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

NCT ID: NCT02632526

Last Updated: 2019-03-21

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1
• Total Enrollment: 96 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2016-02-10
• Study Completion Date: 2016-08-26

Brief Summary

This is a phase I, randomised, single-blind, placebo-controlled, first-in-human (FIH) single and multiple ascending dose study consisting of two parts (Part A [SAD] and Part B [MAD]) to assess the safety, tolerability, pharmacokinetics and pharmacodynamics of AZD5718 in healthy male subjects

Detailed Description

This is a phase I, randomised, single-blind, placebo-controlled, first-in-human (FIH) single and multiple ascending dose study consisting of two parts (Part A [SAD] and Part B [MAD]) to assess the safety, tolerability, pharmacokinetics and pharmacodynamics of AZD5718 in healthy male subjects

Conditions

Healthy Male Subjects; Cardiovascular Disease

Study Design

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

Study Groups

AZD5718 amorphous form, treatment 1 (Part A)

Starting dose 25 mg/day, single ascending dose

Group Type: EXPERIMENTAL

AZD5718 oral suspension amorphous (1 to 100 mg/mL) (Part A)

Intervention Type: DRUG

Single and multiple doses

AZD5718 placebo oral suspension

Intervention Type: DRUG

Single and multiple doses

AZD5718 amorphous form, treatment 2 (Part A)

Single dose of AZD5718 amorphous suspension

Group Type: EXPERIMENTAL

AZD5718 oral suspension amorphous (1 to 100 mg/mL) (Part A)

Intervention Type: DRUG

Single and multiple doses

AZD5718 placebo oral suspension

Intervention Type: DRUG

Single and multiple doses

AZD5718 amorphous form, treatment 3 (Part A)

Single dose of AZD5718 amorphous suspension

Group Type: EXPERIMENTAL

AZD5718 oral suspension amorphous (1 to 100 mg/mL) (Part A)

Intervention Type: DRUG

Single and multiple doses

AZD5718 placebo oral suspension

Intervention Type: DRUG

Single and multiple doses

AZD5718 amorphous form, treatment 4 (Part A)

Single dose of AZD5718 amorphous suspension

Group Type: EXPERIMENTAL

AZD5718 oral suspension amorphous (1 to 100 mg/mL) (Part A)

Intervention Type: DRUG

Single and multiple doses

AZD5718 placebo oral suspension

Intervention Type: DRUG

Single and multiple doses

AZD5718 amorphous form, treatment 5 (Part A)

Single dose of AZD5718 amorphous suspension

Group Type: EXPERIMENTAL

AZD5718 oral suspension amorphous (1 to 100 mg/mL) (Part A)

Intervention Type: DRUG

Single and multiple doses

AZD5718 placebo oral suspension

Intervention Type: DRUG

Single and multiple doses

AZD5718 amorphous form, treatment 6 (Part A)

Single dose of AZD5718 amorphous suspension

Group Type: EXPERIMENTAL

AZD5718 oral suspension amorphous (1 to 100 mg/mL) (Part A)

Intervention Type: DRUG

Single and multiple doses

AZD5718 placebo oral suspension

Intervention Type: DRUG

Single and multiple doses

AZD5718, crystalline form, treatment 7 (Part A)

Crystalline suspension (Part A), dosage lower than highest dose used with amorphous suspension, single ascending dose

Group Type: EXPERIMENTAL

AZD5718 oral suspension crystalline form (1 to 100 mg/mL) (Part A)

Intervention Type: DRUG

Oral suspension single dose

AZD5718 placebo oral suspension

Intervention Type: DRUG

Single and multiple doses

AZD5718 crystalline form, treatment 8 (Part A)

Crystalline suspension (Part A), dosage lower than highest dose used with amorphous suspension, single ascending dose

Group Type: EXPERIMENTAL

AZD5718 oral suspension crystalline form (1 to 100 mg/mL) (Part A)

Intervention Type: DRUG

Oral suspension single dose

AZD5718 placebo oral suspension

Intervention Type: DRUG

Single and multiple doses

AZD5718 amorphous form, treatment 1 (Part B)

Once or twice daily from Days 2 to 9 and single doses on Days 1 and 10, dosage TBD (Part A)

Group Type: EXPERIMENTAL

AZD5718 placebo oral suspension

Intervention Type: DRUG

Single and multiple doses

AZD5718 oral suspension amorphous (1 to 100 mg/mL) (Part B)

Intervention Type: DRUG

Single and multiple doses

AZD5718 amorphous form, treatment 2 (Part B)

Once or twice daily from Days 2 to 9 and single doses on Days 1 and 10, dosage TBD (Part A)

Group Type: EXPERIMENTAL

AZD5718 placebo oral suspension

Intervention Type: DRUG

Single and multiple doses

AZD5718 oral suspension amorphous (1 to 100 mg/mL) (Part B)

Intervention Type: DRUG

Single and multiple doses

AZD5718 amorphous form, treatment 3 (Part B)

Once or twice daily from Days 2 to 9 and single doses on Days 1 and 10, dosage TBD (Part A)

Group Type: EXPERIMENTAL

AZD5718 placebo oral suspension

Intervention Type: DRUG

Single and multiple doses

AZD5718 oral suspension amorphous (1 to 100 mg/mL) (Part B)

Intervention Type: DRUG

Single and multiple doses

AZD5718 amorphous form, treatment 4 (Part B)

Once or twice daily from Days 2 to 9 and single doses on Days 1 and 10, dosage TBD (Part A)

Group Type: EXPERIMENTAL

AZD5718 placebo oral suspension

Intervention Type: DRUG

Single and multiple doses

AZD5718 oral suspension amorphous (1 to 100 mg/mL) (Part B)

