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

Cardiovascular Disease Clinical Trial

Official title:

A Phase I, Randomized, Single-blind, Placebo-controlled Study to Assess the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of AZD5718 After Single and Multiple Ascending Dose Administration to Healthy Male Subjects

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02632526
• Other study ID #: D7550C00001
• Status: Completed
• Phase: Phase 1
• Start date: February 10, 2016
• Est. completion date: August 26, 2016

Study information

• Verified date: December 2018
• Source: AstraZeneca
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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

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

Recruitment information / eligibility

• Status: Completed
• Enrollment: 96
• Est. completion date: August 26, 2016
• Est. primary completion date: August 26, 2016
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Male
• Age group: 18 Years to 50 Years

Eligibility

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

Related Conditions & MeSH terms

• Cardiovascular Disease
• Cardiovascular Diseases
• Healthy Male Subjects

Intervention

Drug:
• AZD5718 oral suspension crystalline form (1 to 100 mg/mL) (Part A)
Oral suspension single dose
• AZD5718 oral suspension amorphous (1 to 100 mg/mL) (Part A)
Single and multiple doses
• AZD5718 placebo oral suspension
Single and multiple doses
• AZD5718 oral suspension amorphous (1 to 100 mg/mL) (Part B)
Single and multiple doses

Locations

Country	Name	City	State
United Kingdom	Research Site	Harrow

Sponsors (1)

