A study to assess the safety and tolerability of single and multiple doses of AZD4831 in healthy male subjects

Study identifier:D6580C00001

ClinicalTrials.gov identifier:NCT02712372

EudraCT identifier:N/A

CTIS identifier:N/A

Terminated/Withdrawn

Official Title

A Phase I, Randomised, Single-Blind, Placebo-controlled Study to Assess the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of AZD4831 After Single and Multiple Ascending Dose Administration to Healthy Male Subjects

Medical condition

cardiovascular disease

Phase

Phase 1

Healthy volunteers

Yes

Study drug

AZD4831, AZD4831 placebo

Sex

Male

Actual Enrollment

Study type

Interventional

Age

18 Years - 50 Years

Date

Study Start Date: 29 Jun 2016

Primary Completion Date: 13 Oct 2016

Study Completion Date: 13 Oct 2016

Study design

Allocation: Randomized
Endpoint Classification: Safety
Intervention Model: Parallel Assignment
Masking: Single Blind
Primary Purpose: Basic Science

Verification:

Verified 01 Sept 2017 by AstraZeneca

Collaborators

Inclusion and exclusion criteria

Exclusion Criteria

Inclusion Criteria
- Provision of signed and dated, written informed consent before any study specific procedures.
- Healthy male subjects aged 18 – 50 years, inclusive, with suitable veins for cannulation or repeated venipuncture.
- Have a body mass index (BMI) between 18 and 29.9 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/biomarker research.
- Subjects must be able to read, speak and understand the German language.
- 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.
- Presence of infection(s) (particularly fungal infection), as judged by the investigator.
- History or current thyroid disease.
- Any clinically significant illness, medical/surgical procedure, or trauma within 4 weeks of the first administration of investigational medicinal product (IMP).
- Any clinically significant abnormalities in clinical chemistry, haematology, or urinalysis results, as judged by the investigator.
- Any positive result on screening for serum hepatitis B surface antigen (HBsAg), anti-hepatitis B core (anti-HBc) antibodies, hepatitis C antibody and human immunodeficiency virus (HIV).
- Abnormal vital signs
- Any clinically significant abnormalities in rhythm, conduction or morphology of the resting ECG and any clinically significant abnormalities in the 12-lead ECG, as considered by the investigator that may interfere with the interpretation of QTc interval changes, including abnormal ST-T-wave morphology, particularly in the protocol defined primary lead or LV hypertrophy.
- Prolonged QTcF > 450 ms or shortened QTcF < 340 ms or family history of long QT syndrome.
- PR(PQ) interval shortening < 120 ms (PR > 110 ms but < 120 ms is acceptable if there is no evidence of ventricular pre-excitation)
- PR (PQ) interval prolongation (> 200 ms) intermittent second (Wenckebach block while asleep is not exclusive) or third degree AV block, or AV dissociation
- Persistent or intermittent complete bundle branch block, incomplete bundle branch block, or intraventricular conduction delay with QRS > 110 ms. Subjects with QRS > 110 ms but < 115 ms are acceptable if there is no evidence of, for example, ventricular hypertrophy or pre-excitation.
- ECG findings suggesting a metabolic or other non-cardiac condition that may confound interpretation of serial changes (such as hypokalemia).
- Known or suspected history of drug abuse, as judged by the investigator.
- Current smokers or those who have smoked or used nicotine products within the previous 3 months.
- History of alcohol abuse or excessive intake of alcohol, as judged by the investigator.
- Positive screen for drugs of abuse, cotinine (nicotine) or alcohol at screening or admission to the unit before the first administration of IMP.
- History of severe allergy/hypersensitivity or ongoing clinically significant allergy/hypersensitivity, as judged by the investigator or history of hypersensitivity to drugs with a similar chemical structure or class to AZD4831.
- Excessive intake of caffeine containing drinks or food (e.g., coffee, tea, chocolate), as judged by the investigator.
-Use of drugs with enzyme inducing properties such as St John’s Wort within 3 weeks before the first administration of IMP.
- Use of any prescribed or non-prescribed medication including antacids, analgesics (other than paracetamol/acetaminophen), herbal remedies, megadose vitamins (intake of 20 to 600 times the recommended daily dose) and minerals during the 2 weeks before the first administration of IMP or longer if the medication has a long half-life.
-Plasma donation within 1 month of screening or any blood donation/blood loss > 500 mL during the 3 months before screening.
-Has received another new chemical entity (defined as a compound which has not been approved for marketing) within 3 months of the first administration of IMP in this study. The period of exclusion begins 3 months after the final dose or 1 month after the last visit whichever is the longest.
-Vulnerable subjects, e.g., kept in detention, protected adults under guardianship, trusteeship, or committed to an institution by governmental or juridical order.
-Involvement of any Astra Zeneca, PAREXEL or study site employee or their close relatives.
-Judgment by the investigator that the subject should not participate in the study if they have any ongoing or recent (i.e., during the screening period) minor medical complaints that may interfere with the interpretation of study data or are considered unlikely to comply with study procedures, restrictions and requirements.
-Subjects who are vegans or have medical dietary restrictions.
-Subjects who cannot communicate reliably with the investigator.
Exclusion from the genetic research:
-Previous bone marrow transplant.
-Non-leukocyte depleted whole blood transfusion within 120 days of the date of the genetic sample collection.

No locations available

Arms	Assigned Interventions
Experimental: Part 1, Dose Level 1 Part 1: Part 1A: Single dose administered in the morning on Day 1 under fasted conditions. Part 1B: Single dose administered in the morning of Day 1 under fed conditions.	Drug: AZD4831 AZD4831 1-50 mg/g oral suspension
Experimental: Part 1, Dose Level 2 Part 1: Part 1A: Single dose administered in the morning on Day 1 under fasted conditions. Part 1B: Single dose administered in the morning of Day 1 under fed conditions.	Drug: AZD4831 AZD4831 1-50 mg/g oral suspension
Experimental: Part 1, Dose Level 3 Part 1: Part 1A: Single dose administered in the morning on Day 1 under fasted conditions. Part 1B: Single dose administered in the morning of Day 1 under fed conditions.	Drug: AZD4831 AZD4831 1-50 mg/g oral suspension
Experimental: Part 1, Dose Level 4 Part 1: Part 1A: Single dose administered in the morning on Day 1 under fasted conditions. Part 1B: Single dose administered in the morning of Day 1 under fed conditions.	Drug: AZD4831 AZD4831 1-50 mg/g oral suspension
Experimental: Part 1, Dose Level 5 Part 1: Part 1A: Single dose administered in the morning on Day 1 under fasted conditions. Part 1B: Single dose administered in the morning of Day 1 under fed conditions.	Drug: AZD4831 AZD4831 1-50 mg/g oral suspension
Experimental: Part 1, Dose Level 6 Part 1: Part 1A: Single dose administered in the morning on Day 1 under fasted conditions. Part 1B: Single dose administered in the morning of Day 1 under fed conditions.	Drug: AZD4831 AZD4831 1-50 mg/g oral suspension
Experimental: Part 2, Dose Level 1 Part 2: Single dose administered in the morning on Day 1 and multiple doses administered once daily, in the morning, Days 3 to 12	Drug: AZD4831 AZD4831 1-50 mg/g oral suspension
Experimental: Part 2, Dose Level 2 Part 2: Single dose administered in the morning on Day 1 and multiple doses administered once daily, in the morning, Days 3 to 12	Drug: AZD4831 AZD4831 1-50 mg/g oral suspension
Experimental: Part 2, Dose Level 3 Part 2: Single dose administered in the morning on Day 1 and multiple doses administered once daily, in the morning, Days 3 to 12	Drug: AZD4831 AZD4831 1-50 mg/g oral suspension
Placebo Comparator: AZD4831 Placebo Part 1: Part 1A: Single dose administered in the morning on Day 1 under fasted conditions. Part 1B: Single dose administered in the morning of Day 1 under fed conditions. Part 2: Single dose administered in the morning on Day 1 and multiple doses administered once daily, in the morning, Days 3 to 12	Drug: AZD4831 placebo AZD4831 placebo oral suspension

Participant Flow

Recruitment Details

Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
Phase 1, first-in-human (FIH) study consisting of 2 parts (Part 1 and Part 2), with Part 1 being split into 2 sub-parts (Part 1A [fasting] and Part 1B [fed]). Part 2 was not performed.

Pre-Assignment Details

Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
The study consisted of a screening period (Day -21 to Day -2). At screening, some of the assessments done were: inclusion/exclusion criteria, demographic data, medical history, concomitant medication, informed consent, adverse event questioning, blood pressure and pulse rate, Electrocardiogram, clinical laboratory evaluations, physical examination.

Reporting Groups

	Description
Part 1 - AZD4831	Participants received 1 dose level of AZD4831 (5 mg, 15 mg, 45 mg, 135 mg, 405 mg) under fasting conditions with 6 participants in each dose level. One cohort (Cohort 3, 45 mg AZD4831) from Part 1A completed Part 1B (fed), receiving another single dose of AZD4831 with a high-calorie, high-fat breakfast. The 2 dosing periods were separated by at least 7 days.
Part 1 - Pooled Placebo	For every 2 participants per dose level of AZD4831, one participant received a matching placebo under fasting condition.

Participant Flow: Overall Study

	Part 1 - AZD4831	Part 1 - Pooled Placebo
STARTED	30	10
COMPLETED	28	10
NOT COMPLETED	2	0
Participant decision	1	0
Severe non-compliance with protocol	1	0

Baseline Characteristics

Analysis Population Description -- Explanation of how the number of participants for analysis was determined.

Reporting Groups

	Description
Part 1 - AZD4831	Participants received 1 dose level of AZD4831 (5 mg, 15 mg, 45 mg, 135 mg, 405 mg) under fasting conditions with 6 participants in each dose level. One cohort (Cohort 3, 45 mg AZD4831) from Part 1A completed Part 1B (fed), receiving another single dose of AZD4831 with a high-calorie, high-fat breakfast. The 2 dosing periods were separated by at least 7 days.
Part 1 - Pooled Placebo	For every 2 participants per dose level of AZD4831, one participant received a matching placebo under fasting condition.

Baseline Measures

	Part 1 - AZD4831	Part 1 - Pooled Placebo	Total
Number of Participants [units: Participants]	30	10	40
Age Continuous [units: Years] Mean ± Standard Deviation	35 ± 10	42 ± 8	NA ± NA ^[1]
Gender, Male/Female [units: Participants]
Female	0	0	0
Male	30	10	40

Outcome Measures

1. Primary Outcome Measure: Safety and tolerability of AZD4831 following oral administration of single ascending doses (SAD; Part 1A and Part 1B) [ Time Frame: Screening (Only serious adverse events, SAEs), Day -1 (Only SAEs), Days 1 to 3, Follow-up 7 to 10 days post (final) dose ]

Measure Type	Primary
Measure Name	Safety and tolerability of AZD4831 following oral administration of single ascending doses (SAD; Part 1A and Part 1B)
Measure Description	To assess the safety and tolerability of AZD4831 in terms of number of participants reporting adverse events (AEs) following oral administration of SAD in Part 1A (fasting) and Part 1B (fed)
Time Frame	Screening (Only serious adverse events, SAEs), Day -1 (Only SAEs), Days 1 to 3, Follow-up 7 to 10 days post (final) dose
Safety Issue?	Yes

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The safety analysis set included all participants who received at least 1 dose of Investigational Medicinal Product (IMP) and for whom any safety post-dose data are available.

Reporting Groups

	Description
Part 1A - AZD4831 5 mg	Participants received single doses of AZD4831 5 mg under fasting conditions.
Part 1A - AZD4831 15 mg	Participants received single doses of AZD4831 15 mg under fasting conditions.
Part 1A - AZD4831 45 mg	Participants received single doses of AZD4831 45 mg under fasting conditions.
Part 1A - AZD4831 135 mg	Participants received single doses of AZD4831 135 mg under fasting conditions.
Part 1A - AZD4831 405 mg	Participants received single doses of AZD4831 405 mg under fasting conditions.
Part 1A - Pooled Placebo	Participants received matching placebo.
Part 1B - AZD4831 45 mg	Participants from Cohort 3 (Part 1A, 45 mg AZD4831) received another dose of 45 mg AZD4831 under fed conditions

Measured Values

	Part 1A - AZD4831 5 mg	Part 1A - AZD4831 15 mg	Part 1A - AZD4831 45 mg	Part 1A - AZD4831 135 mg	Part 1A - AZD4831 405 mg	Part 1A - Pooled Placebo	Part 1B - AZD4831 45 mg
Number of Participants Analyzed [units:participants]	6	6	6	6	6	10	4
Safety and tolerability of AZD4831 following oral administration of single ascending doses (SAD; Part 1A and Part 1B) [units: Participants]
Any adverse event (AE)	2	2	3	3	2	4	0
Any AE with outcome = death	0	0	0	0	0	0	0
Any SAE (including events with outcome = death)	0	0	0	0	0	0	0
Any AE leading to discontinuation of IMP	0	0	0	0	0	0	0

No statistical analysis provided for Safety and tolerability of AZD4831 following oral administration of single ascending doses (SAD; Part 1A and Part 1B)

2. Secondary Outcome Measure: Observed maximum plasma concentration, taken directly from the individual concentration-time curve (Cmax)- For Part 1A (fasting) and Part 1B (fed) [ Time Frame: At predose and at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4,6, 8, 12, 24, 36 and 48 hours postdose (Days 1 to 3) ]

Measure Type	Secondary
Measure Name	Observed maximum plasma concentration, taken directly from the individual concentration-time curve (Cmax)- For Part 1A (fasting) and Part 1B (fed)
Measure Description	To assess the pharmacokinetic (PK) parameter Cmax of AZD4831 following single oral administration of AZD4831 in Part 1A under fasting conditions and following single oral administration of 45 mg AZD4831 in Part 1B under fed conditions
Time Frame	At predose and at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4,6, 8, 12, 24, 36 and 48 hours postdose (Days 1 to 3)
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The PK analysis set consisted of all participants in the safety analysis set who received AZD4831 and who had evaluable PK data, with no major protocol deviations thought to impact on the analysis of the PK data.

