Clinical trial NCT02632526: A Study to Assess the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of AZD5718 After Single and Multiple Ascending Dose Administration to Healthy Male Subjects
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Healthy Male Subjects
Cardiovascular Disease
Keywords: AZD5718 oral suspension crystalline
AZD5718 oral suspension amorphous
Single ascending dose/multiple ascending dose (SAD/MAD)
Placebo-controlled
Safety
Tolerability
Pharmacokinetics
Pharmacodynamics
Lead sponsor: AstraZeneca
Sponsor class: INDUSTRY
First posted: 2015-12-16
Enrollment: 96
Sex: MALE
Minimum age (years): 18
Maximum age (years): 50
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: BASIC_SCIENCE

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

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

Primary outcomes:
measure: 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).
timeFrame: 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 outcomes:
measure: 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
timeFrame: 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)
measure: 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
timeFrame: Day 1 of Part B
measure: 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
timeFrame: 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)
measure: Rate and Extent of Absorption of AZD5718 by Assessment of the Area Under the Plasma Concentration-curve Over the Dosing Interval (AUC(0-τ)) for Part B - Amorphous Suspension
timeFrame: Day 1, Day 9 and Day 10 of Part B
measure: Rate and Extent of Absorption of AZD5718 by Assessment of the Observed Maximum Plasma Concentration (Cmax) for Part A - Amorphous and Crystalline Suspension
timeFrame: 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)
measure: Rate and Extent of Absorption of AZD5718 by Assessment of the Observed Maximum Plasma Concentration (Cmax) for Part B - Amorphous Suspension
timeFrame: Day 1, Day 9 and Day 10 (Part B only)
measure: 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
timeFrame: 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)
measure: 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
timeFrame: Day 1, Day 9 and Day 10 (Part B only)
measure: 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) for Part A - Amorphous and Crystalline Suspension
timeFrame: 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)
measure: 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) for Part B - Amorphous Suspension
timeFrame: Day 1 and Day 10 (Part B only)
measure: 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
timeFrame: 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)
measure: 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
timeFrame: Day 1 and Day 10 of Part B
measure: 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
timeFrame: 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)
measure: 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
timeFrame: 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)
measure: 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
timeFrame: 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)
measure: Rate and Extent of Absorption of AZD5718 by Assessment of the Accumulation Ratio for AUC(0-τ) (RAC AUC(0-τ)) for Part B - Amorphous Suspension
timeFrame: Day 1 and Day 9 (Part B only)
measure: 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
timeFrame: Day 1 and Day 9 (Part B only)
measure: 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
timeFrame: At Day 10 (Part B only)
measure: 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)
timeFrame: At Day 9 and Day 10 (Part B only)
measure: 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)
timeFrame: At Day 9 and Day 10 (Part B only)
measure: 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)
timeFrame: At Day 9 and Day 10 (Part B only)
measure: 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)
timeFrame: Part A pre-dose and pooled intervals up to 24 hours post-dose
measure: 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)
timeFrame: Part A pre-dose and pooled intervals up to 24 hours post-dose
measure: 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)
timeFrame: Part A pre-dose and pooled intervals up to 24 hours post-dose
measure: 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)
timeFrame: Part B only, Day 9 at pooled 3 hour intervals until 24 hours post-dose
measure: 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)
timeFrame: Part B only, Day 9 at pooled 3 hour intervals until 24 hours post-dose
measure: 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)
timeFrame: Part B only, Day 9 at pooled 3 hour intervals until 24 hours post-dose
measure: Pharmacodynamic Analysis by ex Vivo Stimulation of Leukotriene B4 (LTB4) Production Using Calcium Ionophore for Part A -Amorphous and Crystalline Suspension
timeFrame: Admission to 0.5, 1, 2, 3, 4, 6, 8, 24, 36 and 48 hours post-dose (Part A only)
measure: Pharmacodynamic Analysis by ex Vivo Stimulation of LTB4 Production Using Calcium Ionophore for Part B - Amorphous Suspension
timeFrame: Admission, predose and 0.5, 1, 2, 3, 4, 6, 8, 24, 36 and 48 hours post-dose
Other outcomes:
Locations:
city: Harrow
country: United Kingdom
facility: Research Site
Study officials:
affiliation: Parexel
name: Annelize Koch, MBChB, FFPM
role: PRINCIPAL_INVESTIGATOR
References: