AZD4635 Relative Bioavailability Study - Rel Bio

Study identifier:D8730C00002

ClinicalTrials.gov identifier:NCT03710434

EudraCT identifier:2018-003366-14

CTIS identifier:N/A

Study Complete

Official Title

A Phase I, Open-Label Study to Assess the Pharmacokinetics and Relative Bioavailability of AZD4635 in Non-Smoking Healthy Male Subjects, with the Option to Assess Food Effect, pH Effect and Absolute Bioavailability

Medical condition

Healthy Volunteers

Phase

Phase 1

Healthy volunteers

Yes

Study drug

AZD4635 50 mg nano-suspension (reference), AZD4635 solid oral formulation - fasted, AZD4635 solid oral formulation - fed, Lansoprazole and AZD4635 50 mg solid oral formulation, AZD4635 solid oral formulation variant 1 - fasted, AZD4635 solid oral formulation variant 2 - fasted, [14C] AZD4635 IV microtracer - fasted

Sex

Male

Actual Enrollment

Study type

Interventional

Age

18 Years - 55 Years

Date

Study Start Date: 01 Nov 2018

Primary Completion Date: 02 Apr 2019

Study Completion Date: 02 Apr 2019

Study design

Allocation: Randomized
Endpoint Classification: -
Intervention Model: Crossover Assignment
Masking: -
Primary Purpose: Basic Science

Verification:

Verified 01 May 2020 by AstraZeneca

Collaborators

Quotient Sciences Limited

Inclusion and exclusion criteria

Inclusion Criteria

Inclusion Criteria:
1 Provision of signed and dated, written informed consent prior to any study specific procedures.
2 Healthy male subjects aged 18 to 55 years with suitable veins for cannulation or repeated venepuncture and IV infusion.
3 Have a body mass index of 18.0 to 32.0 kg/m2, and weigh at least 50 kg and no more than 100 kg.
4 Must be willing and able to communicate and participate in the whole study
5 Must agree to adhere to the contraception requirements, as precaution should avoid fathering a child by either true abstinence or use together, with their female partner/spouse, a highly effective contraception form of birth control in combination with a barrier method, starting from the time of AZD4635 administration until 90 days after the last dose of AZD4635.
Exclusion Criteria:
1 History of any clinically significant disease or disorder which in investigator opinion, may put volunteer at risk because of participation in the study, or influence results of volunteer’s ability to participate in the study.
2 History or presence of gastrointestinal, hepatic or renal disease, or any other condition known to interfere with absorption, distribution, metabolism or excretion of drugs.
3 Presence of refractory nausea and vomiting or chronic gastrointestinal diseases.
4 Any clinically significant illness, medical/surgical procedure, or trauma within 4 weeks of the first administration of IMP.
5 Any confirmed clinically significant abnormalities in clinical chemistry, haematology or urinalysis as judged by the investigator
6 Any confirmed clinically significant abnormal findings in vital signs, as judged by investigator.
7 BP >140/90 mmHg or history of hypertension.
8 Any confirmed clinically significant abnormal findings in 12-lead ECG, as judged by investigator.
9 Any positive result at screening for serum hepatitis B surface antigen (HBsAg), hepatitis C virus antibody (HCV Ab) or human immunodeficiency virus (HIV) results.
10 Known or suspected history of drug or alcohol abuse within the past 2 years, as judged by the investigator.
11 Has received another new chemical entity (defined as a compound which has not been approved for marketing) within 3 months of 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 longest. Note: subjects consented and screened, but not randomized in this study or a previous Phase I study are not excluded.
12 Plasma donation within 1 month of screening or any blood donation/loss of more than 500 mL of blood during the 3 months prior to screening.
13 History of severe allergy/hypersensitivity or ongoing allergy/hypersensitivity, as judged by the investigator or history of hypersensitivity to drugs with a similar chemical structure or class to AZD4635 or the formulation excipients. Hayfever is allowed unless it is active.
14 Current smokers and those who have smoked within last 12 months. A breath carbon monoxide reading of greater than 10 ppm at screening and admission.
15 Current users of e-cigarettes and nicotine replacement products and those who have used these products within last 12 months.
16 Positive screen for drugs of abuse at screening or admission to the clinical unit or positive screen for alcohol at screening or admission to the clinical unit.
17 Herbal preparations/medications are not allowed throughout the study. These herbal medications include, but are not limited to, St. John's wort, kava, ephedra (ma huang), gingko biloba, dehydroepiandrosterone, yohimbe, saw palmetto, and ginseng. Subjects should stop using these herbal medications 14 days prior to the first dose of AZD4635.
18 Use of any prescribed or nonprescribed medication including antacids, H2 antagonists, PPI, analgesics (other than paracetamol/acetaminophen up to 4 g/day), vitamins and minerals during the two weeks prior to first administration of IMP or longer if medication has a longer half-life. Exceptions may apply on a case by case basis, if considered not to interfere with the objectives of the study, as agreed by the PI and sponsor’s medical monitor.
19 Known or suspected history of alcohol or drug abuse or regular alcohol consumption in males >21 units per week (1 unit = ½ pint beer, or a 25 mL shot of 40% spirit, 1.5 to 2 Units = 125 mL glass of wine, depending on type)
20 Subjects who are study site employees, or immediate family members of a study site or sponsor employee
21 Subjects who have previously been enrolled in this study or have previously received AZD4635.
22 Radiation exposure, including that from the present study, excluding background radiation but including diagnostic x-rays and other medical exposures, exceeding 5 mSv in the last 12 months or 10 mSv in the last 5 years. No occupationally exposed worker, as defined in the Ionising Radiation Regulations 2017, shall participate in the study
23 Subjects who have been enrolled in an ADME study in the last 12 months.
24 Subjects with Gilberts Syndrome or a history of cholecystectomy or gall stones.
25 Judgment by investigator that volunteer should not participate in study if they have any ongoing or recent (ie, during the screening period) minor medical complaints that may interfere with the interpretation of the study data or are considered unlikely to comply with the study procedures, restrictions and requirements.
26 Failure to satisfy the investigator of fitness to participate for any other reason.

Location

Research Site

Ruddington, United Kingdom, NG11 6JS

Arms	Assigned Interventions
Experimental: Part A – nano-suspension Subjects will receive single dose of AZD4635 50mg nano-suspension (reference) in the fasted state.	Drug: AZD4635 50 mg nano-suspension (reference) Subjects will receive a single dose of AZD4635 50 mg nano-suspension (reference) in the fasted state.
Experimental: Part A – solid oral formulation Subjects will receive single dose of AZD4635 50mg solid oral formulation, in the fasted state.	Drug: AZD4635 solid oral formulation - fasted Subjects will receive a single dose of AZD4635 solid oral formulation, in the fasted state.
Experimental: Part B–solid oral formulation with food Subjects will receive a single dose AZD4635 solid oral formulation after high fat meal.	Drug: AZD4635 solid oral formulation - fed Subjects will receive a single dose of AZD4635 solid oral formulation, in the fed state.
Experimental: Part B – solid oral formulation with PPI Subjects will receive 30 mg lansoprazole BID and a single dose of AZD4635 solid oral formulation in the fasted state.	Drug: Lansoprazole and AZD4635 50 mg solid oral formulation Subjects will receive lansoprazole 30 mg BID for 5 days followed by a single dose of AZD4635 50 mg solid oral formulation in the fasted state.
Experimental: Part B – dose exploration 1 If dose adjustment is required, subjects will receive a different single dose (XX mg) of AZD4635 solid oral formulation, in the fasted state.	Drug: AZD4635 solid oral formulation - fasted Subjects will receive a single dose of AZD4635 solid oral formulation, in the fasted state.
Experimental: Part B – dose exploration 2 If dose adjustment is required, subjects will receive a different single dose (YY mg) of AZD4635 solid oral formulation, in the fasted state.	Drug: AZD4635 solid oral formulation - fasted Subjects will receive a single dose of AZD4635 solid oral formulation, in the fasted state.
Experimental: Part B – variant 1 Subjects will receive a single dose of AZD4635 solid oral formulation, variant 1 in the fasted state and optional [14C] AZD4635 IV microtracer.	Drug: AZD4635 solid oral formulation variant 1 - fasted Subjects will receive a single dose of AZD4635 solid oral formulation, variant 1 in the fasted state. Drug: [14C] AZD4635 IV microtracer - fasted Subjects will receive a single dose of [14C] AZD4635 IV microtracer. This intervention will be co-administered with AZD4635 solid oral formulation variant 1.
Experimental: Part B – variant 2 Subjects will receive a single dose of AZD4635 solid oral formulation, variant 2 in the fasted state.	Drug: AZD4635 solid oral formulation variant 2 - fasted Subjects will receive a single dose of AZD4635 solid oral formulation, variant 2 in the fasted state.

Participant Flow

Recruitment Details

Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
Participants were recruited from the Quotient Sciences phase 1 clinical trial unit volunteer panel in November 2018. The first participant was enrolled in November 2018 and the last participant visit was in April 2019.

Pre-Assignment Details

Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
Subjects were screened for eligibility to participate in the study up to 28 days before dosing.

Reporting Groups

	Description
Overall Study	This is included to show the overall number of participants who took part in all six periods of the study

Participant Flow: Overall Study

	Overall Study
STARTED	21
Part A, Period 1	21
Part A, Period 2	20
Part B, Period 3	20
Part B, Period 4	20
Part B, Period 5	20
Part B, Period 6	20
COMPLETED	20
NOT COMPLETED	1
Adverse Event	1

Baseline Characteristics

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

One subject had a pre-dose Adverse Event. The subject was found to have atrial fibrillation at screening (Day -15) and received study drug in Period 1 in error, after which the study drug was withdrawn. The atrial fibrillation had not resolved by the end of the study

Reporting Groups

	Description
Overall Study	This is included to show the overall number of participants who took part in all six periods of the study

Baseline Measures

	Overall Study
Number of Participants [units: Participants]	21
Age Categorical [units: Participants]
<=18 years	0
Between 18 and 65 years	21
>=65 years	0
Sex: Female, Male [units: ]
Female	0
Male	21
Race/Ethnicity, Customized [units: Participants]
Black Or African American	1
White	20

Outcome Measures

1. Primary Outcome Measure: Frel Cmax vs. A [ Time Frame: Pre-dose to Day 6 ]

Measure Type	Primary
Measure Name	Frel Cmax vs. A
Measure Description	Relative bioavailability (Frel) of AZD4635 and metabolites SSP-005174X and SSP-005173X solid oral formulation compared to the nano-suspension reference formulation based on Cmax.
Time Frame	Pre-dose to Day 6
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.
Not calculated for Regimen A (represented by '0'), this is shown in order to present statistics.