Reporting Groups

	Description
Part 1A - AZD4831 5 mg	Participants received single doses of AZD4831 5 mg under fasting conditions.
Part 1A - AZD4831 15 mg	Participants received single doses of AZD4831 15 mg under fasting conditions.
Part 1A - AZD4831 45 mg	Participants received single doses of AZD4831 45 mg under fasting conditions.
Part 1A - AZD4831 135 mg	Participants received single doses of AZD4831 135 mg under fasting conditions.
Part 1A - AZD4831 405 mg	Participants received single doses of AZD4831 405 mg under fasting conditions.
Part 1B - AZD4831 45 mg	Participants from Cohort 3 (Part 1A, 45 mg AZD4831) received another dose of 45 mg AZD4831 under fed conditions

Measured Values

	Part 1A - AZD4831 5 mg	Part 1A - AZD4831 15 mg	Part 1A - AZD4831 45 mg	Part 1A - AZD4831 135 mg	Part 1A - AZD4831 405 mg	Part 1B - AZD4831 45 mg
Number of Participants Analyzed [units:participants]	6	6	6	6	6	4
Observed maximum plasma concentration, taken directly from the individual concentration-time curve (Cmax)- For Part 1A (fasting) and Part 1B (fed) [units: nmol/L] Geometric Mean (Geometric Coefficient of Variation)	14.96 (23.9%)	83.42 (19.4%)	326.1 (27.8%)	1092 (83.1%)	3037 (105.8%)	183.6 (9.4%)

Statistical Analysis 1 for Observed maximum plasma concentration, taken directly from the individual concentration-time curve (Cmax)- For Part 1A (fasting) and Part 1B (fed)

Groups^[1]	Part 1A - AZD4831 5 mg, Part 1A - AZD4831 15 mg, Part 1A - AZD4831 45 mg, Part 1A - AZD4831 135 mg, Part 1A - AZD4831 405 mg
Non-Inferiority/Equivalence Test^[2]	No
Slope^[5]	1.201
Standard Error of the mean	± 0.06383
95% Confidence Interval	( 1.071 to 1.332 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[5]	Other relevant estimation information:
	No text entered.

3. Secondary Outcome Measure: Time to reach maximum plasma concentration, taken directly from the individual concentration-time curve (tmax)- For Part 1A (fasting) and Part 1B (fed) [ Time Frame: At predose and at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4,6, 8, 12, 24, 36 and 48 hours postdose (Days 1 to 3) ]

Measure Type	Secondary
Measure Name	Time to reach maximum plasma concentration, taken directly from the individual concentration-time curve (tmax)- For Part 1A (fasting) and Part 1B (fed)
Measure Description	To assess the PK parameter tmax of AZD4831 following single oral administration of AZD4831 in Part 1A under fasting conditions and following single oral administration of 45 mg AZD4831 in Part 1B under fed conditions
Time Frame	At predose and at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4,6, 8, 12, 24, 36 and 48 hours postdose (Days 1 to 3)
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The PK analysis set consisted of all participants in the safety analysis set who received AZD4831 and who had evaluable PK data, with no major protocol deviations thought to impact on the analysis of the PK data.

Reporting Groups

	Description
Part 1A - AZD4831 5 mg	Participants received single doses of AZD4831 5 mg under fasting conditions.
Part 1A - AZD4831 15 mg	Participants received single doses of AZD4831 15 mg under fasting conditions.
Part 1A - AZD4831 45 mg	Participants received single doses of AZD4831 45 mg under fasting conditions.
Part 1A - AZD4831 135 mg	Participants received single doses of AZD4831 135 mg under fasting conditions.
Part 1A - AZD4831 405 mg	Participants received single doses of AZD4831 405 mg under fasting conditions.
Part 1B - AZD4831 45 mg	Participants from Cohort 3 (Part 1A, 45 mg AZD4831) received another dose of 45 mg AZD4831 under fed conditions

Measured Values

	Part 1A - AZD4831 5 mg	Part 1A - AZD4831 15 mg	Part 1A - AZD4831 45 mg	Part 1A - AZD4831 135 mg	Part 1A - AZD4831 405 mg	Part 1B - AZD4831 45 mg
Number of Participants Analyzed [units:participants]	6	6	6	6	6	4
Time to reach maximum plasma concentration, taken directly from the individual concentration-time curve (tmax)- For Part 1A (fasting) and Part 1B (fed) [units: hour] Median (Full Range)	1.00 (0.50 to 5.98)	0.74 (0.50 to 1.00)	0.51 (0.50 to 1.02)	0.74 (0.50 to 1.50)	0.75 (0.50 to 2.00)	3.00 (2.00 to 4.00)

No statistical analysis provided for Time to reach maximum plasma concentration, taken directly from the individual concentration-time curve (tmax)- For Part 1A (fasting) and Part 1B (fed)

4. Secondary Outcome Measure: Terminal rate constant, estimated by log-linear least squares regression of the terminal part of the concentration-time curve (λz) - For Part 1A (fasting) and Part 1B (fed) [ Time Frame: At predose and at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4,6, 8, 12, 24, 36 and 48 hours postdose (Days 1 to 3) ]

Measure Type	Secondary
Measure Name	Terminal rate constant, estimated by log-linear least squares regression of the terminal part of the concentration-time curve (λz) - For Part 1A (fasting) and Part 1B (fed)
Measure Description	To assess the PK parameter λz of AZD4831 following single oral administration of AZD4831 in Part 1A under fasting conditions and following single oral administration of 45 mg AZD4831 in Part 1B under fed conditions
Time Frame	At predose and at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4,6, 8, 12, 24, 36 and 48 hours postdose (Days 1 to 3)
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The PK analysis set consisted of all participants in the safety analysis set who received AZD4831 and who had evaluable PK data, with no major protocol deviations thought to impact on the analysis of the PK data.

Reporting Groups

	Description
Part 1A - AZD4831 5 mg	Participants received single doses of AZD4831 5 mg under fasting conditions.
Part 1A - AZD4831 15 mg	Participants received single doses of AZD4831 15 mg under fasting conditions.
Part 1A - AZD4831 45 mg	Participants received single doses of AZD4831 45 mg under fasting conditions.
Part 1A - AZD4831 135 mg	Participants received single doses of AZD4831 135 mg under fasting conditions.
Part 1A - AZD4831 405 mg	Participants received single doses of AZD4831 405 mg under fasting conditions.
Part 1B - AZD4831 45 mg	Participants from Cohort 3 (Part 1A, 45 mg AZD4831) received another dose of 45 mg AZD4831 under fed conditions

Measured Values

	Part 1A - AZD4831 5 mg	Part 1A - AZD4831 15 mg	Part 1A - AZD4831 45 mg	Part 1A - AZD4831 135 mg	Part 1A - AZD4831 405 mg	Part 1B - AZD4831 45 mg
Number of Participants Analyzed [units:participants]	6	6	6	6	6	4
Terminal rate constant, estimated by log-linear least squares regression of the terminal part of the concentration-time curve (λz) - For Part 1A (fasting) and Part 1B (fed) [units: 1/hour] Geometric Mean (Geometric Coefficient of Variation)	0.01841 (28.9%)	0.01535 (9.7%)	0.01389 (6.8%)	0.01432 (14.3%)	0.01818 (7.5%)	0.01195 (15.1%)

No statistical analysis provided for Terminal rate constant, estimated by log-linear least squares regression of the terminal part of the concentration-time curve (λz) - For Part 1A (fasting) and Part 1B (fed)

5. Secondary Outcome Measure: Terminal half-life, estimated as (ln2)/λz (t1/2λz) - For Part 1A (fasting) and Part 1B (fed) [ Time Frame: At predose and at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4,6, 8, 12, 24, 36 and 48 hours postdose (Days 1 to 3) ]

Measure Type	Secondary
Measure Name	Terminal half-life, estimated as (ln2)/λz (t1/2λz) - For Part 1A (fasting) and Part 1B (fed)
Measure Description	To assess the PK parameter t1/2λz of AZD4831 following single oral administration of AZD4831 in Part 1A under fasting conditions and following single oral administration of 45 mg AZD4831 in Part 1B under fed conditions
Time Frame	At predose and at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4,6, 8, 12, 24, 36 and 48 hours postdose (Days 1 to 3)
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The PK analysis set consisted of all participants in the safety analysis set who received AZD4831 and who had evaluable PK data, with no major protocol deviations thought to impact on the analysis of the PK data.

