A Study to Assess the Effect of AZD5462 on the Pharmacokinetics of Midazolam, Rosuvastatin and Digoxin

Study identifier:D9090C00003

ClinicalTrials.gov identifier:NCT05395117

EudraCT identifier:N/A

CTIS identifier:N/A

Study Complete

Official Title

A fixed sequence, open-label study to assess the effect of multiple doses of AZD5462 on the pharmacokinetics of oral midazolam (CYP3A4 probe), rosuvastatin (OATP1B1/3, BCRP probe), and digoxin (P-gp probe) in healthy participants

Medical condition

Healthy Participants

Phase

Phase 1

Healthy volunteers

Yes

Study drug

AZD5462, Midazolam, Rosuvastatin, Digoxin

Sex

All

Actual Enrollment

Study type

Interventional

Age

18 Years - 55 Years

Date

Study Start Date: 30 Jun 2022

Primary Completion Date: 12 Sept 2022

Study Completion Date: 12 Sept 2022

Study design

Allocation: Non-randomized
Endpoint Classification: -
Intervention Model: Parallel Assignment
Masking: -
Primary Purpose: Treatment

Verification:

Verified 01 Sept 2024 by AstraZeneca

Collaborators

PAREXEL

Inclusion and exclusion criteria

Inclusion Criteria

- Provision of signed and dated, written informed consent prior to any study specific procedures.
- Healthy male and female participants aged 18 to 55 years with suitable veins for cannulation or repeated venepuncture.
- Females must have a negative pregnancy test at screening and on admission to the unit, must not be lactating and must be of non childbearing potential confirmed at screening.
- Have a Body Mass Index (BMI) between 18 and 32 kg/m2 inclusive and weigh at least 50 kg and no more than 105 kg inclusive at screening.
- Male subject must adhere to the contraception methods details.

Exclusion Criteria

- History of any clinically significant disease or disorder which may either put the participant at risk because of participation in the study, or influence the results or the participant’s ability to participate in the study including but not limited to:
(i) Systemic sclerosis (ie, scleroderma).
(ii) Moderate to severe valvular disease.
(iii) Hypertrophic obstructive cardiomyopathy.
(iv) Restrictive cardiomyopathy.
(v) Gilbert’s syndrome.
(vi) History of vascular or left ventricular aneurysms or prior dissections.
(vii) Any history of joint hypermobility, Marfan’s Syndrome, or any connective tissue
disorder.
- History or presence of gastrointestinal, hepatic, or renal disease, or any other condition known to interfere with absorption, distribution, metabolism, or excretion of drugs.
- Any clinically significant illness, medical/surgical procedure, or trauma within 4 weeks of the first administration of IMPs.
- Any laboratory values with deviations at screening or admission to the study centre.
- Any clinically significant abnormalities in clinical biochemistry, haematology, or urinalysis results.
- Any clinically significant abnormal findings in vital signs after 5 minutes supine rest.
- Any clinically important abnormalities in rhythm, conduction or morphology of the resting electrocardiogram (ECG) and any clinically important abnormalities in the 12-lead ECG.
- Any positive result on screening for serum hepatitis B surface antigen, hepatitis C antibody, and human immunodeficiency virus (HIV) antibody.
- Known or suspected history of drug abuse.
- Has received another new chemical entity within 3 months of the first administration of IMP in this study.
- Plasma donation within 1 month of screening or any blood donation/loss > 500 mL during the 3 months prior to screening.
- History of severe allergy/hypersensitivity or ongoing allergy/hypersensitivity, or history of hypersensitivity to drugs with a similar chemical structure or class to AZD5462.
- Current smokers or those who have smoked or used nicotine products within the 3 months prior to screening.
- Positive screen for drugs of abuse or cotinine at screening or on each admission to the study centre or positive screen for alcohol on admission to the study centre prior to the first administration of the IMP.
- Use of drugs with enzyme-inducing properties such as St John’s Wort within 3 weeks prior to the first administration of IMP.
- Use of any prescribed or non prescribed medication including antacids, analgesics, herbal remedies, megadose vitamins and minerals during the 2 weeks or 5 half-lives of the medication, whichever is longer, prior to the first administration of IMP.
- Known or suspected history of alcohol or drug abuse or excessive intake of alcohol.
- Excessive intake of caffeine-containing drinks or food.
- Involvement of any AstraZeneca, Parexel, or study centre employee or their close relatives.
- Participants who have previously received AZD5462.
- Participants who are vegans or have medical dietary restrictions.
- Vulnerable participants.
- Participants who cannot communicate reliably with the Principal Investigator (PI).
- Clinical signs and symptoms consistent with COVID-19 by appropriate laboratory test within the last 4 weeks prior to screening or on admission.

Location

Research Site

Brooklyn, MD, United States, 21225

Arms	Assigned Interventions
Experimental: Treatment Arm A: High dose Participants will receive the Investigational Medicinal Product (IMP), AZD5462 Dose A starting on Day 6 and continued until Day 18 and the following approved medicinal products: - Midazolam - Rosuvastatin - Digoxin	Drug: AZD5462 Treatment Arm A: Participants will receive the IMP, AZD5462 Dose A starting on Day 6 and continued until Day 18 and the following approved medicinal products: - Midazolam - Rosuvastatin - Digoxin Treatment Arm B: Participants will receive the IMP, AZD5462 Dose B starting on Day 6 and continued until Day 18 and the following approved medicinal products: - Midazolam - Rosuvastatin - Digoxin Drug: Midazolam Participants will receive a single dose of midazolam in the morning of Day 1 and in the morning of Day 15 in both the arms. Drug: Rosuvastatin Participants will receive rosuvastatin as a single dose administered with digoxin at the same time in the morning of Day 2, Day 6, and in the morning of Day 16 in both the arms. Drug: Digoxin Participants will receive digoxin as a single dose administered with rosuvastatin at the same time in the morning of Day 2, Day 6, and in the morning of Day 16 in both the arms.
Experimental: Treatment Arm B: Low dose Participants will receive the IMP, AZD5462 Dose B starting on Day 6 and continued until Day 18 and the following approved medicinal products: - Midazolam - Rosuvastatin - Digoxin	Drug: AZD5462 Treatment Arm A: Participants will receive the IMP, AZD5462 Dose A starting on Day 6 and continued until Day 18 and the following approved medicinal products: - Midazolam - Rosuvastatin - Digoxin Treatment Arm B: Participants will receive the IMP, AZD5462 Dose B starting on Day 6 and continued until Day 18 and the following approved medicinal products: - Midazolam - Rosuvastatin - Digoxin Drug: Midazolam Participants will receive a single dose of midazolam in the morning of Day 1 and in the morning of Day 15 in both the arms. Drug: Rosuvastatin Participants will receive rosuvastatin as a single dose administered with digoxin at the same time in the morning of Day 2, Day 6, and in the morning of Day 16 in both the arms. Drug: Digoxin Participants will receive digoxin as a single dose administered with rosuvastatin at the same time in the morning of Day 2, Day 6, and in the morning of Day 16 in both the arms.

Arms

Assigned Interventions

Experimental: Treatment Arm A: High dose
Participants will receive the Investigational Medicinal Product (IMP), AZD5462 Dose A starting on Day 6 and continued until Day 18 and the following approved medicinal products: - Midazolam - Rosuvastatin - Digoxin

Drug: AZD5462
Treatment Arm A: Participants will receive the IMP, AZD5462 Dose A starting on Day 6 and continued until Day 18 and the following approved medicinal products: - Midazolam - Rosuvastatin - Digoxin Treatment Arm B: Participants will receive the IMP, AZD5462 Dose B starting on Day 6 and continued until Day 18 and the following approved medicinal products: - Midazolam - Rosuvastatin - Digoxin

Drug: Midazolam
Participants will receive a single dose of midazolam in the morning of Day 1 and in the morning of Day 15 in both the arms.

