A Phase I, Safety Tolerability and Pharmacokinetics of AZD4831 to Treat Cardiovascular Disease

Study identifier:D6580C00004

ClinicalTrials.gov identifier:NCT03136991

EudraCT identifier:N/A

CTIS identifier:N/A

Study Complete

Official Title

A Phase I, Randomized, Single-blind, Placebo-controlled Study to Assess the Safety, Tolerability and Pharmacokinetics of AZD4831 after Multiple Ascending Dose Administration to Healthy Male Subjects

Medical condition

cardiovascular disease

Phase

Phase 1

Healthy volunteers

Yes

Study drug

AZD4831, Placebo

Sex

Male

Actual Enrollment

Study type

Interventional

Age

18 Years - 50 Years

Date

Study Start Date: 15 May 2017

Primary Completion Date: 22 Nov 2017

Study Completion Date: 22 Nov 2017

Study design

Allocation: Randomized
Endpoint Classification: -
Intervention Model: Parallel Assignment
Masking: Single Blind
Primary Purpose: Treatment

Verification:

Verified 01 Jan 2020 by AstraZeneca

Collaborators

PAREXEL

Inclusion and exclusion criteria

Inclusion Criteria

• Healthy male participants aged 18 to 50 years (inclusive at Screening) with suitable veins for cannulation or repeated venipuncture.
• Have a BMI between 18 and 30 kg/m2 inclusive and weigh at least 50 kg and no more than 100 kg inclusive.

Exclusion Criteria

• History of any clinically significant disease or disorder which, in the opinion of the Investigator, may either put the subject at risk because of participation in the study, or influence the results or the subject’s ability to participate in the study.
• History or presence of gastrointestinal (GI), hepatic or renal disease, or any other condition known to interfere with absorption, distribution, metabolism, or excretion of drugs.
• 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 IMP.
• Any clinically significant abnormalities in biochemistry, hematology, or urinalysis results, as judged by the Investigator at Screening and/or Day 1, including
a)Alanine aminotransferase (ALT) not within normal range;
b)Aspartate aminotransferase (AST) not within normal range;
c)Creatinine not within normal range;
d)White blood cell (WBC) not within normal range;
e)Hemoglobin not within normal range; and
f)Estimated Glomerular Filtration Rate (eGFR) not within normal range.
• Any positive result on screening for serum hepatitis B surface antigen (HBsAg), hepatitis C antibody and human immunodeficiency virus (HIV) type 1 and 2.
• Abnormal vital signs, after 10 minutes supine rest, at Screening and/or Day 1, defined as any of the following:
a)Systolic BP (SBP) < 90 mmHg or ≥ 140 mmHg
b)Diastolic BP (DBP) < 50 mmHg or ≥ 90 mmHg
c)Pulse < 45 or > 85 beats per minute (bpm)
• Persistent or intermittent complete bundle branch block, incomplete bundle branch block, or interventricular conduction delay with QRS > 110 ms. Participants with QRS > 110 ms but < 115 ms are acceptable if there is no evidence of, for example, ventricular hypertrophy or pre-excitation at Screening and/or Day 1.
• Electrocardiogram findings suggesting a metabolic or other non-cardiac condition that may confound interpretation of serial changes (such as hypokalemia) at Screening and/or Day 1.
• Use of any prescribed or non-prescribed medication (other than paracetamol/acetaminophen), including antacids, analgesics, 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 participants, e.g., kept in detention, protected adults under guardianship, trusteeship, or committed to an institution by governmental or juridical order.