Reporting Groups

	Description
Part 1A - AZD4831 5 mg	Participants received single doses of AZD4831 5 mg under fasting conditions.
Part 1A - AZD4831 15 mg	Participants received single doses of AZD4831 15 mg under fasting conditions.
Part 1A - AZD4831 45 mg	Participants received single doses of AZD4831 45 mg under fasting conditions.
Part 1A - AZD4831 135 mg	Participants received single doses of AZD4831 135 mg under fasting conditions.
Part 1A - AZD4831 405 mg	Participants received single doses of AZD4831 405 mg under fasting conditions.
Part 1B - AZD4831 45 mg	Participants from Cohort 3 (Part 1A, 45 mg AZD4831) received another dose of 45 mg AZD4831 under fed conditions

Measured Values

	Part 1A - AZD4831 5 mg	Part 1A - AZD4831 15 mg	Part 1A - AZD4831 45 mg	Part 1A - AZD4831 135 mg	Part 1A - AZD4831 405 mg	Part 1B - AZD4831 45 mg
Number of Participants Analyzed [units:participants]	6	6	6	6	6	4
Terminal half-life, estimated as (ln2)/λz (t1/2λz) - For Part 1A (fasting) and Part 1B (fed) [units: Hour] Mean (Standard Deviation)	38.81 (11.18)	45.34 (4.307)	50.02 (3.475)	48.80 (6.854)	38.21 (2.906)	58.47 (8.180)

No statistical analysis provided for Terminal half-life, estimated as (ln2)/λz (t1/2λz) - For Part 1A (fasting) and Part 1B (fed)

6. Secondary Outcome Measure: Area under the plasma concentration-curve from time zero to the time of last quantifiable analyte concentration (AUC0-t) - For Part 1A (fasting) and Part 1B (fed) [ Time Frame: At predose and at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4,6, 8, 12, 24, 36 and 48 hours postdose (Days 1 to 3) ]

Measure Type	Secondary
Measure Name	Area under the plasma concentration-curve from time zero to the time of last quantifiable analyte concentration (AUC0-t) - For Part 1A (fasting) and Part 1B (fed)
Measure Description	To assess the PK parameter AUC0-t of AZD4831 following single oral administration of AZD4831 in Part 1A under fasting conditions and following single oral administration of 45 mg AZD4831 in Part 1B under fed conditions
Time Frame	At predose and at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4,6, 8, 12, 24, 36 and 48 hours postdose (Days 1 to 3)
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The PK analysis set consisted of all participants in the safety analysis set who received AZD4831 and who had evaluable PK data, with no major protocol deviations thought to impact on the analysis of the PK data.

Reporting Groups

	Description
Part 1A - AZD4831 5 mg	Participants received single doses of AZD4831 5 mg under fasting conditions.
Part 1A - AZD4831 15 mg	Participants received single doses of AZD4831 15 mg under fasting conditions.
Part 1A - AZD4831 45 mg	Participants received single doses of AZD4831 45 mg under fasting conditions.
Part 1A - AZD4831 135 mg	Participants received single doses of AZD4831 135 mg under fasting conditions.
Part 1A - AZD4831 405 mg	Participants received single doses of AZD4831 405 mg under fasting conditions.
Part 1B - AZD4831 45 mg	Participants from Cohort 3 (Part 1A, 45 mg AZD4831) received another dose of 45 mg AZD4831 under fed conditions

Measured Values

	Part 1A - AZD4831 5 mg	Part 1A - AZD4831 15 mg	Part 1A - AZD4831 45 mg	Part 1A - AZD4831 135 mg	Part 1A - AZD4831 405 mg	Part 1B - AZD4831 45 mg
Number of Participants Analyzed [units:participants]	6	6	6	6	6	4
Area under the plasma concentration-curve from time zero to the time of last quantifiable analyte concentration (AUC0-t) - For Part 1A (fasting) and Part 1B (fed) [units: h*nmol/L] Geometric Mean (Geometric Coefficient of Variation)	294.4 (13.2%)	1444 (16.2%)	6126 (15.1%)	18460 (31.9%)	50350 (35.3%)	5365 (10.6%)

No statistical analysis provided for Area under the plasma concentration-curve from time zero to the time of last quantifiable analyte concentration (AUC0-t) - For Part 1A (fasting) and Part 1B (fed)

7. Secondary Outcome Measure: Area under the concentration-time curve from time zero extrapolated to infinity (AUC) - For Part 1A (fasting) and Part 1B (fed) [ Time Frame: At predose and at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4,6, 8, 12, 24, 36 and 48 hours postdose (Days 1 to 3) ]

Measure Type	Secondary
Measure Name	Area under the concentration-time curve from time zero extrapolated to infinity (AUC) - For Part 1A (fasting) and Part 1B (fed)
Measure Description	To assess the PK parameter AUC of AZD4831 following single oral administration of AZD4831 in Part 1A under fasting conditions and following single oral administration of 45 mg AZD4831 in Part 1B under fed conditions
Time Frame	At predose and at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4,6, 8, 12, 24, 36 and 48 hours postdose (Days 1 to 3)
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The PK analysis set consisted of all participants in the safety analysis set who received AZD4831 and who had evaluable PK data, with no major protocol deviations thought to impact on the analysis of the PK data.

Reporting Groups

	Description
Part 1A - AZD4831 5 mg	Participants received single doses of AZD4831 5 mg under fasting conditions.
Part 1A - AZD4831 15 mg	Participants received single doses of AZD4831 15 mg under fasting conditions.
Part 1A - AZD4831 45 mg	Participants received single doses of AZD4831 45 mg under fasting conditions.
Part 1A - AZD4831 135 mg	Participants received single doses of AZD4831 135 mg under fasting conditions.
Part 1A - AZD4831 405 mg	Participants received single doses of AZD4831 405 mg under fasting conditions.
Part 1B - AZD4831 45 mg	Participants from Cohort 3 (Part 1A, 45 mg AZD4831) received another dose of 45 mg AZD4831 under fed conditions

Measured Values

	Part 1A - AZD4831 5 mg	Part 1A - AZD4831 15 mg	Part 1A - AZD4831 45 mg	Part 1A - AZD4831 135 mg	Part 1A - AZD4831 405 mg	Part 1B - AZD4831 45 mg
Number of Participants Analyzed [units:participants]	6	6	6	6	6	4
Area under the concentration-time curve from time zero extrapolated to infinity (AUC) - For Part 1A (fasting) and Part 1B (fed) [units: h*nmol/L] Geometric Mean (Geometric Coefficient of Variation)	513.9 (13.6%)	1669 (16.4%)	6685 (16.5%)	19360 (32.5%)	52390 (34.3%)	5790 (8.3%)

Statistical Analysis 1 for Area under the concentration-time curve from time zero extrapolated to infinity (AUC) - For Part 1A (fasting) and Part 1B (fed)

Groups^[1]	Part 1A - AZD4831 5 mg, Part 1A - AZD4831 15 mg, Part 1A - AZD4831 45 mg, Part 1A - AZD4831 135 mg, Part 1A - AZD4831 405 mg
Non-Inferiority/Equivalence Test^[2]	No
Slope^[5]	1.060
Standard Error of the mean	± 0.03219
95% Confidence Interval	( 0.9943 to 1.127 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[5]	Other relevant estimation information:
	No text entered.