Drug: Rosuvastatin
Participants will receive rosuvastatin as a single dose administered with digoxin at the same time in the morning of Day 2, Day 6, and in the morning of Day 16 in both the arms.

Drug: Digoxin
Participants will receive digoxin as a single dose administered with rosuvastatin at the same time in the morning of Day 2, Day 6, and in the morning of Day 16 in both the arms.

Experimental: Treatment Arm B: Low dose
Participants will receive the IMP, AZD5462 Dose B starting on Day 6 and continued until Day 18 and the following approved medicinal products: - Midazolam - Rosuvastatin - Digoxin

Drug: Midazolam
Participants will receive a single dose of midazolam in the morning of Day 1 and in the morning of Day 15 in both the arms.

Drug: Rosuvastatin
Participants will receive rosuvastatin as a single dose administered with digoxin at the same time in the morning of Day 2, Day 6, and in the morning of Day 16 in both the arms.

Drug: Digoxin
Participants will receive digoxin as a single dose administered with rosuvastatin at the same time in the morning of Day 2, Day 6, and in the morning of Day 16 in both the arms.

Participant Flow

Recruitment Details

Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
This study was conducted from 30 June 2022 (first participant first visit) to 12 September 2022 (last participant last visit)

Pre-Assignment Details

Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
Participants who met the inclusion and none of the exclusion criteria were enrolled to the study. All study assessments were performed as per the schedule of assessment. All the study assessments were performed as per schedule of assessment.

Reporting Groups

	Description
Treatment Arm A	Participants received AZD5462 Dose A (high dose) from Day 6 and continued up to Day 18 along with Midazolam, Rosuvastatin and Digoxin
Treatment Arm B	Participants received AZD5462 Dose B (low dose) from Day 6 and continued up to Day 18 along with Midazolam, Rosuvastatin and Digoxin

Participant Flow: Overall Study

	Treatment Arm A	Treatment Arm B
STARTED	16	16
COMPLETED	16	15
NOT COMPLETED	0	1
Withdrawal by Subject	0	1

Baseline Characteristics

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

Safety analysis set included all participants who received at least one dose of Investigational Medicinal Product (IMP) in any period for Treatment Arms A or B and for whom any safety post-dose data are available.

Reporting Groups

	Description
Overall Treatment Arms	Participants received AZD5462 Dose A (high dose) or Dose B (low dose) from Day 6 and continued up to Day 18 along with Midazolam, Rosuvastatin and Digoxin

Baseline Measures

	Overall Treatment Arms
Number of Participants [units: Participants]	32
Age Continuous [units: Years] Mean ± Standard Deviation	38.1 ± 8.9
Sex: Female, Male [units: Participants]
Female	3
Male	29
Race/Ethnicity, Customized [units: Participants]
White	16
Black or African American	16
Race/Ethnicity, Customized [units: Participants]
Hispanic or Latino	13
Not Hispanic or Latino	19

Outcome Measures

1. Primary Outcome Measure: Observed maximum plasma concentration (Cmax) of midazolam, rosuvastatin, digoxin, and AZD5462 [ Time Frame: Day 1 to Day 18 (pre and post-dose of study drug administration) ]

Measure Type	Primary
Measure Name	Observed maximum plasma concentration (Cmax) of midazolam, rosuvastatin, digoxin, and AZD5462
Measure Description	The effect of AZD5462 on the Pharmacokinetics (PK) of oral midazolam (CYP3A4 probe), rosuvastatin (OATP1B1/3, BCRP probe), and digoxin (P-gp probe) was assessed.
Time Frame	Day 1 to Day 18 (pre and post-dose of study drug administration)
Safety Issue?

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 subjects who received at least one dose of AZD5462 following single dose of midazolam, rosuvastatin, digoxin, and AZD5462 with at least one reportable post-dose concentration.

Reporting Groups

	Description
Treatment Arm A: High Dose - Period 1	Randomised healthy participants received a single dose of midazolam
Treatment Arm A: High dose - Period 2	Randomised healthy participants received a single dose of rosuvastatin and digoxin
Treatment Arm A: High dose - Period 3	Randomised healthy participants received a single dose of rosuvastatin and digoxin together with AZD5462
Treatment Arm A: High Dose - Period 4	Randomised healthy participants received a single dose of midazolam together with AZD5462
Treatment Arm A: High dose - Period 5	Randomised healthy participants received a single dose of rosuvastatin and digoxin together with AZD5462
Treatment Arm B: Low Dose - Period 1	Randomised healthy participants received a single dose of midazolam
Treatment Arm B: Low Dose - Period 2	Randomised healthy participants received a single dose of rosuvastatin and digoxin
Treatment Arm B: Low Dose - Period 3	Randomised healthy participants received a single dose of rosuvastatin and digoxin together with AZD5462
Treatment Arm B: Low Dose - Period 4	Randomised healthy participants received a single dose of midazolam together with AZD5462
Treatment Arm B: Low Dose - Period 5	Randomised healthy participants received a single dose of rosuvastatin and digoxin together with AZD5462

Measured Values

	Treatment Arm A: High Dose - Period 1	Treatment Arm A: High dose - Period 2	Treatment Arm A: High dose - Period 3	Treatment Arm A: High Dose - Period 4	Treatment Arm A: High dose - Period 5	Treatment Arm B: Low Dose - Period 1	Treatment Arm B: Low Dose - Period 2	Treatment Arm B: Low Dose - Period 3	Treatment Arm B: Low Dose - Period 4	Treatment Arm B: Low Dose - Period 5
Number of Participants Analyzed [units:participants]	16	16	16	16	16	15	15	15	15	15
Observed maximum plasma concentration (Cmax) of midazolam, rosuvastatin, digoxin, and AZD5462 [units: ng/mL] Geometric Mean (Geometric Coefficient of Variation)
Midazolam	10.28 (39.42%)	0 (0%)	0 (0%)	13.99 (36.13%)	0 (0%)	11.44 (41.57%)	0 (0%)	0 (0%)	14.83 (26.31%)	0 (0%)
Rosuvastatin	0 (0%)	4.185 (62.75%)	21.59 (38.54%)	0 (0%)	17.43 (50.26%)	0 (0%)	4.079 (51.27%)	7.633 (78.78%)	0 (0%)	6.119 (84.69%)
Digoxin	0 (0%)	0.8480 (61.31%)	1.347 (68.87%)	0 (0%)	1.680 (40.16%)	0 (0%)	0.9990 (42.05%)	1.922 (32.61%)	0 (0%)	1.427 (38.85%)
AZD5462	0 (0%)	0 (0%)	14.71 (24.63%)	0 (0%)	15.81 (29.58%)	0 (0%)	0 (0%)	2.405 (28.59%)	0 (0%)	2.547 (37.30%)

Statistical Analysis 1 for Observed maximum plasma concentration (Cmax) of midazolam, rosuvastatin, digoxin, and AZD5462

Groups^[1]	Treatment Arm A: High Dose - Period 1, Treatment Arm A: High Dose - Period 4
Other^[5]	132.4685
90% Confidence Interval	( 113.8673 to 154.1082 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Comparison of Midazolam (Period [P]4) vs Midazolam (P1)
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 2 for Observed maximum plasma concentration (Cmax) of midazolam, rosuvastatin, digoxin, and AZD5462

Groups^[1]	Treatment Arm B: Low Dose - Period 1, Treatment Arm B: Low Dose - Period 4
Other^[5]	131.2294
90% Confidence Interval	( 113.2124 to 152.1136 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Comparison of Midazolam (P4) vs Midazolam (P1)
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 3 for Observed maximum plasma concentration (Cmax) of midazolam, rosuvastatin, digoxin, and AZD5462

