Trial Outcomes & Findings for A Safety Study of AZD4041 in Healthy Participants (NCT NCT05233085)

Results Overview

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.

Recruitment status

COMPLETED

Study phase

PHASE1

Target enrollment

36 participants

Primary outcome timeframe

From Day 1 to Day 31

Results posted on

2023-11-27

Participant Flow

Participant milestones

Participant milestones
Measure	Cohort 1: AZD4041 Dose Level 1 Participants received 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 Participants received oral solution of AZD4041 dose level 2 QD directly into the mouth using a syringe from Days 1 to 14.	Cohort 3: AZD4041 Dose Level 3 Participants received 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 Participants received oral solution of placebo equivalent to AZD4041 volume QD directly into the mouth using a syringe from Days 1 to 14.
Overall Study STARTED	9	9	9	9
Overall Study COMPLETED	8	9	9	9
Overall Study NOT COMPLETED	1	0	0	0

Reasons for withdrawal

Reasons for withdrawal
Measure	Cohort 1: AZD4041 Dose Level 1 Participants received 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 Participants received oral solution of AZD4041 dose level 2 QD directly into the mouth using a syringe from Days 1 to 14.	Cohort 3: AZD4041 Dose Level 3 Participants received 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 Participants received oral solution of placebo equivalent to AZD4041 volume QD directly into the mouth using a syringe from Days 1 to 14.
Overall Study Adverse Event	1	0	0	0

Baseline Characteristics

A Safety Study of AZD4041 in Healthy Participants

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Cohort 1: AZD4041 Dose Level 1 n=9 Participants Participants received oral solution of AZD4041 dose level 1 QD directly into the mouth using a syringe from Days 1 to 14.	Cohort 2: AZD4041 Dose Level 2 n=9 Participants Participants received oral solution of AZD4041 dose level 2 QD directly into the mouth using a syringe from Days 1 to 14.	Cohort 3: AZD4041 Dose Level 3 n=9 Participants Participants received 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 n=9 Participants Participants received oral solution of placebo equivalent to AZD4041 volume QD directly into the mouth using a syringe from Days 1 to 14.	Total n=36 Participants Total of all reporting groups
Age, Continuous	41.9 Years STANDARD_DEVIATION 11.7 • n=5 Participants	37.1 Years STANDARD_DEVIATION 8.9 • n=7 Participants	40.2 Years STANDARD_DEVIATION 10.8 • n=5 Participants	41.6 Years STANDARD_DEVIATION 11.6 • n=4 Participants	40.2 Years STANDARD_DEVIATION 10.5 • n=21 Participants
Sex: Female, Male Female	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	1 Participants n=4 Participants	1 Participants n=21 Participants
Sex: Female, Male Male	9 Participants n=5 Participants	9 Participants n=7 Participants	9 Participants n=5 Participants	8 Participants n=4 Participants	35 Participants n=21 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	4 Participants n=5 Participants	3 Participants n=7 Participants	5 Participants n=5 Participants	0 Participants n=4 Participants	12 Participants n=21 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	5 Participants n=5 Participants	6 Participants n=7 Participants	4 Participants n=5 Participants	9 Participants n=4 Participants	24 Participants n=21 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants
Race (NIH/OMB) Asian	1 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants	0 Participants n=4 Participants	2 Participants n=21 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants
Race (NIH/OMB) Black or African American	0 Participants n=5 Participants	1 Participants n=7 Participants	0 Participants n=5 Participants	1 Participants n=4 Participants	2 Participants n=21 Participants
Race (NIH/OMB) White	8 Participants n=5 Participants	8 Participants n=7 Participants	8 Participants n=5 Participants	8 Participants n=4 Participants	32 Participants n=21 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants

PRIMARY outcome

Timeframe: From Day 1 to Day 31

Population: Safety population included all participants who received at least 1 dose of AZD4041 or placebo.

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.

Outcome measures

Outcome measures
Measure	Cohort 1: AZD4041 Dose Level 1 n=9 Participants Participants received oral solution of AZD4041 dose level 1 QD directly into the mouth using a syringe from Days 1 to 14.	Cohort 2: AZD4041 Dose Level 2 n=9 Participants Participants received oral solution of AZD4041 dose level 2 QD directly into the mouth using a syringe from Days 1 to 14.	Cohort 3: AZD4041 Dose Level 3 n=9 Participants Participants received 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 n=9 Participants Participants received oral solution of placebo equivalent to AZD4041 volume QD directly into the mouth using a syringe from Days 1 to 14.
Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs) Any TEAEs	8 Participants	6 Participants	6 Participants	9 Participants
Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs) Any TESAEs	0 Participants	0 Participants	0 Participants	0 Participants

PRIMARY outcome

Timeframe: From Day 1 to Day 31

Population: Safety population included all participants who received at least 1 dose of AZD4041 or placebo.

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).

Outcome measures

Outcome measures
Measure	Cohort 1: AZD4041 Dose Level 1 n=9 Participants Participants received oral solution of AZD4041 dose level 1 QD directly into the mouth using a syringe from Days 1 to 14.	Cohort 2: AZD4041 Dose Level 2 n=9 Participants Participants received oral solution of AZD4041 dose level 2 QD directly into the mouth using a syringe from Days 1 to 14.	Cohort 3: AZD4041 Dose Level 3 n=9 Participants Participants received 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 n=9 Participants Participants received oral solution of placebo equivalent to AZD4041 volume QD directly into the mouth using a syringe from Days 1 to 14.
Number of Participants With Abnormal Vital Signs Reported as TEAEs	1 Participants	0 Participants	0 Participants	0 Participants

PRIMARY outcome

Timeframe: From Day 1 to Day 31

Population: Safety population included all participants who received at least 1 dose of AZD4041 or placebo.

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.

Outcome measures

Outcome measures
Measure	Cohort 1: AZD4041 Dose Level 1 n=9 Participants Participants received oral solution of AZD4041 dose level 1 QD directly into the mouth using a syringe from Days 1 to 14.	Cohort 2: AZD4041 Dose Level 2 n=9 Participants Participants received oral solution of AZD4041 dose level 2 QD directly into the mouth using a syringe from Days 1 to 14.	Cohort 3: AZD4041 Dose Level 3 n=9 Participants Participants received 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 n=9 Participants Participants received oral solution of placebo equivalent to AZD4041 volume QD directly into the mouth using a syringe from Days 1 to 14.
Number of Participants With Abnormal Clinical Laboratory Parameters Reported as TEAEs	0 Participants	0 Participants	0 Participants	0 Participants

PRIMARY outcome

Timeframe: From Day 1 to Day 31

Population: Safety population included all participants who received at least 1 dose of AZD4041 or placebo.

Number of participants with abnormal ECGs reported as TEAEs are reported.

Outcome measures

Outcome measures
Measure	Cohort 1: AZD4041 Dose Level 1 n=9 Participants Participants received oral solution of AZD4041 dose level 1 QD directly into the mouth using a syringe from Days 1 to 14.	Cohort 2: AZD4041 Dose Level 2 n=9 Participants Participants received oral solution of AZD4041 dose level 2 QD directly into the mouth using a syringe from Days 1 to 14.	Cohort 3: AZD4041 Dose Level 3 n=9 Participants Participants received 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 n=9 Participants Participants received oral solution of placebo equivalent to AZD4041 volume QD directly into the mouth using a syringe from Days 1 to 14.
Number of Participants With Abnormal Electrocardiograms (ECGs) Reported as TEAEs Ventricular tachycardia	1 Participants	0 Participants	1 Participants	1 Participants
Number of Participants With Abnormal Electrocardiograms (ECGs) Reported as TEAEs Sinus tachycardia	1 Participants	0 Participants	0 Participants	0 Participants

PRIMARY outcome

Timeframe: Baseline (Days -28 to -1) through Day 17

Population: Safety population included all participants who received at least 1 dose of AZD4041 or placebo.

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).

Outcome measures

Outcome measures
Measure	Cohort 1: AZD4041 Dose Level 1 n=9 Participants Participants received oral solution of AZD4041 dose level 1 QD directly into the mouth using a syringe from Days 1 to 14.	Cohort 2: AZD4041 Dose Level 2 n=9 Participants Participants received oral solution of AZD4041 dose level 2 QD directly into the mouth using a syringe from Days 1 to 14.	Cohort 3: AZD4041 Dose Level 3 n=9 Participants Participants received 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 n=9 Participants Participants received oral solution of placebo equivalent to AZD4041 volume QD directly into the mouth using a syringe from Days 1 to 14.
Number of Participants With Suicidal Ideation or Behavior Assessed Using Columbia Suicide Severity Rating Scale (C-SSRS) Suicidal behavior	0 Participants	0 Participants	0 Participants	0 Participants
Number of Participants With Suicidal Ideation or Behavior Assessed Using Columbia Suicide Severity Rating Scale (C-SSRS) Suicidal ideation	0 Participants	0 Participants	0 Participants	0 Participants

PRIMARY outcome

Timeframe: Baseline (Days -28 to -1) through Day 31

Population: Safety population included all participants who received at least 1 dose of AZD4041 or placebo.

Number of participants with clinically significant findings in physical and neurological examinations are reported.

Outcome measures

Outcome measures
Measure	Cohort 1: AZD4041 Dose Level 1 n=9 Participants Participants received oral solution of AZD4041 dose level 1 QD directly into the mouth using a syringe from Days 1 to 14.	Cohort 2: AZD4041 Dose Level 2 n=9 Participants Participants received oral solution of AZD4041 dose level 2 QD directly into the mouth using a syringe from Days 1 to 14.	Cohort 3: AZD4041 Dose Level 3 n=9 Participants Participants received 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 n=9 Participants Participants received oral solution of placebo equivalent to AZD4041 volume QD directly into the mouth using a syringe from Days 1 to 14.
Number of Participants With Clinically Significant Findings in Physical and Neurological Examinations	0 Participants	0 Participants	0 Participants	0 Participants

PRIMARY outcome

Timeframe: Day -1, pre-dose and 1.5 hours post-dose on Days 1 and 14

Population: Safety population included all participants who received at least 1 dose of AZD4041 or placebo.

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.

Outcome measures

Outcome measures
Measure	Cohort 1: AZD4041 Dose Level 1 n=9 Participants Participants received oral solution of AZD4041 dose level 1 QD directly into the mouth using a syringe from Days 1 to 14.	Cohort 2: AZD4041 Dose Level 2 n=9 Participants Participants received oral solution of AZD4041 dose level 2 QD directly into the mouth using a syringe from Days 1 to 14.	Cohort 3: AZD4041 Dose Level 3 n=9 Participants Participants received 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 n=9 Participants Participants received oral solution of placebo equivalent to AZD4041 volume QD directly into the mouth using a syringe from Days 1 to 14.
Number of Participants With Abnormal Male Hormone Levels as Assessed by the Investigator	0 Participants	0 Participants	0 Participants	0 Participants

SECONDARY outcome

Timeframe: Day 1: Predose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, and 24 hours postdose

Population: Pharmacokinetic (PK) population included all participants who had received at least 1 dose of AZD4041 and had at least 1 PK concentration after dosing.

The Cmax of AZD4041 after Day 1 dose is reported.

Outcome measures

Outcome measures
Measure	Cohort 1: AZD4041 Dose Level 1 n=9 Participants Participants received oral solution of AZD4041 dose level 1 QD directly into the mouth using a syringe from Days 1 to 14.	Cohort 2: AZD4041 Dose Level 2 n=9 Participants Participants received oral solution of AZD4041 dose level 2 QD directly into the mouth using a syringe from Days 1 to 14.	Cohort 3: AZD4041 Dose Level 3 n=9 Participants Participants received 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 Participants received oral solution of placebo equivalent to AZD4041 volume QD directly into the mouth using a syringe from Days 1 to 14.
Maximum Observed Plasma Concentration (Cmax) of AZD4041 After Day 1 Dose	165.93 ng/mL Geometric Coefficient of Variation 24.3	377.85 ng/mL Geometric Coefficient of Variation 25.7	590.78 ng/mL Geometric Coefficient of Variation 12.6	—

SECONDARY outcome

Timeframe: Day 14: Predose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, and 72 hours postdose

Population: Pharmacokinetic (PK) population included all participants who had received at least 1 dose of AZD4041 and had at least 1 PK concentration after dosing. Here, number of participants analyzed (N) indicates those participants who had adequate PK samples and excludes participants with inadequate PK samples due to missed blood draw, an AE, meal deviation, or concomitant medication intake.

The Cmax of AZD4041 after Day 14 dose is reported.

Outcome measures

Outcome measures
Measure	Cohort 1: AZD4041 Dose Level 1 n=8 Participants Participants received oral solution of AZD4041 dose level 1 QD directly into the mouth using a syringe from Days 1 to 14.	Cohort 2: AZD4041 Dose Level 2 n=9 Participants Participants received oral solution of AZD4041 dose level 2 QD directly into the mouth using a syringe from Days 1 to 14.	Cohort 3: AZD4041 Dose Level 3 n=9 Participants Participants received 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 Participants received oral solution of placebo equivalent to AZD4041 volume QD directly into the mouth using a syringe from Days 1 to 14.
Maximum Observed Plasma Concentration (Cmax) of AZD4041 After Day 14 Dose	232.44 ng/mL Geometric Coefficient of Variation 20.7	478.10 ng/mL Geometric Coefficient of Variation 21.7	940.99 ng/mL Geometric Coefficient of Variation 25.7	—

SECONDARY outcome

Timeframe: Day 1: Predose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, and 24 hours postdose

Population: The PK population included all participants who had received at least 1 dose of AZD4041 and had at least 1 PK concentration after dosing.

