Study to collect samples for MIST analysis of Zibotentan and bioavailability of Zibotentan and Dapagliflozin in heatlhy participants

Study identifier:D4325C00003

ClinicalTrials.gov identifier:NCT04991571

EudraCT identifier:N/A

CTIS identifier:N/A

Study Complete

Official Title

A Phase 1, Open-label Study with Two Independent Parts: Collecting Samples for Metabolites in Safety Testing Analysis of Zibotentan after Repeated Administration (Part 1); and a Randomised, Cross-over, Three period, Three-treatment, Single dose Study to Assess the Relative Bioavailability of Different Formulations of Zibotentan and Dapagliflozin (Part 2) in Healthy Adult Participants

Medical condition

Chronic Kidney Disease

Phase

Phase 1

Healthy volunteers

Yes

Study drug

Zibotentan (Treatment A), Dapagliflozin (Treatment A), Zibotentan/Dapagliflozin – Formulation 1 (Treatment B), Zibotentan/Dapagliflozin – Formulation 2 (Treatment C)

Sex

All

Actual Enrollment

Study type

Interventional

Age

18 Years - 50 Years

Date

Study Start Date: 29 Jul 2021

Primary Completion Date: 22 Oct 2021

Study Completion Date: 22 Oct 2021

Study design

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

Verification:

Verified 01 Oct 2022 by AstraZeneca

Collaborators

Inclusion and exclusion criteria

Location

Research Site

Brooklyn, MD, United States, 21225

Arms	Assigned Interventions
Experimental: Part 1 Participants will be administered with zibotentan once daily for 5 days.	Drug: Zibotentan (Treatment A) Zibotentan capsule will be administered orally as multiple doses in Part 1 and as single dose in Part 2.
Experimental: Part 2: Treatment Sequence ABC Each participant will receive 3 single-dose treatments of zibotentan and dapagliflozin (Treatment A; Treatment B; Treatment C) in 3 treatment periods, separated by a washout period of at least 7 days between treatment periods.	Drug: Zibotentan (Treatment A) Zibotentan capsule will be administered orally as multiple doses in Part 1 and as single dose in Part 2. Drug: Dapagliflozin (Treatment A) Dapagliflozin tablet will be administered orally as single dose in Part 2. Drug: Zibotentan/Dapagliflozin – Formulation 1 (Treatment B) Zibotentan/Dapagliflozin tablet will be administered orally as single dose in Part 2. Drug: Zibotentan/Dapagliflozin – Formulation 2 (Treatment C) Zibotentan/Dapagliflozin tablet will be administered orally as single dose in Part 2.
Experimental: Part 2: Treatment Sequence BCA Each participant will receive 3 single-dose treatments of zibotentan and dapagliflozin (Treatment B; Treatment C; Treatment A) in 3 treatment periods, separated by a washout period of at least 7 days between treatment periods.	Drug: Zibotentan (Treatment A) Zibotentan capsule will be administered orally as multiple doses in Part 1 and as single dose in Part 2. Drug: Dapagliflozin (Treatment A) Dapagliflozin tablet will be administered orally as single dose in Part 2. Drug: Zibotentan/Dapagliflozin – Formulation 1 (Treatment B) Zibotentan/Dapagliflozin tablet will be administered orally as single dose in Part 2. Drug: Zibotentan/Dapagliflozin – Formulation 2 (Treatment C) Zibotentan/Dapagliflozin tablet will be administered orally as single dose in Part 2.
Experimental: Part 2: Treatment Sequence CAB Each participant will receive 3 single-dose treatments of zibotentan and dapagliflozin (Treatment C; Treatment A; Treatment B) in 3 treatment periods, separated by a washout period of at least 7 days between treatment periods.	Drug: Zibotentan (Treatment A) Zibotentan capsule will be administered orally as multiple doses in Part 1 and as single dose in Part 2. Drug: Dapagliflozin (Treatment A) Dapagliflozin tablet will be administered orally as single dose in Part 2. Drug: Zibotentan/Dapagliflozin – Formulation 1 (Treatment B) Zibotentan/Dapagliflozin tablet will be administered orally as single dose in Part 2. Drug: Zibotentan/Dapagliflozin – Formulation 2 (Treatment C) Zibotentan/Dapagliflozin tablet will be administered orally as single dose in Part 2.

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 between 29-July-2021 and 22-October-2021 in Baltimore (Parexel Early Phase Clinical Unit).

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.

Reporting Groups

	Description
Part 1	Participants were administered zibotentan once daily for 5 days.
Part 2: Treatment A	Each participant received a single dose of Treatment A.
Part 2: Treatment B	Each participant received a single dose of Treatment B.
Part 2: Treatment C	Each participant received a single dose of Treatment C.