Groups^[1]	Treatment Arm A: High dose - Period 2, Treatment Arm A: High dose - Period 3
Other^[5]	515.9199
90% Confidence Interval	( 434.6144 to 612.4357 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Comparison of Rosuvastatin (P3) vs Rosuvastatin (P2)
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 4 for Observed maximum plasma concentration (Cmax) of midazolam, rosuvastatin, digoxin, and AZD5462

Groups^[1]	Treatment Arm B: Low Dose - Period 2, Treatment Arm B: Low Dose - Period 3
Other^[5]	187.1228
90% Confidence Interval	( 144.5823 to 242.1800 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Comparison of Rosuvastatin (P3) vs Rosuvastatin (P2)
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 5 for Observed maximum plasma concentration (Cmax) of midazolam, rosuvastatin, digoxin, and AZD5462

Groups^[1]	Treatment Arm A: High dose - Period 2, Treatment Arm A: High dose - Period 5
Other^[5]	419.8772
90% Confidence Interval	( 323.7172 to 544.6015 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Comparison of Rosuvastatin (P5) vs Rosuvastatin (P2)
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 6 for Observed maximum plasma concentration (Cmax) of midazolam, rosuvastatin, digoxin, and AZD5462

Groups^[1]	Treatment Arm B: Low Dose - Period 2, Treatment Arm B: Low Dose - Period 5
Other^[5]	153.2084
90% Confidence Interval	( 116.1728 to 202.0510 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Comparison of Rosuvastatin (P5) vs Rosuvastatin (P2)
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 7 for Observed maximum plasma concentration (Cmax) of midazolam, rosuvastatin, digoxin, and AZD5462

Groups^[1]	Treatment Arm A: High dose - Period 2, Treatment Arm A: High dose - Period 3
Other^[5]	158.2431
90% Confidence Interval	( 122.0670 to 205.1404 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Comparison of Digoxin (P3) vs Digoxin (P2)
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 8 for Observed maximum plasma concentration (Cmax) of midazolam, rosuvastatin, digoxin, and AZD5462

Groups^[1]	Treatment Arm B: Low Dose - Period 2, Treatment Arm B: Low Dose - Period 3
Other^[5]	192.3639
90% Confidence Interval	( 164.1678 to 225.4027 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Comparison of Digoxin (P3) vs Digoxin (P2)
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 9 for Observed maximum plasma concentration (Cmax) of midazolam, rosuvastatin, digoxin, and AZD5462

Groups^[1]	Treatment Arm A: High dose - Period 2, Treatment Arm A: High dose - Period 5
Other^[5]	198.6030
90% Confidence Interval	( 156.1878 to 252.5367 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Comparison of Digoxin (P5) vs Digoxin (P2)
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 10 for Observed maximum plasma concentration (Cmax) of midazolam, rosuvastatin, digoxin, and AZD5462

Groups^[1]	Treatment Arm B: Low Dose - Period 2, Treatment Arm B: Low Dose - Period 5
Other^[5]	144.2884
90% Confidence Interval	( 119.5384 to 174.1627 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Comparison of Digoxin (P5) vs Digoxin (P2)
[5]	Other relevant estimation information:
	No text entered.

2. Primary Outcome Measure: Area under plasma concentration-time curve from time zero extrapolated to infinity (AUCinf) of midazolam, rosuvastatin, digoxin, and AZD5462 [ Time Frame: Day 1 to Day 18 (pre and post-dose of study drug administration) ]

Measure Type	Primary
Measure Name	Area under plasma concentration-time curve from time zero extrapolated to infinity (AUCinf) of midazolam, rosuvastatin, digoxin, and AZD5462
Measure Description	The effect of AZD5462 on the PK of oral midazolam (CYP3A4 probe), rosuvastatin (OATP1B1/3, BCRP probe), and digoxin (P-gp probe) was assessed.
Time Frame	Day 1 to Day 18 (pre and post-dose of study drug administration)
Safety Issue?

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 subjects who received at least one dose of AZD5462 following single dose of midazolam, rosuvastatin, digoxin, and AZD5462 with at least one reportable post-dose concentration.

Reporting Groups

	Description
Treatment Arm A: High Dose - Period 1	Randomised healthy participants will receive single dose of midazolam
Treatment Arm A: High dose - Period 2	Randomised healthy participants will receive single dose of rosuvastatin and digoxin
Treatment Arm A: High dose - Period 3	Randomised healthy participants will receive a single dose of rosuvastatin and digoxin together with AZD5462
Treatment Arm A: High Dose - Period 4	Randomised healthy participants will receive a single dose of midazolam together with AZD5462
Treatment Arm A: High dose - Period 5	Randomised healthy participants will receive a single dose of rosuvastatin and digoxin together with AZD5462
Treatment Arm B: Low Dose - Period 1	Randomised healthy participants will receive single dose of midazolam
Treatment Arm B: Low Dose - Period 2	Randomised healthy participants will receive single dose of rosuvastatin and digoxin
Treatment Arm B: Low Dose - Period 3	Randomised healthy participants will receive a single dose of rosuvastatin and digoxin together with AZD5462
Treatment Arm B: Low Dose - Period 4	Randomised healthy participants will receive a single dose of midazolam together with AZD5462
Treatment Arm B: Low Dose - Period 5	Randomised healthy participants will receive a single dose of rosuvastatin and digoxin together with AZD5462

Measured Values

	Treatment Arm A: High Dose - Period 1	Treatment Arm A: High dose - Period 2	Treatment Arm A: High dose - Period 3	Treatment Arm A: High Dose - Period 4	Treatment Arm A: High dose - Period 5	Treatment Arm B: Low Dose - Period 1	Treatment Arm B: Low Dose - Period 2	Treatment Arm B: Low Dose - Period 3	Treatment Arm B: Low Dose - Period 4	Treatment Arm B: Low Dose - Period 5
Number of Participants Analyzed [units:participants]	16	16	16	16	16	15	16	15	15	15
Area under plasma concentration-time curve from time zero extrapolated to infinity (AUCinf) of midazolam, rosuvastatin, digoxin, and AZD5462 [units: h*ng/mL] Geometric Mean (Geometric Coefficient of Variation)
Midazolam	28.38 (44.20%)	0 (0%)	0 (0%)	37.29 (25.10%)	0 (0%)	27.96 (38.21%)	0 (0%)	0 (0%)	31.75 (22.31%)	0 (0%)
Rosuvastatin	0 (0%)	49.77 (45.81%)	87.32 (39.74%)	0 (0%)	60.25 (31.85%)	0 (0%)	43.71 (43.42%)	56.3 (49.29%)	0 (0%)	51.36 (57.16%)
Digoxin	0 (0%)	13.68 (80.28%)	17.29 (30.02%)	0 (0%)	14.90 (20.51%)	0 (0%)	15.73 (27.04%)	18.35 (24.99%)	0 (0%)	15.11 (30.53%)

Statistical Analysis 1 for Area under plasma concentration-time curve from time zero extrapolated to infinity (AUCinf) of midazolam, rosuvastatin, digoxin, and AZD5462

Groups^[1]	Treatment Arm A: High Dose - Period 1, Treatment Arm A: High Dose - Period 4
Other^[5]	128.2619
90% Confidence Interval	( 114.3858 to 143.8214 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Comparison of Midazolam (P4) vs Midazolam (P1)
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 2 for Area under plasma concentration-time curve from time zero extrapolated to infinity (AUCinf) of midazolam, rosuvastatin, digoxin, and AZD5462