The Tmax of AZD4041 after Day 1 dose is reported.

Outcome measures

Outcome measures
Measure	Cohort 1: AZD4041 Dose Level 1 n=9 Participants Participants received oral solution of AZD4041 dose level 1 QD directly into the mouth using a syringe from Days 1 to 14.	Cohort 2: AZD4041 Dose Level 2 n=9 Participants Participants received oral solution of AZD4041 dose level 2 QD directly into the mouth using a syringe from Days 1 to 14.	Cohort 3: AZD4041 Dose Level 3 n=9 Participants Participants received 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 Participants received oral solution of placebo equivalent to AZD4041 volume QD directly into the mouth using a syringe from Days 1 to 14.
Time to Reach Maximum Observed Plasma Concentration (Tmax) of AZD4041 After Day 1 Dose	1.05 Hour Interval 0.5 to 1.53	1.00 Hour Interval 0.25 to 1.5	1.02 Hour Interval 0.55 to 1.5	—

SECONDARY outcome

Timeframe: Day 14: Predose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, and 72 hours postdose

Population: The PK population included all participants who had received at least 1 dose of AZD4041 and had at least 1 PK concentration after dosing. Here, number of participants analyzed (N) indicates those participants who had adequate PK samples and excludes participants with inadequate PK samples due to missed blood draw, an AE, meal deviation, or concomitant medication intake.

The Tmax of AZD4041 after Day 14 dose is reported.

Outcome measures

Outcome measures
Measure	Cohort 1: AZD4041 Dose Level 1 n=8 Participants Participants received oral solution of AZD4041 dose level 1 QD directly into the mouth using a syringe from Days 1 to 14.	Cohort 2: AZD4041 Dose Level 2 n=9 Participants Participants received oral solution of AZD4041 dose level 2 QD directly into the mouth using a syringe from Days 1 to 14.	Cohort 3: AZD4041 Dose Level 3 n=9 Participants Participants received 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 Participants received oral solution of placebo equivalent to AZD4041 volume QD directly into the mouth using a syringe from Days 1 to 14.
Time to Reach Maximum Observed Plasma Concentration (Tmax) of AZD4041 After Day 14 Dose	1.02 Hour Interval 0.5 to 2.0	1.02 Hour Interval 0.5 to 1.52	1.00 Hour Interval 0.5 to 3.02	—

SECONDARY outcome

Timeframe: Day 1: Predose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, and 24 hours postdose

Population: The PK population included all participants who had received at least 1 dose of AZD4041 and had at least 1 PK concentration after dosing.

The AUC0-24 of AZD4041 after Day 1 dose is reported.

Outcome measures

Outcome measures
Measure	Cohort 1: AZD4041 Dose Level 1 n=9 Participants Participants received oral solution of AZD4041 dose level 1 QD directly into the mouth using a syringe from Days 1 to 14.	Cohort 2: AZD4041 Dose Level 2 n=9 Participants Participants received oral solution of AZD4041 dose level 2 QD directly into the mouth using a syringe from Days 1 to 14.	Cohort 3: AZD4041 Dose Level 3 n=9 Participants Participants received 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 Participants received oral solution of placebo equivalent to AZD4041 volume QD directly into the mouth using a syringe from Days 1 to 14.
Area Under the Concentration-time Curve From Time Zero to 24 Hours (AUC0-24) of AZD4041 After Day 1 Dose	1802.21 h*ng/mL Geometric Coefficient of Variation 21.4	3682.61 h*ng/mL Geometric Coefficient of Variation 25.2	6951.39 h*ng/mL Geometric Coefficient of Variation 20.1	—

SECONDARY outcome

Timeframe: Day 1: Predose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, and 24 hours postdose

Population: The PK population included all participants who had received at least 1 dose of AZD4041 and had at least 1 PK concentration after dosing.

The AUC0-t of AZD4041 after Day 1 dose is reported.

Outcome measures

Outcome measures
Measure	Cohort 1: AZD4041 Dose Level 1 n=9 Participants Participants received oral solution of AZD4041 dose level 1 QD directly into the mouth using a syringe from Days 1 to 14.	Cohort 2: AZD4041 Dose Level 2 n=9 Participants Participants received oral solution of AZD4041 dose level 2 QD directly into the mouth using a syringe from Days 1 to 14.	Cohort 3: AZD4041 Dose Level 3 n=9 Participants Participants received 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 Participants received oral solution of placebo equivalent to AZD4041 volume QD directly into the mouth using a syringe from Days 1 to 14.
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	1802.90 h*ng/mL Geometric Coefficient of Variation 21.4	3683.15 h*ng/mL Geometric Coefficient of Variation 25.2	6953.42 h*ng/mL Geometric Coefficient of Variation 20.1	—

SECONDARY outcome

Timeframe: Day 14: Predose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, and 72 hours postdose

Population: The PK population included all participants who had received at least 1 dose of AZD4041 and had at least 1 PK concentration after dosing. Here, number of participants analyzed (N) indicates those participants who had adequate PK samples and excludes participants with inadequate PK samples due to missed blood draw, an AE, meal deviation, or concomitant medication intake.

The AUC0-t of AZD4041 after Day 14 dose is reported.

Outcome measures

Outcome measures
Measure	Cohort 1: AZD4041 Dose Level 1 n=8 Participants Participants received oral solution of AZD4041 dose level 1 QD directly into the mouth using a syringe from Days 1 to 14.	Cohort 2: AZD4041 Dose Level 2 n=9 Participants Participants received oral solution of AZD4041 dose level 2 QD directly into the mouth using a syringe from Days 1 to 14.	Cohort 3: AZD4041 Dose Level 3 n=9 Participants Participants received 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 Participants received oral solution of placebo equivalent to AZD4041 volume QD directly into the mouth using a syringe from Days 1 to 14.
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	4808.19 h*ng/mL Geometric Coefficient of Variation 60.1	9573.98 h*ng/mL Geometric Coefficient of Variation 47.0	20969.29 h*ng/mL Geometric Coefficient of Variation 49.6	—

SECONDARY outcome

Timeframe: Day 1: Predose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, and 24 hours postdose

Population: The PK population included all participants who had received at least 1 dose of AZD4041 and had at least 1 PK concentration after dosing. Here, number of participants analyzed (N) indicates those participants who had adequate PK samples and excludes participants with inadequate PK samples due to missed blood draw, an AE, meal deviation, or concomitant medication intake.

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%.