Intervention Type: DRUG

Single and multiple doses

AZD5718 amorphous/crystalline form, repeat 1 (Part A)

Single dose of AZD5718 amorphous form (Part A) Crystalline form (Part A), dosage lower than highest dose used with amorphous form, single ascending dose

Group Type: EXPERIMENTAL

AZD5718 oral suspension crystalline form (1 to 100 mg/mL) (Part A)

Intervention Type: DRUG

Oral suspension single dose

AZD5718 oral suspension amorphous (1 to 100 mg/mL) (Part A)

Intervention Type: DRUG

Single and multiple doses

AZD5718 placebo oral suspension

Intervention Type: DRUG

Single and multiple doses

AZD5718 amorphous/crystalline form, repeat 2 (Part A)

Single dose of AZD5718 amorphous form (Part A) Crystalline form (Part A), dosage lower than highest dose used with amorphous form, single ascending dose

Group Type: EXPERIMENTAL

AZD5718 oral suspension crystalline form (1 to 100 mg/mL) (Part A)

Intervention Type: DRUG

Oral suspension single dose

AZD5718 oral suspension amorphous (1 to 100 mg/mL) (Part A)

Intervention Type: DRUG

Single and multiple doses

AZD5718 placebo oral suspension

Intervention Type: DRUG

Single and multiple doses

AZD5718 amorphous/crystalline, repeat 3 (Part A)

Single dose of AZD5718 amorphous form (Part A) Crystalline form (Part A), dosage lower than highest dose used with amorphous form, single ascending dose

Group Type: EXPERIMENTAL

AZD5718 oral suspension crystalline form (1 to 100 mg/mL) (Part A)

Intervention Type: DRUG

Oral suspension single dose

AZD5718 oral suspension amorphous (1 to 100 mg/mL) (Part A)

Intervention Type: DRUG

Single and multiple doses

AZD5718 amorphous form, repeat 1 (Part B)

Twice daily dosing (Day 1 - 9) and once daily dosing (Day 10), dosage TBD (Part A)

Group Type: EXPERIMENTAL

AZD5718 placebo oral suspension

Intervention Type: DRUG

Single and multiple doses

AZD5718 oral suspension amorphous (1 to 100 mg/mL) (Part B)

Intervention Type: DRUG

Single and multiple doses

AZD5718 amorphous form, repeat 2 (Part B)

Twice daily dosing (Day 1 - 9) and once daily dosing (Day 10), dosage TBD (Part A)

Group Type: EXPERIMENTAL

AZD5718 placebo oral suspension

Intervention Type: DRUG

Single and multiple doses

AZD5718 oral suspension amorphous (1 to 100 mg/mL) (Part B)

Intervention Type: DRUG

Single and multiple doses

Interventions

AZD5718 oral suspension crystalline form (1 to 100 mg/mL) (Part A)

Oral suspension single dose

Intervention Type: DRUG

AZD5718 oral suspension amorphous (1 to 100 mg/mL) (Part A)

Single and multiple doses

Intervention Type: DRUG

AZD5718 placebo oral suspension

Single and multiple doses

Intervention Type: DRUG

AZD5718 oral suspension amorphous (1 to 100 mg/mL) (Part B)

Single and multiple doses

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

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

2. Healthy male subjects aged 18 - 50 years, inclusive, with suitable veins for cannulation or repeated venepuncture

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 research

Exclusion Criteria

1. 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

2. 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

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

4. Any clinically significant abnormalities in clinical chemistry, haematology, or urinalysis results at screening and check-in, as judged by the investigator, including:

• Alanine aminotransferase (ALT) > upper limit of normal (ULN);
• Aspartate aminotransferase (AST) > ULN;
• Bilirubin (total) > ULN; and
• Gamma glutamyl transpeptidase (GGT) > ULN

5. Any positive result on screening for serum hepatitis B surface antigen (HBsAg), 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:

• Systolic blood pressure(BP) (SBP) < 90mmHg or ≥ 140 mmHg;
• Diastolic BP (DBP) < 50mmHg or ≥ 90 mmHg; and
• Pulse < 45 or > 85 beats per minute (bpm)

8. Any clinically significant abnormalities (at screening and check-in) 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 left ventricular hypertrophy

9. Prolonged QTcF (QT interval corrected for heart rate using Fridericia's formula) > 450 ms or shortened QTcF < 340 ms or family history of long QT syndrome, at screening and check-in

10. PR(PQ) interval (ECG interval measured from the onset of the P wave to the onset of the QRS complex) 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

11. PR (PQ) interval prolongation (> 240 ms) intermittent second (Wenckebach block while asleep is not exclusive) or third degree AV block, or AV dissociation, at screening and check-in

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, for example, ventricular hypertrophy or pre-excitation, at screening and check-in

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 within the 3 months prior to screening

15. Any history of alcohol abuse or excessive intake of alcohol, as judged by the investigator

16. Positive screen for drugs of abuse, alcohol or cotinine (nicotine) at screening or admission to the unit

17. 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 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 administration of IMP 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) within 3 months of the administration of IMP in this study. The period of exclusion is 3 months after the final dose from a previous study

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

24. Involvement of any AstraZeneca, 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 investigator

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

28. Previous bone marrow transplant

29. 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

Annelize Koch, MBChB, FFPM

Role: PRINCIPAL_INVESTIGATOR

Parexel

Locations

Research Site

Harrow, , United Kingdom

Countries

United Kingdom

Other Identifiers

D7550C00001

Identifier Type: -

Identifier Source: org_study_id