Groups^[1]	Treatment Arm B: Low Dose - Period 1, Treatment Arm B: Low Dose - Period 4
Other^[5]	115.4765
90% Confidence Interval	( 102.5169 to 130.0744 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Comparison of Midazolam (P4) vs Midazolam (P1)
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 3 for Area under plasma concentration-time curve from time zero extrapolated to infinity (AUCinf) of midazolam, rosuvastatin, digoxin, and AZD5462

Groups^[1]	Treatment Arm A: High dose - Period 2, Treatment Arm A: High dose - Period 3
Other^[5]	175.4378
90% Confidence Interval	( 157.7260 to 195.1386 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Comparison of Rosuvastatin (P3) vs Rosuvastatin (P2)
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 4 for Area under plasma concentration-time curve from time zero extrapolated to infinity (AUCinf) of midazolam, rosuvastatin, digoxin, and AZD5462

Groups^[1]	Treatment Arm A: High dose - Period 2, Treatment Arm A: High dose - Period 5
Other^[5]	125.8787
90% Confidence Interval	( 109.9821 to 144.0731 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Comparison of Rosuvastatin (P5) vs Rosuvastatin (P2)
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 5 for Area under plasma concentration-time curve from time zero extrapolated to infinity (AUCinf) of midazolam, rosuvastatin, digoxin, and AZD5462

Groups^[1]	Treatment Arm B: Low Dose - Period 2, Treatment Arm B: Low Dose - Period 3
Other^[5]	128.8118
90% Confidence Interval	( 113.6137 to 146.0431 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Comparison of Rosuvastatin (P3) vs Rosuvastatin (P2)
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 6 for Area under plasma concentration-time curve from time zero extrapolated to infinity (AUCinf) of midazolam, rosuvastatin, digoxin, and AZD5462

Groups^[1]	Treatment Arm B: Low Dose - Period 2, Treatment Arm B: Low Dose - Period 5
Other^[5]	121.6475
90% Confidence Interval	( 103.2949 to 143.2609 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Comparison of Rosuvastatin (P5) vs Rosuvastatin (P2)
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 7 for Area under plasma concentration-time curve from time zero extrapolated to infinity (AUCinf) of midazolam, rosuvastatin, digoxin, and AZD5462

Groups^[1]	Treatment Arm A: High dose - Period 2, Treatment Arm A: High dose - Period 3
Other^[5]	133.0683
90% Confidence Interval	( 105.2867 to 168.1807 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Comparison of Digoxin (P3) vs Digoxin (P2)
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 8 for Area under plasma concentration-time curve from time zero extrapolated to infinity (AUCinf) of midazolam, rosuvastatin, digoxin, and AZD5462

Groups^[1]	Treatment Arm A: High dose - Period 2, Treatment Arm A: High dose - Period 5
Other^[5]	109.3189
90% Confidence Interval	( 82.7621 to 144.3972 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Comparison of Digoxin (P5) vs Digoxin (P2)
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 9 for Area under plasma concentration-time curve from time zero extrapolated to infinity (AUCinf) of midazolam, rosuvastatin, digoxin, and AZD5462

Groups^[1]	Treatment Arm B: Low Dose - Period 2, Treatment Arm B: Low Dose - Period 3
Other^[5]	116.6239
90% Confidence Interval	( 105.5617 to 128.8455 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Comparison of Digoxin (P3) vs Digoxin (P2)
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 10 for Area under plasma concentration-time curve from time zero extrapolated to infinity (AUCinf) of midazolam, rosuvastatin, digoxin, and AZD5462

Groups^[1]	Treatment Arm B: Low Dose - Period 2, Treatment Arm B: Low Dose - Period 5
Other^[5]	96.8440
90% Confidence Interval	( 85.1376 to 110.1600 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Comparison of Digoxin (P5) vs Digoxin (P2)
[5]	Other relevant estimation information:
	No text entered.

3. Primary Outcome Measure: Area under plasma concentration-curve from time zero to time of last quantifiable analyte (AUClast) of midazolam, rosuvastatin, digoxin, and AZD5462 [ Time Frame: Day 1 to Day 18 (pre and post-dose of study drug administration) ]

Measure Type	Primary
Measure Name	Area under plasma concentration-curve from time zero to time of last quantifiable analyte (AUClast) of midazolam, rosuvastatin, digoxin, and AZD5462
Measure Description	The effect of AZD5462 on the PK of oral midazolam (CYP3A4 probe), rosuvastatin (OATP1B1/3, BCRP probe), and digoxin (P-gp probe) was assessed.
Time Frame	Day 1 to Day 18 (pre and post-dose of study drug administration)
Safety Issue?

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 subjects who received at least one dose of AZD5462 following single dose of midazolam, rosuvastatin, digoxin, and AZD5462 with at least one reportable post-dose concentration.

Reporting Groups

	Description
Treatment Arm A: High Dose - Period 1	Randomised healthy participants will receive single dose of midazolam
Treatment Arm A: High dose - Period 2	Randomised healthy participants will receive single dose of rosuvastatin and digoxin
Treatment Arm A: High dose - Period 3	Randomised healthy participants will receive a single dose of rosuvastatin and digoxin together with AZD5462
Treatment Arm A: High Dose - Period 4	Randomised healthy participants will receive a single dose of midazolam together with AZD5462
Treatment Arm A: High dose - Period 5	Randomised healthy participants will receive a single dose of rosuvastatin and digoxin together with AZD5462
Treatment Arm B: Low Dose - Period 1	Randomised healthy participants will receive single dose of midazolam
Treatment Arm B: Low Dose - Period 2	Randomised healthy participants will receive single dose of rosuvastatin and digoxin
Treatment Arm B: Low Dose - Period 3	Randomised healthy participants will receive a single dose of rosuvastatin and digoxin together with AZD5462
Treatment Arm B: Low Dose - Period 4	Randomised healthy participants will receive a single dose of midazolam together with AZD5462
Treatment Arm B: Low Dose - Period 5	Randomised healthy participants will receive a single dose of rosuvastatin and digoxin together with AZD5462

Measured Values

	Treatment Arm A: High Dose - Period 1	Treatment Arm A: High dose - Period 2	Treatment Arm A: High dose - Period 3	Treatment Arm A: High Dose - Period 4	Treatment Arm A: High dose - Period 5	Treatment Arm B: Low Dose - Period 1	Treatment Arm B: Low Dose - Period 2	Treatment Arm B: Low Dose - Period 3	Treatment Arm B: Low Dose - Period 4	Treatment Arm B: Low Dose - Period 5
Number of Participants Analyzed [units:participants]	16	16	16	16	16	15	16	15	15	15
Area under plasma concentration-curve from time zero to time of last quantifiable analyte (AUClast) of midazolam, rosuvastatin, digoxin, and AZD5462 [units: h*ng/mL] Geometric Mean (Geometric Coefficient of Variation)
Midazolam	27.19 (42.71%)	0 (0%)	0 (0%)	35.84 (23.94%)	0 (0%)	27.11 (37.89%)	0 (0%)	0 (0%)	30.90 (22.63%)	0 (0%)
Rosuvastatin	0 (0%)	45.08 (51.70%)	82.04 (37.10%)	0 (0%)	62.28 (46.30%)	0 (0%)	42.03 (44.64%)	53.95 (50.34%)	0 (0%)	47.54 (56.78%)
Digoxin	0 (0%)	8.361 (85.04%)	10.63 (52.57%)	0 (0%)	10.08 (30.75%)	0 (0%)	10.80 (34.34%)	13.69 (20.43%)	0 (0%)	10.40 (32.11%)

Statistical Analysis 1 for Area under plasma concentration-curve from time zero to time of last quantifiable analyte (AUClast) of midazolam, rosuvastatin, digoxin, and AZD5462