Reporting Groups

	Description
Regimen A: 50 mg AZD4635 nano-suspension, fasted	Part A, Period 1: single oral dose of 50 mg (40 mL) powder for oral suspension 5.5% (w/w) (referred to as nano-suspension) (reference) in the fasted state (10 h overnight fast) in the morning of Day 1.
Regimen B: 50 mg AZD4635 oral, fasted	Part A, Period 2: single dose of 50 mg solid oral capsule in the fasted state (10 h overnight fast) in the morning of Day 1. Not all of the enrolled subjects' data could be included in the analysis for each metabolite.
Regimen C: 50 mg AZD4635 oral, fed	Part B, Period 3: single dose of 50 mg solid oral capsule after a high fat meal.
Regimen D: 50 mg AZD4635 oral, fasted with lansoprazole	Part B, Period 4: AZD4635 - single dose of 50 mg solid oral capsule in the fasted state. Lansoprazole - administered on Days -4, 03, -2 and -1 as 30 mg twice daily at least 30 minutes before food. On Day 1, subjects received a single dose of lansoprazole following an overnight fast (8 h) and the dose of AZD4635 was administered 2 h later.
Regimen E: 50 mg AZD4635 oral, fasted (variant 1)	Part B, Period 5: AZD4635 - single dose of 50 mg solid oral capsule, variant 1 in the fasted state. The variants had the same quantitative composition as the capsule formulation, but the process parameters and/or input material were altered. [14C]AZD4635 - An IV microtracer dose of AZD4635 was administered with the solid oral formulation. It was administered as a 15 min IV infusion (ending 0.5 h post-oral dose) of a microdose (50 µg) of AZD4635 containing microtracer amounts of 14C (not more than 25.7 kBq/5 mL [694.4 nCi/5 mL]).
Regimen F: 50 mg AZD4635 oral, fasted (variant 2)	Part B, Period 6: single dose of 50 mg solid oral capsule, variant 2 in the fasted state. The variants had the same quantitative composition as the capsule formulation, but the process parameters and/or input material were altered.

Measured Values

	Regimen A: 50 mg AZD4635 nano-suspension, fasted	Regimen B: 50 mg AZD4635 oral, fasted	Regimen C: 50 mg AZD4635 oral, fed	Regimen D: 50 mg AZD4635 oral, fasted with lansoprazole	Regimen E: 50 mg AZD4635 oral, fasted (variant 1)	Regimen F: 50 mg AZD4635 oral, fasted (variant 2)
Number of Participants Analyzed [units:participants]	20	20	20	20	20	20
Frel Cmax vs. A [units: (%)] Geometric Mean (Geometric Coefficient of Variation)
AZD4635	0 (0%)	127.196 (31.9%)	44.261 (32.1%)	99.005 (31.5%)	94.743 (32.5%)	75.654 (30.0%)
SSP-005174X	0 (0%)	110.334 (31.6%)	45.680 (33.1%)	103.214 (30.1%)	93.322 (36.6%)	76.888 (29.1%)
SSP-005173X	0 (0%)	106.373 (30.5%)	54.581 (34.9%)	96.042 (33.0%)	86.160 (34.0%)	78.948 (25.2%)

Statistical Analysis 1 for Frel Cmax vs. A

Groups^[1]	Regimen A: 50 mg AZD4635 nano-suspension, fasted, Regimen B: 50 mg AZD4635 oral, fasted
Other^[5]	127.39
90% Confidence Interval	( 114.77 to 141.41 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Relative Bioavailability Reg B/Reg A: AZD4635 Formal statistical analysis performed on the pharmacokinetic parameter Cmax to assess relative bioavailability of solid oral formulation (test) versus nano-suspension (reference)
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 2 for Frel Cmax vs. A

Groups^[1]	Regimen A: 50 mg AZD4635 nano-suspension, fasted, Regimen B: 50 mg AZD4635 oral, fasted
Other^[5]	111.29
90% Confidence Interval	( 99.45 to 124.54 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Relative Bioavailability Reg B/Reg A: SSP-005174X Formal statistical analysis performed on the pharmacokinetic parameter Cmax to assess relative bioavailability of solid oral formulation (test) versus nano-suspension (reference)
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 3 for Frel Cmax vs. A

Groups^[1]	Regimen A: 50 mg AZD4635 nano-suspension, fasted, Regimen B: 50 mg AZD4635 oral, fasted
Other^[5]	106.41
90% Confidence Interval	( 94.13 to 120.29 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Relative Bioavailability Reg B/Reg A: SSP-005173X Formal statistical analysis performed on the pharmacokinetic parameter Cmax to assess relative bioavailability of solid oral formulation (test) versus nano-suspension (reference)
[5]	Other relevant estimation information:
	No text entered.

2. Primary Outcome Measure: Frel AUC(0-t) vs A ‌ [ Time Frame: Pre-dose to Day 6 ]

Measure Type	Primary
Measure Name	Frel AUC(0-t) vs A ‌
Measure Description	Relative bioavailability (Frel) of AZD4635 and metabolites SSP-005174X and SSP-005173X solid oral formulation compared to the nano-suspension reference formulation based on AUC(0-t).
Time Frame	Pre-dose to Day 6
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.
Not calculated for Regimen A (represented by '0'), this is shown in order to present statistics.

Reporting Groups

	Description
Regimen A: 50 mg AZD4635 nano-suspension, fasted	Part A, Period 1: single oral dose of 50 mg (40 mL) powder for oral suspension 5.5% (w/w) (referred to as nano-suspension) (reference) in the fasted state (10 h overnight fast) in the morning of Day 1.
Regimen B: 50 mg AZD4635 oral, fasted	Part A, Period 2: single dose of 50 mg solid oral capsule in the fasted state (10 h overnight fast) in the morning of Day 1. Not all of the enrolled subjects' data could be included in the analysis for each metabolite.
Regimen C: 50 mg AZD4635 oral, fed	Part B, Period 3: single dose of 50 mg solid oral capsule after a high fat meal.
Regimen D: 50 mg AZD4635 oral, fasted with lansoprazole	Part B, Period 4: AZD4635 - single dose of 50 mg solid oral capsule in the fasted state. Lansoprazole - administered on Days -4, 03, -2 and -1 as 30 mg twice daily at least 30 minutes before food. On Day 1, subjects received a single dose of lansoprazole following an overnight fast (8 h) and the dose of AZD4635 was administered 2 h later.
Regimen E: 50 mg AZD4635 oral, fasted (variant 1)	Part B, Period 5: AZD4635 - single dose of 50 mg solid oral capsule, variant 1 in the fasted state. The variants had the same quantitative composition as the capsule formulation, but the process parameters and/or input material were altered. [14C]AZD4635 - An IV microtracer dose of AZD4635 was administered with the solid oral formulation. It was administered as a 15 min IV infusion (ending 0.5 h post-oral dose) of a microdose (50 µg) of AZD4635 containing microtracer amounts of 14C (not more than 25.7 kBq/5 mL [694.4 nCi/5 mL]).
Regimen F: 50 mg AZD4635 oral, fasted (variant 2)	Part B, Period 6: single dose of 50 mg solid oral capsule, variant 2 in the fasted state. The variants had the same quantitative composition as the capsule formulation, but the process parameters and/or input material were altered.

Measured Values

	Regimen A: 50 mg AZD4635 nano-suspension, fasted	Regimen B: 50 mg AZD4635 oral, fasted	Regimen C: 50 mg AZD4635 oral, fed	Regimen D: 50 mg AZD4635 oral, fasted with lansoprazole	Regimen E: 50 mg AZD4635 oral, fasted (variant 1)	Regimen F: 50 mg AZD4635 oral, fasted (variant 2)
Number of Participants Analyzed [units:participants]	20	20	20	20	20	20
Frel AUC(0-t) vs A ‌ [units: (%)] Geometric Mean (Geometric Coefficient of Variation)
AZD4635	0 (0%)	110.575 (13.2%)	87.921 (15.7%)	96.583 (18.9%)	99.604 (13.6%)	91.561 (14.6%)
SSP-005174X	0 (0%)	99.075 (9.7%)	92.449 (8.8%)	98.824 (12.1%)	101.725 (19.3%)	95.962 (11.2%)
SSP-005173X	0 (0%)	100.808 (20.2%)	93.405 (19.5%)	94.509 (25.8%)	98.292 (25.6%)	91.242 (16.3%)

Statistical Analysis 1 for Frel AUC(0-t) vs A ‌

Groups^[1]	Regimen A: 50 mg AZD4635 nano-suspension, fasted, Regimen B: 50 mg AZD4635 oral, fasted
Other^[5]	110.03
90% Confidence Interval	( 103.20 to 117.32 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Relative Bioavailability Reg B/Reg A: AZD4635 Formal statistical analysis performed on the pharmacokinetic parameter AUC(0-t) to assess relative bioavailability of solid oral formulation (test) versus nano-suspension (reference)
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 2 for Frel AUC(0-t) vs A ‌

Groups^[1]	Regimen A: 50 mg AZD4635 nano-suspension, fasted, Regimen B: 50 mg AZD4635 oral, fasted
Other^[5]	99.15
90% Confidence Interval	( 94.19 to 104.37 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Relative Bioavailability Reg B/Reg A: SSP-005174X Formal statistical analysis performed on the pharmacokinetic parameter AUC(0-t) to assess relative bioavailability of solid oral formulation (test) versus nano-suspension (reference)
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 3 for Frel AUC(0-t) vs A ‌

Groups^[1]	Regimen A: 50 mg AZD4635 nano-suspension, fasted, Regimen B: 50 mg AZD4635 oral, fasted
Other^[5]	100.58
90% Confidence Interval	( 92.26 to 109.63 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Relative Bioavailability Reg B/Reg A: SSP-005173X Formal statistical analysis performed on the pharmacokinetic parameter AUC(0-t) to assess relative bioavailability of solid oral formulation (test) versus nano-suspension (reference)
[5]	Other relevant estimation information:
	No text entered.

3. Primary Outcome Measure: Frel AUC vs A [ Time Frame: Pre-dose to Day 6 ]

Measure Type	Primary
Measure Name	Frel AUC vs A
Measure Description	Relative bioavailability (Frel) of AZD4635 and metabolites SSP-005174X and SSP-005173X solid oral formulation compared to the nano-suspension reference formulation based on AUC.
Time Frame	Pre-dose to Day 6
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.
Not calculated for Regimen A (represented by '0'), this is shown in order to present statistics.

Reporting Groups

	Description
Regimen A: 50 mg AZD4635 nano-suspension, fasted	Part A, Period 1: single oral dose of 50 mg (40 mL) powder for oral suspension 5.5% (w/w) (referred to as nano-suspension) (reference) in the fasted state (10 h overnight fast) in the morning of Day 1.
Regimen B: 50 mg AZD4635 oral, fasted	Part A, Period 2: single dose of 50 mg solid oral capsule in the fasted state (10 h overnight fast) in the morning of Day 1. Not all of the enrolled subjects' data could be included in the analysis for each metabolite.
Regimen C: 50 mg AZD4635 oral, fed	Part B, Period 3: single dose of 50 mg solid oral capsule after a high fat meal. Not all of the enrolled subjects' data could be included in the analysis for each metabolite.
Regimen D: 50 mg AZD4635 oral, fasted with lansoprazole	Part B, Period 4: AZD4635 - single dose of 50 mg solid oral capsule in the fasted state. Lansoprazole - administered on Days -4, 03, -2 and -1 as 30 mg twice daily at least 30 minutes before food. On Day 1, subjects received a single dose of lansoprazole following an overnight fast (8 h) and the dose of AZD4635 was administered 2 h later. Not all of the enrolled subjects' data could be included in the analysis for each metabolite.
Regimen E: 50 mg AZD4635 oral, fasted (variant 1)	Part B, Period 5: AZD4635 - single dose of 50 mg solid oral capsule, variant 1 in the fasted state. The variants had the same quantitative composition as the capsule formulation, but the process parameters and/or input material were altered. [14C]AZD4635 - An IV microtracer dose of AZD4635 was administered with the solid oral formulation. It was administered as a 15 min IV infusion (ending 0.5 h post-oral dose) of a microdose (50 µg) of AZD4635 containing microtracer amounts of 14C (not more than 25.7 kBq/5 mL [694.4 nCi/5 mL]). Not all of the enrolled subjects' data could be included in the analysis for each metabolite.
Regimen F: 50 mg AZD4635 oral, fasted (variant 2)	Part B, Period 6: single dose of 50 mg solid oral capsule, variant 2 in the fasted state. The variants had the same quantitative composition as the capsule formulation, but the process parameters and/or input material were altered. Not all of the enrolled subjects' data could be included in the analysis for each metabolite.

Measured Values

	Regimen A: 50 mg AZD4635 nano-suspension, fasted	Regimen B: 50 mg AZD4635 oral, fasted	Regimen C: 50 mg AZD4635 oral, fed	Regimen D: 50 mg AZD4635 oral, fasted with lansoprazole	Regimen E: 50 mg AZD4635 oral, fasted (variant 1)	Regimen F: 50 mg AZD4635 oral, fasted (variant 2)
Number of Participants Analyzed [units:participants]	20	20	20	20	20	20
Frel AUC vs A [units: (%)] Geometric Mean (Geometric Coefficient of Variation)
AZD463	0 (0%)	109.505 (12.8%)	88.031 (15.9%)	97.662 (17.2%)	100.034 (13.6%)	91.550 (14.3%)
SSP-005174X	0 (0%)	99.451 (9.5%)	92.247 (8.9%)	98.583 (12.0%)	101.417 (19.2%)	95.723 (11.2%)
SSP-005173X	0 (0%)	110.381 (10.1%)	98.493 (8.2%)	90.615 (15.6%)	101.413 (12.1%)	90.723 (16.8%)

Statistical Analysis 1 for Frel AUC vs A

Groups^[1]	Regimen A: 50 mg AZD4635 nano-suspension, fasted, Regimen B: 50 mg AZD4635 oral, fasted
Other^[5]	109.35
90% Confidence Interval	( 102.60 to 116.54 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Relative Bioavailability Reg B/Reg A: AZD4635 Formal statistical analysis performed on the pharmacokinetic parameter AUC to assess relative bioavailability of solid oral formulation (test) versus nano-suspension (reference)
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 2 for Frel AUC vs A

Groups^[1]	Regimen A: 50 mg AZD4635 nano-suspension, fasted, Regimen B: 50 mg AZD4635 oral, fasted
Other^[5]	99.53
90% Confidence Interval	( 94.62 to 104.68 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Relative Bioavailability Reg B/Reg A: SSP-005174X Formal statistical analysis performed on the pharmacokinetic parameter AUC to assess relative bioavailability of solid oral formulation (test) versus nano-suspension (reference)
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 3 for Frel AUC vs A

Groups^[1]	Regimen A: 50 mg AZD4635 nano-suspension, fasted, Regimen B: 50 mg AZD4635 oral, fasted
Other^[5]	110.44
90% Confidence Interval	( 101.48 to 120.20 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Relative Bioavailability Reg B/Reg A: SSP-005173X Formal statistical analysis performed on the pharmacokinetic parameter AUC to assess relative bioavailability of solid oral formulation (test) versus nano-suspension (reference)
[5]	Other relevant estimation information:
	No text entered.

4. Secondary Outcome Measure: Tmax [ Time Frame: Pre-dose to Day 6 ]

Measure Type	Secondary
Measure Name	Tmax
Measure Description	Tmax: time to reach peak or maximum observed concentration following drug administration.
Time Frame	Pre-dose to Day 6
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.
[14C]AZD4635 not calculated for Regimen A, B, C, D or F (represented by '0').

Reporting Groups

	Description
Regimen A: 50 mg AZD4635 nano-suspension, fasted	Part A, Period 1: single oral dose of 50 mg (40 mL) powder for oral suspension 5.5% (w/w) (referred to as nano-suspension) (reference) in the fasted state (10 h overnight fast) in the morning of Day 1.
Regimen B: 50 mg AZD4635 oral, fasted	Part A, Period 2: single dose of 50 mg solid oral capsule in the fasted state (10 h overnight fast) in the morning of Day 1.
Regimen C: 50 mg AZD4635 oral, fed	Part B, Period 3: single dose of 50 mg solid oral capsule after a high fat meal.
Regimen D: 50 mg AZD4635 oral, fasted with lansoprazole	Part B, Period 4: AZD4635 - single dose of 50 mg solid oral capsule in the fasted state. Lansoprazole - administered on Days -4, 03, -2 and -1 as 30 mg twice daily at least 30 minutes before food. On Day 1, subjects received a single dose of lansoprazole following an overnight fast (8 h) and the dose of AZD4635 was administered 2 h later.
Regimen E: 50 mg AZD4635 oral, fasted (variant 1)	Part B, Period 5: AZD4635 - single dose of 50 mg solid oral capsule, variant 1 in the fasted state. The variants had the same quantitative composition as the capsule formulation, but the process parameters and/or input material were altered. [14C]AZD4635 - An IV microtracer dose of AZD4635 was administered with the solid oral formulation. It was administered as a 15 min IV infusion (ending 0.5 h post-oral dose) of a microdose (50 µg) of AZD4635 containing microtracer amounts of 14C (not more than 25.7 kBq/5 mL [694.4 nCi/5 mL]).
Regimen F: 50 mg AZD4635 oral, fasted (variant 2)	Part B, Period 6: single dose of 50 mg solid oral capsule, variant 2 in the fasted state. The variants had the same quantitative composition as the capsule formulation, but the process parameters and/or input material were altered.

Measured Values

	Regimen A: 50 mg AZD4635 nano-suspension, fasted	Regimen B: 50 mg AZD4635 oral, fasted	Regimen C: 50 mg AZD4635 oral, fed	Regimen D: 50 mg AZD4635 oral, fasted with lansoprazole	Regimen E: 50 mg AZD4635 oral, fasted (variant 1)	Regimen F: 50 mg AZD4635 oral, fasted (variant 2)
Number of Participants Analyzed [units:participants]	20	20	20	20	20	20
Tmax [units: (h)] Median (Full Range)
AZD4635	1.000 (0.50 to 2.00)	1.500 (1.00 to 2.00)	4.000 (1.50 to 6.00)	1.500 (1.00 to 2.00)	1.500 (0.50 to 2.01)	1.500 (1.00 to 4.00)
SSP-005174X	1.000 (0.98 to 1.53)	1.500 (1.00 to 2.00)	2.033 (1.50 to 6.00)	1.500 (1.00 to 2.00)	1.500 (1.00 to 2.01)	1.500 (1.00 to 4.00)
SSP-005173X	1.500 (1.00 to 2.07)	1.500 (1.00 to 2.01)	4.000 (1.50 to 6.00)	1.500 (1.00 to 4.00)	1.504 (1.50 to 2.03)	2.000 (1.00 to 4.07)
[14C]AZD4635	0 (0 to 0)	0 (0 to 0)	0 (0 to 0)	0 (0 to 0)	0.251 (0.23 to 1.25)	0 (0 to 0)

No statistical analysis provided for Tmax

5. Secondary Outcome Measure: Cmax [ Time Frame: Pre-dose to Day 6 ]

Measure Type	Secondary
Measure Name	Cmax
Measure Description	Cmax: maximum observed plasma (peak) drug concentration.
Time Frame	Pre-dose to Day 6
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.
[14C]AZD4635 not calculated for Regimen A, B, C, D or F (represented by '0').

Reporting Groups

	Description
Regimen A: 50 mg AZD4635 nano-suspension, fasted	Part A, Period 1: single oral dose of 50 mg (40 mL) powder for oral suspension 5.5% (w/w) (referred to as nano-suspension) (reference) in the fasted state (10 h overnight fast) in the morning of Day 1.
Regimen B: 50 mg AZD4635 oral, fasted	Part A, Period 2: single dose of 50 mg solid oral capsule in the fasted state (10 h overnight fast) in the morning of Day 1.
Regimen C: 50 mg AZD4635 oral, fed	Part B, Period 3: single dose of 50 mg solid oral capsule after a high fat meal.
Regimen D: 50 mg AZD4635 oral, fasted with lansoprazole	Part B, Period 4: AZD4635 - single dose of 50 mg solid oral capsule in the fasted state. Lansoprazole - administered on Days -4, 03, -2 and -1 as 30 mg twice daily at least 30 minutes before food. On Day 1, subjects received a single dose of lansoprazole following an overnight fast (8 h) and the dose of AZD4635 was administered 2 h later.
Regimen E: 50 mg AZD4635 oral, fasted (variant 1)	Part B, Period 5: AZD4635 - single dose of 50 mg solid oral capsule, variant 1 in the fasted state. The variants had the same quantitative composition as the capsule formulation, but the process parameters and/or input material were altered. [14C]AZD4635 - An IV microtracer dose of AZD4635 was administered with the solid oral formulation. It was administered as a 15 min IV infusion (ending 0.5 h post-oral dose) of a microdose (50 µg) of AZD4635 containing microtracer amounts of 14C (not more than 25.7 kBq/5 mL [694.4 nCi/5 mL]).
Regimen F: 50 mg AZD4635 oral, fasted (variant 2)	Part B, Period 6: single dose of 50 mg solid oral capsule, variant 2 in the fasted state. The variants had the same quantitative composition as the capsule formulation, but the process parameters and/or input material were altered.

Measured Values

	Regimen A: 50 mg AZD4635 nano-suspension, fasted	Regimen B: 50 mg AZD4635 oral, fasted	Regimen C: 50 mg AZD4635 oral, fed	Regimen D: 50 mg AZD4635 oral, fasted with lansoprazole	Regimen E: 50 mg AZD4635 oral, fasted (variant 1)	Regimen F: 50 mg AZD4635 oral, fasted (variant 2)
Number of Participants Analyzed [units:participants]	20	20	20	20	20	20
Cmax [units: ng/mL (pg/mL for [14C]AZD4635)] Geometric Mean (Geometric Coefficient of Variation)
AZD4635	281 (17.9%)	355 (28.6%)	157 (24.0%)	351 (26.5%)	336 (25.8%)	268 (24.5%)
SSP-005174X	38.5 (35.3%)	45.2 (30.3%)	20.6 (37.9%)	46.7 (31.6%)	42.2 (35.8%)	34.8 (25.3%)
SSP-005173X	7.65 (66.5%)	8.97 (49.2%)	4.90 (57.0%)	8.61 (52.7%)	7.73 (58.9%)	7.08 (49.8%)
[14C]AZD4635	0 (0%)	0 (0%)	0 (0%)	0 (0%)	694 (37.2%)	0 (0%)

Statistical Analysis 1 for Cmax

Groups^[1]	Regimen B: 50 mg AZD4635 oral, fasted, Regimen C: 50 mg AZD4635 oral, fed
Other^[5]	44.26
90% Confidence Interval	( 39.94 to 49.06 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Relative Bioavailability Reg C/Reg B: AZD4635 Formal statistical analysis performed on the pharmacokinetic parameter Cmax to assess relative bioavailability of fed versus fasted solid oral formulation
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 2 for Cmax

Groups^[1]	Regimen B: 50 mg AZD4635 oral, fasted, Regimen D: 50 mg AZD4635 oral, fasted with lansoprazole
Other^[5]	99.00
90% Confidence Interval	( 89.33 to 109.73 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Relative Bioavailability Reg D/Reg B: AZD4635 Formal statistical analysis performed on the pharmacokinetic parameter Cmax to assess relative bioavailability of PPI versus fasted solid oral formulation
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 3 for Cmax

Groups^[1]	Regimen B: 50 mg AZD4635 oral, fasted, Regimen E: 50 mg AZD4635 oral, fasted (variant 1)
Other^[5]	94.74
90% Confidence Interval	( 85.48 to 105.01 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Relative Bioavailability Reg E/Reg B: AZD4635 Formal statistical analysis performed on the pharmacokinetic parameter Cmax to assess relative bioavailability of variant 1 versus fasted solid oral formulation
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 4 for Cmax

Groups^[1]	Regimen B: 50 mg AZD4635 oral, fasted, Regimen F: 50 mg AZD4635 oral, fasted (variant 2)
Other^[5]	75.65
90% Confidence Interval	( 68.26 to 83.85 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Relative Bioavailability Reg F/Reg B: AZD4635 Formal statistical analysis performed on the pharmacokinetic parameter Cmax to assess relative bioavailability of variant 2 versus fasted solid oral formulation
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 5 for Cmax

Groups^[1]	Regimen B: 50 mg AZD4635 oral, fasted, Regimen C: 50 mg AZD4635 oral, fed
Other^[5]	45.68
90% Confidence Interval	( 40.89 to 51.03 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Relative Bioavailability Reg C/Reg B: SSP-005174X Formal statistical analysis performed on the pharmacokinetic parameter Cmax to assess relative bioavailability of fed versus fasted solid oral formulation
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 6 for Cmax

Groups^[1]	Regimen B: 50 mg AZD4635 oral, fasted, Regimen D: 50 mg AZD4635 oral, fasted with lansoprazole
Other^[5]	103.21
90% Confidence Interval	( 92.39 to 115.31 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Relative Bioavailability Reg D/Reg B: SSP-005174X Formal statistical analysis performed on the pharmacokinetic parameter Cmax to assess relative bioavailability of PPI versus fasted solid oral formulation
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 7 for Cmax

Groups^[1]	Regimen B: 50 mg AZD4635 oral, fasted, Regimen E: 50 mg AZD4635 oral, fasted (variant 1)
Other^[5]	93.32
90% Confidence Interval	( 83.53 to 104.26 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Relative Bioavailability Reg E/Reg B: SSP-005174X Formal statistical analysis performed on the pharmacokinetic parameter Cmax to assess relative bioavailability of variant 1 versus fasted solid oral formulation
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 8 for Cmax

Groups^[1]	Regimen B: 50 mg AZD4635 oral, fasted, Regimen F: 50 mg AZD4635 oral, fasted (variant 2)
Other^[5]	76.89
90% Confidence Interval	( 68.82 to 85.90 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Relative Bioavailability Reg F/Reg B: SSP-005174X Formal statistical analysis performed on the pharmacokinetic parameter Cmax to assess relative bioavailability of variant 2 versus fasted solid oral formulation
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 9 for Cmax

Groups^[1]	Regimen B: 50 mg AZD4635 oral, fasted, Regimen C: 50 mg AZD4635 oral, fed
Other^[5]	54.58
90% Confidence Interval	( 48.37 to 61.59 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Relative Bioavailability Reg C/Reg B: SSP-005173X Formal statistical analysis performed on the pharmacokinetic parameter Cmax to assess relative bioavailability of fed versus fasted solid oral formulation
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 10 for Cmax

Groups^[1]	Regimen B: 50 mg AZD4635 oral, fasted, Regimen D: 50 mg AZD4635 oral, fasted with lansoprazole
Other^[5]	96.04
90% Confidence Interval	( 85.12 to 108.37 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Relative Bioavailability Reg D/Reg B: SSP-005173X Formal statistical analysis performed on the pharmacokinetic parameter Cmax to assess relative bioavailability of PPI versus fasted solid oral formulation
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 11 for Cmax

Groups^[1]	Regimen B: 50 mg AZD4635 oral, fasted, Regimen E: 50 mg AZD4635 oral, fasted (variant 1)
Other^[5]	86.16
90% Confidence Interval	( 76.36 to 97.22 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Relative Bioavailability Reg E/Reg B: SSP-005173X Formal statistical analysis performed on the pharmacokinetic parameter Cmax to assess relative bioavailability of variant 1 versus fasted solid oral formulation
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 12 for Cmax

Groups^[1]	Regimen B: 50 mg AZD4635 oral, fasted, Regimen F: 50 mg AZD4635 oral, fasted (variant 2)
Other^[5]	78.95
90% Confidence Interval	( 69.97 to 89.08 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Relative Bioavailability Reg F/Reg B: SSP-005173X Formal statistical analysis performed on the pharmacokinetic parameter Cmax to assess relative bioavailability of variant 2 versus fasted solid oral formulation
[5]	Other relevant estimation information:
	No text entered.

6. Secondary Outcome Measure: AUC(0-t) [ Time Frame: Pre-dose to Day 6 ]

Measure Type	Secondary
Measure Name	AUC(0-t)
Measure Description	AUC(0-t): area under the plasma concentration-time curve from time zero to time t.
Time Frame	Pre-dose to Day 6
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.
[14C]AZD4635 not calculated for Regimen A, B, C, D or F (represented by '0').

Reporting Groups

	Description
Regimen A: 50 mg AZD4635 nano-suspension, fasted	Part A, Period 1: single oral dose of 50 mg (40 mL) powder for oral suspension 5.5% (w/w) (referred to as nano-suspension) (reference) in the fasted state (10 h overnight fast) in the morning of Day 1.
Regimen B: 50 mg AZD4635 oral, fasted	Part A, Period 2: single dose of 50 mg solid oral capsule in the fasted state (10 h overnight fast) in the morning of Day 1.
Regimen C: 50 mg AZD4635 oral, fed	Part B, Period 3: single dose of 50 mg solid oral capsule after a high fat meal.
Regimen D: 50 mg AZD4635 oral, fasted with lansoprazole	Part B, Period 4: AZD4635 - single dose of 50 mg solid oral capsule in the fasted state. Lansoprazole - administered on Days -4, 03, -2 and -1 as 30 mg twice daily at least 30 minutes before food. On Day 1, subjects received a single dose of lansoprazole following an overnight fast (8 h) and the dose of AZD4635 was administered 2 h later.
Regimen E: 50 mg AZD4635 oral, fasted (variant 1)	Part B, Period 5: AZD4635 - single dose of 50 mg solid oral capsule, variant 1 in the fasted state. The variants had the same quantitative composition as the capsule formulation, but the process parameters and/or input material were altered. [14C]AZD4635 - An IV microtracer dose of AZD4635 was administered with the solid oral formulation. It was administered as a 15 min IV infusion (ending 0.5 h post-oral dose) of a microdose (50 µg) of AZD4635 containing microtracer amounts of 14C (not more than 25.7 kBq/5 mL [694.4 nCi/5 mL]).
Regimen F: 50 mg AZD4635 oral, fasted (variant 2)	Part B, Period 6: single dose of 50 mg solid oral capsule, variant 2 in the fasted state. The variants had the same quantitative composition as the capsule formulation, but the process parameters and/or input material were altered.

