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

NCT ID: NCT03400488

Last Updated: 2018-06-15

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1
• Total Enrollment: 32 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2018-01-16
• Study Completion Date: 2018-06-12

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.

Detailed Description

This study will be a Phase 1, randomized, single-blind, placebo-controlled, single and multiple ascending dose sequential group design in up to 48 healthy male Japanese subjects, performed at a single study center. The planned number of cohorts is 4 but up to 6 cohorts may be included if the Safety Review Committee (SRC) considers it necessary to repeat a dose level or if additional dose steps are required. Screening will be completed between Days -28 and -1. Primarily gradual escalation of the dose will be conducted with the oral suspension. Eight subjects will participate in each cohort. Four ascending dose levels are planned. Within each cohort 6 subjects will be randomised to receive AZD5718 and 2 subjects randomised to receive placebo. Each subject will receive one dose of AZD5718 or placebo on the first dosing day (Day 1, single ascending dose, SAD) and on Days 3 to 10 (multiple ascending dose, MAD). On Day 2 no dose will be given to the subject. In total each subject will receive 9 doses. Dosing for each ascending dose cohort will proceed after the SRC has evaluated the safety, tolerability and other relevant data of a completed cohort. The subjects will stay at the study site until 48 hours post-dose and will return 7 to 10 days after dosing for a follow-up visit. Each subject will be involved in the study for 7 weeks.

Conditions

Coronary Artery Disease

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: SINGLE

Study Groups

AZD5718

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.

Group Type: EXPERIMENTAL

AZD5718 oral suspension

Intervention Type: 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.

Placebo

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.

Group Type: PLACEBO_COMPARATOR

Placebo matching AZD5817 oral suspension

Intervention Type: 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.

Interventions

AZD5718 oral suspension

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.

Intervention Type: DRUG

Placebo matching AZD5817 oral suspension

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.

Intervention Type: OTHER

Eligibility Criteria

Inclusion Criteria

1. Provision of signed and dated, written informed consent prior to any study specific procedures

2. 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.

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/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.

Exclusion Criteria

1. 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.

2. History or presence of gastrointestinal, hepatic or renal disease or any other condition known to interfere with absorption, distribution, metabolism or excretion of drugs.

3. Any clinically important illness, medical/surgical procedure or trauma within 4 weeks of the first administration of investigational medicinal product (IMP).

4. Any clinically important abnormalities in clinical chemistry, hematology or urinalysis results as judged by the Investigator.

5. Any positive result on Screening for serum hepatitis B surface antigen, hepatitis C antibody and human immunodeficiency virus (HIV).

6. Suspicion or known Gilbert's syndrome.

7. 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)

8. 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.

9. 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.

10. 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.

11. 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.

12. 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.

13. Known or suspected history of drug abuse as judged by the Investigator.

14. Current smokers or those who have smoked or used nicotine products (including e-cigarettes within the previous 3 months).

15. History of alcohol abuse or excessive intake of alcohol as judged by the Investigator.

16. Positive screen for drugs of abuse or cotinine (nicotine) at screening and check-in (excluding cotinine).

17. History of severe allergy/hypersensitivity or ongoing clinically important allergy/hypersensitivity, as judged by the Investigator or history of hypersensitivity to drugs with a similar chemical structure or class to AZD5718.

18. Excessive intake of caffeine-containing drinks or food (e.g., coffee, tea, chocolate,) as judged by the Investigator.

19. Use of drugs with enzyme inducing properties such as St John's Wort within 3 weeks prior to the first administration of IMP.

20. 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 prior to the first administration of investigational product or longer if the medication has a long half-life.

21. Plasma donation within 1 month of Screening or any blood donation/blood loss > 500 mL during the 3 months prior to Screening.

22. Has received another new chemical entity (defined as a compound which has not been approved for marketing in the US) within 30 days or at least 5 half-lives (whichever is longer) of the first administration of investigational drug in this study. Note: subjects consented and screened, but not randomized in this study or a previous phase I study, are not excluded.

23. Subjects who have previously received AZD5718.

24. Involvement of any Astra Zeneca, PAREXEL or study site employee or their close relatives.

25. 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.

26. Subjects who are vegans or have medical dietary restrictions.

27. Subjects who cannot communicate reliably with the study team.

28. Vulnerable subjects, e.g., kept in detention, protected adults under guardianship, trusteeship, or committed to an institution by governmental or juridical order.

In addition, any of the following is regarded as a criterion for exclusion from the genetic research:

29. Previous bone marrow transplant.

30. Non-leukocyte depleted whole blood transfusion within 120 days of the date of the genetic sample collection.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 50 Years
• Eligible Sex: MALE
• Accepts Healthy Volunteers: Yes

Sponsors

AstraZeneca

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

David Han, Dr

Role: PRINCIPAL_INVESTIGATOR

PAREXEL Early Phase Clinical Unit-Los Angeles

Locations

Research Site

Glendale, California, United States

Countries

United States

Other Identifiers

D7550C00004

Identifier Type: -

Identifier Source: org_study_id