A Safety Study of AZD4041 in Healthy Participants

Phase 1

Completed

Conditions: Opioid Use Disorder (OUD)

Interventions: Drug: AZD4041
Other: Placebo

Registration Number: NCT05233085

Lead Sponsor: AstraZeneca

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.

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 36

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Cohort 3: AZD4041 Dose Level 3	AZD4041	Participants will receive oral solution of AZD4041 dose level 3 QD directly into the mouth using a syringe from Days 1 to 14.
Cohorts 1-3: Pooled Placebo	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.
Cohort 1: AZD4041 Dose Level 1	AZD4041	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.
Cohort 2: AZD4041 Dose Level 2	AZD4041	Participants will receive oral solution of AZD4041 dose level 2 QD directly into the mouth using a syringe from Days 1 to 14.

Primary Outcome Measures

Name	Time	Method
Number of Participants With Suicidal Ideation or Behavior Assessed Using Columbia Suicide Severity Rating Scale (C-SSRS)	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	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	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)	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	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	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	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 Outcome Measures

Name	Time	Method
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	The Cmax of AZD4041 after Day 1 dose is reported.
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	The Cmax of AZD4041 after Day 14 dose is reported.
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	The Tmax of AZD4041 after Day 1 dose is reported.
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	The Tmax of AZD4041 after Day 14 dose is reported.
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	The AUC0-24 of AZD4041 after Day 1 dose is reported.
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	The AUC0-t of AZD4041 after Day 1 dose is reported.
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	The AUC0-t of AZD4041 after Day 14 dose is reported.
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	The AUC0-inf of AZD4041 after Day 1 dose is reported. This PK parameter (AUC0-inf) requiring apparent elimination rate constant (λz) estimation was not evaluable for Cohorts 1 and 3 due to meeting either the exclusion criteria R\^2 \< 0.8 or the extrapolated area \> 20%.
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	The AUCτ of AZD4041 calculated after Day 14 dose is reported.
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	The Ctrough of AZD4041 is reported.
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	The Cτ of AZD4041 after Day 14 dose is reported.
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	The t1/2,z of AZD4041 after Day 1 dose is reported. This PK parameter (t1/2,z) requiring λz estimation was not evaluable for Cohorts 1 and 3 due to meeting either the exclusion criteria R\^2 \< 0.8 or the extrapolated area \> 20%.
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	The t1/2,z of AZD4041 after Day 14 dose is reported.
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	The t1/2Eff of AZD4041 after Day 14 dose is reported.
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	The RAC(Cmax) of AZD4041 is reported.
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	The RAC(AUC) of AZD4041 is reported.
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	The CL/F of AZD4041 after Day 1 dose is reported. This PK parameter (CL/F) requiring λz estimation was not evaluable for Cohorts 1 and 3 due to meeting either the exclusion criteria R\^2 \< 0.8 or the extrapolated area \> 20%.
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	The CL/Fss of AZD4041 after Day 14 dose is reported.
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	The Vz/F of AZD4041 after Day 1 dose is reported. This PK parameter (Vz/F) requiring λz estimation was not evaluable for Cohorts 1 and 3 due to meeting either the exclusion criteria R\^2 \< 0.8 or the extrapolated area \> 20%.
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	The Vz/Fss of AZD4041 after Day 14 dose is reported.
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	The λZ of AZD4041 after Day 14 dose is reported.
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	The Ae0-24 of AZD4041 after Day 1 dose is reported.
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	The Ae0-24 of AZD4041 after Day 14 dose is reported.
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	The fe/F0-24 of AZD4041 after Day 1 dose is reported.
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	The fe/F0-24 of AZD4041 after Day 14 dose is reported.
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	The CLR 0-24 of AZD4041 after Day 1 dose is reported. Apparent renal clearance was calculated as: Ae (0-24) / AUC0-24 on Day 1.
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	The CLR 0-24 of AZD4041 after Day 14 dose is reported. Apparent renal clearance was calculated as: Ae (0-24) / AUCτ on Day 14.
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)	The CSF concentration as a percentage of total plasma concentration of AZD4041 in cohorts 2 and 3 is reported.
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)	The CSF concentration as a percentage of free plasma concentration of AZD4041 in cohorts 2 and 3 is reported.
Day 14 / Day 1 Ratio of 4-β-hydroxy-cholesterol Concentrations	Pre-dose Day 1 and 24 hours post Day 14 dose	Day 14 / Day 1 ratio of 4-β-hydroxy-cholesterol concentrations is reported.