A Randomized, Double-Blind, Placebo-Controlled Study to Assess the Safety, Tolerability, and Pharmacokinetics of Multiple Ascending Doses of AZD4041 in Healthy Adult Subjects
Overview
- Phase
- Phase 1
- Intervention
- AZD4041
- Conditions
- Opioid Use Disorder (OUD)
- Sponsor
- AstraZeneca
- Enrollment
- 36
- Locations
- 1
- Primary Endpoint
- Number of Participants With Suicidal Ideation or Behavior Assessed Using Columbia Suicide Severity Rating Scale (C-SSRS)
- Status
- Completed
- Last Updated
- 2 years ago
Overview
Brief Summary
This is a Phase 1, single-centre, randomized, double-blind, placebo-controlled, multiple ascending doses (MAD) study in healthy male and female adult participants.
The study will include up to 48 participants (12 participants per cohort) who will be randomized 9:3 to active drug or placebo. Each cohort will receive AZD4041 or placebo in a MAD study.
A sequential cohort MAD design will be employed to assure that higher doses are administered to healthy participants only after lower doses have demonstrated an acceptable safety profile.
The total study duration will be up to 59 days (including Screening) per participant.
Investigators
Eligibility Criteria
Inclusion Criteria
- Not provided
Exclusion Criteria
- Not provided
Arms & Interventions
Cohort 1: AZD4041 Dose Level 1
Participants will receive oral solution of AZD4041 dose level 1 once daily (QD) directly into the mouth using a syringe from Days 1 to 14.
Intervention: AZD4041
Cohort 2: AZD4041 Dose Level 2
Participants will receive oral solution of AZD4041 dose level 2 QD directly into the mouth using a syringe from Days 1 to 14.
Intervention: AZD4041
Cohort 3: AZD4041 Dose Level 3
Participants will receive oral solution of AZD4041 dose level 3 QD directly into the mouth using a syringe from Days 1 to 14.
Intervention: AZD4041
Cohorts 1-3: Pooled Placebo
Participants will receive oral solution of placebo equivalent to AZD4041 volume QD directly into the mouth using a syringe from Days 1 to 14.
Intervention: Placebo
Outcomes
Primary Outcomes
Number of Participants With Suicidal Ideation or Behavior Assessed Using Columbia Suicide Severity Rating Scale (C-SSRS)
Time Frame: Baseline (Days -28 to -1) through Day 17
The C-SSRS is described as a scale developed at Columbia University that has 2-6 questions each in categories of Suicidal Ideation, Intensity of Ideation, Suicidal Behavior, and Actual Attempts. Four constructs were measured. Severity of Suicidal ideation is rated on a 5-point ordinal scale. Intensity of ideation is comprised of 5 items (frequency, duration, controllability, deterrents, and reason for ideation), each rated on a 5-point ordinal scale. Suicidal behavior is rated on a nominal scale that includes actual, aborted, and interrupted attempts; preparatory behavior; and non-suicidal self-injurious behavior. Lethality, assesses actual attempts; actual lethality is rated on a 6-point ordinal scale, and if actual lethality is 0, potential lethality of attempts is rated on a 3-point ordinal scale.The higher the C-SSRS score, the higher the suicide risk (ie. worse outcome).
Number of Participants With Clinically Significant Findings in Physical and Neurological Examinations
Time Frame: Baseline (Days -28 to -1) through Day 31
Number of participants with clinically significant findings in physical and neurological examinations are reported.
Number of Participants With Abnormal Clinical Laboratory Parameters Reported as TEAEs
Time Frame: From Day 1 to Day 31
Number of participants with abnormal clinical laboratory parameters reported as TEAEs are reported. Abnormal clinical laboratory parameters defined as any abnormal finding during analysis of general biochemistry, hematology, and urinalysis.
Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs)
Time Frame: From Day 1 to Day 31
An adverse event (AE) is any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. A serious adverse event (SAE) is an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. The TEAEs are defined as events present at baseline that worsened in intensity after administration of study drug or events absent at baseline that emerged after administration of study drug.
Number of Participants With Abnormal Vital Signs Reported as TEAEs
Time Frame: From Day 1 to Day 31
Number of participants with abnormal vital signs reported as TEAEs are reported. Abnormal vital signs are defined as any abnormal finding in the vital sign parameters (blood pressure, pulse rate, and body temperature).
Number of Participants With Abnormal Electrocardiograms (ECGs) Reported as TEAEs
Time Frame: From Day 1 to Day 31
Number of participants with abnormal ECGs reported as TEAEs are reported.
Number of Participants With Abnormal Male Hormone Levels as Assessed by the Investigator
Time Frame: Day -1, pre-dose and 1.5 hours post-dose on Days 1 and 14
Male hormone levels investigated included testosterone, luteinizing hormone, follicle stimulating hormone, and inhibin B. Number of Participants with abnormal male hormone levels as assessed by the investigator are reported.