Groups^[1]	Treatment Arm A: High Dose - Period 1, Treatment Arm A: High Dose - Period 4
Other^[5]	129.0899
90% Confidence Interval	( 114.9995 to 144.9068 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Comparison of Midazolam (P4) vs Midazolam (P1)
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 2 for Area under plasma concentration-curve from time zero to time of last quantifiable analyte (AUClast) of midazolam, rosuvastatin, digoxin, and AZD5462

Groups^[1]	Treatment Arm B: Low Dose - Period 1, Treatment Arm B: Low Dose - Period 4
Other^[5]	115.7840
90% Confidence Interval	( 102.8278 to 130.3727 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Comparison of Midazolam (P4) vs Midazolam (P1)
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 3 for Area under plasma concentration-curve from time zero to time of last quantifiable analyte (AUClast) of midazolam, rosuvastatin, digoxin, and AZD5462

Groups^[1]	Treatment Arm A: High dose - Period 2, Treatment Arm A: High dose - Period 3
Other^[5]	181.9802
90% Confidence Interval	( 161.8886 to 204.5654 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Comparison of Rosuvastatin (P3) vs Rosuvastatin (P2)
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 4 for Area under plasma concentration-curve from time zero to time of last quantifiable analyte (AUClast) of midazolam, rosuvastatin, digoxin, and AZD5462

Groups^[1]	Treatment Arm A: High dose - Period 2, Treatment Arm A: High dose - Period 5
Other^[5]	140.1573
90% Confidence Interval	( 119.9086 to 163.8252 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Comparison of Rosuvastatin (P5) vs Rosuvastatin (P2)
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 5 for Area under plasma concentration-curve from time zero to time of last quantifiable analyte (AUClast) of midazolam, rosuvastatin, digoxin, and AZD5462

Groups^[1]	Treatment Arm B: Low Dose - Period 2, Treatment Arm B: Low Dose - Period 3
Other^[5]	128.3611
90% Confidence Interval	( 113.1798 to 145.5787 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Comparison of Rosuvastatin (P3) vs Rosuvastatin (P2)
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 6 for Area under plasma concentration-curve from time zero to time of last quantifiable analyte (AUClast) of midazolam, rosuvastatin, digoxin, and AZD5462

Groups^[1]	Treatment Arm B: Low Dose - Period 2, Treatment Arm B: Low Dose - Period 5
Other^[5]	117.3424
90% Confidence Interval	( 100.8420 to 136.5427 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Comparison of Rosuvastatin (P5) vs Rosuvastatin (P2)
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 7 for Area under plasma concentration-curve from time zero to time of last quantifiable analyte (AUClast) of midazolam, rosuvastatin, digoxin, and AZD5462

Groups^[1]	Treatment Arm A: High dose - Period 2, Treatment Arm A: High dose - Period 3
Other^[5]	130.5799
90% Confidence Interval	( 111.6533 to 152.7148 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Comparison of Digoxin (P3) vs Digoxin (P2)
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 8 for Area under plasma concentration-curve from time zero to time of last quantifiable analyte (AUClast) of midazolam, rosuvastatin, digoxin, and AZD5462

Groups^[1]	Treatment Arm A: High dose - Period 2, Treatment Arm A: High dose - Period 5
Other^[5]	121.1600
90% Confidence Interval	( 92.5033 to 158.6944 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Comparison of Digoxin (P5) vs Digoxin (P2)
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 9 for Area under plasma concentration-curve from time zero to time of last quantifiable analyte (AUClast) of midazolam, rosuvastatin, digoxin, and AZD5462

Groups^[1]	Treatment Arm B: Low Dose - Period 2, Treatment Arm B: Low Dose - Period 3
Other^[5]	126.7536
90% Confidence Interval	( 113.4295 to 141.6428 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Comparison of Digoxin (P3) vs Digoxin (P2)
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 10 for Area under plasma concentration-curve from time zero to time of last quantifiable analyte (AUClast) of midazolam, rosuvastatin, digoxin, and AZD5462

Groups^[1]	Treatment Arm B: Low Dose - Period 2, Treatment Arm B: Low Dose - Period 5
Other^[5]	97.5191
90% Confidence Interval	( 84.0381 to 113.1626 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Comparison of Digoxin (P5) vs Digoxin (P2)
[5]	Other relevant estimation information:
	No text entered.

4. Primary Outcome Measure: Time to reach maximum plasma concentration (tmax) of midazolam, rosuvastatin, digoxin, and AZD5462 [ Time Frame: Day 1 to Day 18 (pre and post-dose of study drug administration) ]

Measure Type	Primary
Measure Name	Time to reach maximum plasma concentration (tmax) of midazolam, rosuvastatin, digoxin, and AZD5462
Measure Description	The effect of AZD5462 on the PK of oral midazolam (CYP3A4 probe), rosuvastatin (OATP1B1/3, BCRP probe), and digoxin (P-gp probe) was assessed.
Time Frame	Day 1 to Day 18 (pre and post-dose of study drug administration)
Safety Issue?

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 subjects who received at least one dose of AZD5462 following single dose of midazolam, rosuvastatin, digoxin, and AZD5462 with at least one reportable post-dose concentration.

Reporting Groups

	Description
Treatment Arm A: High Dose - Period 1	Randomised healthy participants will receive single dose of midazolam
Treatment Arm A: High dose - Period 2	Randomised healthy participants will receive single dose of rosuvastatin and digoxin
Treatment Arm A: High dose - Period 3	Randomised healthy participants will receive a single dose of rosuvastatin and digoxin together with AZD5462
Treatment Arm A: High Dose - Period 4	Randomised healthy participants will receive a single dose of midazolam together with AZD5462
Treatment Arm A: High dose - Period 5	Randomised healthy participants will receive a single dose of rosuvastatin and digoxin together with AZD5462
Treatment Arm B: Low Dose - Period 1	Randomised healthy participants will receive single dose of midazolam
Treatment Arm B : Low Dose - Period 2	Randomised healthy participants will receive single dose of rosuvastatin and digoxin
Treatment Arm B: Low Dose - Period 3	Randomised healthy participants will receive a single dose of rosuvastatin and digoxin together with AZD5462
Treatment Arm B: Low Dose - Period 4	Randomised healthy participants will receive a single dose of midazolam together with AZD5462
Treatment Arm B: Low Dose - Period 5	Randomised healthy participants will receive a single dose of rosuvastatin and digoxin together with AZD5462

Measured Values

	Treatment Arm A: High Dose - Period 1	Treatment Arm A: High dose - Period 2	Treatment Arm A: High dose - Period 3	Treatment Arm A: High Dose - Period 4	Treatment Arm A: High dose - Period 5	Treatment Arm B: Low Dose - Period 1	Treatment Arm B : Low Dose - Period 2	Treatment Arm B: Low Dose - Period 3	Treatment Arm B: Low Dose - Period 4	Treatment Arm B: Low Dose - Period 5
Number of Participants Analyzed [units:participants]	16	16	16	16	16	15	16	15	15	15
Time to reach maximum plasma concentration (tmax) of midazolam, rosuvastatin, digoxin, and AZD5462 [units: hour (h)] Median (Full Range)
Midazolam	0.50 (0.25 to 1.02)	0 (0 to 0)	0 (0 to 0)	0.52 (0.50 to 2.02)	0 (0 to 0)	0.52 (0.50 to 1.52)	0 (0 to 0)	0 (0 to 0)	0.54 (0.25 to 0.78)	0 (0 to 0)
Rosuvastatin	0 (0 to 0)	3.41 (1.47 to 5.10)	1.00 (0.68 to 1.48)	0 (0 to 0)	0.90 (0.67 to 2.12)	0 (0 to 0)	5.02 (1.10 to 6.05)	1.03 (0.35 to 4.00)	0 (0 to 0)	1.01 (0.67 to 5.00)
Digoxin	0 (0 to 0)	1.00 (0.72 to 3.00)	1.00 (0.68 to 3.02)	0 (0 to 0)	0.90 (0.67 to 1.50)	0 (0 to 0)	1.50 (0.70 to 3.98)	0.67 (0.35 to 1.52)	0 (0 to 0)	1.00 (0.67 to 2.00)
AZD5462	0 (0 to 0)	0 (0 to 0)	0.68 (0.32 to 1.00)	0 (0 to 0)	0.67 (0.33 to 0.92)	0 (0 to 0)	0 (0 to 0)	0.67 (0.33 to 0.68)	0 (0 to 0)	0.67 (0.33 to 1.00)

