Overview

This trial has been completed.

Conditions healthy male subjects, cardiovascular disease
Treatments azd5718 oral suspension crystalline form (1 to 100 mg/ml) (part a), azd5718 oral suspension amorphous (1 to 100 mg/ml) (part a), azd5718 placebo oral suspension, azd5718 oral suspension amorphous (1 to 100 mg/ml) (part b)
Phase phase 1
Sponsor AstraZeneca
Start date February 2016
End date August 2016
Trial size 8 participants
Trial identifier NCT02632526, D7550C00001

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

United States No locations recruiting
Other Countries No locations recruiting

Study Design

Allocation randomized
Endpoint classification safety study
Intervention model parallel assignment
Masking single blind (subject)
Primary purpose basic science
Arm
(Experimental)
Starting dose 25 mg/day, single ascending dose
azd5718 oral suspension amorphous (1 to 100 mg/ml) (part a)
Single and multiple doses
azd5718 placebo oral suspension
Single and multiple doses
(Experimental)
Single dose of AZD5718 amorphous suspension
azd5718 oral suspension amorphous (1 to 100 mg/ml) (part a)
Single and multiple doses
azd5718 placebo oral suspension
Single and multiple doses
(Experimental)
Single dose of AZD5718 amorphous suspension
azd5718 oral suspension amorphous (1 to 100 mg/ml) (part a)
Single and multiple doses
azd5718 placebo oral suspension
Single and multiple doses
(Experimental)
Single dose of AZD5718 amorphous suspension
azd5718 oral suspension amorphous (1 to 100 mg/ml) (part a)
Single and multiple doses
azd5718 placebo oral suspension
Single and multiple doses
(Experimental)
Single dose of AZD5718 amorphous suspension
azd5718 oral suspension amorphous (1 to 100 mg/ml) (part a)
Single and multiple doses
azd5718 placebo oral suspension
Single and multiple doses
(Experimental)
Single dose of AZD5718 amorphous suspension
azd5718 oral suspension amorphous (1 to 100 mg/ml) (part a)
Single and multiple doses
azd5718 placebo oral suspension
Single and multiple doses
(Experimental)
Crystalline suspension (Part A), dosage lower than highest dose used with amorphous suspension, single ascending dose
azd5718 oral suspension crystalline form (1 to 100 mg/ml) (part a)
Oral suspension single dose
azd5718 placebo oral suspension
Single and multiple doses
(Experimental)
Crystalline suspension (Part A), dosage lower than highest dose used with amorphous suspension, single ascending dose
azd5718 oral suspension crystalline form (1 to 100 mg/ml) (part a)
Oral suspension single dose
azd5718 placebo oral suspension
Single and multiple doses
(Experimental)
Once or twice daily from Days 2 to 9 and single doses on Days 1 and 10, dosage TBD (Part A)
azd5718 placebo oral suspension
Single and multiple doses
azd5718 oral suspension amorphous (1 to 100 mg/ml) (part b)
Single and multiple doses
(Experimental)
Once or twice daily from Days 2 to 9 and single doses on Days 1 and 10, dosage TBD (Part A)
azd5718 placebo oral suspension
Single and multiple doses
azd5718 oral suspension amorphous (1 to 100 mg/ml) (part b)
Single and multiple doses
(Experimental)
Once or twice daily from Days 2 to 9 and single doses on Days 1 and 10, dosage TBD (Part A)
azd5718 placebo oral suspension
Single and multiple doses
azd5718 oral suspension amorphous (1 to 100 mg/ml) (part b)
Single and multiple doses
(Experimental)
Once or twice daily from Days 2 to 9 and single doses on Days 1 and 10, dosage TBD (Part A)
azd5718 placebo oral suspension
Single and multiple doses
azd5718 oral suspension amorphous (1 to 100 mg/ml) (part b)
Single and multiple doses
(Experimental)
Single dose of AZD5718 amorphous form (Part A) Crystalline form (Part A), dosage lower than highest dose used with amorphous form, single ascending dose
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
(Experimental)
Single dose of AZD5718 amorphous form (Part A) Crystalline form (Part A), dosage lower than highest dose used with amorphous form, single ascending dose
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
(Experimental)
Single dose of AZD5718 amorphous form (Part A) Crystalline form (Part A), dosage lower than highest dose used with amorphous form, single ascending dose
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
(Experimental)
Twice daily dosing (Day 1 - 9) and once daily dosing (Day 10), dosage TBD (Part A)
azd5718 placebo oral suspension
Single and multiple doses
azd5718 oral suspension amorphous (1 to 100 mg/ml) (part b)
Single and multiple doses
(Experimental)
Twice daily dosing (Day 1 - 9) and once daily dosing (Day 10), dosage TBD (Part A)
azd5718 placebo oral suspension
Single and multiple doses
azd5718 oral suspension amorphous (1 to 100 mg/ml) (part b)
Single and multiple doses