Outcome measures

Outcome measures
Measure	Cohort 1: AZD4041 Dose Level 1 Participants received oral solution of AZD4041 dose level 1 QD directly into the mouth using a syringe from Days 1 to 14.	Cohort 2: AZD4041 Dose Level 2 n=1 Participants Participants received oral solution of AZD4041 dose level 2 QD directly into the mouth using a syringe from Days 1 to 14.	Cohort 3: AZD4041 Dose Level 3 Participants received 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 Participants received oral solution of placebo equivalent to AZD4041 volume QD directly into the mouth using a syringe from Days 1 to 14.
Area Under the Concentration-time Curve Extrapolated to Infinity (AUC0-inf) of AZD4041 After Day 1 Dose	—	3000.93 h*ng/mL Interval 3000.93 to 3000.93	—	—

SECONDARY outcome

Timeframe: Day 14: Predose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, and 72 hours postdose

Population: The PK population included all participants who had received at least 1 dose of AZD4041 and had at least 1 PK concentration after dosing. Here, number of participants analyzed (N) indicates those participants who had adequate PK samples and excludes participants with inadequate PK samples due to missed blood draw, an AE, meal deviation, or concomitant medication intake.

The AUCτ of AZD4041 calculated after Day 14 dose is reported.

Outcome measures

Outcome measures
Measure	Cohort 1: AZD4041 Dose Level 1 n=8 Participants Participants received oral solution of AZD4041 dose level 1 QD directly into the mouth using a syringe from Days 1 to 14.	Cohort 2: AZD4041 Dose Level 2 n=9 Participants Participants received oral solution of AZD4041 dose level 2 QD directly into the mouth using a syringe from Days 1 to 14.	Cohort 3: AZD4041 Dose Level 3 n=9 Participants Participants received 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 Participants received oral solution of placebo equivalent to AZD4041 volume QD directly into the mouth using a syringe from Days 1 to 14.
Area Under the Concentration-time Curve Over the Dosing Interval at Steady State (AUCτ) of AZD4041 After Day 14 Dose	3022.57 h*ng/mL Geometric Coefficient of Variation 41.3	6306.52 h*ng/mL Geometric Coefficient of Variation 34.4	12622.32 h*ng/mL Geometric Coefficient of Variation 36.0	—

SECONDARY outcome

Timeframe: Predose on Days 2 (Day 1, 24-hours), 3, 4, 5, 6, 7, 8, 9, 10, 14

Population: The PK population included all participants who had received at least 1 dose of AZD4041 and had at least 1 PK concentration after dosing. Here, number analyzed (n) denotes those participants who were analyzed for the specified time points.

The Ctrough of AZD4041 is reported.

Outcome measures

Outcome measures
Measure	Cohort 1: AZD4041 Dose Level 1 n=9 Participants Participants received oral solution of AZD4041 dose level 1 QD directly into the mouth using a syringe from Days 1 to 14.	Cohort 2: AZD4041 Dose Level 2 n=9 Participants Participants received oral solution of AZD4041 dose level 2 QD directly into the mouth using a syringe from Days 1 to 14.	Cohort 3: AZD4041 Dose Level 3 n=9 Participants Participants received 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 Participants received oral solution of placebo equivalent to AZD4041 volume QD directly into the mouth using a syringe from Days 1 to 14.
Observed Concentration at the End of the Dosing Interval (Ctrough) of AZD4041 Day 2	45.5 ng/mL Geometric Coefficient of Variation 39.2	86.2 ng/mL Geometric Coefficient of Variation 45.2	193 ng/mL Geometric Coefficient of Variation 35.2	—
Observed Concentration at the End of the Dosing Interval (Ctrough) of AZD4041 Day 3	62.5 ng/mL Geometric Coefficient of Variation 46.9	113 ng/mL Geometric Coefficient of Variation 48.9	285 ng/mL Geometric Coefficient of Variation 39.4	—
Observed Concentration at the End of the Dosing Interval (Ctrough) of AZD4041 Day 4	64.9 ng/mL Geometric Coefficient of Variation 52.4	124 ng/mL Geometric Coefficient of Variation 56.2	314 ng/mL Geometric Coefficient of Variation 43.9	—
Observed Concentration at the End of the Dosing Interval (Ctrough) of AZD4041 Day 5	65.4 ng/mL Geometric Coefficient of Variation 54.6	134 ng/mL Geometric Coefficient of Variation 48.4	317 ng/mL Geometric Coefficient of Variation 46.2	—
Observed Concentration at the End of the Dosing Interval (Ctrough) of AZD4041 Day 6	69.3 ng/mL Geometric Coefficient of Variation 63.6	139 ng/mL Geometric Coefficient of Variation 56.5	336 ng/mL Geometric Coefficient of Variation 46.5	—
Observed Concentration at the End of the Dosing Interval (Ctrough) of AZD4041 Day 7	68.4 ng/mL Geometric Coefficient of Variation 64.8	141 ng/mL Geometric Coefficient of Variation 55.2	331 ng/mL Geometric Coefficient of Variation 45.8	—
Observed Concentration at the End of the Dosing Interval (Ctrough) of AZD4041 Day 8	73.2 ng/mL Geometric Coefficient of Variation 55.6	158 ng/mL Geometric Coefficient of Variation 53.6	359 ng/mL Geometric Coefficient of Variation 44.4	—
Observed Concentration at the End of the Dosing Interval (Ctrough) of AZD4041 Day 9	73.3 ng/mL Geometric Coefficient of Variation 59.1	152 ng/mL Geometric Coefficient of Variation 61.6	349 ng/mL Geometric Coefficient of Variation 49.9	—
Observed Concentration at the End of the Dosing Interval (Ctrough) of AZD4041 Day 10	75.0 ng/mL Geometric Coefficient of Variation 62.8	158 ng/mL Geometric Coefficient of Variation 62.9	341 ng/mL Geometric Coefficient of Variation 46.9	—
Observed Concentration at the End of the Dosing Interval (Ctrough) of AZD4041 Day 14	82.0 ng/mL Geometric Coefficient of Variation 64.6	164 ng/mL Geometric Coefficient of Variation 70.8	371 ng/mL Geometric Coefficient of Variation 51.9	—

SECONDARY outcome

Timeframe: Day 14: Predose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, and 72 hours postdose

Population: The PK population included all participants who had received at least 1 dose of AZD4041 and had at least 1 PK concentration after dosing. Here, number of participants analyzed (N) indicates those participants who had adequate PK samples and excludes participants with inadequate PK samples due to missed blood draw, an AE, meal deviation, or concomitant medication intake.

The Cτ of AZD4041 after Day 14 dose is reported.

