completion: June 12, 2018
• Last Updated: June 15, 2018

Record last verified: 2018-06

Locations

US (1)