Primary Outcomes

Measure
Safety and tolerability of AZD5718 by assessment of the number of subjects with adverse events
time frame: From screening to last follow-up visit, up to 6 weeks (Part A) and up to 8 weeks (Part B)
Safety and tolerability of AZD5718 by assessment of vital signs (blood pressure)
time frame: From screening to last follow-up visit, up to 6 weeks (Part A) and up to 8 weeks (Part B)
Safety and tolerability of AZD5718 by assessment of vital signs (pulse rate)
time frame: From screening to last follow-up visit, up to 6 weeks (Part A) and up to 8 weeks (Part B)
Safety and tolerability of AZD5718 by assessment of electrocardiograms (ECGs) (digital ECGs)
time frame: From screening to Day 3 (Part A) and Day 12 (Part B)
Safety and tolerability of AZD5718 by assessment of electrocardiograms (ECGs) (telemetry)
time frame: Day of admission (at least 4 hours) (Part A)
Safety and tolerability of AZD5718 by assessment of physical examinations
time frame: Screening (Part A)
Safety and tolerability of AZD5718 by laboratory assessments
time frame: Screening (Part A)
Safety and tolerability of AZD5718 by assessment of ECGs (telemetry)
time frame: Pre-dose Day 1 (Part B)
Safety and tolerability of AZD5718 by assessment of physical examinations
time frame: Predose (Day 1) (Part B)
Safety and tolerability of AZD5718 by assessment of laboratory assessments
time frame: Predose Day 1(Part B)
Safety and tolerability of AZD5718 by assessment of the number of adverse events
time frame: From screening to last follow-up visit, up to 6 weeks (Part A) and up to 8 weeks (Part B)
Safety and tolerability of AZD5718 by assessment of electrocardiograms (ECGs) (telemetry)
time frame: Pre-dose Day 1 (Part A)
Safety and tolerability of AZD5718 by assessment of electrocardiograms (ECGs) (telemetry)
time frame: Up to 48 hours post-dose (Part A)
Safety and tolerability of AZD5718 by assessment of physical examinations
time frame: Predose Day 1 (Part A)
Safety and tolerability of AZD5718 by assessment of physical examinations
time frame: Post-dose Day 1 (Part A)
Safety and tolerability of AZD5718 by laboratory assessments
time frame: Predose (Day 1) (Part A)
Safety and tolerability of AZD5718 by laboratory assessments
time frame: Up to 72 hours post-dose (Part A)
Safety and tolerability of AZD5718 by laboratory assessments
time frame: Last Follow-up visit (7 to 10 days after Day 1 dose) (Part A)
Safety and tolerability of AZD5718 by assessment of ECGs (telemetry)
time frame: Pre-dose Day 10 (Part B)
Safety and tolerability of AZD5718 by assessment of ECGs (telemetry)
time frame: Up to 24 hours post dose Day 1 (Part B)
Safety and tolerability of AZD5718 by assessment of ECGs (telemetry)
time frame: Up to 24 hours post dose Day 10 (Part B)
Safety and tolerability of AZD5718 by assessment of physical examinations
time frame: Up to 48 hours post-dose (Day 1) (Part B)
Safety and tolerability of AZD5718 by assessment of physical examinations
time frame: Post-dose Day 12 (Part B)
Safety and tolerability of AZD5718 by assessment of physical examinations
time frame: At last follow-up visit (7 to 10 days after final study drug dose given on Day 10) (Part B)
Safety and tolerability of AZD5718 by assessment of laboratory assessments
time frame: Predose (Day 3) (Part B)
Safety and tolerability of AZD5718 by assessment of laboratory assessments
time frame: Predose (Day 5) (Part B)
Safety and tolerability of AZD5718 by assessment of laboratory assessments
time frame: Up to 24 hours post-dose Day 1 (Part B)
Safety and tolerability of AZD5718 by assessment of laboratory assessments
time frame: Up to 48 hours post-dose (Day 12) (Part B)
Safety and tolerability of AZD5718 by assessment of laboratory assessments
time frame: At the follow-up visit (7 to 10 days after last study drug dose given on Day 10) (Part B)

