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
Overview
- Phase
- Phase 1
- Intervention
- AZD5718 oral suspension crystalline form (1 to 100 mg/mL) (Part A)
- Conditions
- Healthy Male Subjects
- Sponsor
- AstraZeneca
- Enrollment
- 96
- Locations
- 1
- Primary Endpoint
- 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).
- Status
- Completed
- Last Updated
- 7 years ago
Overview
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
Investigators
Eligibility Criteria
Inclusion Criteria
- •Provision of signed and dated, written informed consent prior to any study specific procedures
- •Healthy male subjects aged 18 - 50 years, inclusive, with suitable veins for cannulation or repeated venepuncture
- •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
- •Provision of signed, written and dated informed consent for optional genetic research
Exclusion Criteria
- •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
- •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
- •Any clinically significant illness, medical/surgical procedure, or trauma within 4 weeks of the administration of investigational medicinal product (IMP)
- •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
- •Any positive result on screening for serum hepatitis B surface antigen (HBsAg), hepatitis C antibody and human immunodeficiency virus (HIV)
- •Suspicion or known Gilbert's syndrome
Arms & Interventions
AZD5718, crystalline form, treatment 7 (Part A)
Crystalline suspension (Part A), dosage lower than highest dose used with amorphous suspension, single ascending dose
Intervention: AZD5718 oral suspension crystalline form (1 to 100 mg/mL) (Part A)
AZD5718, crystalline form, treatment 7 (Part A)
Crystalline suspension (Part A), dosage lower than highest dose used with amorphous suspension, single ascending dose
Intervention: AZD5718 placebo oral suspension
AZD5718 amorphous form, treatment 1 (Part A)
Starting dose 25 mg/day, single ascending dose
Intervention: AZD5718 oral suspension amorphous (1 to 100 mg/mL) (Part A)
AZD5718 amorphous form, treatment 1 (Part A)
Starting dose 25 mg/day, single ascending dose
Intervention: AZD5718 placebo oral suspension
AZD5718 amorphous form, treatment 2 (Part A)
Single dose of AZD5718 amorphous suspension
Intervention: AZD5718 oral suspension amorphous (1 to 100 mg/mL) (Part A)
AZD5718 amorphous form, treatment 2 (Part A)
Single dose of AZD5718 amorphous suspension
Intervention: AZD5718 placebo oral suspension
AZD5718 amorphous form, treatment 3 (Part A)
Single dose of AZD5718 amorphous suspension
Intervention: AZD5718 oral suspension amorphous (1 to 100 mg/mL) (Part A)
AZD5718 amorphous form, treatment 3 (Part A)
Single dose of AZD5718 amorphous suspension
Intervention: AZD5718 placebo oral suspension
AZD5718 amorphous form, treatment 4 (Part A)
Single dose of AZD5718 amorphous suspension
Intervention: AZD5718 oral suspension amorphous (1 to 100 mg/mL) (Part A)
AZD5718 amorphous form, treatment 4 (Part A)
Single dose of AZD5718 amorphous suspension
Intervention: AZD5718 placebo oral suspension
AZD5718 amorphous form, treatment 5 (Part A)
Single dose of AZD5718 amorphous suspension
Intervention: AZD5718 oral suspension amorphous (1 to 100 mg/mL) (Part A)
AZD5718 amorphous form, treatment 5 (Part A)
Single dose of AZD5718 amorphous suspension
Intervention: AZD5718 placebo oral suspension
AZD5718 amorphous form, treatment 6 (Part A)
Single dose of AZD5718 amorphous suspension
Intervention: AZD5718 oral suspension amorphous (1 to 100 mg/mL) (Part A)
AZD5718 amorphous form, treatment 6 (Part A)
Single dose of AZD5718 amorphous suspension
Intervention: AZD5718 placebo oral suspension
AZD5718 crystalline form, treatment 8 (Part A)
Crystalline suspension (Part A), dosage lower than highest dose used with amorphous suspension, single ascending dose
Intervention: AZD5718 oral suspension crystalline form (1 to 100 mg/mL) (Part A)
AZD5718 crystalline form, treatment 8 (Part A)
Crystalline suspension (Part A), dosage lower than highest dose used with amorphous suspension, single ascending dose
Intervention: AZD5718 placebo oral suspension
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)
Intervention: AZD5718 placebo oral suspension
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)
Intervention: AZD5718 oral suspension amorphous (1 to 100 mg/mL) (Part B)
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)
Intervention: AZD5718 placebo oral suspension
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)
Intervention: AZD5718 oral suspension amorphous (1 to 100 mg/mL) (Part B)
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)
Intervention: AZD5718 placebo oral suspension
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)
Intervention: AZD5718 oral suspension amorphous (1 to 100 mg/mL) (Part B)
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)
Intervention: AZD5718 placebo oral suspension
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)
Intervention: AZD5718 oral suspension amorphous (1 to 100 mg/mL) (Part B)
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
Intervention: AZD5718 oral suspension crystalline form (1 to 100 mg/mL) (Part A)