Measured Values

	Regimen A: 50 mg AZD4635 nano-suspension, fasted	Regimen B: 50 mg AZD4635 oral, fasted	Regimen C: 50 mg AZD4635 oral, fed	Regimen D: 50 mg AZD4635 oral, fasted with lansoprazole	Regimen E: 50 mg AZD4635 oral, fasted (variant 1)	Regimen F: 50 mg AZD4635 oral, fasted (variant 2)
Number of Participants Analyzed [units:participants]	20	20	20	20	20	20
AUC(0-t) [units: ng.h/mL (pg.h/mL for [14C]AZD4635)] Geometric Mean (Geometric Coefficient of Variation)
AZD4635	1780 (33.6%)	1880 (28.3%)	1650 (32.2%)	1810 (30.3%)	1870 (30.1%)	1720 (32.3%)
SSP-005174X	228 (23.0%)	230 (22.4%)	213 (21.3%)	227 (20.8%)	234 (27.2%)	221 (23.2%)
SSP-005173X	60.4 (41.3%)	62.5 (48.6%)	58.4 (42.2%)	59.1 (35.4%)	61.5 (44.3%)	57.1 (42.0%)
[14C]AZD4635	0 (0%)	0 (0%)	0 (0%)	0 (0%)	2430 (27.5%)	0 (0%)

Statistical Analysis 1 for AUC(0-t)

Groups^[1]	Regimen B: 50 mg AZD4635 oral, fasted, Regimen C: 50 mg AZD4635 oral, fed
Other^[5]	87.92
90% Confidence Interval	( 82.54 to 93.65 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Relative Bioavailability Reg C/Reg B: AZD4635 Formal statistical analysis performed on the pharmacokinetic parameter AUC(0-t) to assess relative bioavailability of fed versus fasted solid oral formulation
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 2 for AUC(0-t)

Groups^[1]	Regimen B: 50 mg AZD4635 oral, fasted, Regimen D: 50 mg AZD4635 oral, fasted with lansoprazole
Other^[5]	96.58
90% Confidence Interval	( 90.68 to 102.87 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Relative Bioavailability Reg D/Reg B: AZD4635 Formal statistical analysis performed on the pharmacokinetic parameter AUC(0-t) to assess relative bioavailability of PPI versus fasted solid oral formulation
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 3 for AUC(0-t)

Groups^[1]	Regimen B: 50 mg AZD4635 oral, fasted, Regimen E: 50 mg AZD4635 oral, fasted (variant 1)
Other^[5]	99.60
90% Confidence Interval	( 93.51 to 106.09 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Relative Bioavailability Reg E/Reg B: AZD4635 Formal statistical analysis performed on the pharmacokinetic parameter AUC(0-t) to assess relative bioavailability of variant 1 versus fasted solid oral formulation
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 4 for AUC(0-t)

Groups^[1]	Regimen B: 50 mg AZD4635 oral, fasted, Regimen F: 50 mg AZD4635 oral, fasted (variant 2)
Other^[5]	91.56
90% Confidence Interval	( 85.96 to 97.53 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Relative Bioavailability Reg F/Reg B: AZD4635 Formal statistical analysis performed on the pharmacokinetic parameter AUC(0-t) to assess relative bioavailability of variant 2 versus fasted solid oral formulation
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 5 for AUC(0-t)

Groups^[1]	Regimen B: 50 mg AZD4635 oral, fasted, Regimen C: 50 mg AZD4635 oral, fed
Other^[5]	92.45
90% Confidence Interval	( 87.89 to 97.24 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Relative Bioavailability Reg C/Reg B: SSP-005174X Formal statistical analysis performed on the pharmacokinetic parameter AUC(0-t) to assess relative bioavailability of fed versus fasted solid oral formulation
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 6 for AUC(0-t)

Groups^[1]	Regimen B: 50 mg AZD4635 oral, fasted, Regimen D: 50 mg AZD4635 oral, fasted with lansoprazole
Other^[5]	98.82
90% Confidence Interval	( 93.95 to 103.95 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Relative Bioavailability Reg D/Reg B: SSP-005174X Formal statistical analysis performed on the pharmacokinetic parameter AUC(0-t) to assess relative bioavailability of PPI versus fasted solid oral formulation
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 7 for AUC(0-t)

Groups^[1]	Regimen B: 50 mg AZD4635 oral, fasted, Regimen E: 50 mg AZD4635 oral, fasted (variant 1)
Other^[5]	101.73
90% Confidence Interval	( 96.71 to 107.00 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Relative Bioavailability Reg E/Reg B: SSP-005174X Formal statistical analysis performed on the pharmacokinetic parameter AUC(0-t) to assess relative bioavailability of variant 1 versus fasted solid oral formulation
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 8 for AUC(0-t)

Groups^[1]	Regimen B: 50 mg AZD4635 oral, fasted, Regimen F: 50 mg AZD4635 oral, fasted (variant 2)
Other^[5]	95.96
90% Confidence Interval	( 91.23 to 100.94 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Relative Bioavailability Reg F/Reg B: SSP-005174X Formal statistical analysis performed on the pharmacokinetic parameter AUC(0-t) to assess relative bioavailability of variant 2 versus fasted solid oral formulation
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 9 for AUC(0-t)

Groups^[1]	Regimen B: 50 mg AZD4635 oral, fasted, Regimen C: 50 mg AZD4635 oral, fed
Other^[5]	93.40
90% Confidence Interval	( 85.80 to 101.68 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Relative Bioavailability Reg C/Reg B: SSP-005173X Formal statistical analysis performed on the pharmacokinetic parameter AUC(0-t) to assess relative bioavailability of fed versus fasted solid oral formulation
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 10 for AUC(0-t)

Groups^[1]	Regimen B: 50 mg AZD4635 oral, fasted, Regimen D: 50 mg AZD4635 oral, fasted with lansoprazole
Other^[5]	94.51
90% Confidence Interval	( 86.81 to 102.89 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Relative Bioavailability Reg D/Reg B: SSP-005173X Formal statistical analysis performed on the pharmacokinetic parameter AUC(0-t) to assess relative bioavailability of PPI versus fasted solid oral formulation
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 11 for AUC(0-t)

Groups^[1]	Regimen B: 50 mg AZD4635 oral, fasted, Regimen E: 50 mg AZD4635 oral, fasted (variant 1)
Other^[5]	98.29
90% Confidence Interval	( 90.29 to 107.00 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Relative Bioavailability Reg E/Reg B: SSP-005173X Formal statistical analysis performed on the pharmacokinetic parameter AUC(0-t) to assess relative bioavailability of variant 1 versus fasted solid oral formulation
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 12 for AUC(0-t)

Groups^[1]	Regimen B: 50 mg AZD4635 oral, fasted, Regimen F: 50 mg AZD4635 oral, fasted (variant 2)
Other^[5]	91.24
90% Confidence Interval	( 83.81 to 99.33 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Relative Bioavailability Reg F/Reg B: SSP-005173X Formal statistical analysis performed on the pharmacokinetic parameter AUC(0-t) to assess relative bioavailability of variant 2 versus fasted solid oral formulation
[5]	Other relevant estimation information:
	No text entered.

7. Secondary Outcome Measure: AUC(0-48) [ Time Frame: Pre-dose to Day 6 ]

Measure Type	Secondary
Measure Name	AUC(0-48)
Measure Description	AUC(0-48): area under the plasma concentration-time curve from time zero to 48 h post-dose.
Time Frame	Pre-dose to Day 6
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.
[14C]AZD4635 not calculated for Regimen A, B, C, D or F (represented by '0').

Reporting Groups

	Description
Regimen A: 50 mg AZD4635 nano-suspension, fasted	Part A, Period 1: single oral dose of 50 mg (40 mL) powder for oral suspension 5.5% (w/w) (referred to as nano-suspension) (reference) in the fasted state (10 h overnight fast) in the morning of Day 1.
Regimen B: 50 mg AZD4635 oral, fasted	Part A, Period 2: single dose of 50 mg solid oral capsule in the fasted state (10 h overnight fast) in the morning of Day 1.
Regimen C: 50 mg AZD4635 oral, fed	Part B, Period 3: single dose of 50 mg solid oral capsule after a high fat meal.
Regimen D: 50 mg AZD4635 oral, fasted with lansoprazole	Part B, Period 4: AZD4635 - single dose of 50 mg solid oral capsule in the fasted state. Lansoprazole - administered on Days -4, 03, -2 and -1 as 30 mg twice daily at least 30 minutes before food. On Day 1, subjects received a single dose of lansoprazole following an overnight fast (8 h) and the dose of AZD4635 was administered 2 h later.
Regimen E: 50 mg AZD4635 oral, fasted (variant 1)	Part B, Period 5: AZD4635 - single dose of 50 mg solid oral capsule, variant 1 in the fasted state. The variants had the same quantitative composition as the capsule formulation, but the process parameters and/or input material were altered. [14C]AZD4635 - An IV microtracer dose of AZD4635 was administered with the solid oral formulation. It was administered as a 15 min IV infusion (ending 0.5 h post-oral dose) of a microdose (50 µg) of AZD4635 containing microtracer amounts of 14C (not more than 25.7 kBq/5 mL [694.4 nCi/5 mL]).
Regimen F: 50 mg AZD4635 oral, fasted (variant 2)	Part B, Period 6: single dose of 50 mg solid oral capsule, variant 2 in the fasted state. The variants had the same quantitative composition as the capsule formulation, but the process parameters and/or input material were altered.

Measured Values

	Regimen A: 50 mg AZD4635 nano-suspension, fasted	Regimen B: 50 mg AZD4635 oral, fasted	Regimen C: 50 mg AZD4635 oral, fed	Regimen D: 50 mg AZD4635 oral, fasted with lansoprazole	Regimen E: 50 mg AZD4635 oral, fasted (variant 1)	Regimen F: 50 mg AZD4635 oral, fasted (variant 2)
Number of Participants Analyzed [units:participants]	20	20	20	20	20	20
AUC(0-48) [units: ng.h/mL (pg.h/mL for [14C]AZD4635)] Geometric Mean (Geometric Coefficient of Variation)
AZD4635	1750 (30.5%)	1830 (26.0%)	1580 (30.0%)	1790 (27.0%)	1820 (28.9%)	1670 (30.4%)
SSP-005174X	220 (24.1%)	222 (22.6%)	202 (21.7%)	220 (21.6%)	224 (27.3%)	213 (23.2%)
SSP-005173X	68.6 (39.2%)	69.9 (38.5%)	69.7 (34.6%)	69.2 (30.4%)	70.2 (37.6%)	67.1 (36.1%)
[14C]AZD4635	0 (0%)	0 (0%)	0 (0%)	0 (0%)	2500 (25.4%)	0 (0%)

No statistical analysis provided for AUC(0-48)

8. Secondary Outcome Measure: AUC [ Time Frame: Pre-dose to Day 6 ]

Measure Type	Secondary
Measure Name	AUC
Measure Description	AUC: area under the plasma concentration-time curve from time zero to infinity.
Time Frame	Pre-dose to Day 6
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.
[14C]AZD4635 not calculated for Regimen A, B, C, D or F (represented by '0').