Location

Research Site

Glendale, CA, United States, 91206

Arms	Assigned Interventions
Active Comparator: Cohort 1 Participants will receive AZD4831 5 mg/placebo oral suspension.	Drug: AZD4831 Participants will receive AZD4831 once daily, orally, for a period of 10 days. Note: Additional doses (for cohorts 2,3&4) are provisional and could be adjusted based on the emerging data after the review of all available safety or other pertinent data from the previous dose by the Safety Review Committee (SRC). Drug: Placebo Participants will receive placebo matching the AZD4831 dose, once daily, orally, for a period of 10 days.
Active Comparator: Cohort 2 Participants will receive AZD4831 (Additional dose 1)/placebo oral suspension.	Drug: AZD4831 Participants will receive AZD4831 once daily, orally, for a period of 10 days. Note: Additional doses (for cohorts 2,3&4) are provisional and could be adjusted based on the emerging data after the review of all available safety or other pertinent data from the previous dose by the Safety Review Committee (SRC). Drug: Placebo Participants will receive placebo matching the AZD4831 dose, once daily, orally, for a period of 10 days.
Active Comparator: Cohort 3 Participants will receive AZD4831 (Additional dose 2)/placebo oral suspension.	Drug: AZD4831 Participants will receive AZD4831 once daily, orally, for a period of 10 days. Note: Additional doses (for cohorts 2,3&4) are provisional and could be adjusted based on the emerging data after the review of all available safety or other pertinent data from the previous dose by the Safety Review Committee (SRC). Drug: Placebo Participants will receive placebo matching the AZD4831 dose, once daily, orally, for a period of 10 days.
Active Comparator: Cohort 4 Participants will receive AZD4831 (Additional dose 3)/placebo oral suspension.	Drug: AZD4831 Participants will receive AZD4831 once daily, orally, for a period of 10 days. Note: Additional doses (for cohorts 2,3&4) are provisional and could be adjusted based on the emerging data after the review of all available safety or other pertinent data from the previous dose by the Safety Review Committee (SRC). Drug: Placebo Participants will receive placebo matching the AZD4831 dose, once daily, orally, for a period of 10 days.

Participant Flow

Recruitment Details

Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
A total of 38 healthy male participants aged 18 to 50 years were enrolled in 4 cohorts. Ten participants in each cohort. This study was conducted in PAREXEL Early Phase Clinical Unit – Los Angeles. The first participant was enrolled on 15 May 2017 and the last visit was on 22 November 2017.

Pre-Assignment Details

Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
Eligible participants signed informed consent form (ICF) & entered a screening period of a maximum of 28 days, inclusion/exclusion criteria were checked for any clinically significant illness or disease that would have influenced the results of the study, specifically infections, skin disorder or allergy or thyroid disease.

Reporting Groups

	Description
Placebo	Participants received placebo once daily.
AZD4831 5 mg	Participants received 5 mg of AZD4831 oral solution once daily.
AZD4831 10mg	Participants received 10 mg of AZD4831 oral solution once daily.
AZD4831 15 mg	Participants received 15 mg AZD4831 oral solution once daily.
AZD4831 45 mg	Participants received 45 mg AZD4831 oral solution once daily.

Participant Flow: Overall Study

	Placebo	AZD4831 5 mg	AZD4831 10mg	AZD4831 15 mg	AZD4831 45 mg
STARTED	8	8	8	8	6
COMPLETED	5	7	8	7	0
NOT COMPLETED	3	1	0	1	6
Withdrawal by Subject	1	1	0	0	1
Stopping criteria	1	0	0	0	3
Withdrawal criteria (generalized rash)	1	0	0	1	2

Baseline Characteristics

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

Reporting Groups

	Description
Placebo	Participants received placebo once daily.
AZD4831 5 mg	Participants received 5 mg of AZD4831 oral solution once daily.
AZD4831 10mg	Participants received 10 mg of AZD4831 oral solution once daily.
AZD4831 15 mg	Participants received 15 mg AZD4831 oral solution once daily.
AZD4831 45 mg	Participants received 45 mg AZD4831 oral solution once daily.