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
Intervention: AZD5718 oral suspension amorphous (1 to 100 mg/mL) (Part A)
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
Intervention: AZD5718 placebo oral suspension
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
Intervention: AZD5718 oral suspension crystalline form (1 to 100 mg/mL) (Part A)
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
Intervention: AZD5718 oral suspension amorphous (1 to 100 mg/mL) (Part A)
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
Intervention: AZD5718 placebo oral suspension
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
Intervention: AZD5718 oral suspension crystalline form (1 to 100 mg/mL) (Part A)
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
Intervention: AZD5718 oral suspension amorphous (1 to 100 mg/mL) (Part A)
AZD5718 amorphous form, repeat 1 (Part B)
Twice daily dosing (Day 1 - 9) and once daily dosing (Day 10), dosage TBD (Part A)
Intervention: AZD5718 placebo oral suspension
AZD5718 amorphous form, repeat 1 (Part B)
Twice daily dosing (Day 1 - 9) and once daily dosing (Day 10), dosage TBD (Part A)
Intervention: AZD5718 oral suspension amorphous (1 to 100 mg/mL) (Part B)
AZD5718 amorphous form, repeat 2 (Part B)
Twice daily dosing (Day 1 - 9) and once daily dosing (Day 10), dosage TBD (Part A)
Intervention: AZD5718 placebo oral suspension
AZD5718 amorphous form, repeat 2 (Part B)
Twice daily dosing (Day 1 - 9) and once daily dosing (Day 10), dosage TBD (Part A)
Intervention: AZD5718 oral suspension amorphous (1 to 100 mg/mL) (Part B)
Outcomes
Primary Outcomes
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).
Time Frame: 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)
To assess the safety and tolerability of AZD5718 following oral administration of SAD (Part A) and MAD (Part B).
Secondary Outcomes
- 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(Day 1 of 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)) for Part A - Amorphous and Crystalline Suspension(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))
- 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(Day 1, Day 9 and Day 10 of Part B)
- 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(Day 1, Day 9 and Day 10 (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) for Part B - Amorphous Suspension(Day 1 and Day 10 of Part B)
- Pharmacodynamic Analysis by ex Vivo Stimulation of LTB4 Production Using Calcium Ionophore for Part B - Amorphous Suspension(Admission, predose and 0.5, 1, 2, 3, 4, 6, 8, 24, 36 and 48 hours post-dose)
- 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(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))
- Rate and Extent of Absorption of AZD5718 by Assessment of the Observed Maximum Plasma Concentration (Cmax) for Part B - Amorphous Suspension(Day 1, Day 9 and Day 10 (Part B only))
- 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(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))
- 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(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))
- 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)(At Day 9 and Day 10 (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) for Part A - Amorphous and Crystalline Suspension(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))
- 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(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))
- 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(Day 1 and Day 9 (Part B only))
- 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(Day 1 and Day 9 (Part B only))
- Rate and Extent of Absorption of AZD5718 by Assessment of the Observed Maximum Plasma Concentration (Cmax) for Part A - Amorphous and Crystalline Suspension(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))
- 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(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))
- 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(Day 1 and Day 10 (Part B only))
- 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(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))
- 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(At Day 10 (Part B only))
- 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)(Part A pre-dose and pooled intervals up to 24 hours post-dose)
- 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)(Part A pre-dose and pooled intervals up to 24 hours post-dose)
- 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)(Part B only, Day 9 at pooled 3 hour intervals until 24 hours post-dose)
- 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)(Part A pre-dose and pooled intervals up to 24 hours post-dose)
- 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)(Part B only, Day 9 at pooled 3 hour intervals until 24 hours post-dose)
- 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)(Part B only, Day 9 at pooled 3 hour intervals until 24 hours post-dose)
- Pharmacodynamic Analysis by ex Vivo Stimulation of Leukotriene B4 (LTB4) Production Using Calcium Ionophore for Part A -Amorphous and Crystalline Suspension(Admission to 0.5, 1, 2, 3, 4, 6, 8, 24, 36 and 48 hours post-dose (Part A only))