Outcome measures

Outcome measures
Measure	Cohort 1: AZD4041 Dose Level 1 n=8 Participants Participants received oral solution of AZD4041 dose level 1 QD directly into the mouth using a syringe from Days 1 to 14.	Cohort 2: AZD4041 Dose Level 2 n=9 Participants Participants received oral solution of AZD4041 dose level 2 QD directly into the mouth using a syringe from Days 1 to 14.	Cohort 3: AZD4041 Dose Level 3 n=9 Participants Participants received 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 Participants received oral solution of placebo equivalent to AZD4041 volume QD directly into the mouth using a syringe from Days 1 to 14.
Concentration at the End of the Dosing Interval (Cτ) of AZD4041 After Day 14 Dose	81.23 ng/mL Geometric Coefficient of Variation 63.2	168.42 ng/mL Geometric Coefficient of Variation 62.0	358.37 ng/mL Geometric Coefficient of Variation 56.5	—

SECONDARY outcome

Timeframe: Day 1: Predose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, and 24 hours postdose

Population: The PK population included all participants who had received at least 1 dose of AZD4041 and had at least 1 PK concentration after dosing. Here, number of participants analyzed (N) indicates those participants who had adequate PK samples and excludes participants with inadequate PK samples due to missed blood draw, an AE, meal deviation, or concomitant medication intake.

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%.

Outcome measures

Outcome measures
Measure	Cohort 1: AZD4041 Dose Level 1 Participants received oral solution of AZD4041 dose level 1 QD directly into the mouth using a syringe from Days 1 to 14.	Cohort 2: AZD4041 Dose Level 2 n=1 Participants Participants received oral solution of AZD4041 dose level 2 QD directly into the mouth using a syringe from Days 1 to 14.	Cohort 3: AZD4041 Dose Level 3 Participants received 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 Participants received oral solution of placebo equivalent to AZD4041 volume QD directly into the mouth using a syringe from Days 1 to 14.
Terminal Elimination Half-life (t1/2,z) of AZD4041 After Day 1 Dose	—	8.30 hour Interval 8.3 to 8.3	—	—

SECONDARY outcome

Timeframe: Day 14: Predose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, and 72 hours postdose

Population: The PK population included all participants who had received at least 1 dose of AZD4041 and had at least 1 PK concentration after dosing. Here, number of participants analyzed (N) indicates those participants who had adequate PK samples and excludes participants with inadequate PK samples due to missed blood draw, an AE, meal deviation, or concomitant medication intake.

The t1/2,z of AZD4041 after Day 14 dose is reported.

Outcome measures

Outcome measures
Measure	Cohort 1: AZD4041 Dose Level 1 n=6 Participants Participants received oral solution of AZD4041 dose level 1 QD directly into the mouth using a syringe from Days 1 to 14.	Cohort 2: AZD4041 Dose Level 2 n=9 Participants Participants received oral solution of AZD4041 dose level 2 QD directly into the mouth using a syringe from Days 1 to 14.	Cohort 3: AZD4041 Dose Level 3 n=7 Participants Participants received 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 Participants received oral solution of placebo equivalent to AZD4041 volume QD directly into the mouth using a syringe from Days 1 to 14.
Terminal Elimination Half-life (t1/2,z) of AZD4041 After Day 14 Dose	18.87 Hour Geometric Coefficient of Variation 27.5	20.07 Hour Geometric Coefficient of Variation 33.4	23.22 Hour Geometric Coefficient of Variation 20.3	—

SECONDARY outcome

Timeframe: Day 14: Predose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, and 72 hours postdose

Population: The PK population included all participants who had received at least 1 dose of AZD4041 and had at least 1 PK concentration after dosing. Here, number of participants analyzed (N) indicates those participants who had adequate PK samples and excludes participants with inadequate PK samples due to missed blood draw, an AE, meal deviation, or concomitant medication intake.

The t1/2Eff of AZD4041 after Day 14 dose is reported.

Outcome measures

Outcome measures
Measure	Cohort 1: AZD4041 Dose Level 1 n=8 Participants Participants received oral solution of AZD4041 dose level 1 QD directly into the mouth using a syringe from Days 1 to 14.	Cohort 2: AZD4041 Dose Level 2 n=9 Participants Participants received oral solution of AZD4041 dose level 2 QD directly into the mouth using a syringe from Days 1 to 14.	Cohort 3: AZD4041 Dose Level 3 n=9 Participants Participants received 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 Participants received oral solution of placebo equivalent to AZD4041 volume QD directly into the mouth using a syringe from Days 1 to 14.
Effective Half-life (t1/2Eff) of AZD4041 After Day 14 Dose	17.02 Hour Geometric Coefficient of Variation 50.9	18.35 Hour Geometric Coefficient of Variation 38.7	20.33 Hour Geometric Coefficient of Variation 34.2	—

SECONDARY outcome

Timeframe: 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

Population: The PK population included all participants who had received at least 1 dose of AZD4041 and had at least 1 PK concentration after dosing. Here, number of participants analyzed (N) indicates those participants who had adequate PK samples and excludes participants with inadequate PK samples due to missed blood draw, an AE, meal deviation, or concomitant medication intake.

The RAC(Cmax) of AZD4041 is reported.

Outcome measures

Outcome measures
Measure	Cohort 1: AZD4041 Dose Level 1 n=8 Participants Participants received oral solution of AZD4041 dose level 1 QD directly into the mouth using a syringe from Days 1 to 14.	Cohort 2: AZD4041 Dose Level 2 n=9 Participants Participants received oral solution of AZD4041 dose level 2 QD directly into the mouth using a syringe from Days 1 to 14.	Cohort 3: AZD4041 Dose Level 3 n=9 Participants Participants received 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 Participants received oral solution of placebo equivalent to AZD4041 volume QD directly into the mouth using a syringe from Days 1 to 14.
Accumulation Ratio Evaluated by Comparing Day 14 Cmax to Day 1 Cmax (RAC[Cmax]) of AZD4041	1.38 Ratio Geometric Coefficient of Variation 20.9	1.27 Ratio Geometric Coefficient of Variation 22.4	1.59 Ratio Geometric Coefficient of Variation 16.0	—

SECONDARY outcome

Timeframe: 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

Population: The PK population included all participants who had received at least 1 dose of AZD4041 and had at least 1 PK concentration after dosing. Here, number of participants analyzed (N) indicates those participants who had adequate PK samples and excludes participants with inadequate PK samples due to missed blood draw, an AE, meal deviation, or concomitant medication intake.

The RAC(AUC) of AZD4041 is reported.

Outcome measures

Outcome measures
Measure	Cohort 1: AZD4041 Dose Level 1 n=8 Participants Participants received oral solution of AZD4041 dose level 1 QD directly into the mouth using a syringe from Days 1 to 14.	Cohort 2: AZD4041 Dose Level 2 n=9 Participants Participants received oral solution of AZD4041 dose level 2 QD directly into the mouth using a syringe from Days 1 to 14.	Cohort 3: AZD4041 Dose Level 3 n=9 Participants Participants received 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 Participants received oral solution of placebo equivalent to AZD4041 volume QD directly into the mouth using a syringe from Days 1 to 14.
Accumulation Ratio Evaluated by Comparing Day 14 AUCτ to Day 1 AUC0-24 (RAC[AUC]) of AZD4041	1.66 Ratio Geometric Coefficient of Variation 25.3	1.71 Ratio Geometric Coefficient of Variation 21.7	1.82 Ratio Geometric Coefficient of Variation 22.1	—

SECONDARY outcome

Timeframe: Day 1: Predose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, and 24 hours postdose

Population: The PK population included all participants who had received at least 1 dose of AZD4041 and had at least 1 PK concentration after dosing. Here, number of participants analyzed (N) indicates those participants who had adequate PK samples and excludes participants with inadequate PK samples due to missed blood draw, an AE, meal deviation, or concomitant medication intake.