Reporting Groups

	Description
Regimen A: 50 mg AZD4635 nano-suspension, fasted	Part A, Period 1: single oral dose of 50 mg (40 mL) powder for oral suspension 5.5% (w/w) (referred to as nano-suspension) (reference) in the fasted state (10 h overnight fast) in the morning of Day 1. Not all of the enrolled subjects' data could be included in the analysis for each metabolite.
Regimen B: 50 mg AZD4635 oral, fasted	Part A, Period 2: single dose of 50 mg solid oral capsule in the fasted state (10 h overnight fast) in the morning of Day 1. Not all of the enrolled subjects' data could be included in the analysis for each metabolite.
Regimen C: 50 mg AZD4635 oral, fed	Part B, Period 3: single dose of 50 mg solid oral capsule after a high fat meal. Not all of the enrolled subjects' data could be included in the analysis for each metabolite.
Regimen D: 50 mg AZD4635 oral, fasted with lansoprazole	Part B, Period 4: AZD4635 - single dose of 50 mg solid oral capsule in the fasted state. Lansoprazole - administered on Days -4, 03, -2 and -1 as 30 mg twice daily at least 30 minutes before food. On Day 1, subjects received a single dose of lansoprazole following an overnight fast (8 h) and the dose of AZD4635 was administered 2 h later. Not all of the enrolled subjects' data could be included in the analysis for each metabolite.
Regimen E: 50 mg AZD4635 oral, fasted (variant 1)	Part B, Period 5: AZD4635 - single dose of 50 mg solid oral capsule, variant 1 in the fasted state. The variants had the same quantitative composition as the capsule formulation, but the process parameters and/or input material were altered. [14C]AZD4635 - An IV microtracer dose of AZD4635 was administered with the solid oral formulation. It was administered as a 15 min IV infusion (ending 0.5 h post-oral dose) of a microdose (50 µg) of AZD4635 containing microtracer amounts of 14C (not more than 25.7 kBq/5 mL [694.4 nCi/5 mL]). Not all of the enrolled subjects' data could be included in the analysis for each metabolite.
Regimen F: 50 mg AZD4635 oral, fasted (variant 2)	Part B, Period 6: single dose of 50 mg solid oral capsule, variant 2 in the fasted state. The variants had the same quantitative composition as the capsule formulation, but the process parameters and/or input material were altered. Not all of the enrolled subjects' data could be included in the analysis for each metabolite.

Measured Values

	Regimen A: 50 mg AZD4635 nano-suspension, fasted	Regimen B: 50 mg AZD4635 oral, fasted	Regimen C: 50 mg AZD4635 oral, fed	Regimen D: 50 mg AZD4635 oral, fasted with lansoprazole	Regimen E: 50 mg AZD4635 oral, fasted (variant 1)	Regimen F: 50 mg AZD4635 oral, fasted (variant 2)
Number of Participants Analyzed [units:participants]	20	20	20	20	20	20
AUC [units: ng.h/mL (pg.h/mL for [14C]AZD4635)] Geometric Mean (Geometric Coefficient of Variation)
AZD4635	1890 (29.8%)	1920 (27.5%)	1690 (31.8%)	1870 (27.8%)	1920 (29.7%)	1760 (32.2%)
SSP-005174X	233 (22.2%)	235 (21.9%)	216 (20.8%)	231 (20.6%)	238 (26.8%)	225 (22.6%)
SSP-005173X	76.2 (24.2%)	85.7 (38.3%)	81.8 (20.1%)	83.4 (32.1%)	85.4 (16.4%)	88.2 (33.2%)
[14C]AZD4635	0 (0%)	0 (0%)	0 (0%)	0 (0%)	2640 (27.4%)	0 (0%)

Statistical Analysis 1 for AUC

Groups^[1]	Regimen B: 50 mg AZD4635 oral, fasted, Regimen C: 50 mg AZD4635 oral, fed
Other^[5]	88.03
90% Confidence Interval	( 82.77 to 93.63 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Relative Bioavailability Reg C/Reg B: AZD4635 Formal statistical analysis performed on the pharmacokinetic parameter AUC to assess relative bioavailability of fed versus fasted solid oral formulation
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 2 for AUC

Groups^[1]	Regimen B: 50 mg AZD4635 oral, fasted, Regimen D: 50 mg AZD4635 oral, fasted with lansoprazole
Other^[5]	97.66
90% Confidence Interval	( 91.82 to 103.88 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Relative Bioavailability Reg D/Reg B: AZD4635 Formal statistical analysis performed on the pharmacokinetic parameter AUC to assess relative bioavailability of PPI versus fasted solid oral formulation
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 3 for AUC

Groups^[1]	Regimen B: 50 mg AZD4635 oral, fasted, Regimen E: 50 mg AZD4635 oral, fasted (variant 1)
Other^[5]	100.03
90% Confidence Interval	( 94.05 to 106.40 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Relative Bioavailability Reg E/Reg B: AZD4635 Formal statistical analysis performed on the pharmacokinetic parameter AUC to assess relative bioavailability of variant 1 versus fasted solid oral formulation
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 4 for AUC

Groups^[1]	Regimen B: 50 mg AZD4635 oral, fasted, Regimen F: 50 mg AZD4635 oral, fasted (variant 2)
Other^[5]	91.55
90% Confidence Interval	( 86.07 to 97.37 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Relative Bioavailability Reg F/Reg B: AZD4635 Formal statistical analysis performed on the pharmacokinetic parameter AUC to assess relative bioavailability of variant 2 versus fasted solid oral formulation
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 5 for AUC

Groups^[1]	Regimen B: 50 mg AZD4635 oral, fasted, Regimen C: 50 mg AZD4635 oral, fed
Other^[5]	92.25
90% Confidence Interval	( 87.77 to 96.95 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Relative Bioavailability Reg C/Reg B: SSP-005174X Formal statistical analysis performed on the pharmacokinetic parameter AUC to assess relative bioavailability of fed versus fasted solid oral formulation
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 6 for AUC

Groups^[1]	Regimen B: 50 mg AZD4635 oral, fasted, Regimen D: 50 mg AZD4635 oral, fasted with lansoprazole
Other^[5]	98.58
90% Confidence Interval	( 93.80 to 103.61 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Relative Bioavailability Reg D/Reg B: SSP-005174X Formal statistical analysis performed on the pharmacokinetic parameter AUC to assess relative bioavailability of PPI versus fasted solid oral formulation
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 7 for AUC

Groups^[1]	Regimen B: 50 mg AZD4635 oral, fasted, Regimen E: 50 mg AZD4635 oral, fasted (variant 1)
Other^[5]	101.42
90% Confidence Interval	( 96.50 to 106.59 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Relative Bioavailability Reg E/Reg B: SSP-005174X Formal statistical analysis performed on the pharmacokinetic parameter AUC to assess relative bioavailability of variant 1 versus fasted solid oral formulation
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 8 for AUC

Groups^[1]	Regimen B: 50 mg AZD4635 oral, fasted, Regimen F: 50 mg AZD4635 oral, fasted (variant 2)
Other^[5]	95.72
90% Confidence Interval	( 91.08 to 100.60 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Relative Bioavailability Reg F/Reg B: SSP-005174X Formal statistical analysis performed on the pharmacokinetic parameter AUC to assess relative bioavailability of variant 2 versus fasted solid oral formulation
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 9 for AUC

Groups^[1]	Regimen B: 50 mg AZD4635 oral, fasted, Regimen C: 50 mg AZD4635 oral, fed
Other^[5]	97.85
90% Confidence Interval	( 89.97 to 106.41 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Relative Bioavailability Reg C/Reg B: SSP-005173X Formal statistical analysis performed on the pharmacokinetic parameter AUC to assess relative bioavailability of fed versus fasted solid oral formulation
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 10 for AUC

Groups^[1]	Regimen B: 50 mg AZD4635 oral, fasted, Regimen D: 50 mg AZD4635 oral, fasted with lansoprazole
Other^[5]	91.94
90% Confidence Interval	( 84.34 to 100.22 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Relative Bioavailability Reg D/Reg B: SSP-005173X Formal statistical analysis performed on the pharmacokinetic parameter AUC to assess relative bioavailability of PPI versus fasted solid oral formulation
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 11 for AUC

Groups^[1]	Regimen B: 50 mg AZD4635 oral, fasted, Regimen E: 50 mg AZD4635 oral, fasted (variant 1)
Other^[5]	100.94
90% Confidence Interval	( 92.96 to 109.61 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Relative Bioavailability Reg E/Reg B: SSP-005173X Formal statistical analysis performed on the pharmacokinetic parameter AUC to assess relative bioavailability of variant 1 versus fasted solid oral formulation
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 12 for AUC

Groups^[1]	Regimen B: 50 mg AZD4635 oral, fasted, Regimen F: 50 mg AZD4635 oral, fasted (variant 2)
Other^[5]	93.06
90% Confidence Interval	( 85.67 to 101.09 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Relative Bioavailability Reg F/Reg B: SSP-005173X Formal statistical analysis performed on the pharmacokinetic parameter AUC to assess relative bioavailability of variant 2 versus fasted solid oral formulation
[5]	Other relevant estimation information:
	No text entered.

9. Secondary Outcome Measure: F Cmax [ Time Frame: Pre-dose to Day 6 ]

Measure Type	Secondary
Measure Name	F Cmax
Measure Description	F Cmax: absolute bioavailability based on Cmax.
Time Frame	Pre-dose to Day 6
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.