Participant Flow: Overall Study

	Part 1	Part 2: Treatment A	Part 2: Treatment B	Part 2: Treatment C
STARTED	7	7	6	7
COMPLETED	7	7	5	7
NOT COMPLETED	0	0	1	0
Lost to Follow-up	0	0	1	0

Baseline Characteristics

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

Part 1: The enrolled set consisted of all participants who were enrolled and assigned to treatment. Part 2: The randomised set consisted of all subjects randomised in Part 2.

Reporting Groups

	Description
Part 1	Participants were administered zibotentan once daily for 5 days.
Part 2: Treatment A	Each participant received a single dose of Treatment A.
Part 2: Treatment B	Each participant received a single dose of Treatment B.
Part 2: Treatment C	Each participant received a single dose of Treatment C.

Baseline Measures

	Part 1	Part 2: Treatment A	Part 2: Treatment B	Part 2: Treatment C	Total
Number of Participants [units: Participants]	7	7	6	7	27
Age Continuous [units: years] Mean ± Standard Deviation	38.9 ± 9.4	33.4 ± 4.8	35.2 ± 6.5	34.4 ± 7.2	NA ± NA ^[1]
Sex: Female, Male [units: Participants]
Female	0	0	0	0	0
Male	7	7	6	7	27
Race (NIH/OMB) [units: Participants]
American Indian or Alaska Native	0	0	0	0	0
Asian	0	0	0	1	1
Native Hawaiian or Other Pacific Islander	0	0	0	0	0
Black or African American	4	6	5	4	19
White	3	1	1	2	7
More than one race	0	0	0	0	0
Unknown or Not Reported	0	0	0	0	0
Ethnicity (NIH/OMB) [units: Participants]
Hispanic or Latino	1	2	1	1	5
Not Hispanic or Latino	6	5	5	6	22
Unknown or Not Reported	0	0	0	0	0

Outcome Measures

1. Primary Outcome Measure: Part 2: Area under plasma concentration time curve from zero to infinity (AUCinf) [ Time Frame: Day 1 through Day 3 of each treatment period ]

Measure Type	Primary
Measure Name	Part 2: Area under plasma concentration time curve from zero to infinity (AUCinf)
Measure Description	Relative bioavailability of zibotentan and dapagliflozin after dosing with two different fixed-dose combination (FDC) formulations and dosing with separate formulations of zibotentan and dapagliflozin were evaluated.
Time Frame	Day 1 through Day 3 of each treatment period
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The pharmacokinetics (PK) analysis set consisted of all participants in the safety analysis set for Part 2 who have at least 1 quantifiable post-dose concentration for zibotentan or dapagliflozin, with no important protocol deviations of AEs considered to impact the PK data.

Reporting Groups

	Description
Part 2: Treatment A	Each participant received a single dose of Treatment A.
Part 2: Treatment B	Each participant received a single dose of Treatment B.
Part 2: Treatment C	Each participant received a single dose of Treatment C.

Measured Values

	Part 2: Treatment A	Part 2: Treatment B	Part 2: Treatment C
Number of Participants Analyzed [units:participants]	19	20	19
Part 2: Area under plasma concentration time curve from zero to infinity (AUCinf) [units: hng/mL (hournanogram/milliliter)] Geometric Mean (Geometric Coefficient of Variation)
Zibotentan	2056 (20.74%)	2188 (29.53%)	2162 (16.33%)
Dapagliflozin	482.5 (19.19%)	500.7 (17.66%)	494.1 (15.23%)

Statistical Analysis 1 for Part 2: Area under plasma concentration time curve from zero to infinity (AUCinf)

Groups^[1]	Part 2: Treatment A, Part 2: Treatment B
Method^[3]	ANOVA
Other^[5]	106.03
90% Confidence Interval	( 97.58 to 115.21 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Statistical comparison of Zibotentan PK Parameters for treatment A vs Treatment B.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	Result based on analysis of variance (ANOVA) of log transformed PK parameter.
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 2 for Part 2: Area under plasma concentration time curve from zero to infinity (AUCinf)

Groups^[1]	Part 2: Treatment A, Part 2: Treatment C
Method^[3]	ANOVA
Other^[5]	105.77
90% Confidence Interval	( 97.30 to 114.99 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Statistical comparison of Zibotentan PK Parameters for treatment A vs Treatment C.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	Result based on analysis of variance (ANOVA) of log transformed PK parameter.
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 3 for Part 2: Area under plasma concentration time curve from zero to infinity (AUCinf)