Lead Sponsor	Collaborator
AstraZeneca

Country where clinical trial is conducted

United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Safety and Tolerability of AZD5718 by Assessment of the Number of Participants With Adverse Events Following Oral Administration of SAD (Part A) and MAD (Part B).	To assess the safety and tolerability of AZD5718 following oral administration of SAD (Part A) and MAD (Part B).	From screening to last followup visit (7-10 days after last dose), up to 6 weeks (Part A) and up to 8 weeks (Part B)
Secondary	Rate and Extent of Absorption of AZD5718 by Assessment of the Area Under the Plasma Concentration-curve From Time Zero Extrapolated to Infinity (AUC) for Part A - Amorphous and Crystalline Suspension	To assess area under the concentration-time curve from time zero extrapolated to infinity and was estimated by AUC(0-last) + Clast/?z (Clast - the last observed quantifiable concentration) following a single administration of AZD5718 Amorphous and Crystalline suspension (Part A only)	At post-dose (Days 1 to 3); 0.5, 1, 2, 3, 4, 6, 8, 24, 36 and 48 hours post-dose and folow up (Day 4 - 72 hours post-dose) (Part A only)
Secondary	Rate and Extent of Absorption of AZD5718 by Assessment of the Area Under Plasma Concentration-time Curve From Time Zero Extrapolated to Infinity (AUC) for Part B - Amorphous Suspension	To assess the rate and extent of absorption of AZD5718 by evaluation of the area under plasma concentration-time curve from time zero extrapolated to infinity (AUC) following a single AZD5718 dose on Day 1 and multiple daily dosing on Days 9 or 10 under fasted conditions (Part B)	Day 1 of Part B
Secondary	Rate and Extent of Absorption of AZD5718 by Assessment of the Area Under the Plasma Concentration-curve From Time Zero to Time of Last Quantifiable Concentration (AUC(0-last)) for Part A - Amorphous and Crystalline Suspension	To assess area under the area under the plasma concentration-curve from time zero to the time of last quantifiable concentration (AUC(0-last)) following a single administration of AZD5718 Amorphous and Crystalline suspension (Part A only)	At post-dose (Days 1 to 3); 0.5, 1, 2, 3, 4, 6, 8, 24, 36 and 48 hours post-dose and folow up (Day 4 - 72 hours post-dose) (Part A only)
Secondary	Rate and Extent of Absorption of AZD5718 by Assessment of the Area Under the Plasma Concentration-curve Over the Dosing Interval (AUC(0-t)) for Part B - Amorphous Suspension	To assess the rate and extent of absorption of AZD5718 by evaluation of the area under the plasma concentration-curve over the dosing interval (AUC(0-t)) following a single AZD5718 dose on Day 1 and multiple daily dosing on Days 9 or 10 under fasted conditions (Part B)	Day 1, Day 9 and Day 10 of Part B
Secondary	Rate and Extent of Absorption of AZD5718 by Assessment of the Observed Maximum Plasma Concentration (Cmax) for Part A - Amorphous and Crystalline Suspension	To assess observed maximum plasma concentration (Cmax) following a single administration of AZD5718 Amorphous and Crystalline suspension (Part A only)	At post-dose (Days 1 to 3); 0.5, 1, 2, 3, 4, 6, 8, 24, 36 and 48 hours post-dose and folow up (Day 4 - 72 hours post-dose) (Part A only)
Secondary	Rate and Extent of Absorption of AZD5718 by Assessment of the Observed Maximum Plasma Concentration (Cmax) for Part B - Amorphous Suspension	To assess the rate and extent of absorption of AZD5718 by evaluation of the observed maximum plasma concentration (Cmax) following a single AZD5718 dose on Day 1 and multiple daily dosing on Days 9 or 10 under fasted conditions (Part B)	Day 1, Day 9 and Day 10 (Part B only)
Secondary	Rate and Extent of Absorption of AZD5718 by Assessment of the Time to Reach the Observed Maximum Plasma Concentration (Tmax) for Part A - Amorphous and Crystalline Suspension	To assess the time to reach the observed maximum plasma concentration (tmax) following a single administration of AZD5718 Amorphous and Crystalline suspension (Part A only)	At post-dose (Days 1 to 3); 0.5, 1, 2, 3, 4, 6, 8, 24, 36 and 48 hours post-dose and folow up (Day 4 - 72 hours post-dose) (Part A only)
Secondary	Rate and Extent of Absorption of AZD5718 by Assessment of the Time to Reach the Observed Maximum Plasma Concentration (Tmax) for Part B - Amorphous Suspension	To assess the rate and extent of absorption of AZD5718 by evaluation of the time to reach the observed maximum plasma concentration (tmax) following a single AZD5718 dose on Day 1 and multiple daily dosing on Days 9 or 10 under fasted conditions (Part B)	Day 1, Day 9 and Day 10 (Part B only)
Secondary	Rate and Extent of Absorption of AZD5718 by Assessment of the Half-life Associated With Terminal Slope of a Semi-logarithmic Plasma Concentration-time Curve (t½?z) for Part A - Amorphous and Crystalline Suspension	To assess Rate and extent of absorption of AZD5718 by assessment of the half-life associated with terminal slope of a semi-logarithmic plasma concentration-time curve (t½?z) following a single administration of AZD5718 Amorphous and Crystalline suspension (Part A only)	At post-dose (Days 1 to 3); 0.5, 1, 2, 3, 4, 6, 8, 24, 36 and 48 hours post-dose and folow up (Day 4 - 72 hours post-dose) (Part A only)