Reporting Groups

	Description
Regimen A: 50 mg AZD4635 nano-suspension, fasted	Part A, Period 1: single oral dose of 50 mg (40 mL) powder for oral suspension 5.5% (w/w) (referred to as nano-suspension) (reference) in the fasted state (10 h overnight fast) in the morning of Day 1. Not all of the enrolled subjects' data could be included in the analysis for each metabolite.
Regimen B: 50 mg AZD4635 oral, fasted	Part A, Period 2: single dose of 50 mg solid oral capsule in the fasted state (10 h overnight fast) in the morning of Day 1.
Regimen C: 50 mg AZD4635 oral, fed	Part B, Period 3: single dose of 50 mg solid oral capsule after a high fat meal.
Regimen D: 50 mg AZD4635 oral, fasted with lansoprazole	Part B, Period 4: AZD4635 - single dose of 50 mg solid oral capsule in the fasted state. Lansoprazole - administered on Days -4, 03, -2 and -1 as 30 mg twice daily at least 30 minutes before food. On Day 1, subjects received a single dose of lansoprazole following an overnight fast (8 h) and the dose of AZD4635 was administered 2 h later.
Regimen E: 50 mg AZD4635 oral, fasted (variant 1)	Part B, Period 5: AZD4635 - single dose of 50 mg solid oral capsule, variant 1 in the fasted state. The variants had the same quantitative composition as the capsule formulation, but the process parameters and/or input material were altered. [14C]AZD4635 - An IV microtracer dose of AZD4635 was administered with the solid oral formulation. It was administered as a 15 min IV infusion (ending 0.5 h post-oral dose) of a microdose (50 µg) of AZD4635 containing microtracer amounts of 14C (not more than 25.7 kBq/5 mL [694.4 nCi/5 mL]).
Regimen F: 50 mg AZD4635 oral, fasted (variant 2)	Part B, Period 6: single dose of 50 mg solid oral capsule, variant 2 in the fasted state. The variants had the same quantitative composition as the capsule formulation, but the process parameters and/or input material were altered.

Measured Values

	Regimen A: 50 mg AZD4635 nano-suspension, fasted	Regimen B: 50 mg AZD4635 oral, fasted	Regimen C: 50 mg AZD4635 oral, fed	Regimen D: 50 mg AZD4635 oral, fasted with lansoprazole	Regimen E: 50 mg AZD4635 oral, fasted (variant 1)	Regimen F: 50 mg AZD4635 oral, fasted (variant 2)
Number of Participants Analyzed [units:participants]	20	20	20	20	20	20
F Cmax [units: (%)] Geometric Mean (Geometric Coefficient of Variation)	40.316 (41.1%)	51.977 (38.7%)	23.006 (35.5%)	51.460 (41.0%)	49.245 (41.0%)	39.323 (37.9%)

No statistical analysis provided for F Cmax

10. Secondary Outcome Measure: F AUC(0-t) [ Time Frame: Pre-dose to Day 6 ]

Measure Type	Secondary
Measure Name	F AUC(0-t)
Measure Description	F AUC(0-t): absolute bioavailability based on AUC(0-t).
Time Frame	Pre-dose to Day 6
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.

Reporting Groups

	Description
Regimen A: 50 mg AZD4635 nano-suspension, fasted	Part A, Period 1: single oral dose of 50 mg (40 mL) powder for oral suspension 5.5% (w/w) (referred to as nano-suspension) (reference) in the fasted state (10 h overnight fast) in the morning of Day 1. Not all of the enrolled subjects' data could be included in the analysis for each metabolite.
Regimen B: 50 mg AZD4635 oral, fasted	Part A, Period 2: single dose of 50 mg solid oral capsule in the fasted state (10 h overnight fast) in the morning of Day 1.
Regimen C: 50 mg AZD4635 oral, fed	Part B, Period 3: single dose of 50 mg solid oral capsule after a high fat meal.
Regimen D: 50 mg AZD4635 oral, fasted with lansoprazole	Part B, Period 4: AZD4635 - single dose of 50 mg solid oral capsule in the fasted state. Lansoprazole - administered on Days -4, 03, -2 and -1 as 30 mg twice daily at least 30 minutes before food. On Day 1, subjects received a single dose of lansoprazole following an overnight fast (8 h) and the dose of AZD4635 was administered 2 h later.
Regimen E: 50 mg AZD4635 oral, fasted (variant 1)	Part B, Period 5: AZD4635 - single dose of 50 mg solid oral capsule, variant 1 in the fasted state. The variants had the same quantitative composition as the capsule formulation, but the process parameters and/or input material were altered. [14C]AZD4635 - An IV microtracer dose of AZD4635 was administered with the solid oral formulation. It was administered as a 15 min IV infusion (ending 0.5 h post-oral dose) of a microdose (50 µg) of AZD4635 containing microtracer amounts of 14C (not more than 25.7 kBq/5 mL [694.4 nCi/5 mL]).
Regimen F: 50 mg AZD4635 oral, fasted (variant 2)	Part B, Period 6: single dose of 50 mg solid oral capsule, variant 2 in the fasted state. The variants had the same quantitative composition as the capsule formulation, but the process parameters and/or input material were altered.

Measured Values

	Regimen A: 50 mg AZD4635 nano-suspension, fasted	Regimen B: 50 mg AZD4635 oral, fasted	Regimen C: 50 mg AZD4635 oral, fed	Regimen D: 50 mg AZD4635 oral, fasted with lansoprazole	Regimen E: 50 mg AZD4635 oral, fasted (variant 1)	Regimen F: 50 mg AZD4635 oral, fasted (variant 2)
Number of Participants Analyzed [units:participants]	20	20	20	20	20	20
F AUC(0-t) [units: (%)] Geometric Mean (Geometric Coefficient of Variation)	72.050 (14.1%)	78.586 (12.9%)	69.094 (17.4%)	75.901 (17.3%)	78.275 (10.8%)	71.954 (12.2%)

No statistical analysis provided for F AUC(0-t)

11. Secondary Outcome Measure: F AUC [ Time Frame: Pre-dose to Day 6 ]

Measure Type	Secondary
Measure Name	F AUC
Measure Description	F AUC: absolute bioavailability based on AUC.
Time Frame	Pre-dose to Day 6
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.

Reporting Groups

	Description
Regimen A: 50 mg AZD4635 nano-suspension, fasted	Part A, Period 1: single oral dose of 50 mg (40 mL) powder for oral suspension 5.5% (w/w) (referred to as nano-suspension) (reference) in the fasted state (10 h overnight fast) in the morning of Day 1. Not all of the enrolled subjects' data could be included in the analysis for each metabolite.
Regimen B: 50 mg AZD4635 oral, fasted	Part A, Period 2: single dose of 50 mg solid oral capsule in the fasted state (10 h overnight fast) in the morning of Day 1. Not all of the enrolled subjects' data could be included in the analysis for each metabolite.
Regimen C: 50 mg AZD4635 oral, fed	Part B, Period 3: single dose of 50 mg solid oral capsule after a high fat meal. Not all of the enrolled subjects' data could be included in the analysis for each metabolite.
Regimen D: 50 mg AZD4635 oral, fasted with lansoprazole	Part B, Period 4: AZD4635 - single dose of 50 mg solid oral capsule in the fasted state. Lansoprazole - administered on Days -4, 03, -2 and -1 as 30 mg twice daily at least 30 minutes before food. On Day 1, subjects received a single dose of lansoprazole following an overnight fast (8 h) and the dose of AZD4635 was administered 2 h later. Not all of the enrolled subjects' data could be included in the analysis for each metabolite.
Regimen E: 50 mg AZD4635 oral, fasted (variant 1)	Part B, Period 5: AZD4635 - single dose of 50 mg solid oral capsule, variant 1 in the fasted state. The variants had the same quantitative composition as the capsule formulation, but the process parameters and/or input material were altered. [14C]AZD4635 - An IV microtracer dose of AZD4635 was administered with the solid oral formulation. It was administered as a 15 min IV infusion (ending 0.5 h post-oral dose) of a microdose (50 µg) of AZD4635 containing microtracer amounts of 14C (not more than 25.7 kBq/5 mL [694.4 nCi/5 mL]). Not all of the enrolled subjects' data could be included in the analysis for each metabolite.
Regimen F: 50 mg AZD4635 oral, fasted (variant 2)	Part B, Period 6: single dose of 50 mg solid oral capsule, variant 2 in the fasted state. The variants had the same quantitative composition as the capsule formulation, but the process parameters and/or input material were altered. Not all of the enrolled subjects' data could be included in the analysis for each metabolite.

Measured Values

	Regimen A: 50 mg AZD4635 nano-suspension, fasted	Regimen B: 50 mg AZD4635 oral, fasted	Regimen C: 50 mg AZD4635 oral, fed	Regimen D: 50 mg AZD4635 oral, fasted with lansoprazole	Regimen E: 50 mg AZD4635 oral, fasted (variant 1)	Regimen F: 50 mg AZD4635 oral, fasted (variant 2)
Number of Participants Analyzed [units:participants]	20	20	20	20	20	20
F AUC [units: (%)] Geometric Mean (Geometric Coefficient of Variation)	67.741 (14.6%)	74.131 (12.9%)	64.504 (16.7%)	72.282 (17.1%)	73.618 (10.8%)	67.505 (12.4%)

No statistical analysis provided for F AUC

12. Secondary Outcome Measure: Safety and Tolerability [ Time Frame: Screening (Day -28) to Follow-up (7-10 days after final dose) ]

Measure Type	Secondary
Measure Name	Safety and Tolerability
Measure Description	Subjects with at least 1 Treatment Emergent Adverse Event (TEAE)
Time Frame	Screening (Day -28) to Follow-up (7-10 days after final dose)
Safety Issue?	Yes

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.

Reporting Groups

	Description
Regimen A: 50 mg AZD4635 nano-suspension, fasted	Part A, Period 1: single oral dose of 50 mg (40 mL) powder for oral suspension 5.5% (w/w) (referred to as nano-suspension) (reference) in the fasted state (10 h overnight fast) in the morning of Day 1.
Regimen B: 50 mg AZD4635 oral, fasted	Part A, Period 2: single dose of 50 mg solid oral capsule in the fasted state (10 h overnight fast) in the morning of Day 1.
Regimen C: 50 mg AZD4635 oral, fed	Part B, Period 3: single dose of 50 mg solid oral capsule after a high fat meal.
Regimen D: 50 mg AZD4635 oral, fasted with lansoprazole	Part B, Period 4: AZD4635 - single dose of 50 mg solid oral capsule in the fasted state. Lansoprazole - administered on Days -4, 03, -2 and -1 as 30 mg twice daily at least 30 minutes before food. On Day 1, subjects received a single dose of lansoprazole following an overnight fast (8 h) and the dose of AZD4635 was administered 2 h later.
Regimen E: 50 mg AZD4635 oral, fasted (variant 1)	Part B, Period 5: AZD4635 - single dose of 50 mg solid oral capsule, variant 1 in the fasted state. The variants had the same quantitative composition as the capsule formulation, but the process parameters and/or input material were altered. [14C]AZD4635 - An IV microtracer dose of AZD4635 was administered with the solid oral formulation. It was administered as a 15 min IV infusion (ending 0.5 h post-oral dose) of a microdose (50 µg) of AZD4635 containing microtracer amounts of 14C (not more than 25.7 kBq/5 mL [694.4 nCi/5 mL]).
Regimen F: 50 mg AZD4635 oral, fasted (variant 2)	Part B, Period 6: single dose of 50 mg solid oral capsule, variant 2 in the fasted state. The variants had the same quantitative composition as the capsule formulation, but the process parameters and/or input material were altered.