Baseline Measures

	Placebo	AZD4831 5 mg	AZD4831 10mg	AZD4831 15 mg	AZD4831 45 mg	Total
Number of Participants [units: Participants]	8	8	8	8	6	38
Age Continuous [units: Years] Mean ± Standard Deviation	30.9 ± 7.24	35.8 ± 6.65	33.9 ± 10.22	33.9 ± 6.20	30.8 ± 3.77	33.9 ± 7.17
Sex/Gender, Customized [units: Participants] Male	8	8	8	8	5	37
Race (NIH/OMB) [units: Participants]
American Indian or Alaska Native	0	0	0	0	0	0
Asian	1	1	0	1	0	3
Native Hawaiian or Other Pacific Islander	0	0	0	0	0	0
Black or African American	2	4	2	3	0	11
White	5	3	5	4	4	21
More than one race	0	0	0	0	0	0
Unknown or Not Reported	0	0	1	0	1	2
Ethnicity (NIH/OMB) [units: Participants]
Hispanic or Latino	3	3	1	1	1	9
Not Hispanic or Latino	5	5	7	7	4	28
Unknown or Not Reported	0	0	0	0	0	0

Outcome Measures

1. Primary Outcome Measure: Number of participants with adverse events (AEs) [ Time Frame: From Screening (Day -28 to Day -2) until Final follow-up (Day 24) ]

Measure Type	Primary
Measure Name	Number of participants with adverse events (AEs)
Measure Description	To assess the safety and tolerability of AZD4831 following oral administration of multiple ascending doses.
Time Frame	From Screening (Day -28 to Day -2) until Final follow-up (Day 24)
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.
Safety Analysis Set: All participants who received at least one dose of AZD4831 and for whom any safety post-dose data were available were included in the safety analysis for the study.

Reporting Groups

	Description
Placebo	Participants received placebo once daily.
AZD4831 5 mg	Participants received 5 mg of AZD4831 oral solution once daily.
AZD4831 10 mg	Participants received 10 mg of AZD4831 oral solution once daily.
AZD4831 15 mg	Participants received 15 mg AZD4831 oral solution once daily.
AZD4831 45 mg	Participants received 45 mg AZD4831 oral solution once daily.

Measured Values

	Placebo	AZD4831 5 mg	AZD4831 10 mg	AZD4831 15 mg	AZD4831 45 mg
Number of Participants Analyzed [units:participants]	8	8	8	8	5
Number of participants with adverse events (AEs) [units: Participants]
Any AE	4	2	3	3	2
Any AE with outcome = death	0	0	0	0	0
Any SAE (including events with outcome = death)	0	0	0	0	0
Any AE leading to discontinuation of IMP	1	0	0	1	2

No statistical analysis provided for Number of participants with adverse events (AEs)

2. Secondary Outcome Measure: Area under the plasma concentration-curve over 24 hours (AUCτ) [ Time Frame: At Day 1, Day 10 and Day 14 ]

Measure Type	Secondary
Measure Name	Area under the plasma concentration-curve over 24 hours (AUCτ)
Measure Description	To assess AUCτ of AZD4831 after multiple oral dosing.
Time Frame	At Day 1, Day 10 and Day 14
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 pharmacokinetic (PK) analysis set consisted of all participants in the safety analysis set who received AZD4831 and who have evaluable PK data, with no major protocol deviations thought to impact on the analysis of the PK data.

Reporting Groups

	Description
AZD4831 5 mg	Participants received 5 mg of AZD4831 oral solution once daily.
AZD4831 10 mg	Participants received 10 mg of AZD4831 oral solution once daily.
AZD4831 15 mg	Participants received 15 mg AZD4831 oral solution once daily.
AZD4831 45 mg	Participants received 45 mg AZD4831 oral solution once daily.

Measured Values

	AZD4831 5 mg	AZD4831 10 mg	AZD4831 15 mg	AZD4831 45 mg
Number of Participants Analyzed [units:participants]	8	8	8	5
Area under the plasma concentration-curve over 24 hours (AUCτ) [units: h*nmol/L] Geometric Mean (Geometric Coefficient of Variation)
DAY 1	206.1 (16.95%)	438.1 (19.53%)	660.8 (11.11%)	2381 (9.687%)
DAY 10	655.5 (19.59%)	0 (0%)	2208 (18.58%)	0 (0%)
DAY 14	0 (0%)	1450 (24.72%)	0 (0%)	0 (0%)

Statistical Analysis 1 for Area under the plasma concentration-curve over 24 hours (AUCτ)

Groups^[1]	AZD4831 5 mg, AZD4831 10 mg, AZD4831 15 mg
Slope^[5]	1.111
Standard Error of the mean	± 0.09501
90% Confidence Interval	( 0.9135 to 1.309 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[5]	Other relevant estimation information:
	No text entered.