8. Secondary Outcome Measure: Apparent clearance for parent drug estimated as dose divided by AUC (CL/F) - For Part 1A (fasting) and Part 1B (fed) [ Time Frame: At predose and at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4,6, 8, 12, 24, 36 and 48 hours postdose (Days 1 to 3) ]

Measure Type	Secondary
Measure Name	Apparent clearance for parent drug estimated as dose divided by AUC (CL/F) - For Part 1A (fasting) and Part 1B (fed)
Measure Description	To assess the PK parameter CL/F of AZD4831 following single oral administration of AZD4831 in Part 1A under fasting conditions and following single oral administration of 45 mg AZD4831 in Part 1B under fed conditions
Time Frame	At predose and at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4,6, 8, 12, 24, 36 and 48 hours postdose (Days 1 to 3)
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The PK analysis set consisted of all participants in the safety analysis set who received AZD4831 and who had evaluable PK data, with no major protocol deviations thought to impact on the analysis of the PK data.

Reporting Groups

	Description
Part 1A - AZD4831 5 mg	Participants received single doses of AZD4831 5 mg under fasting conditions.
Part 1A - AZD4831 15 mg	Participants received single doses of AZD4831 15 mg under fasting conditions.
Part 1A - AZD4831 45 mg	Participants received single doses of AZD4831 45 mg under fasting conditions.
Part 1A - AZD4831 135 mg	Participants received single doses of AZD4831 135 mg under fasting conditions.
Part 1A - AZD4831 405 mg	Participants received single doses of AZD4831 405 mg under fasting conditions.
Part 1B - AZD4831 45 mg	Participants from Cohort 3 (Part 1A, 45 mg AZD4831) received another dose of 45 mg AZD4831 under fed conditions

Measured Values

	Part 1A - AZD4831 5 mg	Part 1A - AZD4831 15 mg	Part 1A - AZD4831 45 mg	Part 1A - AZD4831 135 mg	Part 1A - AZD4831 405 mg	Part 1B - AZD4831 45 mg
Number of Participants Analyzed [units:participants]	6	6	6	6	6	4
Apparent clearance for parent drug estimated as dose divided by AUC (CL/F) - For Part 1A (fasting) and Part 1B (fed) [units: Litre/hour (L/h)] Mean (Standard Deviation)	29.26 (4.100)	27.15 (4.395)	20.33 (3.205)	21.83 (8.207)	24.11 (7.242)	23.28 (1.999)

No statistical analysis provided for Apparent clearance for parent drug estimated as dose divided by AUC (CL/F) - For Part 1A (fasting) and Part 1B (fed)

9. Secondary Outcome Measure: Mean Residence Time (MRT) - For Part 1A (fasting) and Part 1B (fed) [ Time Frame: At predose and at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4,6, 8, 12, 24, 36 and 48 hours postdose (Days 1 to 3) ]

Measure Type	Secondary
Measure Name	Mean Residence Time (MRT) - For Part 1A (fasting) and Part 1B (fed)
Measure Description	To assess the PK parameter MRT of AZD4831 following single oral administration of AZD4831 in Part 1A under fasting conditions and following single oral administration of 45 mg AZD4831 in Part 1B under fed conditions
Time Frame	At predose and at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4,6, 8, 12, 24, 36 and 48 hours postdose (Days 1 to 3)
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The PK analysis set consisted of all participants in the safety analysis set who received AZD4831 and who had evaluable PK data, with no major protocol deviations thought to impact on the analysis of the PK data.

Reporting Groups

	Description
Part 1A - AZD4831 5 mg	Participants received single doses of AZD4831 5 mg under fasting conditions.
Part 1A - AZD4831 15 mg	Participants received single doses of AZD4831 15 mg under fasting conditions.
Part 1A - AZD4831 45 mg	Participants received single doses of AZD4831 45 mg under fasting conditions.
Part 1A - AZD4831 135 mg	Participants received single doses of AZD4831 135 mg under fasting conditions.
Part 1A - AZD4831 405 mg	Participants received single doses of AZD4831 405 mg under fasting conditions.
Part 1B - AZD4831 45 mg	Participants from Cohort 3 (Part 1A, 45 mg AZD4831) received another dose of 45 mg AZD4831 under fed conditions

Measured Values

	Part 1A - AZD4831 5 mg	Part 1A - AZD4831 15 mg	Part 1A - AZD4831 45 mg	Part 1A - AZD4831 135 mg	Part 1A - AZD4831 405 mg	Part 1B - AZD4831 45 mg
Number of Participants Analyzed [units:participants]	6	6	6	6	6	4
Mean Residence Time (MRT) - For Part 1A (fasting) and Part 1B (fed) [units: Hour] Mean (Standard Deviation)	54.46 (15.56)	56.02 (5.107)	61.98 (5.670)	57.40 (10.79)	44.86 (8.786)	69.48 (10.05)

No statistical analysis provided for Mean Residence Time (MRT) - For Part 1A (fasting) and Part 1B (fed)

10. Secondary Outcome Measure: Apparent volume of distribution for parent drug at terminal phase (Vz/F) - For Part 1A (fasting) and Part 1B (fed) [ Time Frame: At predose and at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4,6, 8, 12, 24, 36 and 48 hours postdose (Days 1 to 3) ]

Measure Type	Secondary
Measure Name	Apparent volume of distribution for parent drug at terminal phase (Vz/F) - For Part 1A (fasting) and Part 1B (fed)
Measure Description	To assess the PK parameter Vz/F of AZD4831 following single oral administration of AZD4831 in Part 1A under fasting conditions and following single oral administration of 45 mg AZD4831 in Part 1B under fed conditions
Time Frame	At predose and at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4,6, 8, 12, 24, 36 and 48 hours postdose (Days 1 to 3)
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The PK analysis set consisted of all participants in the safety analysis set who received AZD4831 and who had evaluable PK data, with no major protocol deviations thought to impact on the analysis of the PK data.