Secondary Outcomes
- Maximum Observed Plasma Concentration (Cmax) of AZD4041 After Day 1 Dose(Day 1: Predose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, and 24 hours postdose)
- Maximum Observed Plasma Concentration (Cmax) of AZD4041 After Day 14 Dose(Day 14: Predose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, and 72 hours postdose)
- Time to Reach Maximum Observed Plasma Concentration (Tmax) of AZD4041 After Day 1 Dose(Day 1: Predose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, and 24 hours postdose)
- Time to Reach Maximum Observed Plasma Concentration (Tmax) of AZD4041 After Day 14 Dose(Day 14: Predose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, and 72 hours postdose)
- Area Under the Concentration-time Curve From Time Zero to 24 Hours (AUC0-24) of AZD4041 After Day 1 Dose(Day 1: Predose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, and 24 hours postdose)
- Area Under the Concentration-time Curve From Time 0 (Dose Administration) to the Time of Last Quantifiable Concentration (AUC0-t) of AZD4041 After Day 1 Dose(Day 1: Predose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, and 24 hours postdose)
- Area Under the Concentration-time Curve From Time 0 (Dose Administration) to the Time of Last Quantifiable Concentration (AUC0-t) of AZD4041 After Day 14 Dose(Day 14: Predose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, and 72 hours postdose)
- Area Under the Concentration-time Curve Extrapolated to Infinity (AUC0-inf) of AZD4041 After Day 1 Dose(Day 1: Predose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, and 24 hours postdose)
- Area Under the Concentration-time Curve Over the Dosing Interval at Steady State (AUCτ) of AZD4041 After Day 14 Dose(Day 14: Predose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, and 72 hours postdose)
- Observed Concentration at the End of the Dosing Interval (Ctrough) of AZD4041(Predose on Days 2 (Day 1, 24-hours), 3, 4, 5, 6, 7, 8, 9, 10, 14)
- Concentration at the End of the Dosing Interval (Cτ) of AZD4041 After Day 14 Dose(Day 14: Predose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, and 72 hours postdose)
- Terminal Elimination Half-life (t1/2,z) of AZD4041 After Day 1 Dose(Day 1: Predose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, and 24 hours postdose)
- Terminal Elimination Half-life (t1/2,z) of AZD4041 After Day 14 Dose(Day 14: Predose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, and 72 hours postdose)
- Effective Half-life (t1/2Eff) of AZD4041 After Day 14 Dose(Day 14: Predose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, and 72 hours postdose)
- Accumulation Ratio Evaluated by Comparing Day 14 Cmax to Day 1 Cmax (RAC[Cmax]) of AZD4041(Day 1: Predose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, and 24 hours postdose; Day 14: Predose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, and 72 hours postdose)
- Accumulation Ratio Evaluated by Comparing Day 14 AUCτ to Day 1 AUC0-24 (RAC[AUC]) of AZD4041(Day 1: Predose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, and 24 hours postdose; Day 14: Predose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, and 72 hours postdose)
- Apparent Total Clearance (CL/F) of AZD4041 After Day 1 Dose(Day 1: Predose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, and 24 hours postdose)
- Apparent Total Clearance at Steady State (CL/Fss) of AZD4041 After Day 14 Dose(Day 14: Predose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, and 72 hours postdose)
- Apparent Volume of Distribution (Vz/F) of AZD4041 After Day 1 Dose(Day 1: Predose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, and 24 hours postdose)
- Apparent Volume of Distribution at Steady State (Vz/Fss) of AZD4041 After Day 14 Dose(Day 14: Predose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, and 72 hours postdose)
- Apparent Elimination Rate Constant (λZ) of AZD4041 After Day 14 Dose(Day 14: Predose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, and 72 hours postdose)
- Amount of AZD4041 Excreted Unchanged in Urine Over the 24-hour Dosing Interval (Ae0-24) After Day 1 Dose(Day 1: Predose spot collection, and 0 to 6 hours, 6 to 12 hours, and 12 to 24 hours postdose)
- Amount of AZD4041 Excreted Unchanged in Urine Over the 24-hour Dosing Interval (Ae0-24) After Day 14 Dose(Day 14: Predose spot collection, and 0 to 6 hours, 6 to 12 hours, and 12 to 24 hours postdose)
- Apparent Fraction of AZD4041 Excreted Unchanged in Urine Over the 24-hours Dosing Interval (fe/F0-24) After Day 1 Dose(Day 1: Predose spot collection, and 0 to 6 hours, 6 to 12 hours, and 12 to 24 hours postdose)
- Apparent Fraction of AZD4041 Excreted Unchanged in Urine Over the 24-hours Dosing Interval (fe/F0-24) After Day 14 Dose(Day 14: Predose spot collection, and 0 to 6 hours, 6 to 12 hours, and 12 to 24 hours postdose)
- Apparent Renal Clearance Over the 24-hours Dosing Interval (CLR 0-24) of AZD4041 After Day 1 Dose(Day 1: Predose spot collection, and 0 to 6 hours, 6 to 12 hours, and 12 to 24 hours postdose)
- Apparent Renal Clearance Over the 24-hours Dosing Interval (CLR 0-24) of AZD4041 After Day 14 Dose(Day 14: Predose spot collection, and 0 to 6 hours, 6 to 12 hours, and 12 to 24 hours postdose)
- Cerebrospinal Fluid (CSF) Concentration as a Percentage of Total Plasma Concentration of AZD4041 in Cohorts 2 and 3(Day 14 post dose (approximately 3 hours ± 1 hour))
- CSF Concentration as a Percentage of Free Plasma Concentration of AZD4041 in Cohorts 2 and 3(Day 14 post dose (approximately 3 hours ± 1 hour))
- Day 14 / Day 1 Ratio of 4-β-hydroxy-cholesterol Concentrations(Pre-dose Day 1 and 24 hours post Day 14 dose)