3. Secondary Outcome Measure: Observed maximum concentration, taken directly from the individual concentration-time curve (Cmax) of AZD4831 [ Time Frame: At Day 1, Day 10 and Day 14 ]

Measure Type	Secondary
Measure Name	Observed maximum concentration, taken directly from the individual concentration-time curve (Cmax) of AZD4831
Measure Description	To assess Cmax of AZD4831 after multiple oral dosing.
Time Frame	At Day 1, Day 10 and Day 14
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 pharmacokinetic (PK) analysis set consisted of all participants in the safety analysis set who received AZD4831 and who have evaluable PK data, with no major protocol deviations thought to impact on the analysis of the PK data.

Reporting Groups

	Description
AZD4831 5 mg	Participants received 5 mg of AZD4831 oral solution once daily.
AZD4831 10 mg	Participants received 10 mg of AZD4831 oral solution once daily.
AZD4831 15 mg	Participants received 15 mg AZD4831 oral solution once daily.
AZD4831 45 mg	Participants received 45 mg AZD4831 oral solution once daily.

Measured Values

	AZD4831 5 mg	AZD4831 10 mg	AZD4831 15 mg	AZD4831 45 mg
Number of Participants Analyzed [units:participants]	8	8	8	5
Observed maximum concentration, taken directly from the individual concentration-time curve (Cmax) of AZD4831 [units: nmol/L] Geometric Mean (Geometric Coefficient of Variation)
DAY 1	16.48 (17.66%)	48.93 (24.74%)	66.25 (37.09%)	236.2 (52.70%)
DAY 10	37.28 (19.14%)	0 (0%)	145.7 (19.66%)	0 (0%)
DAY 14	0 (0%)	92.96 (21.04%)	0 (0%)	0 (0%)

Statistical Analysis 1 for Observed maximum concentration, taken directly from the individual concentration-time curve (Cmax) of AZD4831

Groups^[1]	AZD4831 5 mg, AZD4831 10 mg, AZD4831 15 mg
Slope^[5]	1.252
Standard Error of the mean	± 0.09010
90% Confidence Interval	( 1.064 to 1.439 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[5]	Other relevant estimation information:
	No text entered.

4. Secondary Outcome Measure: Time to reach maximum concentration, taken directly from the individual concentration-time curve (tmax) of AZD4831 [ Time Frame: At Day 1, Day 10 and Day 14 ]

Measure Type	Secondary
Measure Name	Time to reach maximum concentration, taken directly from the individual concentration-time curve (tmax) of AZD4831
Measure Description	To assess tmax of AZD4831 after multiple oral dosing.
Time Frame	At Day 1, Day 10 and Day 14
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 pharmacokinetic (PK) analysis set consisted of all participants in the safety analysis set who received AZD4831 and who have evaluable PK data, with no major protocol deviations thought to impact on the analysis of the PK data.

Reporting Groups

	Description
AZD4831 5 mg	Participants received 5 mg of AZD4831 oral solution once daily.
AZD4831 10 mg	Participants received 10 mg of AZD4831 oral solution once daily.
AZD4831 15 mg	Participants received 15 mg AZD4831 oral solution once daily.
AZD4831 45 mg	Participants received 45 mg AZD4831 oral solution once daily.

Measured Values

	AZD4831 5 mg	AZD4831 10 mg	AZD4831 15 mg	AZD4831 45 mg
Number of Participants Analyzed [units:participants]	8	8	8	5
Time to reach maximum concentration, taken directly from the individual concentration-time curve (tmax) of AZD4831 [units: Hours] Median (Full Range)
DAY 1	1.01 (0.25 to 2.00)	1.00 (0.45 to 1.50)	1.00 (0.25 to 1.52)	0.55 (0.50 to 3.00)
DAY 10	1.75 (0.53 to 4.05)	0 (0 to 0)	1 (0.50 to 3.00)	0 (0 to 0)
DAY 14	0 (0 to 0)	1.00 (0.50 to 4.00)	0 (0 to 0)	0 (0 to 0)