Secondary Outcomes

Measure
Rate and extent of absorption of AZD5718 by assessment of the observed maximum plasma concentration (Cmax)
time frame: Pre-dose (Day 1) until 48 hours post-dose (Part A) and Day 1, 9 and 10 (Part B)
Rate and extent of absorption of AZD5718 by assessment of the time to reach the observed maximum plasma concentration (tmax)
time frame: Pre-dose (Day 1) until 48 hours post-dose (Part A) and Day 1, 9 and 10 (Part B)
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 (t½λz)
time frame: Pre-dose (Day 1) until 48 hours post-dose (Part A only) and Day 10 (Part B)
Rate and extent of absorption of AZD5718 by assessment of the area under the plasma concentration-curve from time zero extrapolated to infinity (AUC)
time frame: Pre-dose (Day 1) until 48 hours post-dose (Part A only) and Day 10 up to 48 hours post-dose (Part B only)
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)
time frame: Pre-dose (Day 1) until 48 hours post-dose (Part A only) and Day 10 until 48 hours post-dose (Part B only)
Rate and extent of absorption of AZD5718 by assessment of the mean residence time from time zero extrapolated to infinity (MRT)
time frame: Pre-dose (Day 1) until 48 hours post-dose (Part A only), Day 10 until 48 hours post-dose (Part B only)
Rate and extent of absorption of AZD5718 by assessment of the apparent volume of distribution during the terminal phase after extravascular administration (Vz/F)
time frame: Pre-dose (Day 1) until 48 hours post-dose (Part A only)
Rate and extent of absorption of AZD5718 by assessment of the area under the plasma concentration-time curve from time zero to time of last quantifiable concentration divided by dose (AUC(0-last)/D)
time frame: Pre-dose (Day 1) until 48 hours post-dose (Part A only)
Rate and extent of absorption of AZD5718 by assessment of the area under the plasma concentration-time curve from time zero extrapolated to infinity divided by dose (AUC/D)
time frame: Pre-dose (Day 1) until 48 hours post-dose (Part A only)
Rate and extent of absorption of AZD5718 by assessment of the observed maximum plasma concentration divided by the dose administered (Cmax/D)
time frame: Pre-dose (Day 1) until 48 hours post-dose (Part A only) and the morning and evening Day 9 (Part B)
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))
time frame: Pre-dose (Day 1) until 48 hours post-dose (Part A) and Day 10 only up to 48 hours post-dose (Part B only)
Rate and extent of absorption of AZD5718 by assessment of the area under the plasma concentration-curve over the dosing interval (AUC(0-τ))
time frame: Morning and evening (Day 1 and Day 9), Day 10 until 48 hours post-dose (Part B only)
Rate and extent of absorption of AZD5718 by assessment of the area under the plasma concentration-curve over the dosing interval divided by the dose administered (AUC(0-τ)/D)
time frame: Morning and evening (Day 9) or morning only (Part B only)
Rate and extent of absorption of AZD5718 by assessment of the observed minimum concentration (Cmin)
time frame: Morning and evening (Day 9) or morning only (Part B only)
Rate and extent of absorption of AZD5718 by assessment of the observed average concentration (Cavg)
time frame: Morning and evening (Day 9) or morning only (Part B only)
Rate and extent of absorption of AZD5718 by assessment of the AUC(0-τ) (Day 10) divided by the AUC(0-τ) (Day 1)
time frame: Morning and evening (Day 1 and 9) (Part B only)
Rate and extent of absorption of AZD5718 by assessment of the Cmax (Day 10) divided by the Cmax (Day 1)
time frame: Morning and evening (Day 9) or morning only (Part B only)
Rate and extent of absorption of AZD5718 by assessment of the amount of analyte excreted into the urine from time t1 to t2 (Ae(t1-t2))
time frame: Part A pre-dose and pooled intervals up to 24 hours post-dose, Part B only, Day 9 at pooled 3 hour intervals until 24 hours post-first dose
Rate and extent of absorption of AZD5718 by assessment of the fraction of dose excreted in urine from time t1 to t2 (fe(t1-t2))
time frame: Part A pre-dose and pooled intervals up to 24 hours post-dose, Part B only, Day 9 at pooled 3 hour intervals until 24 hours post-first dose
Rate and extent of absorption of AZD5718 by assessment of the cumulative amount of analyte excreted at the last sampling interval (Ae(0-last))
time frame: Part A predose and pooled intervals up to 24 hours post-dose, Part B only, Day 9 at pooled 3 hour intervals until 24 hours post-first dose
Rate and extent of absorption of AZD5718 by assessment of the fraction of dose excreted unchanged in urine from time zero to the last measured time point for an analyte estimated by dividing Ae(0-last) by dose (fe(0-last))
time frame: Part A pre-dose up to 24 hours post-dose, Part B only, Day 9 at pooled 3 hour intervals until 24 hours post-first dose
Rate and extent of absorption of AZD5718 by assessment of the renal clearance (CLR)
time frame: Part B only, Day 9 at pooled 3 hour intervals until 24 hours post-first dose
Pharmacodynamic analysis by ex vivo stimulation of LTB4 production using calcium ionophore
time frame: Admission to 48 hours post-dose on Day 1 (Part A), Admission, predose and 24 hours post-dose Day 1, pre-dose Day 2 to Day 9, pre-dose Day 10 until 48 hours post-dose
To evaluate the relative bioavailability between the amorphous and crystalline form of AZD5718 (Part A) by assessment of Cmax
time frame: Predose until 48 hours post dose
To evaluate the relative bioavailability between the amorphous and crystalline form of AZD5718 (Part A) by assessment of AUC
time frame: Predose until 48 hours post-dose

Eligibility Criteria

Male participants from 18 years up to 50 years old.

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

Additional Information

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
Principal investigator Annelize Koch, MBChB, FFPM
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
Trial information was received from ClinicalTrials.gov and was last updated in October 2016.
Information provided to ClinicalTrials.gov by AstraZeneca.