Reporting Groups

	Description
Part 1A - AZD4831 5 mg	Participants received single doses of AZD4831 5 mg under fasting conditions.
Part 1A - AZD4831 15 mg	Participants received single doses of AZD4831 15 mg under fasting conditions.
Part 1A - AZD4831 45 mg	Participants received single doses of AZD4831 45 mg under fasting conditions.
Part 1A - AZD4831 135 mg	Participants received single doses of AZD4831 135 mg under fasting conditions.
Part 1A - AZD4831 405 mg	Participants received single doses of AZD4831 405 mg under fasting conditions.
Part 1B - AZD4831 45 mg	Participants from Cohort 3 (Part 1A, 45 mg AZD4831) received another dose of 45 mg AZD4831 under fed conditions

Measured Values

	Part 1A - AZD4831 5 mg	Part 1A - AZD4831 15 mg	Part 1A - AZD4831 45 mg	Part 1A - AZD4831 135 mg	Part 1A - AZD4831 405 mg	Part 1B - AZD4831 45 mg
Number of Participants Analyzed [units:participants]	6	6	6	6	6	4
Apparent volume of distribution for parent drug at terminal phase (Vz/F) - For Part 1A (fasting) and Part 1B (fed) [units: Litre (L)] Mean (Standard Deviation)	1597 (293.7)	1777 (321.8)	1458 (182.2)	1562 (694.2)	1348 (484.7)	1962 (303.6)

No statistical analysis provided for Apparent volume of distribution for parent drug at terminal phase (Vz/F) - For Part 1A (fasting) and Part 1B (fed)

11. Secondary Outcome Measure: Area under the plasma concentration-time curve from time zero to time of last quantifiable analyte concentration divided by the dose administered (AUC0-t/D) - For Part 1A (fasting) and Part 1B (fed) [ Time Frame: At predose and at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4,6, 8, 12, 24, 36 and 48 hours postdose (Days 1 to 3) ]

Measure Type	Secondary
Measure Name	Area under the plasma concentration-time curve from time zero to time of last quantifiable analyte concentration divided by the dose administered (AUC0-t/D) - For Part 1A (fasting) and Part 1B (fed)
Measure Description	To assess the PK parameter AUC0-t/D of AZD4831 following single oral administration of AZD4831 in Part 1A under fasting conditions and following single oral administration of 45 mg AZD4831 in Part 1B under fed conditions
Time Frame	At predose and at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4,6, 8, 12, 24, 36 and 48 hours postdose (Days 1 to 3)
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The PK analysis set consisted of all participants in the safety analysis set who received AZD4831 and who had evaluable PK data, with no major protocol deviations thought to impact on the analysis of the PK data.

Reporting Groups

	Description
Part 1A - AZD4831 5 mg	Participants received single doses of AZD4831 5 mg under fasting conditions.
Part 1A - AZD4831 15 mg	Participants received single doses of AZD4831 15 mg under fasting conditions.
Part 1A - AZD4831 45 mg	Participants received single doses of AZD4831 45 mg under fasting conditions.
Part 1A - AZD4831 135 mg	Participants received single doses of AZD4831 135 mg under fasting conditions.
Part 1A - AZD4831 405 mg	Participants received single doses of AZD4831 405 mg under fasting conditions.
Part 1B - AZD4831 45 mg	Participants from Cohort 3 (Part 1A, 45 mg AZD4831) received another dose of 45 mg AZD4831 under fed conditions

Measured Values

	Part 1A - AZD4831 5 mg	Part 1A - AZD4831 15 mg	Part 1A - AZD4831 45 mg	Part 1A - AZD4831 135 mg	Part 1A - AZD4831 405 mg	Part 1B - AZD4831 45 mg
Number of Participants Analyzed [units:participants]	6	6	6	6	6	4
Area under the plasma concentration-time curve from time zero to time of last quantifiable analyte concentration divided by the dose administered (AUC0-t/D) - For Part 1A (fasting) and Part 1B (fed) [units: h*nmol/L/umol] Geometric Mean (Geometric Coefficient of Variation)	0.01971 (13.2%)	0.03222 (16.2%)	0.04558 (15.1%)	0.04579 (31.9%)	0.04162 (35.3%)	0.03992 (10.6%)

No statistical analysis provided for Area under the plasma concentration-time curve from time zero to time of last quantifiable analyte concentration divided by the dose administered (AUC0-t/D) - For Part 1A (fasting) and Part 1B (fed)

12. Secondary Outcome Measure: Area under the plasma concentration-time curve from time zero extrapolated to infinity divided by the dose administered (AUC/D) - For Part 1A (fasting) and Part 1B (fed) [ Time Frame: At predose and at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4,6, 8, 12, 24, 36 and 48 hours postdose (Days 1 to 3) ]

Measure Type	Secondary
Measure Name	Area under the plasma concentration-time curve from time zero extrapolated to infinity divided by the dose administered (AUC/D) - For Part 1A (fasting) and Part 1B (fed)
Measure Description	To assess the PK parameter AUC/D of AZD4831 following single oral administration of AZD4831 in Part 1A under fasting conditions and following single oral administration of 45 mg AZD4831 in Part 1B under fed conditions
Time Frame	At predose and at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4,6, 8, 12, 24, 36 and 48 hours postdose (Days 1 to 3)
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The PK analysis set consisted of all participants in the safety analysis set who received AZD4831 and who had evaluable PK data, with no major protocol deviations thought to impact on the analysis of the PK data.

Reporting Groups

	Description
Part 1A - AZD4831 5 mg	Participants received single doses of AZD4831 5 mg under fasting conditions.
Part 1A - AZD4831 15 mg	Participants received single doses of AZD4831 15 mg under fasting conditions.
Part 1A - AZD4831 45 mg	Participants received single doses of AZD4831 45 mg under fasting conditions.
Part 1A - AZD4831 135 mg	Participants received single doses of AZD4831 135 mg under fasting conditions.
Part 1A - AZD4831 405 mg	Participants received single doses of AZD4831 405 mg under fasting conditions.
Part 1B - AZD4831 45 mg	Participants from Cohort 3 (Part 1A, 45 mg AZD4831) received another dose of 45 mg AZD4831 under fed conditions

Measured Values

	Part 1A - AZD4831 5 mg	Part 1A - AZD4831 15 mg	Part 1A - AZD4831 45 mg	Part 1A - AZD4831 135 mg	Part 1A - AZD4831 405 mg	Part 1B - AZD4831 45 mg
Number of Participants Analyzed [units:participants]	6	6	6	6	6	4
Area under the plasma concentration-time curve from time zero extrapolated to infinity divided by the dose administered (AUC/D) - For Part 1A (fasting) and Part 1B (fed) [units: h*nmol/L/umol] Geometric Mean (Geometric Coefficient of Variation)	0.03441 (13.6%)	0.03725 (16.4%)	0.04974 (16.5%)	0.04801 (32.5%)	0.04331 (34.3%)	0.04308 (8.3%)

No statistical analysis provided for Area under the plasma concentration-time curve from time zero extrapolated to infinity divided by the dose administered (AUC/D) - For Part 1A (fasting) and Part 1B (fed)

13. Secondary Outcome Measure: Observed maximum plasma concentration divided by the dose administered (Cmax/D) - For Part 1A (fasting) and Part 1B (fed) [ Time Frame: At predose and at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4,6, 8, 12, 24, 36 and 48 hours postdose (Days 1 to 3) ]

Measure Type	Secondary
Measure Name	Observed maximum plasma concentration divided by the dose administered (Cmax/D) - For Part 1A (fasting) and Part 1B (fed)
Measure Description	To assess the PK parameter Cmax/D of AZD4831 following single oral administration of AZD4831 in Part 1A under fasting conditions and following single oral administration of 45 mg AZD4831 in Part 1B under fed conditions
Time Frame	At predose and at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4,6, 8, 12, 24, 36 and 48 hours postdose (Days 1 to 3)
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The PK analysis set consisted of all participants in the safety analysis set who received AZD4831 and who had evaluable PK data, with no major protocol deviations thought to impact on the analysis of the PK data.