No statistical analysis provided for Time to reach maximum concentration, taken directly from the individual concentration-time curve (tmax) of AZD4831

5. Secondary Outcome Measure: Terminal half-life, estimated as (ln2)/λz (t1/2λz) [ Time Frame: At Day 10 and Day 14 ]

Measure Type	Secondary
Measure Name	Terminal half-life, estimated as (ln2)/λz (t1/2λz)
Measure Description	To assess t1/2,λz of AZD4831 after multiple oral dosing.
Time Frame	At Day 10 and Day 14
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 pharmacokinetic (PK) analysis set consisted of all participants in the safety analysis set who received AZD4831 and who have evaluable PK data, with no major protocol deviations thought to impact on the analysis of the PK data.

Reporting Groups

	Description
AZD4831 5 mg	Participants received 5 mg of AZD4831 oral solution once daily.
AZD4831 10 mg	Participants received 10 mg of AZD4831 oral solution once daily.
AZD4831 15 mg	Participants received 15 mg AZD4831 oral solution once daily.
AZD4831 45 mg	Participants received 45 mg AZD4831 oral solution once daily.

Measured Values

	AZD4831 5 mg	AZD4831 10 mg	AZD4831 15 mg	AZD4831 45 mg
Number of Participants Analyzed [units:participants]	8	8	8	5
Terminal half-life, estimated as (ln2)/λz (t1/2λz) [units: hours] Mean (Standard Deviation)
DAY 10	53.32 (16.32)	0 (0)	71.84 (10.11)	0 (0)
DAY 14	0 (0)	72.65 (14.65)	0 (0)	0 (0)

No statistical analysis provided for Terminal half-life, estimated as (ln2)/λz (t1/2λz)

6. Secondary Outcome Measure: Apparent clearance for parent drug (CL/F) estimated as dose divided by AUCτ of AZD4831 [ Time Frame: At Day 10 and Day 14 ]

Measure Type	Secondary
Measure Name	Apparent clearance for parent drug (CL/F) estimated as dose divided by AUCτ of AZD4831
Measure Description	To assess CL/F of AZD4831 after multiple oral dosing.
Time Frame	At Day 10 and Day 14
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 pharmacokinetic (PK) analysis set consisted of all participants in the safety analysis set who received AZD4831 and who have evaluable PK data, with no major protocol deviations thought to impact on the analysis of the PK data.

Reporting Groups

	Description
AZD4831 5 mg	Participants received 5 mg of AZD4831 oral solution once daily.
AZD4831 10 mg	Participants received 10 mg of AZD4831 oral solution once daily.
AZD4831 15 mg	Participants received 15 mg AZD4831 oral solution once daily.
AZD4831 45 mg	Participants received 45 mg AZD4831 oral solution once daily.

Measured Values

	AZD4831 5 mg	AZD4831 10 mg	AZD4831 15 mg	AZD4831 45 mg
Number of Participants Analyzed [units:participants]	8	8	8	5
Apparent clearance for parent drug (CL/F) estimated as dose divided by AUCτ of AZD4831 [units: liters/hours] Mean (Standard Deviation)
DAY 10	23.15 (4.375)	0 (0)	20.58 (3.634)	0 (0)
DAY 14	0 (0)	21.13 (5.069)	0 (0)	0 (0)

No statistical analysis provided for Apparent clearance for parent drug (CL/F) estimated as dose divided by AUCτ of AZD4831

7. Secondary Outcome Measure: Mean residence time (MRT) [ Time Frame: At Day 10 and Day 14 ]

Measure Type	Secondary
Measure Name	Mean residence time (MRT)
Measure Description	To assess MRT of AZD4831 after multiple oral dosing.
Time Frame	At Day 10 and Day 14
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 pharmacokinetic (PK) analysis set consisted of all participants in the safety analysis set who received AZD4831 and who have evaluable PK data, with no major protocol deviations thought to impact on the analysis of the PK data.