No statistical analysis provided for Time to reach maximum plasma concentration (tmax) of midazolam, rosuvastatin, digoxin, and AZD5462

5. Primary Outcome Measure: Half-life associated with terminal slope (λz) of a semi logarithmic concentration-time curve (t½λz) of midazolam, rosuvastatin, digoxin, and AZD5462 [ Time Frame: Day 1 to Day 18 (pre and post-dose of study drug administration) ]

Measure Type	Primary
Measure Name	Half-life associated with terminal slope (λz) of a semi logarithmic concentration-time curve (t½λz) of midazolam, rosuvastatin, digoxin, and AZD5462
Measure Description	The effect of AZD5462 on the PK of oral midazolam (CYP3A4 probe), rosuvastatin (OATP1B1/3, BCRP probe), and digoxin (P-gp probe) was assessed.
Time Frame	Day 1 to Day 18 (pre and post-dose of study drug administration)
Safety Issue?

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 subjects who received at least one dose of AZD5462 following single dose of midazolam, rosuvastatin, digoxin, and AZD5462 with at least one reportable post-dose concentration.

Reporting Groups

	Description
Treatment Arm A: High Dose - Period 1	Randomised healthy participants will receive single dose of midazolam
Treatment Arm A: High dose - Period 2	Randomised healthy participants will receive single dose of rosuvastatin and digoxin
Treatment Arm A: High dose - Period 3	Randomised healthy participants will receive a single dose of rosuvastatin and digoxin together with AZD5462
Treatment Arm A: High Dose - Period 4	Randomised healthy participants will receive a single dose of midazolam together with AZD5462
Treatment Arm A: High dose - Period 5	Randomised healthy participants will receive a single dose of rosuvastatin and digoxin together with AZD5462
Treatment Arm B: Low Dose - Period 1	Randomised healthy participants will receive single dose of midazolam
Treatment Arm B: Low Dose - Period 2	Randomised healthy participants will receive single dose of rosuvastatin and digoxin
Treatment Arm B: Low Dose - Period 3	Randomised healthy participants will receive a single dose of rosuvastatin and digoxin together with AZD5462
Treatment Arm B: Low Dose - Period 4	Randomised healthy participants will receive a single dose of midazolam together with AZD5462
Treatment Arm B: Low Dose - Period 5	Randomised healthy participants will receive a single dose of rosuvastatin and digoxin together with AZD5462

Measured Values

	Treatment Arm A: High Dose - Period 1	Treatment Arm A: High dose - Period 2	Treatment Arm A: High dose - Period 3	Treatment Arm A: High Dose - Period 4	Treatment Arm A: High dose - Period 5	Treatment Arm B: Low Dose - Period 1	Treatment Arm B: Low Dose - Period 2	Treatment Arm B: Low Dose - Period 3	Treatment Arm B: Low Dose - Period 4	Treatment Arm B: Low Dose - Period 5
Number of Participants Analyzed [units:participants]	16	16	16	16	16	15	16	15	15	15
Half-life associated with terminal slope (λz) of a semi logarithmic concentration-time curve (t½λz) of midazolam, rosuvastatin, digoxin, and AZD5462 [units: h] Mean (Standard Deviation)
Midazolam	5.781 (1.652)	0 (0)	0 (0)	6.168 (1.901)	0 (0)	4.626 (1.966)	0 (0)	0 (0)	5.046 (1.962)	0 (0)
Rosuvastatin	0 (0)	27.27 (14.95)	28.33 (22.19)	0 (0)	17.89 (5.665)	0 (0)	13.67 (6.930)	17.46 (8.563)	0 (0)	24.75 (26.54)
Digoxin	0 (0)	45.58 (20.28)	54.66 (22.16)	0 (0)	44.72 (11.95)	0 (0)	43.95 (7.973)	38.88 (8.088)	0 (0)	42.78 (14.59)

No statistical analysis provided for Half-life associated with terminal slope (λz) of a semi logarithmic concentration-time curve (t½λz) of midazolam, rosuvastatin, digoxin, and AZD5462

6. Primary Outcome Measure: Area under the plasma concentration-time curve from time zero to 12 hours after dosing [AUC(0-12)] of midazolam, rosuvastatin, digoxin, and AZD5462 [ Time Frame: Day 1 to Day 18 (pre and post-dose of study drug administration) ]

Measure Type	Primary
Measure Name	Area under the plasma concentration-time curve from time zero to 12 hours after dosing [AUC(0-12)] of midazolam, rosuvastatin, digoxin, and AZD5462
Measure Description	The effect of AZD5462 on the PK of oral midazolam (CYP3A4 probe), rosuvastatin (OATP1B1/3, BCRP probe), and digoxin (P-gp probe) was assessed.
Time Frame	Day 1 to Day 18 (pre and post-dose of study drug administration)
Safety Issue?

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 subjects who received at least one dose of AZD5462 following single dose of midazolam, rosuvastatin, digoxin, and AZD5462 with at least one reportable post-dose concentration.

Reporting Groups

	Description
Treatment Arm A: High Dose - Period 1	Randomised healthy participants will receive single dose of midazolam
Treatment Arm A: High dose - Period 2	Randomised healthy participants will receive single dose of rosuvastatin and digoxin
Treatment Arm A: High dose - Period 3	Randomised healthy participants will receive a single dose of rosuvastatin and digoxin together with AZD5462
Treatment Arm A: High Dose - Period 4	Randomised healthy participants will receive a single dose of midazolam together with AZD5462
Treatment Arm A: High dose - Period 5	Randomised healthy participants will receive a single dose of rosuvastatin and digoxin together with AZD5462
Treatment Arm B: Low Dose - Period 1	Randomised healthy participants will receive single dose of midazolam
Treatment Arm B: Low Dose - Period 2	Randomised healthy participants will receive single dose of rosuvastatin and digoxin
Treatment Arm B: Low Dose - Period 3	Randomised healthy participants will receive a single dose of rosuvastatin and digoxin together with AZD5462
Treatment Arm B: Low Dose - Period 4	Randomised healthy participants will receive a single dose of midazolam together with AZD5462
Treatment Arm B: Low Dose - Period 5	Randomised healthy participants will receive a single dose of rosuvastatin and digoxin together with AZD5462

Measured Values

	Treatment Arm A: High Dose - Period 1	Treatment Arm A: High dose - Period 2	Treatment Arm A: High dose - Period 3	Treatment Arm A: High Dose - Period 4	Treatment Arm A: High dose - Period 5	Treatment Arm B: Low Dose - Period 1	Treatment Arm B: Low Dose - Period 2	Treatment Arm B: Low Dose - Period 3	Treatment Arm B: Low Dose - Period 4	Treatment Arm B: Low Dose - Period 5
Number of Participants Analyzed [units:participants]	16	16	16	16	16	15	16	15	15	15
Area under the plasma concentration-time curve from time zero to 12 hours after dosing [AUC(0-12)] of midazolam, rosuvastatin, digoxin, and AZD5462 [units: h*μmol/L] Geometric Mean (Geometric Coefficient of Variation)	0 (0%)	0 (0%)	24.26 (39.18%)	0 (0%)	26.52 (31.79%)	0 (0%)	0 (0%)	3.976 (32.54%)	0 (0%)	4.155 (29.22%)

No statistical analysis provided for Area under the plasma concentration-time curve from time zero to 12 hours after dosing [AUC(0-12)] of midazolam, rosuvastatin, digoxin, and AZD5462

7. Primary Outcome Measure: Ctrough (observed lowest concentration before the next dose is administered) of midazolam, rosuvastatin, digoxin, and AZD5462 [ Time Frame: Day 1 to Day 18 (pre and post-dose of study drug administration) ]

Measure Type	Primary
Measure Name	Ctrough (observed lowest concentration before the next dose is administered) of midazolam, rosuvastatin, digoxin, and AZD5462
Measure Description	The effect of AZD5462 on the PK of oral midazolam (CYP3A4 probe), rosuvastatin (OATP1B1/3, BCRP probe), and digoxin (P-gp probe) was assessed.
Time Frame	Day 1 to Day 18 (pre and post-dose of study drug administration)
Safety Issue?