Secondary	Rate and Extent of Absorption of AZD5718 by Assessment of the Half-life Associated With Terminal Slope of a Semi-logarithmic Plasma Concentration-time Curve (t½?z) for Part B - Amorphous Suspension	To assess the rate and extent of absorption of AZD5718 by evaluation of the half-life associated with terminal slope of a semi-logarithmic plasma concentration-time curve (t½?z) following a single AZD5718 dose on Day 1 and multiple daily dosing on Days 9 or 10 under fasted conditions (Part B)	Day 1 and Day 10 (Part B only)
Secondary	Rate and Extent of Absorption of AZD5718 by Assessment of the Apparent Total Body Clearance After Extravascular Administration Estimated as Dose Divided by AUC (CL/F) for Part A - Amorphous and Crystalline Suspension	To assess rate and extent of absorption of AZD5718 by assessment of the apparent total body clearance after extravascular administration estimated as dose divided by AUC (CL/F) following a single administration of AZD5718 Amorphous and Crystalline suspension (Part A only)	At post-dose (Days 1 to 3); 0.5, 1, 2, 3, 4, 6, 8, 24, 36 and 48 hours post-dose and folow up (Day 4 - 72 hours post-dose) (Part A only)
Secondary	Rate and Extent of Absorption of AZD5718 by Assessment of the Apparent Total Body Clearance After Extravascular Administration Estimated as Dose Divided by AUC (CL/F) for Part B - Amorphous Suspension	To assess rate and extent of absorption of AZD5718 by assessment of the Rate and extent of absorption of AZD5718 by assessment of CL/F estimated as dose divided by AUC (for Day 1 only) and dose divided by AUCt on Day 10 following a single AZD5718 dose on Day 1 and multiple daily dosing on Days 9 or 10 under fasted conditions (Part B)	Day 1 and Day 10 of Part B
Secondary	Rate and Extent of Absorption of AZD5718 by Assessment of the Apparent Volume of Distribution During the Terminal Phase After Extravascular Administration (Vz/F) for Part A - Amorphous and Crystalline Suspension	To assess rate and extent of absorption of AZD5718 by assessment of the apparent volume of distribution during the terminal phase after extravascular administration (Vz/F) following a single administration of AZD5718 Amorphous and Crystalline suspension (Part A only)	At post-dose (Days 1 to 3); 0.5, 1, 2, 3, 4, 6, 8, 24, 36 and 48 hours post-dose and folow up (Day 4 - 72 hours post-dose)
Secondary	To Evaluate the Relative Bioavailability Between the Amorphous and Crystalline Form of AZD5718 (Part A) by Assessment of AUC for Part A - Amorphous and Crystalline Suspension	To assess the relative bioavailability by AUC between the cohort receiving the crystalline suspension and the corresponding data from the cohort receiving the same dose of the amorphous suspension (Part A only). Crystalline suspension was compared to the reference amorphous suspension.; Note: Geometric mean ratios for crystalline/amorphous suspensions were calculated	At post-dose (Days 1 to 3); 0.5, 1, 2, 3, 4, 6, 8,12, 24, 36, and 48 hours post-dose and folow up (Day 4 - 72 hours post-dose)
Secondary	To Evaluate the Relative Bioavailability Between the Amorphous and Crystalline Form of AZD5718 (Part A) by Assessment of Cmax for Part A - Amorphous and Crystalline Suspension	To assess the relative bioavailability by Cmax between the cohort receiving the crystalline suspension and the corresponding data from the cohort receiving the same dose of the amorphous suspension (Part A only). Crystalline suspension was compared to the reference amorphous suspension.; Note: Geometric mean ratios for crystalline/amorphous suspensions were calculated	At post-dose (Days 1 to 3); 0.5, 1, 2, 3, 4, 6, 8, 24, 36 and 48 hours post-dose and folow up (Day 4 - 72 hours post-dose) (Part A only)
Secondary	Rate and Extent of Absorption of AZD5718 by Assessment of the Accumulation Ratio for AUC(0-t) (RAC AUC(0-t)) for Part B - Amorphous Suspension	To assess rate and extent of absorption of AZD5718 by assessment of the Rate and extent of absorption of AZD5718 by assessment of accumulation ratio for AUC(0-t) (RAC AUC(0-t)) following a single AZD5718 dose on Day 1 and multiple daily dosing on Days 9 or 10 under fasted conditions (Part B) Accumulation ratio calculated as AUC0-t Day 10/AUC0-t Day 1 (first dose) for Part B under fasted condition and presented values for Day 10	Day 1 and Day 9 (Part B only)
Secondary	Rate and Extent of Absorption of AZD5718 by Assessment of the Accumulation Ratio for Cmax (RAC Cmax) for Part B (Amorphous Suspension) Under Fasted Condition	To assess the rate and extent of absorption of AZD5718 by evaluation of accumulation ratio for Cmax (RAC Cmax) following a single AZD5718 dose on Day 1 and multiple daily dosing on Days 9 or 10 under fasted conditions (Part B). Accumulation ratio calculated as Cmax Day 10/Cmax Day 1 (first dose) for Part B under fasted condition.	Day 1 and Day 9 (Part B only)