Groups^[1]	Part 2: Treatment B, Part 2: Treatment C
Method^[3]	ANOVA
Other^[5]	100.24
90% Confidence Interval	( 92.25 to 108.92 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Statistical comparison of Zibotentan PK Parameters for treatment B vs Treatment C.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	Result based on analysis of variance (ANOVA) of log transformed PK parameter.
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 4 for Part 2: Area under plasma concentration time curve from zero to infinity (AUCinf)

Groups^[1]	Part 2: Treatment A, Part 2: Treatment B
Method^[3]	ANOVA
Other^[5]	102.25
90% Confidence Interval	( 99.26 to 105.33 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Statistical comparison of Dapagliflozin PK Parameters for treatment A vs Treatment B.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	Result based on analysis of variance (ANOVA) of log transformed PK parameter.
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 5 for Part 2: Area under plasma concentration time curve from zero to infinity (AUCinf)

Groups^[1]	Part 2: Treatment A, Part 2: Treatment C
Method^[3]	ANOVA
Other^[5]	102.21
90% Confidence Interval	( 99.28 to 105.22 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Statistical comparison of Dapagliflozin PK Parameters for treatment A vs Treatment C.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	Result based on analysis of variance (ANOVA) of log transformed PK parameter.
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 6 for Part 2: Area under plasma concentration time curve from zero to infinity (AUCinf)

Groups^[1]	Part 2: Treatment B, Part 2: Treatment C
Method^[3]	ANOVA
Other^[5]	100.04
90% Confidence Interval	( 97.13 to 103.04 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Statistical comparison of Dapagliflozin PK Parameters for treatment B vs Treatment C.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	Result based on analysis of variance (ANOVA) of log transformed PK parameter.
[5]	Other relevant estimation information:
	No text entered.

2. Primary Outcome Measure: Part 2: Area under the plasma concentration curve from zero to the last quantifiable concentration (AUClast) [ Time Frame: Day 1 through Day 3 of each treatment period ]

Measure Type	Primary
Measure Name	Part 2: Area under the plasma concentration curve from zero to the last quantifiable concentration (AUClast)
Measure Description	Relative bioavailability of zibotentan and dapagliflozin after dosing with two different FDC formulations and dosing with separate formulations of zibotentan and dapagliflozin were evaluated.
Time Frame	Day 1 through Day 3 of each treatment period
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The PK analysis set consisted of all participants in the safety analysis set for Part 2 who have at least 1 quantifiable post-dose concentration for zibotentan or dapagliflozin, with no important protocol deviations of AEs considered to impact the PK data.

Reporting Groups

	Description
Part 2: Treatment A	Each participant received a single dose of Treatment A.
Part 2: Treatment B	Each participant received a single dose of Treatment B.
Part 2: Treatment C	Each participant received a single dose of Treatment C.

Measured Values

	Part 2: Treatment A	Part 2: Treatment B	Part 2: Treatment C
Number of Participants Analyzed [units:participants]	19	20	19
Part 2: Area under the plasma concentration curve from zero to the last quantifiable concentration (AUClast) [units: h*ng/mL] Geometric Mean (Geometric Coefficient of Variation)
Zibotentan	2046 (20.80%)	2178 (29.59%)	2153 (16.39%)
Dapagliflozin	472.7 (19.04%)	488.5 (17.21%)	483.7 (14.84%)

Statistical Analysis 1 for Part 2: Area under the plasma concentration curve from zero to the last quantifiable concentration (AUClast)

Groups^[1]	Part 2: Treatment A, Part 2: Treatment B
Method^[3]	ANOVA
Other^[5]	106.06
90% Confidence Interval	( 97.59 to 115.26 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Statistical comparison of Zibotentan PK Parameters for treatment A vs Treatment B.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	Result based on analysis of variance (ANOVA) of log transformed PK parameter.
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 2 for Part 2: Area under the plasma concentration curve from zero to the last quantifiable concentration (AUClast)

Groups^[1]	Part 2: Treatment A, Part 2: Treatment C
Method^[3]	ANOVA
Other^[5]	105.87
90% Confidence Interval	( 97.38 to 115.12 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Statistical comparison of Zibotentan PK Parameters for treatment A vs Treatment C.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	Result based on analysis of variance (ANOVA) of log transformed PK parameter.
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 3 for Part 2: Area under the plasma concentration curve from zero to the last quantifiable concentration (AUClast)

Groups^[1]	Part 2: Treatment B, Part 2: Treatment C
Method^[3]	ANOVA
Other^[5]	100.17
90% Confidence Interval	( 92.18 to 108.87 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Statistical comparison of Zibotentan PK Parameters for treatment B vs Treatment C.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	Result based on analysis of variance (ANOVA) of log transformed PK parameter.
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 4 for Part 2: Area under the plasma concentration curve from zero to the last quantifiable concentration (AUClast)