Reporting Groups

	Description
AZD4831 5 mg	Participants received 5 mg of AZD4831 oral solution once daily.
AZD4831 10 mg	Participants received 10 mg of AZD4831 oral solution once daily.
AZD4831 15 mg	Participants received 15 mg AZD4831 oral solution once daily.
AZD4831 45 mg	Participants received 45 mg AZD4831 oral solution once daily.

Measured Values

	AZD4831 5 mg	AZD4831 10 mg	AZD4831 15 mg	AZD4831 45 mg
Number of Participants Analyzed [units:participants]	8	8	8	5
Mean residence time (MRT) [units: Hours] Mean (Standard Deviation)
DAY 10	68.32 (11.52)	0 (0)	69.36 (10.27)	0 (0)
DAY 14	0 (0)	71.86 (11.33)	0 (0)	0 (0)

No statistical analysis provided for Mean residence time (MRT)

8. Secondary Outcome Measure: Apparent volume of distribution for parent drug at terminal phase Vz/F(extravascular administration), estimated by dividing the apparent clearance (CL/F) by λz of AZD4831 [ Time Frame: At Day 10 and Day 14 ]

Measure Type	Secondary
Measure Name	Apparent volume of distribution for parent drug at terminal phase Vz/F(extravascular administration), estimated by dividing the apparent clearance (CL/F) by λz of AZD4831
Measure Description	To assess Vz/F of AZD4831 after multiple oral dosing.
Time Frame	At Day 10 and Day 14
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 pharmacokinetic (PK) analysis set consisted of all participants in the safety analysis set who received AZD4831 and who have evaluable PK data, with no major protocol deviations thought to impact on the analysis of the PK data.

Reporting Groups

	Description
AZD4831 5 mg	Participants received 5 mg of AZD4831 oral solution once daily.
AZD4831 10 mg	Participants received 10 mg of AZD4831 oral solution once daily.
AZD4831 15 mg	Participants received 15 mg AZD4831 oral solution once daily.
AZD4831 45 mg	Participants received 45 mg AZD4831 oral solution once daily.

Measured Values

	AZD4831 5 mg	AZD4831 10 mg	AZD4831 15 mg	AZD4831 45 mg
Number of Participants Analyzed [units:participants]	8	8	8	5
Apparent volume of distribution for parent drug at terminal phase Vz/F(extravascular administration), estimated by dividing the apparent clearance (CL/F) by λz of AZD4831 [units: liters] Mean (Standard Deviation)
DAY 10	1732 (412.6)	0 (0)	2118 (425.7)	0 (0)
DAY 14	0 (0)	2175 (593.7)	0 (0)	0 (0)

No statistical analysis provided for Apparent volume of distribution for parent drug at terminal phase Vz/F(extravascular administration), estimated by dividing the apparent clearance (CL/F) by λz of AZD4831

9. Secondary Outcome Measure: Accumulation ratio calculated as AUCτ Day 10/ AUCτ Day 1 (Rac AUC) of AZD4831 [ Time Frame: At Day 10 and Day 14 ]

Measure Type	Secondary
Measure Name	Accumulation ratio calculated as AUCτ Day 10/ AUCτ Day 1 (Rac AUC) of AZD4831
Measure Description	To assess Rac AUC of AZD4831 after multiple oral dosing.
Time Frame	At Day 10 and Day 14
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 pharmacokinetic (PK) analysis set consisted of all participants in the safety analysis set who received AZD4831 and who have evaluable PK data, with no major protocol deviations thought to impact on the analysis of the PK data.

Reporting Groups

	Description
AZD4831 5 mg	Participants received 5 mg of AZD4831 oral solution once daily.
AZD4831 10 mg	Participants received 10 mg of AZD4831 oral solution once daily.
AZD4831 15 mg	Participants received 15 mg AZD4831 oral solution once daily.
AZD4831 45 mg	Participants received 45 mg AZD4831 oral solution once daily.