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 subjects who received at least one dose of AZD5462 following single dose of midazolam, rosuvastatin, digoxin, and AZD5462 with at least one reportable post-dose concentration.

Reporting Groups

	Description
Treatment Arm A: High Dose - Period 1	Randomised healthy participants will receive single dose of midazolam
Treatment Arm A: High dose - Period 2	Randomised healthy participants will receive single dose of rosuvastatin and digoxin
Treatment Arm A: High dose - Period 3	Randomised healthy participants will receive a single dose of rosuvastatin and digoxin together with AZD5462
Treatment Arm A: High Dose - Period 4	Randomised healthy participants will receive a single dose of midazolam together with AZD5462
Treatment Arm A: High dose - Period 5	Randomised healthy participants will receive a single dose of rosuvastatin and digoxin together with AZD5462
Treatment Arm B: Low Dose - Period 1	Randomised healthy participants will receive single dose of midazolam
Treatment Arm B: Low Dose - Period 2	Randomised healthy participants will receive single dose of rosuvastatin and digoxin
Treatment Arm B: Low Dose - Period 3	Randomised healthy participants will receive a single dose of rosuvastatin and digoxin together with AZD5462
Treatment Arm B: Low Dose - Period 4	Randomised healthy participants will receive a single dose of midazolam together with AZD5462
Treatment Arm B: Low Dose - Period 5	Randomised healthy participants will receive a single dose of rosuvastatin and digoxin together with AZD5462

Measured Values

	Treatment Arm A: High Dose - Period 1	Treatment Arm A: High dose - Period 2	Treatment Arm A: High dose - Period 3	Treatment Arm A: High Dose - Period 4	Treatment Arm A: High dose - Period 5	Treatment Arm B: Low Dose - Period 1	Treatment Arm B: Low Dose - Period 2	Treatment Arm B: Low Dose - Period 3	Treatment Arm B: Low Dose - Period 4	Treatment Arm B: Low Dose - Period 5
Number of Participants Analyzed [units:participants]	16	16	16	16	16	15	16	15	15	15
Ctrough (observed lowest concentration before the next dose is administered) of midazolam, rosuvastatin, digoxin, and AZD5462 [units: μmol/L] Geometric Mean (Geometric Coefficient of Variation)	0 (0%)	0 (0%)	0.1936 (76.75%)	0.1466 (87.67%)	0.1425 (60.54%)	0 (0%)	0 (0%)	0.03335 (64.01%)	0.03306 (53.84%)	0.02778 (45.00%)

No statistical analysis provided for Ctrough (observed lowest concentration before the next dose is administered) of midazolam, rosuvastatin, digoxin, and AZD5462

8. Secondary Outcome Measure: Number of participants with adverse events (AEs) [ Time Frame: Day ≤ -28 (Screening) Up to Final Follow-up (FU) Visit (Day 24) ]

Measure Type	Secondary
Measure Name	Number of participants with adverse events (AEs)
Measure Description	The safety and tolerability of AZD5462 alone and in combination with midazolam, rosuvastatin, and digoxin was examined.
Time Frame	Day ≤ -28 (Screening) Up to Final Follow-up (FU) Visit (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.
All participants who received at least one dose of IMP in any period for Treatment Arms A or B and for whom any safety post-dose data were available.

Reporting Groups

	Description
Treatment Arm A: High Dose - Period 1	Randomised healthy participants received a single dose of midazolam
Treatment Arm A: High dose - Period 2	Randomised healthy participants received a single dose of rosuvastatin and digoxin
Treatment Arm A: High dose - Period 3	Randomised healthy participants received a single dose of rosuvastatin and digoxin together with AZD5462
Treatment Arm A: High Dose - Period 4	Randomised healthy participants received a single dose of midazolam together with AZD5462
Treatment Arm A: High dose - Period 5	Randomised healthy participants received a single dose of rosuvastatin and digoxin together with AZD5462
Treatment Arm B: Low Dose - Period 1	Randomised healthy participants received a single dose of midazolam
Treatment Arm B: Low Dose - Period 2	Randomised healthy participants received a single dose of rosuvastatin and digoxin
Treatment Arm B: Low Dose - Period 3	Randomised healthy participants received a single dose of rosuvastatin and digoxin together with AZD5462
Treatment Arm B: Low Dose - Period 4	Randomised healthy participants received a single dose of midazolam together with AZD5462
Treatment Arm B: Low Dose - Period 5	Randomised healthy participants received a single dose of rosuvastatin and digoxin together with AZD5462

Measured Values

	Treatment Arm A: High Dose - Period 1	Treatment Arm A: High dose - Period 2	Treatment Arm A: High dose - Period 3	Treatment Arm A: High Dose - Period 4	Treatment Arm A: High dose - Period 5	Treatment Arm B: Low Dose - Period 1	Treatment Arm B: Low Dose - Period 2	Treatment Arm B: Low Dose - Period 3	Treatment Arm B: Low Dose - Period 4	Treatment Arm B: Low Dose - Period 5
Number of Participants Analyzed [units:participants]	16	16	16	16	16	16	16	16	16	16
Number of participants with adverse events (AEs) [units: Participants]
Any Adverse Event (AE)	1	5	6	1	8	2	0	3	1	4
Any Serious Adverse Event (SAE)	0	0	0	0	0	0	0	0	0	0
Any SAE with outcome of death	0	0	0	0	0	0	0	0	0	0
Any AE leading to discontinuation of investigational medicinal product (IMP)	0	0	1	0	0	0	0	1	0	0

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

Serious Adverse Events

Time Frame	Day ≤ -28 (Screening) Up to Final Follow-up (FU) Visit (Day 24)
Additional Description	No text entered.