Groups^[1]	Part 2: Treatment A, Part 2: Treatment B
Method^[3]	ANOVA
Other^[5]	102.20
90% Confidence Interval	( 99.37 to 105.10 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Statistical comparison of Dapagliflozin PK Parameters for treatment A vs Treatment B.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	Result based on analysis of variance (ANOVA) of log transformed PK parameter.
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 5 for Part 2: Area under the plasma concentration curve from zero to the last quantifiable concentration (AUClast)

Groups^[1]	Part 2: Treatment A, Part 2: Treatment C
Method^[3]	ANOVA
Other^[5]	102.19
90% Confidence Interval	( 99.36 to 105.10 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Statistical comparison of Dapagliflozin PK Parameters for treatment A vs Treatment C.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	Result based on analysis of variance (ANOVA) of log transformed PK parameter.
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 6 for Part 2: Area under the plasma concentration curve from zero to the last quantifiable concentration (AUClast)

Groups^[1]	Part 2: Treatment B, Part 2: Treatment C
Method^[3]	ANOVA
Other^[5]	100.01
90% Confidence Interval	( 97.24 to 102.85 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Statistical comparison of Dapagliflozin PK Parameters for treatment B vs Treatment C.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	Result based on analysis of variance (ANOVA) of log transformed PK parameter.
[5]	Other relevant estimation information:
	No text entered.

3. Primary Outcome Measure: Part 2: Maximum observed plasma drug concentration (Cmax) [ Time Frame: Day 1 through Day 3 of each treatment period ]

Measure Type	Primary
Measure Name	Part 2: Maximum observed plasma drug concentration (Cmax)
Measure Description	Relative bioavailability of zibotentan and dapagliflozin after dosing with two different FDC formulations and dosing with separate formulations of zibotentan and dapagliflozin were evaluated.
Time Frame	Day 1 through Day 3 of each treatment period
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The PK analysis set consisted of all participants in the safety analysis set for Part 2 who have at least 1 quantifiable post-dose concentration for zibotentan or dapagliflozin, with no important protocol deviations of AEs considered to impact the PK data.

Reporting Groups

	Description
Part 2: Treatment A	Each participant received a single dose of Treatment A.
Part 2: Treatment B	Each participant received a single dose of Treatment B.
Part 2: Treatment C	Each participant received a single dose of Treatment C.

Measured Values

	Part 2: Treatment A	Part 2: Treatment B	Part 2: Treatment C
Number of Participants Analyzed [units:participants]	19	20	19
Part 2: Maximum observed plasma drug concentration (Cmax) [units: nanogram/millilitre (ng/mL)] Geometric Mean (Geometric Coefficient of Variation)
Zibotentan	229.9 (16.23%)	235.6 (18.98%)	234.4 (16.37%)
Dapagliflozin	119.8 (26.47%)	137.7 (30.89%)	140.8 (27.04%)

Statistical Analysis 1 for Part 2: Maximum observed plasma drug concentration (Cmax)

Groups^[1]	Part 2: Treatment A, Part 2: Treatment B
Method^[3]	ANOVA
Other^[5]	102.28
90% Confidence Interval	( 95.44 to 109.60 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Statistical comparison of Zibotentan PK Parameters for treatment A vs Treatment B.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	Result based on analysis of variance (ANOVA) of log transformed PK parameter
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 2 for Part 2: Maximum observed plasma drug concentration (Cmax)

Groups^[1]	Part 2: Treatment A, Part 2: Treatment C
Method^[3]	ANOVA
Other^[5]	101.80
90% Confidence Interval	( 94.95 to 109.15 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Statistical comparison of Zibotentan PK Parameters for treatment A vs Treatment C.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	Result based on analysis of variance (ANOVA) of log transformed PK parameter.
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 3 for Part 2: Maximum observed plasma drug concentration (Cmax)

Groups^[1]	Part 2: Treatment B, Part 2: Treatment C
Method^[3]	ANOVA
Other^[5]	100.46
90% Confidence Interval	( 93.75 to 107.66 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Statistical comparison of Zibotentan PK Parameters for treatment A vs Treatment B.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	Result based on analysis of variance (ANOVA) of log transformed PK parameter.
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 4 for Part 2: Maximum observed plasma drug concentration (Cmax)

Groups^[1]	Part 2: Treatment A, Part 2: Treatment B
Method^[3]	ANOVA
Other^[5]	115.32
90% Confidence Interval	( 100.64 to 132.13 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Statistical comparison of Dapagliflozin PK Parameters for treatment A vs Treatment B.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	Result based on analysis of variance (ANOVA) of log transformed PK parameter.
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 5 for Part 2: Maximum observed plasma drug concentration (Cmax)