Measured Values

	Regimen A: 50 mg AZD4635 nano-suspension, fasted	Regimen B: 50 mg AZD4635 oral, fasted	Regimen C: 50 mg AZD4635 oral, fed	Regimen D: 50 mg AZD4635 oral, fasted with lansoprazole	Regimen E: 50 mg AZD4635 oral, fasted (variant 1)	Regimen F: 50 mg AZD4635 oral, fasted (variant 2)
Number of Participants Analyzed [units:participants]	20	20	20	20	20	20
Safety and Tolerability [units: Participants]	4	9	6	4	5	5

No statistical analysis provided for Safety and Tolerability

Serious Adverse Events

Time Frame	From Screening (Day -28) to Follow-up (7- 10 days after final dose).
Additional Description	No text entered.

Reporting Groups

	Description
Regimen A: 50 mg AZD4635 nano-suspension, fasted	Part A, Period 1: single oral dose of 50 mg (40 mL) powder for oral suspension 5.5% (w/w) (referred to as nano-suspension) (reference) in the fasted state (10 h overnight fast) in the morning of Day 1.
Regimen B: 50 mg AZD4635 oral, fasted	Part A, Period 2: single dose of 50 mg solid oral capsule in the fasted state (10 h overnight fast) in the morning of Day 1.
Regimen C: 50 mg AZD4635 oral, fed	Part B, Period 3: single dose of 50 mg solid oral capsule after a high fat meal.
Regimen D: 50 mg AZD4635 oral, fasted with lansoprazole	Part B, Period 4: AZD4635 - single dose of 50 mg solid oral capsule in the fasted state. Lansoprazole - administered on Days -4, 03, -2 and -1 as 30 mg twice daily at least 30 minutes before food. On Day 1, subjects received a single dose of lansoprazole following an overnight fast (8 h) and the dose of AZD4635 was administered 2 h later.
Regimen E: 50 mg AZD4635 oral, fasted (variant 1)	Part B, Period 5: AZD4635 - single dose of 50 mg solid oral capsule, variant 1 in the fasted state. The variants had the same quantitative composition as the capsule formulation, but the process parameters and/or input material were altered. [14C]AZD4635 - An IV microtracer dose of AZD4635 was administered with the solid oral formulation. It was administered as a 15 min IV infusion (ending 0.5 h post-oral dose) of a microdose (50 µg) of AZD4635 containing microtracer amounts of 14C (not more than 25.7 kBq/5 mL [694.4 nCi/5 mL]).
Regimen F: 50 mg AZD4635 oral, fasted (variant 2)	Part B, Period 6: single dose of 50 mg solid oral capsule, variant 2 in the fasted state. The variants had the same quantitative composition as the capsule formulation, but the process parameters and/or input material were altered.

Serious Adverse Events

	Regimen A: 50 mg AZD4635 nano-suspension, fasted	Regimen B: 50 mg AZD4635 oral, fasted	Regimen C: 50 mg AZD4635 oral, fed	Regimen D: 50 mg AZD4635 oral, fasted with lansoprazole	Regimen E: 50 mg AZD4635 oral, fasted (variant 1)	Regimen F: 50 mg AZD4635 oral, fasted (variant 2)
Total, serious adverse events
# participants affected / at risk	0/20 (0.00%)	0/20 (0.00%)	0/20 (0.00%)	0/20 (0.00%)	0/20 (0.00%)	0/20 (0.00%)

Other Adverse Events

Time Frame	From Screening (Day -28) to Follow-up (7- 10 days after final dose).
Additional Description	No text entered.

Frequency Threshold

Threshold above which other adverse events are reported	0%

Reporting Groups

	Description
Regimen A: 50 mg AZD4635 nano-suspension, fasted	Part A, Period 1: single oral dose of 50 mg (40 mL) powder for oral suspension 5.5% (w/w) (referred to as nano-suspension) (reference) in the fasted state (10 h overnight fast) in the morning of Day 1.
Regimen B: 50 mg AZD4635 oral, fasted	Part A, Period 2: single dose of 50 mg solid oral capsule in the fasted state (10 h overnight fast) in the morning of Day 1.
Regimen C: 50 mg AZD4635 oral, fed	Part B, Period 3: single dose of 50 mg solid oral capsule after a high fat meal.
Regimen D: 50 mg AZD4635 oral, fasted with lansoprazole	Part B, Period 4: AZD4635 - single dose of 50 mg solid oral capsule in the fasted state. Lansoprazole - administered on Days -4, 03, -2 and -1 as 30 mg twice daily at least 30 minutes before food. On Day 1, subjects received a single dose of lansoprazole following an overnight fast (8 h) and the dose of AZD4635 was administered 2 h later.
Regimen E: 50 mg AZD4635 oral, fasted (variant 1)	Part B, Period 5: AZD4635 - single dose of 50 mg solid oral capsule, variant 1 in the fasted state. The variants had the same quantitative composition as the capsule formulation, but the process parameters and/or input material were altered. [14C]AZD4635 - An IV microtracer dose of AZD4635 was administered with the solid oral formulation. It was administered as a 15 min IV infusion (ending 0.5 h post-oral dose) of a microdose (50 µg) of AZD4635 containing microtracer amounts of 14C (not more than 25.7 kBq/5 mL [694.4 nCi/5 mL]).
Regimen F: 50 mg AZD4635 oral, fasted (variant 2)	Part B, Period 6: single dose of 50 mg solid oral capsule, variant 2 in the fasted state. The variants had the same quantitative composition as the capsule formulation, but the process parameters and/or input material were altered.

Other Adverse Events

Regimen A: 50 mg AZD4635 nano-suspension, fasted

Regimen B: 50 mg AZD4635 oral, fasted

Regimen C: 50 mg AZD4635 oral, fed

Regimen D: 50 mg AZD4635 oral, fasted with lansoprazole

Regimen E: 50 mg AZD4635 oral, fasted (variant 1)

Regimen F: 50 mg AZD4635 oral, fasted (variant 2)

Total, other (not including serious) adverse events

# participants affected / at risk

4/20 (20.00%)

9/20 (45.00%)

6/20 (30.00%)

4/20 (20.00%)

5/20 (25.00%)

Eye disorders

Visual Impairment¹,^†

# participants affected / at risk

0/20 (0.00%)

1/20 (5.00%)

0/20 (0.00%)

# events

Gastrointestinal disorders

Nausea¹,^†

# participants affected / at risk

1/20 (5.00%)

2/20 (10.00%)

1/20 (5.00%)

3/20 (15.00%)

2/20 (10.00%)

1/20 (5.00%)

# events

Gastrointestinal disorders

Toothache¹,^†

# participants affected / at risk

0/20 (0.00%)

2/20 (10.00%)

0/20 (0.00%)

# events

Infections and infestations

Hordeolum¹,^†

# participants affected / at risk

0/20 (0.00%)

1/20 (5.00%)

0/20 (0.00%)

# events

Infections and infestations

Influenza¹,^†

# participants affected / at risk

0/20 (0.00%)

1/20 (5.00%)

0/20 (0.00%)

# events

Infections and infestations

Nasopharyngitis¹,^†

# participants affected / at risk

0/20 (0.00%)

1/20 (5.00%)

0/20 (0.00%)

1/20 (5.00%)

0/20 (0.00%)

# events

Infections and infestations

Upper respiratory tract infection¹,^†

# participants affected / at risk

0/20 (0.00%)

1/20 (5.00%)

0/20 (0.00%)

# events

Infections and infestations

Viral upper respiratory tract infections¹,^†

# participants affected / at risk

0/20 (0.00%)

1/20 (5.00%)

0/20 (0.00%)

# events

Investigations

Alanine aminotransferase increased¹,^†

# participants affected / at risk

0/20 (0.00%)

1/20 (5.00%)

0/20 (0.00%)

# events

Investigations

Aspartate aminotransferase increased¹,^†

# participants affected / at risk

0/20 (0.00%)

1/20 (5.00%)

# events

Investigations

Blood creatine phosphokinase increased¹,^†

# participants affected / at risk

0/20 (0.00%)

1/20 (5.00%)

# events

Musculoskeletal and connective tissue disorders

Musculoskeletal pain¹,^†

# participants affected / at risk

0/20 (0.00%)

1/20 (5.00%)

0/20 (0.00%)

# events

Musculoskeletal and connective tissue disorders

Pain in extremity¹,^†

# participants affected / at risk

0/20 (0.00%)

1/20 (5.00%)

0/20 (0.00%)

# events

Nervous system disorders

Dizziness¹,^†

# participants affected / at risk

3/20 (15.00%)

2/20 (10.00%)

3/20 (15.00%)

2/20 (10.00%)

# events

Nervous system disorders

Headache¹,^†

# participants affected / at risk

1/20 (5.00%)

2/20 (10.00%)

1/20 (5.00%)

0/20 (0.00%)

1/20 (5.00%)

2/20 (10.00%)

# events

Psychiatric disorders

Euphoric mood¹,^†

# participants affected / at risk

0/20 (0.00%)

1/20 (5.00%)

# events

†	Events were collected by systematic assessment
1	Term from vocabulary, MedDRA 21.1

Certain Agreements

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

There is NOT 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.

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:	Medical Science Director
Organization:	AstraZeneca AB
Phone	+46 301 398 4770
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

Sharan Sidhu

Quotient Sciences Limited (indemnified by Medical Protection Society)

Sponsors

Collaborators

Inclusion Criteria

Research Site

Trial Results Summaries