Reporting Groups

	Description
Treatment Arm A: High Dose - Period 1	Randomised healthy participants received a single dose of midazolam
Treatment Arm A: High dose - Period 2	Randomised healthy participants received a single dose of rosuvastatin and digoxin
Treatment Arm A: High dose - Period 3	Randomised healthy participants received a single dose of rosuvastatin and digoxin together with AZD5462
Treatment Arm A: High Dose - Period 4	Randomised healthy participants received a single dose of midazolam together with AZD5462
Treatment Arm A: High dose - Period 5	Randomised healthy participants received a single dose of rosuvastatin and digoxin together with AZD5462
Treatment Arm B: Low Dose - Period 1	Randomised healthy participants received a single dose of midazolam
Treatment Arm B: Low Dose - Period 2	Randomised healthy participants received a single dose of rosuvastatin and digoxin
Treatment Arm B: Low Dose - Period 3	Randomised healthy participants received a single dose of rosuvastatin and digoxin together with AZD5462
Treatment Arm B: Low Dose - Period 4	Randomised healthy participants received a single dose of midazolam together with AZD5462
Treatment Arm B: Low Dose - Period 5	Randomised healthy participants received a single dose of rosuvastatin and digoxin together with AZD5462

Serious Adverse Events

	Treatment Arm A: High Dose - Period 1	Treatment Arm A: High dose - Period 2	Treatment Arm A: High dose - Period 3	Treatment Arm A: High Dose - Period 4	Treatment Arm A: High dose - Period 5	Treatment Arm B: Low Dose - Period 1	Treatment Arm B: Low Dose - Period 2	Treatment Arm B: Low Dose - Period 3	Treatment Arm B: Low Dose - Period 4	Treatment Arm B: Low Dose - Period 5
Total, serious adverse events
# participants affected / at risk	0/16 (0.00%)	0/16 (0.00%)	0/16 (0.00%)	0/16 (0.00%)	0/16 (0.00%)	0/16 (0.00%)	0/16 (0.00%)	0/16 (0.00%)	0/16 (0.00%)	0/16 (0.00%)

Other Adverse Events

Time Frame	Day ≤ -28 (Screening) Up to Final Follow-up (FU) Visit (Day 24)
Additional Description	No text entered.

Frequency Threshold

Threshold above which other adverse events are reported	0%

Reporting Groups

	Description
Treatment Arm A: High Dose - Period 1	Randomised healthy participants received a single dose of midazolam
Treatment Arm A: High dose - Period 2	Randomised healthy participants received a single dose of rosuvastatin and digoxin
Treatment Arm A: High dose - Period 3	Randomised healthy participants received a single dose of rosuvastatin and digoxin together with AZD5462
Treatment Arm A: High Dose - Period 4	Randomised healthy participants received a single dose of midazolam together with AZD5462
Treatment Arm A: High dose - Period 5	Randomised healthy participants received a single dose of rosuvastatin and digoxin together with AZD5462
Treatment Arm B: Low Dose - Period 1	Randomised healthy participants received a single dose of midazolam
Treatment Arm B: Low Dose - Period 2	Randomised healthy participants received a single dose of rosuvastatin and digoxin
Treatment Arm B: Low Dose - Period 3	Randomised healthy participants received a single dose of rosuvastatin and digoxin together with AZD5462
Treatment Arm B: Low Dose - Period 4	Randomised healthy participants received a single dose of midazolam together with AZD5462
Treatment Arm B: Low Dose - Period 5	Randomised healthy participants received a single dose of rosuvastatin and digoxin together with AZD5462

Other Adverse Events

Treatment Arm A: High Dose - Period 1

Treatment Arm A: High dose - Period 2

Treatment Arm A: High dose - Period 3

Treatment Arm A: High Dose - Period 4

Treatment Arm A: High dose - Period 5

Treatment Arm B: Low Dose - Period 1

Treatment Arm B: Low Dose - Period 2

Treatment Arm B: Low Dose - Period 3

Treatment Arm B: Low Dose - Period 4

Treatment Arm B: Low Dose - Period 5

Total, other (not including serious) adverse events

# participants affected / at risk

1/16 (6.25%)

5/16 (31.25%)

6/16 (37.50%)

1/16 (6.25%)

8/16 (50.00%)

2/16 (12.50%)

0/16 (0.00%)

3/16 (18.75%)

1/16 (6.25%)

4/16 (25.00%)

Nervous system disorders

Headache¹

# participants affected / at risk

0/16 (0.00%)

1/16 (6.25%)

0/16 (0.00%)

1/16 (6.25%)

# events

Nervous system disorders

Dizziness¹

# participants affected / at risk

0/16 (0.00%)

1/16 (6.25%)

0/16 (0.00%)

# events

Eye disorders

Photophobia¹

# participants affected / at risk

0/16 (0.00%)

1/16 (6.25%)

0/16 (0.00%)

# events

Cardiac disorders

Ventricular tachycardia¹

# participants affected / at risk

0/16 (0.00%)

1/16 (6.25%)

0/16 (0.00%)

# events

Cardiac disorders

Supraventricular tachycardia¹

# participants affected / at risk

0/16 (0.00%)

1/16 (6.25%)

0/16 (0.00%)

# events

Gastrointestinal disorders

Bowel movement irregularity¹

# participants affected / at risk

0/16 (0.00%)

1/16 (6.25%)

0/16 (0.00%)

1/16 (6.25%)

0/16 (0.00%)

# events

Respiratory, thoracic and mediastinal disorders

Dry throat¹

# participants affected / at risk

0/16 (0.00%)

1/16 (6.25%)

0/16 (0.00%)

# events

Skin and subcutaneous tissue disorders

Dermatitis¹

# participants affected / at risk

0/16 (0.00%)

1/16 (6.25%)

0/16 (0.00%)

# events

Skin and subcutaneous tissue disorders

Rash¹

# participants affected / at risk

0/16 (0.00%)

1/16 (6.25%)

0/16 (0.00%)

# events

Skin and subcutaneous tissue disorders

Alopecia¹

# participants affected / at risk

0/16 (0.00%)

1/16 (6.25%)

0/16 (0.00%)

# events

Musculoskeletal and connective tissue disorders

Arthralgia¹

# participants affected / at risk

0/16 (0.00%)

1/16 (6.25%)

0/16 (0.00%)

# events

Musculoskeletal and connective tissue disorders

Back pain¹

# participants affected / at risk

0/16 (0.00%)

1/16 (6.25%)

0/16 (0.00%)

# events

Musculoskeletal and connective tissue disorders

Tendonitis¹

# participants affected / at risk

0/16 (0.00%)

1/16 (6.25%)

0/16 (0.00%)

# events

General disorders

Feeling hot¹

# participants affected / at risk

0/16 (0.00%)

1/16 (6.25%)

0/16 (0.00%)

# events

General disorders

Medical device site dermatitis¹

# participants affected / at risk

1/16 (6.25%)

0/16 (0.00%)

2/16 (12.50%)

0/16 (0.00%)

8/16 (50.00%)

1/16 (6.25%)

0/16 (0.00%)

1/16 (6.25%)

# events

General disorders

Catheter site pain¹

# participants affected / at risk

0/16 (0.00%)

1/16 (6.25%)

# events

General disorders

Catheter site swelling¹

# participants affected / at risk

0/16 (0.00%)

1/16 (6.25%)

0/16 (0.00%)

# events

General disorders

Fatigue¹

# participants affected / at risk

0/16 (0.00%)

1/16 (6.25%)

0/16 (0.00%)

# events

General disorders

Feeling cold¹

# participants affected / at risk

0/16 (0.00%)

1/16 (6.25%)

0/16 (0.00%)

# events

General disorders

Xerosis¹

# participants affected / at risk

0/16 (0.00%)

1/16 (6.25%)

# events

Investigations

Electrocardiogram PR prolongation¹

# participants affected / at risk

0/16 (0.00%)

1/16 (6.25%)

0/16 (0.00%)

# events

†	Events were collected by systematic assessment
1	Term from vocabulary, MedDRA version 25.0

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: No unpublished information contained herein may be disclosed without prior written approval from AstraZeneca AB. Access to this document must be restricted to relevant parties.

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
None

Results Point of Contact

Name/Title:	Global Clinical Lead
Organization:	AstraZeneca AB
Phone	1-877-240-9479
E-mail:	[email protected]

Documents available

redacted CSR Synopsis
Download
Trial Results Summaries
Available here

Contacts

Contact

AstraZeneca Clinical Study Information Center

1-877-240-9479

information.center@astrazeneca.com

Sponsors

Collaborators

Inclusion Criteria

Exclusion Criteria

Research Site

redacted CSR Synopsis

Trial Results Summaries