Measured Values

	AZD4831 5 mg	AZD4831 10 mg	AZD4831 15 mg	AZD4831 45 mg
Number of Participants Analyzed [units:participants]	8	8	8	5
Accumulation ratio calculated as AUCτ Day 10/ AUCτ Day 1 (Rac AUC) of AZD4831 [units: Hours] Mean (Full Range)
DAY 10	3.215 (2.70 to 4.38)	0 (0 to 0)	3.435 (2.70 to 4.91)	0 (0 to 0)
DAY 14	0 (0 to 0)	3.364 (2.23 to 4.24)	0 (0 to 0)	0 (0 to 0)

No statistical analysis provided for Accumulation ratio calculated as AUCτ Day 10/ AUCτ Day 1 (Rac AUC) of AZD4831

10. Secondary Outcome Measure: Accumulation ratio calculated as Cmax Day 10/ Cmax Day 1 (Rac Cmax) of AZD4831 [ Time Frame: At Day 10 and Day 14 ]

Measure Type	Secondary
Measure Name	Accumulation ratio calculated as Cmax Day 10/ Cmax Day 1 (Rac Cmax) of AZD4831
Measure Description	To assess Rac Cmax of AZD4831 after multiple oral dosing.
Time Frame	At Day 10 and Day 14
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 pharmacokinetic (PK) analysis set consisted of all participants in the safety analysis set who received AZD4831 and who have evaluable PK data, with no major protocol deviations thought to impact on the analysis of the PK data.

Reporting Groups

	Description
AZD4831 5 mg	Participants received 5 mg of AZD4831 oral solution once daily.
AZD4831 10 mg	Participants received 10 mg of AZD4831 oral solution once daily.
AZD4831 15 mg	Participants received 15 mg AZD4831 oral solution once daily.
AZD4831 45 mg	Participants received 45 mg AZD4831 oral solution once daily.

Measured Values

	AZD4831 5 mg	AZD4831 10 mg	AZD4831 15 mg	AZD4831 45 mg
Number of Participants Analyzed [units:participants]	8	8	8	5
Accumulation ratio calculated as Cmax Day 10/ Cmax Day 1 (Rac Cmax) of AZD4831 [units: Hours] Mean (Full Range)
DAY 10	2.305 (1.64 to 3.14)	0 (0 to 0)	2.536 (1.38 to 4.27)	0 (0 to 0)
DAY 14	0 (0 to 0)	1.922 (1.42 to 2.47)	0 (0 to 0)	0 (0 to 0)

No statistical analysis provided for Accumulation ratio calculated as Cmax Day 10/ Cmax Day 1 (Rac Cmax) of AZD4831

Serious Adverse Events

Time Frame	Adverse Events were collected from the start of randomization throughout the Treatment Period up to and including the Final Follow-up Visit. Serious Adverse Events were recorded from the time of informed consent.
Additional Description	An adverse event was the development of an undesirable medical condition or the deterioration of a pre-existing medical condition following or during exposure to a pharmaceutical product, whether or not considered causally related to the product.

Reporting Groups

	Description
Placebo	Participants received placebo once daily.
AZD4831 5 mg	Participants received 5 mg of AZD4831 oral solution once daily.
AZD4831 10mg	Participants received 10 mg of AZD4831 oral solution once daily.
AZD4831 15 mg	Participants received 15 mg AZD4831 oral solution once daily.
AZD4831 45 mg	Participants received 45 mg AZD4831 oral solution once daily.

Serious Adverse Events

	Placebo	AZD4831 5 mg	AZD4831 10mg	AZD4831 15 mg	AZD4831 45 mg
Total, serious adverse events
# participants affected / at risk	0/8 (0.00%)	0/8 (0.00%)	0/8 (0.00%)	0/8 (0.00%)	0/5 (0.00%)

Other Adverse Events

Time Frame	Adverse Events were collected from the start of randomization throughout the Treatment Period up to and including the Final Follow-up Visit. Serious Adverse Events were recorded from the time of informed consent.
Additional Description	An adverse event was the development of an undesirable medical condition or the deterioration of a pre-existing medical condition following or during exposure to a pharmaceutical product, whether or not considered causally related to the product.