Groups^[1]	Part 2: Treatment A, Part 2: Treatment C
Method^[3]	ANOVA
Other^[5]	118.19
90% Confidence Interval	( 102.99 to 135.62 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Statistical comparison of Dapagliflozin PK Parameters for treatment A vs Treatment C.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	Result based on analysis of variance (ANOVA) of log transformed PK parameter.
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 6 for Part 2: Maximum observed plasma drug concentration (Cmax)

Groups^[1]	Part 2: Treatment B, Part 2: Treatment C
Method^[3]	ANOVA
Other^[5]	97.57
90% Confidence Interval	( 85.16 to 111.80 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Statistical comparison of Dapagliflozin PK Parameters for treatment B vs Treatment C.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	Result based on analysis of variance (ANOVA) of log transformed PK parameter.
[5]	Other relevant estimation information:
	No text entered.

4. Primary Outcome Measure: Part 2: Observed concentration at 24 hours post-dose (C24) [ Time Frame: Day 1 through Day 3 of each treatment period ]

Measure Type	Primary
Measure Name	Part 2: Observed concentration at 24 hours post-dose (C24)
Measure Description	Relative bioavailability of zibotentan and dapagliflozin after dosing with two different FDC formulations and dosing with separate formulations of zibotentan and dapagliflozin were evaluated.
Time Frame	Day 1 through Day 3 of each treatment period
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The PK analysis set consisted of all participants in the safety analysis set for Part 2 who have at least 1 quantifiable post-dose concentration for zibotentan or dapagliflozin, with no important protocol deviations of AEs considered to impact the PK data.

Reporting Groups

	Description
Part 2: Treatment A	Each participant received a single dose of Treatment A.
Part 2: Treatment B	Each participant received a single dose of Treatment B.
Part 2: Treatment C	Each participant received a single dose of Treatment C.

Measured Values

	Part 2: Treatment A	Part 2: Treatment B	Part 2: Treatment C
Number of Participants Analyzed [units:participants]	19	20	19
Part 2: Observed concentration at 24 hours post-dose (C24) [units: ng/mL] Geometric Mean (Geometric Coefficient of Variation)
Zibotentan	19.69 (58.64%)	20.88 (69.58%)	21.26 (36.52%)
Dapagliflozin	3.446 (27.96%)	3.443 (28.49%)	3.294 (16.90%)

Statistical Analysis 1 for Part 2: Observed concentration at 24 hours post-dose (C24)

Groups^[1]	Part 2: Treatment A, Part 2: Treatment B
Method^[3]	ANOVA
Other^[5]	106.16
90% Confidence Interval	( 88.92 to 126.73 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Statistical comparison of Zibotentan PK Parameters for treatment A vs Treatment B.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	Result based on analysis of variance (ANOVA) of log transformed PK parameter.
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 2 for Part 2: Observed concentration at 24 hours post-dose (C24)

Groups^[1]	Part 2: Treatment A, Part 2: Treatment C
Method^[3]	ANOVA
Other^[5]	109.78
90% Confidence Interval	( 91.87 to 131.19 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Statistical comparison of Zibotentan PK Parameters for treatment A vs Treatment C.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	Result based on analysis of variance (ANOVA) of log transformed PK parameter.
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 3 for Part 2: Observed concentration at 24 hours post-dose (C24)

Groups^[1]	Part 2: Treatment B, Part 2: Treatment C
Method^[3]	ANOVA
Other^[5]	96.70
90% Confidence Interval	( 81.00 to 115.44 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Statistical comparison of Zibotentan PK Parameters for treatment B vs Treatment C.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	Result based on analysis of variance (ANOVA) of log transformed PK parameter.
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 4 for Part 2: Observed concentration at 24 hours post-dose (C24)

Groups^[1]	Part 2: Treatment A, Part 2: Treatment B
Method^[3]	ANOVA
Other^[5]	97.21
90% Confidence Interval	( 91.18 to 103.64 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Statistical comparison of Dapagliflozin PK Parameters for treatment A vs Treatment B.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	Result based on analysis of variance (ANOVA) of log transformed PK parameter.
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 5 for Part 2: Observed concentration at 24 hours post-dose (C24)

Groups^[1]	Part 2: Treatment A, Part 2: Treatment C
Method^[3]	ANOVA
Other^[5]	95.66
90% Confidence Interval	( 89.71 to 102.00 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Statistical comparison of Dapagliflozin PK Parameters for treatment A vs Treatment C.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	Result based on analysis of variance (ANOVA) of log transformed PK parameter.
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 6 for Part 2: Observed concentration at 24 hours post-dose (C24)

Groups^[1]	Part 2: Treatment B, Part 2: Treatment C
Method^[3]	ANOVA
Other^[5]	101.62
90% Confidence Interval	( 95.32 to 108.34 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Statistical comparison of Dapagliflozin PK Parameters for treatment B vs Treatment C.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	Result based on analysis of variance (ANOVA) of log transformed PK parameter.
[5]	Other relevant estimation information:
	No text entered.