Reporting Groups

	Description
Part 1A - AZD4831 5 mg	Participants received single doses of AZD4831 5 mg under fasting conditions.
Part 1A - AZD4831 15 mg	Participants received single doses of AZD4831 15 mg under fasting conditions.
Part 1A - AZD4831 45 mg	Participants received single doses of AZD4831 45 mg under fasting conditions.
Part 1A - AZD4831 135 mg	Participants received single doses of AZD4831 135 mg under fasting conditions.
Part 1A - AZD4831 405 mg	Participants received single doses of AZD4831 405 mg under fasting conditions.
Part 1B - AZD4831 45 mg	Participants from Cohort 3 (Part 1A, 45 mg AZD4831) received another dose of 45 mg AZD4831 under fed conditions

Measured Values

	Part 1A - AZD4831 5 mg	Part 1A - AZD4831 15 mg	Part 1A - AZD4831 45 mg	Part 1A - AZD4831 135 mg	Part 1A - AZD4831 405 mg	Part 1B - AZD4831 45 mg
Number of Participants Analyzed [units:participants]	6	6	6	6	6	4
Observed maximum plasma concentration divided by the dose administered (Cmax/D) - For Part 1A (fasting) and Part 1B (fed) [units: nmol/L/umol] Geometric Mean (Geometric Coefficient of Variation)	0.001001 (23.9%)	0.001862 (19.4%)	0.002427 (27.8%)	0.002708 (83.1%)	0.002510 (105.8%)	0.001366 (9.4%)

No statistical analysis provided for Observed maximum plasma concentration divided by the dose administered (Cmax/D) - For Part 1A (fasting) and Part 1B (fed)

14. Secondary Outcome Measure: Cumulative amount of analyte excreted at time t [Ae(0-t)] - For Part 1A (fasting) only [ Time Frame: Spot sample at predose and pooled urine at 0-3, 3-6, 6-9, 9-12, 12-24, 24-36 and 36-48 hours postdose ]

Measure Type	Secondary
Measure Name	Cumulative amount of analyte excreted at time t [Ae(0-t)] - For Part 1A (fasting) only
Measure Description	To assess the urine PK parameter Ae(0-t) of AZD4831 following single oral administration of AZD4831 in Part 1A under fasting conditions
Time Frame	Spot sample at predose and pooled urine at 0-3, 3-6, 6-9, 9-12, 12-24, 24-36 and 36-48 hours postdose
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The PK analysis set consisted of all participants in the safety analysis set who received AZD4831 and who had evaluable PK data, with no major protocol deviations thought to impact on the analysis of the PK data.

Reporting Groups

	Description
Part 1A - AZD4831 5 mg	Participants received single doses of AZD4831 5 mg under fasting conditions.
Part 1A - AZD4831 15 mg	Participants received single doses of AZD4831 15 mg under fasting conditions.
Part 1A - AZD4831 45 mg	Participants received single doses of AZD4831 45 mg under fasting conditions.
Part 1A - AZD4831 135 mg	Participants received single doses of AZD4831 135 mg under fasting conditions.
Part 1A - AZD4831 405 mg	Participants received single doses of AZD4831 405 mg under fasting conditions.

Measured Values

	Part 1A - AZD4831 5 mg	Part 1A - AZD4831 15 mg	Part 1A - AZD4831 45 mg	Part 1A - AZD4831 135 mg	Part 1A - AZD4831 405 mg
Number of Participants Analyzed [units:participants]	6	6	6	6	6
Cumulative amount of analyte excreted at time t [Ae(0-t)] - For Part 1A (fasting) only [units: nmol] Mean (Standard Deviation)	4561 (1059)	14460 (829.8)	37650 (8572)	116000 (39240)	349300 (194400)

No statistical analysis provided for Cumulative amount of analyte excreted at time t [Ae(0-t)] - For Part 1A (fasting) only

15. Secondary Outcome Measure: Cumulative fraction of dose excreted unchanged in urine (Cumfe0-48) - For Part 1A (fasting) only [ Time Frame: Spot sample at predose and pooled urine at 0-3, 3-6, 6-9, 9-12, 12-24, 24-36 and 36-48 hours postdose ]

Measure Type	Secondary
Measure Name	Cumulative fraction of dose excreted unchanged in urine (Cumfe0-48) - For Part 1A (fasting) only
Measure Description	To assess the urine PK parameter Cumfe0-48 of AZD4831 following single oral administration of AZD4831 in Part 1A under fasting conditions
Time Frame	Spot sample at predose and pooled urine at 0-3, 3-6, 6-9, 9-12, 12-24, 24-36 and 36-48 hours postdose
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The PK analysis set consisted of all participants in the safety analysis set who received AZD4831 and who had evaluable PK data, with no major protocol deviations thought to impact on the analysis of the PK data.

Reporting Groups

	Description
Part 1A - AZD4831 5 mg	Participants received single doses of AZD4831 5 mg under fasting conditions.
Part 1A - AZD4831 15 mg	Participants received single doses of AZD4831 15 mg under fasting conditions.
Part 1A - AZD4831 45 mg	Participants received single doses of AZD4831 45 mg under fasting conditions.
Part 1A - AZD4831 135 mg	Participants received single doses of AZD4831 135 mg under fasting conditions.
Part 1A - AZD4831 405 mg	Participants received single doses of AZD4831 405 mg under fasting conditions.

Measured Values

	Part 1A - AZD4831 5 mg	Part 1A - AZD4831 15 mg	Part 1A - AZD4831 45 mg	Part 1A - AZD4831 135 mg	Part 1A - AZD4831 405 mg
Number of Participants Analyzed [units:participants]	6	6	6	6	6
Cumulative fraction of dose excreted unchanged in urine (Cumfe0-48) - For Part 1A (fasting) only [units: Percentage] Mean (Standard Deviation)	30.54 (7.089)	32.28 (1.852)	28.01 (6.337)	28.76 (9.732)	28.88 (16.07)

No statistical analysis provided for Cumulative fraction of dose excreted unchanged in urine (Cumfe0-48) - For Part 1A (fasting) only

16. Secondary Outcome Measure: Renal clearance, estimated by dividing Ae(0-t) by AUC(0-t) (CLR) - For Part 1A (fasting) only [ Time Frame: Spot sample at predose and pooled urine at 0-3, 3-6, 6-9, 9-12, 12-24, 24-36 and 36-48 hours postdose ]

Measure Type	Secondary
Measure Name	Renal clearance, estimated by dividing Ae(0-t) by AUC(0-t) (CLR) - For Part 1A (fasting) only
Measure Description	To assess the urine PK parameter CLR of AZD4831 following single oral administration of AZD4831 in Part 1A under fasting conditions
Time Frame	Spot sample at predose and pooled urine at 0-3, 3-6, 6-9, 9-12, 12-24, 24-36 and 36-48 hours postdose
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The PK analysis set consisted of all participants in the safety analysis set who received AZD4831 and who had evaluable PK data, with no major protocol deviations thought to impact on the analysis of the PK data.