Frequency Threshold

Threshold above which other adverse events are reported	2%

Reporting Groups

	Description
Placebo	Participants received placebo once daily.
AZD4831 5 mg	Participants received 5 mg of AZD4831 oral solution once daily.
AZD4831 10mg	Participants received 10 mg of AZD4831 oral solution once daily.
AZD4831 15 mg	Participants received 15 mg AZD4831 oral solution once daily.
AZD4831 45 mg	Participants received 45 mg AZD4831 oral solution once daily.

Other Adverse Events

Placebo

AZD4831 5 mg

AZD4831 10mg

AZD4831 15 mg

AZD4831 45 mg

Total, other (not including serious) adverse events

# participants affected / at risk

4/8 (50.00%)

2/8 (25.00%)

3/8 (37.50%)

2/5 (40.00%)

Skin and subcutaneous tissue disorders

Dermatitis contact¹

# participants affected / at risk

0/8 (0.00%)

2/8 (25.00%)

1/8 (12.50%)

0/5 (0.00%)

Skin and subcutaneous tissue disorders

Rash¹

# participants affected / at risk

0/8 (0.00%)

2/8 (25.00%)

0/5 (0.00%)

Skin and subcutaneous tissue disorders

Rash generalized¹

# participants affected / at risk

1/8 (12.50%)

0/8 (0.00%)

2/5 (40.00%)

Nervous system disorders

Headache¹

# participants affected / at risk

2/8 (25.00%)

1/8 (12.50%)

0/8 (0.00%)

1/5 (20.00%)

Respiratory, thoracic and mediastinal disorders

Dry throat¹

# participants affected / at risk

0/8 (0.00%)

1/8 (12.50%)

1/5 (20.00%)

Skin and subcutaneous tissue disorders

Dry skin¹

# participants affected / at risk

0/8 (0.00%)

1/5 (20.00%)

Skin and subcutaneous tissue disorders

Pruritus generalised¹

# participants affected / at risk

0/8 (0.00%)

1/5 (20.00%)

Respiratory, thoracic and mediastinal disorders

Cough¹

# participants affected / at risk

0/8 (0.00%)

1/8 (12.50%)

0/5 (0.00%)

Respiratory, thoracic and mediastinal disorders

Throat tightness¹

# participants affected / at risk

0/8 (0.00%)

1/5 (20.00%)

Gastrointestinal disorders

Diarrhoea¹

# participants affected / at risk

0/8 (0.00%)

1/5 (20.00%)

Gastrointestinal disorders

Faeces discoloured¹

# participants affected / at risk

0/8 (0.00%)

1/8 (12.50%)

0/8 (0.00%)

0/5 (0.00%)

Gastrointestinal disorders

Faeces soft¹

# participants affected / at risk

0/8 (0.00%)

1/8 (12.50%)

0/8 (0.00%)

0/5 (0.00%)

General disorders

Fatigue¹

# participants affected / at risk

0/8 (0.00%)

1/5 (20.00%)

General disorders

Swelling¹

# participants affected / at risk

1/8 (12.50%)

0/8 (0.00%)

0/5 (0.00%)

General disorders

Vessel puncture site bruise¹

# participants affected / at risk

1/8 (12.50%)

0/8 (0.00%)

0/5 (0.00%)

Infections and infestations

Upper respiratory tract infection¹

# participants affected / at risk

0/8 (0.00%)

1/8 (12.50%)

0/8 (0.00%)

0/5 (0.00%)

Injury, poisoning and procedural complications

Arthropod sting¹

# participants affected / at risk

0/8 (0.00%)

1/5 (20.00%)

Vascular disorders

Phlebitis¹

# participants affected / at risk

1/8 (12.50%)

0/8 (0.00%)

0/5 (0.00%)

†	Events were collected by systematic assessment
1	Term from vocabulary, MedDRA version 20.1

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. The investigator and members of his/her research team must not disclose such information without prior written approval from the sponsor.

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

David Han

California Clinical Trials Medical Group 1560 East Chevy Chase Dr., Suite 140 Glendale, CA 91206

Sponsors

Collaborators

Inclusion Criteria

Exclusion Criteria

Research Site

Trial Results Summaries