5. Secondary Outcome Measure: Part 2: Time to reach peak or maximum observed concentration (tmax) [ Time Frame: Day 1 through Day 3 of each treatment period ]

Measure Type	Secondary
Measure Name	Part 2: Time to reach peak or maximum observed concentration (tmax)
Measure Description	Relative bioavailability of zibotentan and dapagliflozin after dosing with two different FDC formulations and dosing with separate formulations of zibotentan and dapagliflozin will be evaluated.
Time Frame	Day 1 through Day 3 of each treatment period
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The PK analysis set consisted of all participants in the safety analysis set for Part 2 who have at least 1 quantifiable post-dose concentration for zibotentan or dapagliflozin, with no important protocol deviations of AEs considered to impact the PK data.

Reporting Groups

	Description
Part 2: Treatment A	Each participant received a single dose of Treatment A.
Part 2: Treatment B	Each participant received a single dose of Treatment B.
Part 2: Treatment C	Each participant received a single dose of Treatment C.

Measured Values

	Part 2: Treatment A	Part 2: Treatment B	Part 2: Treatment C
Number of Participants Analyzed [units:participants]	19	20	19
Part 2: Time to reach peak or maximum observed concentration (tmax) [units: h (hour)] Median (Full Range)
Zibotentan	2.37 (1.00 to 5.07)	2.25 (0.97 to 5.05)	2.03 (1.02 to 4.00)
Dapagliflozin	1.02 (0.65 to 1.67)	0.83 (0.65 to 2.02)	1.00 (0.65 to 2.00)

No statistical analysis provided for Part 2: Time to reach peak or maximum observed concentration (tmax)

6. Secondary Outcome Measure: Part 2: Terminal rate constant (λz) [ Time Frame: Day 1 through Day 3 of each treatment period ]

Measure Type	Secondary
Measure Name	Part 2: Terminal rate constant (λz)
Measure Description	Relative bioavailability of zibotentan and dapagliflozin after dosing with two different FDC formulations and dosing with separate formulations of zibotentan and dapagliflozin will be evaluated.
Time Frame	Day 1 through Day 3 of each treatment period
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The PK analysis set consisted of all participants in the safety analysis set for Part 2 who have at least 1 quantifiable post-dose concentration for zibotentan or dapagliflozin, with no important protocol deviations of AEs considered to impact the PK data.

Reporting Groups

	Description
Part 2: Treatment A	Each participant received a single dose of Treatment A.
Part 2: Treatment B	Each participant received a single dose of Treatment B.
Part 2: Treatment C	Each participant received a single dose of Treatment C.

Measured Values

	Part 2: Treatment A	Part 2: Treatment B	Part 2: Treatment C
Number of Participants Analyzed [units:participants]	19	20	19
Part 2: Terminal rate constant (λz) [units: 1/h (hour)] Geometric Mean (Geometric Coefficient of Variation)
Zibotentan	0.09411 (19.40%)	0.09638 (17.47%)	0.09540 (14.59%)
Dapagliflozin	0.05312 (28.64%)	0.05272 (23.33%)	0.05076 (28.44%)

No statistical analysis provided for Part 2: Terminal rate constant (λz)

7. Secondary Outcome Measure: Part 2: Half life associated with λz (t½λz) [ Time Frame: Day 1 through Day 3 of each treatment period ]

Measure Type	Secondary
Measure Name	Part 2: Half life associated with λz (t½λz)
Measure Description	Relative bioavailability of zibotentan and dapagliflozin after dosing with two different FDC formulations and dosing with separate formulations of zibotentan and dapagliflozin will be evaluated.
Time Frame	Day 1 through Day 3 of each treatment period
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The PK analysis set consisted of all participants in the safety analysis set for Part 2 who have at least 1 quantifiable post-dose concentration for zibotentan or dapagliflozin, with no important protocol deviations of AEs considered to impact the PK data.

Reporting Groups

	Description
Part 2: Treatment A	Each participant received a single dose of Treatment A.
Part 2: Treatment B	Each participant received a single dose of Treatment B.
Part 2: Treatment C	Each participant received a single dose of Treatment C.