Reporting Groups

	Description
Part 1A - AZD4831 5 mg	Participants received single doses of AZD4831 5 mg under fasting conditions.
Part 1A - AZD4831 15 mg	Participants received single doses of AZD4831 15 mg under fasting conditions.
Part 1A - AZD4831 45 mg	Participants received single doses of AZD4831 45 mg under fasting conditions.
Part 1A - AZD4831 135 mg	Participants received single doses of AZD4831 135 mg under fasting conditions.
Part 1A - AZD4831 405 mg	Participants received single doses of AZD4831 405 mg under fasting conditions.

Measured Values

	Part 1A - AZD4831 5 mg	Part 1A - AZD4831 15 mg	Part 1A - AZD4831 45 mg	Part 1A - AZD4831 135 mg	Part 1A - AZD4831 405 mg
Number of Participants Analyzed [units:participants]	6	6	6	6	6
Renal clearance, estimated by dividing Ae(0-t) by AUC(0-t) (CLR) - For Part 1A (fasting) only [units: Litre/hour (L/h)] Mean (Standard Deviation)	15.42 (3.271)	14.54 (1.825)	9.790 (1.386)	9.459 (1.402)	8.882 (3.704)

No statistical analysis provided for Renal clearance, estimated by dividing Ae(0-t) by AUC(0-t) (CLR) - For Part 1A (fasting) only

Serious Adverse Events

Time Frame	Screening (Only SAEs), Day -1 (Only SAEs), Days 1 to 3, Follow-up 7 to 10 days post (final) dose.
Additional Description	No text entered.

Reporting Groups

	Description
Part 1A - AZD4831 5 mg	Participants received single doses of AZD4831 5 mg under fasting conditions.
Part 1A - AZD4831 15 mg	Participants received single doses of AZD4831 15 mg under fasting conditions.
Part 1A - AZD4831 45 mg	Participants received single doses of AZD4831 45 mg under fasting conditions.
Part 1A - AZD4831 135 mg	Participants received single doses of AZD4831 135 mg under fasting conditions.
Part 1A - AZD4831 405 mg	Participants received single doses of AZD4831 405 mg under fasting conditions.
Part 1A - Pooled Placebo	Participants received matching placebo.
Part 1B - AZD4831 45 mg	Participants from Cohort 3 (Part 1A, 45 mg AZD4831) received another dose of 45 mg AZD4831 under fed conditions

Serious Adverse Events

	Part 1A - AZD4831 5 mg	Part 1A - AZD4831 15 mg	Part 1A - AZD4831 45 mg	Part 1A - AZD4831 135 mg	Part 1A - AZD4831 405 mg	Part 1A - Pooled Placebo	Part 1B - AZD4831 45 mg
Total, serious adverse events
# participants affected / at risk	0/6 (0.00%)	0/6 (0.00%)	0/6 (0.00%)	0/6 (0.00%)	0/6 (0.00%)	0/10 (0.00%)	0/4 (0.00%)

Other Adverse Events

Time Frame	Screening (Only SAEs), Day -1 (Only SAEs), Days 1 to 3, Follow-up 7 to 10 days post (final) dose.
Additional Description	No text entered.

Frequency Threshold

Threshold above which other adverse events are reported	0%

Reporting Groups

	Description
Part 1A - AZD4831 5 mg	Participants received single doses of AZD4831 5 mg under fasting conditions.
Part 1A - AZD4831 15 mg	Participants received single doses of AZD4831 15 mg under fasting conditions.
Part 1A - AZD4831 45 mg	Participants received single doses of AZD4831 45 mg under fasting conditions.
Part 1A - AZD4831 135 mg	Participants received single doses of AZD4831 135 mg under fasting conditions.
Part 1A - AZD4831 405 mg	Participants received single doses of AZD4831 405 mg under fasting conditions.
Part 1A - Pooled Placebo	Participants received matching placebo.
Part 1B - AZD4831 45 mg	Participants from Cohort 3 (Part 1A, 45 mg AZD4831) received another dose of 45 mg AZD4831 under fed conditions

Other Adverse Events

Part 1A - AZD4831 5 mg

Part 1A - AZD4831 15 mg

Part 1A - AZD4831 45 mg

Part 1A - AZD4831 135 mg

Part 1A - AZD4831 405 mg

Part 1A - Pooled Placebo

Part 1B - AZD4831 45 mg

Total, other (not including serious) adverse events

# participants affected / at risk

2/6 (33.33%)

3/6 (50.00%)

2/6 (33.33%)

4/10 (40.00%)

0/4 (0.00%)

Nervous system disorders

Headache¹

# participants affected / at risk

0/6 (0.00%)

1/6 (16.67%)

2/6 (33.33%)

1/6 (16.67%)

0/6 (0.00%)

4/10 (40.00%)

0/4 (0.00%)

# events

Skin and subcutaneous tissue disorders

Rash maculo-papular¹

# participants affected / at risk

0/6 (0.00%)

1/6 (16.67%)

2/6 (33.33%)

0/10 (0.00%)

0/4 (0.00%)

# events

Infections and infestations

Gastroenteritis¹

# participants affected / at risk

0/6 (0.00%)

1/6 (16.67%)

0/6 (0.00%)

0/10 (0.00%)

0/4 (0.00%)

# events

Infections and infestations

Nasopharyngitis¹

# participants affected / at risk

0/6 (0.00%)

1/6 (16.67%)

0/6 (0.00%)

0/10 (0.00%)

0/4 (0.00%)

# events

Infections and infestations

Rhinitis¹

# participants affected / at risk

0/6 (0.00%)

1/6 (16.67%)

0/10 (0.00%)

0/4 (0.00%)

# events

Respiratory, thoracic and mediastinal disorders

Oropharyngeal pain¹

# participants affected / at risk

1/6 (16.67%)

0/6 (0.00%)

1/6 (16.67%)

0/10 (0.00%)

0/4 (0.00%)

# events

Respiratory, thoracic and mediastinal disorders

Epistaxis¹

# participants affected / at risk

0/6 (0.00%)

1/6 (16.67%)

0/6 (0.00%)

0/10 (0.00%)

0/4 (0.00%)

# events

Psychiatric disorders

Restlessness¹

# participants affected / at risk

1/6 (16.67%)

0/6 (0.00%)

1/10 (10.00%)

0/4 (0.00%)

# events

†	Events were collected by systematic assessment
1	Term from vocabulary, MedDRA version 19.1

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

The agreement is:

	The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
	The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days . The sponsor cannot require changes to the communication and cannot extend the embargo.
	Other disclosure agreement that restricts the right of the PI to discuss or publish trial results after the trial is completed. Restriction Description: All clinical study findings and documents will be regarded as confidential and property of the sponsor. No unpublished information contained herein may be disclosed without prior written approval from AstraZeneca AB.

Limitations and Caveats

Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
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Results Point of Contact

Name/Title:	Global Clinical Leader
Organization:	AstraZeneca AB
Phone	+46 766 346712
E-mail:	[email protected]

Documents available

Trial Results Summaries
Available here

Contacts

Contact

AstraZeneca Clinical Study Information Center

1-877-240-9479

information.center@astrazeneca.com

Investigators

Principal Investigator

Rainard Fuhr

PAREXEL Early Phase Clinical Unit Berlin, On the premises of Klinikum Westend, Haus 31, Spandauer Damm 130, 14050 Berlin, Germany

Sponsors

Collaborators

Exclusion Criteria

Trial Results Summaries