Secondary	Rate and Extent of Absorption of AZD5718 by Assessment of the Temporal Change Parameter in Systemic Exposure (TCP) for Part B (Amorphous Suspension) Under Fasted Condition	To assess rate and extent of absorption of AZD5718 by assessment of the temporal change parameter in systemic exposure (TCP) following a single AZD5718 dose on Day 1 and multiple daily dosing on Days 9 or 10 under fasted conditions (Part B).; TCP calculated as AUCtDay10/AUCDay 1 and presented values for Day 10	At Day 10 (Part B only)
Secondary	Rate and Extent of Absorption of AZD5718 by Assessment of the Effect of Food Following Administration of 180 mg AZD5718 With Food (Part B Day 9) and Fasted (Part B Day 10)	The effect of food was evaluated by the assessment of the PK parameter (Cmax) following multiple daily doses of 180 mg AZD5718 under fasted condition (Part B Day 10) and immediately following a high-fat breakfast (Part B Day 9)	At Day 9 and Day 10 (Part B only)
Secondary	Rate and Extent of Absorption of AZD5718 by Assessment of the Effect of Food Following Administration of 180 mg AZD5718 With Food (Part B Day 9) and Fasted (Part B Day 10)	The effect of food was evaluated by the assessment of the PK parameter (AUC(0-t) following multiple daily doses of 180 mg AZD5718 under fasted condition (Part B Day 10) and immediately following a high-fat breakfast (Part B Day 9)	At Day 9 and Day 10 (Part B only)
Secondary	Rate and Extent of Absorption of AZD5718 by Assessment of the Effect of Food Following Administration of 180 mg AZD5718 With Food (Part B Day 9) and Fasted (Part B Day 10)	The effect of food was evaluated by the assessment of the PK parameter(tmax) following multiple daily doses of 180 mg AZD5718 under fasted condition (Part B Day 10) and immediately following a high-fat breakfast (Part B Day 9)	At Day 9 and Day 10 (Part B only)
Secondary	Rate and Extent of Absorption of AZD5718 by Assessment of Cumulative Amount of Analyte Excreted at the Last Sampling Interval (CumAe0-24) Following a Single Administration of AZD5718 Amorphous and Crystalline Suspension (Part A)	To assess urine PK parameter (CumAe0-24) after a single administration of AZD5718 Amorphous suspension in Part A	Part A pre-dose and pooled intervals up to 24 hours post-dose
Secondary	Rate and Extent of Absorption of AZD5718 by Assessment of Percentage of Dose Excreted Unchanged Into the Urine From 0 to 24 Hours (Cumfe0-24) Following a Single Administration of AZD5718 Amorphous and Crystalline Suspension (Part A)	To assess urine PK parameter (Cumfe0-24) estimated by dividing Ae(0-last) by dose after a single administration of AZD5718 Amorphous suspension in Part A	Part A pre-dose and pooled intervals up to 24 hours post-dose
Secondary	Rate and Extent of Absorption of AZD5718 by Assessment of Renal Clearance (CLR) Following a Single Administration of AZD5718 Amorphous and Crystalline Suspension (Part A)	To assess the urine PK parameter (CLR) after a single administration of AZD5718 Amorphous suspension in Part A	Part A pre-dose and pooled intervals up to 24 hours post-dose
Secondary	Rate and Extent of Absorption of AZD5718 by Assessment of Cumulative Amount of Analyte Excreted From 0 to 24 Hours (CumAe0-24) Following a Multiple Daily Doses Administration of AZD5718 Amorphous Suspension (Part B Day 9)	To assess the urine PK parameter (CumAe0-24) after a single administration of AZD5718 Amorphous suspension in Part B Day 9	Part B only, Day 9 at pooled 3 hour intervals until 24 hours post-dose
Secondary	Rate and Extent of Absorption of AZD5718 by Assessment of Percentage of Dose Excreted Unchanged Into the Urine From 0 to 24 Hours (Cumfe0-24) Following a Multiple Daily Doses Administration of AZD5718 Amorphous Suspension (Part B Day 9)	To assess urine PK parameter (Cumfe0-24) estimated by dividing Ae(0-last) by dose after a single administration of AZD5718 Amorphous suspension in Part B Day 9	Part B only, Day 9 at pooled 3 hour intervals until 24 hours post-dose
Secondary	Rate and Extent of Absorption of AZD5718 by Assessment of Renal Clearance (CLR) Following a Multiple Daily Doses Administration of AZD5718 Amorphous Suspension (Part B Day 9)	To assess the urine PK parameter (CLR) after a single administration of AZD5718 Amorphous suspension in Part B Day 9	Part B only, Day 9 at pooled 3 hour intervals until 24 hours post-dose
Secondary	Pharmacodynamic Analysis by ex Vivo Stimulation of Leukotriene B4 (LTB4) Production Using Calcium Ionophore for Part A -Amorphous and Crystalline Suspension	To assess the change from baseline in the ex vivo stimulated LTB4 production using calcium ionophore in venous blood samples following a single administration of AZD5718 Amorphous and Crystalline suspension (Part A only)	Admission to 0.5, 1, 2, 3, 4, 6, 8, 24, 36 and 48 hours post-dose (Part A only)
Secondary	Pharmacodynamic Analysis by ex Vivo Stimulation of LTB4 Production Using Calcium Ionophore for Part B - Amorphous Suspension	To assess the change from baseline in the ex vivo stimulated LTB4 production using calcium ionophore in venous blood samples following multiple administration of AZD5718 Amorphous suspension (Part B only)	Admission, predose and 0.5, 1, 2, 3, 4, 6, 8, 24, 36 and 48 hours post-dose