Measured Values

	Part 2: Treatment A	Part 2: Treatment B	Part 2: Treatment C
Number of Participants Analyzed [units:participants]	19	20	19
Part 2: Half life associated with λz (t½λz) [units: h (hour)] Geometric Mean (Geometric Coefficient of Variation)
Zibotentan	7.365 (19.40%)	7.192 (17.47%)	7.266 (14.59%)
Dapagliflozin	13.05 (28.64%)	13.15 (23.33%)	13.66 (28.44%)

No statistical analysis provided for Part 2: Half life associated with λz (t½λz)

8. Secondary Outcome Measure: Part 2: Apparent total body clearance of drug from plasma after extravascular administration (CL/F) [ Time Frame: Day 1 through Day 3 of each treatment period ]

Measure Type	Secondary
Measure Name	Part 2: Apparent total body clearance of drug from plasma after extravascular administration (CL/F)
Measure Description	Relative bioavailability of zibotentan and dapagliflozin after dosing with two different FDC formulations and dosing with separate formulations of zibotentan and dapagliflozin will be evaluated.
Time Frame	Day 1 through Day 3 of each treatment period
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The PK analysis set consisted of all participants in the safety analysis set for Part 2 who have at least 1 quantifiable post-dose concentration for zibotentan or dapagliflozin, with no important protocol deviations of AEs considered to impact the PK data.

Reporting Groups

	Description
Part 2: Treatment A	Each participant received a single dose of Treatment A.
Part 2: Treatment B	Each participant received a single dose of Treatment B.
Part 2: Treatment C	Each participant received a single dose of Treatment C.

Measured Values

	Part 2: Treatment A	Part 2: Treatment B	Part 2: Treatment C
Number of Participants Analyzed [units:participants]	19	20	19
Part 2: Apparent total body clearance of drug from plasma after extravascular administration (CL/F) [units: Litre/hour (L/h)] Geometric Mean (Geometric Coefficient of Variation)
Zibotentan	2.432 (20.74%)	2.285 (29.53%)	2.313 (16.33%)
Dapagliflozin	20.72 (19.19%)	19.97 (17.66%)	20.24 (15.23%)

No statistical analysis provided for Part 2: Apparent total body clearance of drug from plasma after extravascular administration (CL/F)

9. Secondary Outcome Measure: Part 2: Volume of distribution at steady state following extravascular administration (Vz/F) [ Time Frame: Day 1 through Day 3 of each treatment period ]

Measure Type	Secondary
Measure Name	Part 2: Volume of distribution at steady state following extravascular administration (Vz/F)
Measure Description	Relative bioavailability of zibotentan and dapagliflozin after dosing with two different FDC formulations and dosing with separate formulations of zibotentan and dapagliflozin will be evaluated.
Time Frame	Day 1 through Day 3 of each treatment period
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The PK analysis set consisted of all participants in the safety analysis set for Part 2 who have at least 1 quantifiable post-dose concentration for zibotentan or dapagliflozin, with no important protocol deviations of AEs considered to impact the PK data.

Reporting Groups

	Description
Part 2: Treatment A	Each participant received a single dose of Treatment A.
Part 2: Treatment B	Each participant received a single dose of Treatment B.
Part 2: Treatment C	Each participant received a single dose of Treatment C.

Measured Values

	Part 2: Treatment A	Part 2: Treatment B	Part 2: Treatment C
Number of Participants Analyzed [units:participants]	19	20	19
Part 2: Volume of distribution at steady state following extravascular administration (Vz/F) [units: Litre (L)] Geometric Mean (Geometric Coefficient of Variation)
Zibotentan	25.84 (18.08%)	23.71 (27.38%)	24.25 (17.53%)
Dapagliflozin	390.1 (28.59%)	378.9 (25.76%)	398.8 (26.84%)

No statistical analysis provided for Part 2: Volume of distribution at steady state following extravascular administration (Vz/F)

10. Secondary Outcome Measure: Part 1 and Part 2: Number of adverse events and serious adverse events [ Time Frame: From Screening to Follow-up Visit (approximately 40 days for Part 1 and 49 days for Part 2) ]

Measure Type	Secondary
Measure Name	Part 1 and Part 2: Number of adverse events and serious adverse events
Measure Description	Safety and tolerability of zibotentan and dapagliflozin was assessed.
Time Frame	From Screening to Follow-up Visit (approximately 40 days for Part 1 and 49 days for Part 2)
Safety Issue?	Yes

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The safety analysis set included all participants who received at least 1 dose of zibotentan and/or dapagliflozin, and for whom any safety post-dose data are available. The number of participants under each treatment arm here refers to the number of total participants who were given the particular treatment in each arm.