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%.

Outcome measures

Outcome measures
Measure	Cohort 1: AZD4041 Dose Level 1 Participants received oral solution of AZD4041 dose level 1 QD directly into the mouth using a syringe from Days 1 to 14.	Cohort 2: AZD4041 Dose Level 2 n=1 Participants Participants received oral solution of AZD4041 dose level 2 QD directly into the mouth using a syringe from Days 1 to 14.	Cohort 3: AZD4041 Dose Level 3 Participants received 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 Participants received oral solution of placebo equivalent to AZD4041 volume QD directly into the mouth using a syringe from Days 1 to 14.
Apparent Total Clearance (CL/F) of AZD4041 After Day 1 Dose	—	5.00 L/hour Interval 5.0 to 5.0	—	—

SECONDARY outcome

Timeframe: Day 14: Predose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, and 72 hours postdose

Population: The PK population included all participants who had received at least 1 dose of AZD4041 and had at least 1 PK concentration after dosing. Here, number of participants analyzed (N) indicates those participants who had adequate PK samples and excludes participants with inadequate PK samples due to missed blood draw, an AE, meal deviation, or concomitant medication intake.

The CL/Fss of AZD4041 after Day 14 dose is reported.

Outcome measures

Outcome measures
Measure	Cohort 1: AZD4041 Dose Level 1 n=8 Participants Participants received oral solution of AZD4041 dose level 1 QD directly into the mouth using a syringe from Days 1 to 14.	Cohort 2: AZD4041 Dose Level 2 n=9 Participants Participants received oral solution of AZD4041 dose level 2 QD directly into the mouth using a syringe from Days 1 to 14.	Cohort 3: AZD4041 Dose Level 3 n=9 Participants Participants received 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 Participants received oral solution of placebo equivalent to AZD4041 volume QD directly into the mouth using a syringe from Days 1 to 14.
Apparent Total Clearance at Steady State (CL/Fss) of AZD4041 After Day 14 Dose	2.48 L/hour Geometric Coefficient of Variation 41.3	2.38 L/hour Geometric Coefficient of Variation 34.4	1.98 L/hour Geometric Coefficient of Variation 36.0	—

SECONDARY outcome

Timeframe: Day 1: Predose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, and 24 hours postdose

Population: The PK population included all participants who had received at least 1 dose of AZD4041 and had at least 1 PK concentration after dosing. Here, number of participants analyzed (N) indicates those participants who had adequate PK samples and excludes participants with inadequate PK samples due to missed blood draw, an AE, meal deviation, or concomitant medication intake.

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%.

Outcome measures

Outcome measures
Measure	Cohort 1: AZD4041 Dose Level 1 Participants received oral solution of AZD4041 dose level 1 QD directly into the mouth using a syringe from Days 1 to 14.	Cohort 2: AZD4041 Dose Level 2 n=1 Participants Participants received oral solution of AZD4041 dose level 2 QD directly into the mouth using a syringe from Days 1 to 14.	Cohort 3: AZD4041 Dose Level 3 Participants received 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 Participants received oral solution of placebo equivalent to AZD4041 volume QD directly into the mouth using a syringe from Days 1 to 14.
Apparent Volume of Distribution (Vz/F) of AZD4041 After Day 1 Dose	—	59.90 L Interval 59.9 to 59.9	—	—

SECONDARY outcome

Timeframe: Day 14: Predose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, and 72 hours postdose

Population: The PK population included all participants who had received at least 1 dose of AZD4041 and had at least 1 PK concentration after dosing. Here, number of participants analyzed (N) indicates those participants who had adequate PK samples and excludes participants with inadequate PK samples due to missed blood draw, an AE, meal deviation, or concomitant medication intake.

The Vz/Fss of AZD4041 after Day 14 dose is reported.

Outcome measures

Outcome measures
Measure	Cohort 1: AZD4041 Dose Level 1 n=8 Participants Participants received oral solution of AZD4041 dose level 1 QD directly into the mouth using a syringe from Days 1 to 14.	Cohort 2: AZD4041 Dose Level 2 n=9 Participants Participants received oral solution of AZD4041 dose level 2 QD directly into the mouth using a syringe from Days 1 to 14.	Cohort 3: AZD4041 Dose Level 3 n=9 Participants Participants received 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 Participants received oral solution of placebo equivalent to AZD4041 volume QD directly into the mouth using a syringe from Days 1 to 14.
Apparent Volume of Distribution at Steady State (Vz/Fss) of AZD4041 After Day 14 Dose	79.50 L Geometric Coefficient of Variation 21.8	68.90 L Geometric Coefficient of Variation 25.5	75.90 L Geometric Coefficient of Variation 16.0	—

SECONDARY outcome

Timeframe: Day 14: Predose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, and 72 hours postdose

Population: The PK population included all participants who had received at least 1 dose of AZD4041 and had at least 1 PK concentration after dosing. Here, number of participants analyzed (N) indicates those participants who had adequate PK samples and excludes participants with inadequate PK samples due to missed blood draw, an AE, meal deviation, or concomitant medication intake.

The λZ of AZD4041 after Day 14 dose is reported.

Outcome measures

Outcome measures
Measure	Cohort 1: AZD4041 Dose Level 1 n=6 Participants Participants received oral solution of AZD4041 dose level 1 QD directly into the mouth using a syringe from Days 1 to 14.	Cohort 2: AZD4041 Dose Level 2 n=9 Participants Participants received oral solution of AZD4041 dose level 2 QD directly into the mouth using a syringe from Days 1 to 14.	Cohort 3: AZD4041 Dose Level 3 n=7 Participants Participants received 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 Participants received oral solution of placebo equivalent to AZD4041 volume QD directly into the mouth using a syringe from Days 1 to 14.
Apparent Elimination Rate Constant (λZ) of AZD4041 After Day 14 Dose	0.0367 1/hour Geometric Coefficient of Variation 27.5	0.0345 1/hour Geometric Coefficient of Variation 33.4	0.0298 1/hour Geometric Coefficient of Variation 20.3	—

SECONDARY outcome

Timeframe: Day 1: Predose spot collection, and 0 to 6 hours, 6 to 12 hours, and 12 to 24 hours postdose

Population: The PK population included all participants who had received at least 1 dose of AZD4041 and had at least 1 PK concentration after dosing. Here, number of participants analyzed (N) indicates those participants who had adequate urine PK samples and excludes participants with inadequate urine PK samples due to missed urine collection, an AE, meal deviation, or concomitant medication intake.

The Ae0-24 of AZD4041 after Day 1 dose is reported.

Outcome measures

Outcome measures
Measure	Cohort 1: AZD4041 Dose Level 1 n=8 Participants Participants received oral solution of AZD4041 dose level 1 QD directly into the mouth using a syringe from Days 1 to 14.	Cohort 2: AZD4041 Dose Level 2 n=9 Participants Participants received oral solution of AZD4041 dose level 2 QD directly into the mouth using a syringe from Days 1 to 14.	Cohort 3: AZD4041 Dose Level 3 n=8 Participants Participants received 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 Participants received oral solution of placebo equivalent to AZD4041 volume QD directly into the mouth using a syringe from Days 1 to 14.
Amount of AZD4041 Excreted Unchanged in Urine Over the 24-hour Dosing Interval (Ae0-24) After Day 1 Dose	59209.58 ng Geometric Coefficient of Variation 71.1	161067.17 ng Geometric Coefficient of Variation 71.1	411420.17 ng Geometric Coefficient of Variation 45.7	—

SECONDARY outcome

Timeframe: Day 14: Predose spot collection, and 0 to 6 hours, 6 to 12 hours, and 12 to 24 hours postdose

Population: The PK population included all participants who had received at least 1 dose of AZD4041 and had at least 1 PK concentration after dosing. Here, number of participants analyzed (N) indicates those participants who had adequate urine PK samples and excludes participants with inadequate urine PK samples due to missed urine collection, an AE, meal deviation, or concomitant medication intake.

The Ae0-24 of AZD4041 after Day 14 dose is reported.

Outcome measures

Outcome measures
Measure	Cohort 1: AZD4041 Dose Level 1 n=6 Participants Participants received oral solution of AZD4041 dose level 1 QD directly into the mouth using a syringe from Days 1 to 14.	Cohort 2: AZD4041 Dose Level 2 n=8 Participants Participants received oral solution of AZD4041 dose level 2 QD directly into the mouth using a syringe from Days 1 to 14.	Cohort 3: AZD4041 Dose Level 3 n=8 Participants Participants received 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 Participants received oral solution of placebo equivalent to AZD4041 volume QD directly into the mouth using a syringe from Days 1 to 14.
Amount of AZD4041 Excreted Unchanged in Urine Over the 24-hour Dosing Interval (Ae0-24) After Day 14 Dose	177681.47 ng Geometric Coefficient of Variation 55.3	334754.86 ng Geometric Coefficient of Variation 99.2	1095233.64 ng Geometric Coefficient of Variation 39.7	—

SECONDARY outcome

Timeframe: Day 1: Predose spot collection, and 0 to 6 hours, 6 to 12 hours, and 12 to 24 hours postdose

Population: The PK population included all participants who had received at least 1 dose of AZD4041 and had at least 1 PK concentration after dosing. Here, number of participants analyzed (N) indicates those participants who had adequate urine PK samples and excludes participants with inadequate urine PK samples due to missed urine collection, an AE, meal deviation, or concomitant medication intake.

The fe/F0-24 of AZD4041 after Day 1 dose is reported.

Outcome measures

Outcome measures
Measure	Cohort 1: AZD4041 Dose Level 1 n=8 Participants Participants received oral solution of AZD4041 dose level 1 QD directly into the mouth using a syringe from Days 1 to 14.	Cohort 2: AZD4041 Dose Level 2 n=9 Participants Participants received oral solution of AZD4041 dose level 2 QD directly into the mouth using a syringe from Days 1 to 14.	Cohort 3: AZD4041 Dose Level 3 n=8 Participants Participants received 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 Participants received oral solution of placebo equivalent to AZD4041 volume QD directly into the mouth using a syringe from Days 1 to 14.
Apparent Fraction of AZD4041 Excreted Unchanged in Urine Over the 24-hours Dosing Interval (fe/F0-24) After Day 1 Dose	0.79 Percentage Geometric Coefficient of Variation 71.1	1.07 Percentage Geometric Coefficient of Variation 71.1	1.65 Percentage Geometric Coefficient of Variation 45.7	—

SECONDARY outcome

Timeframe: Day 14: Predose spot collection, and 0 to 6 hours, 6 to 12 hours, and 12 to 24 hours postdose

Population: The PK population included all participants who had received at least 1 dose of AZD4041 and had at least 1 PK concentration after dosing. Here, number of participants analyzed (N) indicates those participants who had adequate urine PK samples and excludes participants with inadequate urine PK samples due to missed urine collection, an AE, meal deviation, or concomitant medication intake.

The fe/F0-24 of AZD4041 after Day 14 dose is reported.

Outcome measures

Outcome measures
Measure	Cohort 1: AZD4041 Dose Level 1 n=6 Participants Participants received oral solution of AZD4041 dose level 1 QD directly into the mouth using a syringe from Days 1 to 14.	Cohort 2: AZD4041 Dose Level 2 n=8 Participants Participants received oral solution of AZD4041 dose level 2 QD directly into the mouth using a syringe from Days 1 to 14.	Cohort 3: AZD4041 Dose Level 3 n=8 Participants Participants received 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 Participants received oral solution of placebo equivalent to AZD4041 volume QD directly into the mouth using a syringe from Days 1 to 14.
Apparent Fraction of AZD4041 Excreted Unchanged in Urine Over the 24-hours Dosing Interval (fe/F0-24) After Day 14 Dose	2.37 Percentage Geometric Coefficient of Variation 55.3	2.23 Percentage Geometric Coefficient of Variation 99.2	4.38 Percentage Geometric Coefficient of Variation 39.7	—

SECONDARY outcome

Timeframe: Day 1: Predose spot collection, and 0 to 6 hours, 6 to 12 hours, and 12 to 24 hours postdose

Population: The PK population included all participants who had received at least 1 dose of AZD4041 and had at least 1 PK concentration after dosing. Here, number of participants analyzed (N) indicates those participants who had adequate urine PK samples and excludes participants with inadequate urine PK samples due to missed urine collection, an AE, meal deviation, or concomitant medication intake.

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.