Reporting Groups

	Description
Part 1	Participants were administered zibotentan once daily for 5 days.
Part 2: Treatment A	Each participant received a single dose of Treatment A.
Part 2: Treatment B	Each participant received a single dose of Treatment B.
Part 2: Treatment C	Each participant received a single dose of Treatment C.

Measured Values

	Part 1	Part 2: Treatment A	Part 2: Treatment B	Part 2: Treatment C
Number of Participants Analyzed [units:participants]	7	19	20	19
Part 1 and Part 2: Number of adverse events and serious adverse events [units: Participants]
Any AE	5	5	3	3
Any SAE	0	0	0	0
Any SAE with outcome death	0	0	0	0
Any AE leading to discontinuation of IP	0	0	0	0
Any possibly related AE	4	3	3	3
Any possibly related SAE	0	0	0	0

No statistical analysis provided for Part 1 and Part 2: Number of adverse events and serious adverse events

Serious Adverse Events

Time Frame	From screening to follow-up visit (approximately 40 days for Part 1 and 49 days for Part 2).
Additional Description	The safety analysis set included all participants who received at least 1 dose of zibotentan and/or dapagliflozin, and for whom any safety post-dose data are available.

Reporting Groups

	Description
Part 1	Participants were administered zibotentan once daily for 5 days.
Part 2: Treatment A	Each participant received a single dose of Treatment A.
Part 2: Treatment B	Each participant received a single dose of Treatment B.
Part 2: Treatment C	Each participant received a single dose of Treatment C.

Serious Adverse Events

	Part 1	Part 2: Treatment A	Part 2: Treatment B	Part 2: Treatment C
Total, serious adverse events
# participants affected / at risk	0/7 (0.00%)	0/19 (0.00%)	0/20 (0.00%)	0/19 (0.00%)

Other Adverse Events

Time Frame	From screening to follow-up visit (approximately 40 days for Part 1 and 49 days for Part 2).
Additional Description	The safety analysis set included all participants who received at least 1 dose of zibotentan and/or dapagliflozin, and for whom any safety post-dose data are available.

Frequency Threshold

Threshold above which other adverse events are reported	0%

Reporting Groups

	Description
Part 1	Participants were administered zibotentan once daily for 5 days.
Part 2: Treatment A	Each participant received a single dose of Treatment A.
Part 2: Treatment B	Each participant received a single dose of Treatment B.
Part 2: Treatment C	Each participant received a single dose of Treatment C.

Other Adverse Events

Part 1

Part 2: Treatment A

Part 2: Treatment B

Part 2: Treatment C

Total, other (not including serious) adverse events

# participants affected / at risk

5/7 (71.43%)

5/19 (26.32%)

3/20 (15.00%)

3/19 (15.79%)

Infections and infestations

Streptococcal urinary tract infection¹

# participants affected / at risk

1/7 (14.29%)

0/19 (0.00%)

0/20 (0.00%)

0/19 (0.00%)

# events

Nervous system disorders

Dizziness¹

# participants affected / at risk

1/7 (14.29%)

0/19 (0.00%)

0/20 (0.00%)

1/19 (5.26%)

# events

Nervous system disorders

Headache¹

# participants affected / at risk

3/7 (42.86%)

3/19 (15.79%)

3/20 (15.00%)

3/19 (15.79%)

# events

Gastrointestinal disorders

Constipation¹

# participants affected / at risk

1/7 (14.29%)

0/19 (0.00%)

0/20 (0.00%)

0/19 (0.00%)

# events

Gastrointestinal disorders

Dry mouth¹

# participants affected / at risk

1/7 (14.29%)

0/19 (0.00%)

0/20 (0.00%)

0/19 (0.00%)

# events

Gastrointestinal disorders

Nausea¹

# participants affected / at risk

0/7 (0.00%)

1/19 (5.26%)

1/20 (5.00%)

0/19 (0.00%)

# events

General disorders

Vessel puncture site bruise¹

# participants affected / at risk

0/7 (0.00%)

1/19 (5.26%)

0/20 (0.00%)

0/19 (0.00%)

# events

General disorders

Vessel puncture site swelling¹

# participants affected / at risk

0/7 (0.00%)

1/19 (5.26%)

0/20 (0.00%)

0/19 (0.00%)

# events

†	Events were collected by systematic assessment
1	Term from vocabulary, MedDRA version 24.1

Certain Agreements

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

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

The agreement is:

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

Limitations and Caveats

Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
No text entered.

Results Point of Contact

Name/Title:	Global Clinical Lead
Organization:	AstraZeneca Clinical Study Information Center
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