Outcome measures

Outcome measures
Measure	Cohort 1: AZD4041 Dose Level 1 n=8 Participants Participants received oral solution of AZD4041 dose level 1 QD directly into the mouth using a syringe from Days 1 to 14.	Cohort 2: AZD4041 Dose Level 2 n=9 Participants Participants received oral solution of AZD4041 dose level 2 QD directly into the mouth using a syringe from Days 1 to 14.	Cohort 3: AZD4041 Dose Level 3 n=8 Participants Participants received 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 Participants received oral solution of placebo equivalent to AZD4041 volume QD directly into the mouth using a syringe from Days 1 to 14.
Apparent Renal Clearance Over the 24-hours Dosing Interval (CLR 0-24) of AZD4041 After Day 1 Dose	0.0328 L/hour Geometric Coefficient of Variation 65.3	0.0437 L/hour Geometric Coefficient of Variation 72.1	0.0582 L/hour Geometric Coefficient of Variation 56.1	—

SECONDARY outcome

Timeframe: Day 14: Predose spot collection, and 0 to 6 hours, 6 to 12 hours, and 12 to 24 hours postdose

Population: The PK population included all participants who had received at least 1 dose of AZD4041 and had at least 1 PK concentration after dosing. Here, number of participants analyzed (N) indicates those participants who had adequate urine PK samples and excludes participants with inadequate urine PK samples due to missed urine collection, an AE, meal deviation, or concomitant medication intake.

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.

Outcome measures

Outcome measures
Measure	Cohort 1: AZD4041 Dose Level 1 n=6 Participants Participants received oral solution of AZD4041 dose level 1 QD directly into the mouth using a syringe from Days 1 to 14.	Cohort 2: AZD4041 Dose Level 2 n=8 Participants Participants received oral solution of AZD4041 dose level 2 QD directly into the mouth using a syringe from Days 1 to 14.	Cohort 3: AZD4041 Dose Level 3 n=8 Participants Participants received 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 Participants received oral solution of placebo equivalent to AZD4041 volume QD directly into the mouth using a syringe from Days 1 to 14.
Apparent Renal Clearance Over the 24-hours Dosing Interval (CLR 0-24) of AZD4041 After Day 14 Dose	0.0536 L/hour Geometric Coefficient of Variation 21.5	0.0521 L/hour Geometric Coefficient of Variation 106.4	0.0916 L/hour Geometric Coefficient of Variation 71.2	—

SECONDARY outcome

Timeframe: Day 14 post dose (approximately 3 hours ± 1 hour)

Population: The PK population included all participants who had received at least 1 dose of AZD4041 and had at least 1 PK concentration after dosing. Here, number of participants analyzed (N) indicates those participants who had adequate CSF PK samples and excludes participants with inadequate CSF PK samples due to missed CSF draw, an AE, meal deviation, or concomitant medication intake.

The CSF concentration as a percentage of total plasma concentration of AZD4041 in cohorts 2 and 3 is reported.

Outcome measures

Outcome measures
Measure	Cohort 1: AZD4041 Dose Level 1 n=6 Participants Participants received oral solution of AZD4041 dose level 1 QD directly into the mouth using a syringe from Days 1 to 14.	Cohort 2: AZD4041 Dose Level 2 n=9 Participants Participants received oral solution of AZD4041 dose level 2 QD directly into the mouth using a syringe from Days 1 to 14.	Cohort 3: AZD4041 Dose Level 3 Participants received 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 Participants received oral solution of placebo equivalent to AZD4041 volume QD directly into the mouth using a syringe from Days 1 to 14.
Cerebrospinal Fluid (CSF) Concentration as a Percentage of Total Plasma Concentration of AZD4041 in Cohorts 2 and 3	4.91 Percentage Geometric Coefficient of Variation 13.3	5.28 Percentage Geometric Coefficient of Variation 16.3	—	—

SECONDARY outcome

Timeframe: Day 14 post dose (approximately 3 hours ± 1 hour)

Population: The PK population included all participants who had received at least 1 dose of AZD4041 and had at least 1 PK concentration after dosing. Here, number of participants analyzed (N) indicates those participants who had adequate CSF PK samples and excludes participants with inadequate CSF PK samples due to missed CSF draw, an AE, meal deviation, or concomitant medication intake.

The CSF concentration as a percentage of free plasma concentration of AZD4041 in cohorts 2 and 3 is reported.

Outcome measures

Outcome measures
Measure	Cohort 1: AZD4041 Dose Level 1 n=6 Participants Participants received oral solution of AZD4041 dose level 1 QD directly into the mouth using a syringe from Days 1 to 14.	Cohort 2: AZD4041 Dose Level 2 n=9 Participants Participants received oral solution of AZD4041 dose level 2 QD directly into the mouth using a syringe from Days 1 to 14.	Cohort 3: AZD4041 Dose Level 3 Participants received 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 Participants received oral solution of placebo equivalent to AZD4041 volume QD directly into the mouth using a syringe from Days 1 to 14.
CSF Concentration as a Percentage of Free Plasma Concentration of AZD4041 in Cohorts 2 and 3	27.44 Percentage Geometric Coefficient of Variation 13.3	29.51 Percentage Geometric Coefficient of Variation 16.3	—	—

SECONDARY outcome

Timeframe: Pre-dose Day 1 and 24 hours post Day 14 dose

Population: Pharmacodynamic (PD) population included all participants who had received at least 1 dose of AZD4041 or placebo and had at least 1 plasma 4-β-hydroxy-cholesterol concentration after dosing.

Day 14 / Day 1 ratio of 4-β-hydroxy-cholesterol concentrations is reported.

Outcome measures

Outcome measures
Measure	Cohort 1: AZD4041 Dose Level 1 n=8 Participants Participants received oral solution of AZD4041 dose level 1 QD directly into the mouth using a syringe from Days 1 to 14.	Cohort 2: AZD4041 Dose Level 2 n=9 Participants Participants received oral solution of AZD4041 dose level 2 QD directly into the mouth using a syringe from Days 1 to 14.	Cohort 3: AZD4041 Dose Level 3 n=9 Participants Participants received 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 n=9 Participants Participants received oral solution of placebo equivalent to AZD4041 volume QD directly into the mouth using a syringe from Days 1 to 14.
Day 14 / Day 1 Ratio of 4-β-hydroxy-cholesterol Concentrations	1.00 Ratio Geometric Coefficient of Variation 28.67	1.02 Ratio Geometric Coefficient of Variation 18.83	0.95 Ratio Geometric Coefficient of Variation 18.74	0.79 Ratio Geometric Coefficient of Variation 26.41

Adverse Events

Cohort 1: AZD4041 Dose Level 1

Serious events: 0 serious events

Other events: 8 other events

Deaths: 0 deaths

Cohort 2: AZD4041 Dose Level 2

Serious events: 0 serious events

Other events: 6 other events

Deaths: 0 deaths

Cohort 3: AZD4041 Dose Level 3

Serious events: 0 serious events

Other events: 6 other events

Deaths: 0 deaths

Cohorts 1-3: Pooled Placebo

Serious events: 0 serious events

Other events: 9 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Additional Information

Global Clinical Lead

AstraZeneca Clinical study Information Center

Phone: +1-877-240-9479

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee MedImmune has 60 days to review results communications prior to public release and may delete information that compromises ongoing studies or is considered proprietary. This restriction is not intended to compromise the objective scientific integrity of the manuscript, it being understood that results shall be published regardless of outcome.
Publication restrictions are in place

Restriction type: OTHER