Study to Collect Samples for MIST Analysis of Zibotentan and Bioavailability of Zibotentan and Dapagliflozin in Heatlhy Participants

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

The study will have 2 independent parts:

Part 1 of the study is intended to collect samples for Metabolites in Safety Testing (MIST) analysis after administration of multiple doses of zibotentan.

Part 2 of the study is designed to evaluate the 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.

Study Overview

• Status: Completed
• Conditions: Chronic Kidney Disease
• Intervention / Treatment: Drug: Zibotentan (Treatment A); Drug: Dapagliflozin (Treatment A); Drug: Zibotentan/Dapagliflozin - Formulation 1 (Treatment B); Drug: Zibotentan/Dapagliflozin - Formulation 2 (Treatment C)

Detailed Description

Part 1 will be an open-label, non-randomised, single treatment period. A single treatment period during which participants will be resident at the study centre from 2 days before dosing (Day -2) until the morning of Day 6.

Part 2 will be an open-label, randomised, 3-period, 3-treatment, cross-over single dose study. Participants will be randomised to one of 3 treatment sequences and will receive 3 single-dose study interventions. Participants will be resident at the study centre from 2 days before dosing (Day -2) until Day 3 of the last treatment sequence.

Participants who were enrolled in Part 1 may not be enrolled in Part 2.

• Study Type: Interventional
• Enrollment (Actual): 27
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Maryland
    • Brooklyn, Maryland, United States, 21225
      • Research Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 50 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

For inclusion in the study participants should fulfil the following criteria:

1. Participants with suitable veins for cannulation or repeated venipuncture.
2. Females must have a negative pregnancy test at the Screening Visit and within 24 hours prior to dosing, must not be lactating and must be of non- childbearing potential
3. Male participant must adhere to the contraception methods.
4. Have a BMI between 18 and 29.9 kg/m^2 inclusive and weigh at least 50 kg and no more than 100 kg inclusive.
5. Provision of signed and dated, written informed consent prior to any study specific procedures.

Exclusion Criteria:

Participants will not enter the study if any of the following exclusion criteria are fulfilled:

1. History or presence of gastrointestinal, hepatic or renal disease or any important disease or disorder.
2. Any clinically important illness, medical/surgical procedure or trauma within 4 weeks of the first administration of study intervention.
3. Any clinically significant abnormalities in clinical chemistry, haematology, or urinalysis.
4. Any positive result on screening for serum hepatitis B surface antigen, hepatitis C antibody, and Human immunodeficiency virus antibody.
5. Abnormal vital signs. 6 History of drug abuse or alcohol abuse.

7. History of severe allergy/hypersensitivity or ongoing clinically important allergy/hypersensitivity.

8. Participants who are vegans or have medical dietary restrictions. 9. Participants tested positive for COVID-19 at the time of randomisation or have been previously hospitalised with COVID-19 infection.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Part 1: Metabolites in Safety Testing sampling	Plasma sample will be collected to understand the PK profiling of zibotentan metabolites and to meet the regulatory requirements.	Day 1 through Day 6 (pre-dose, 30 min; 1, 2, 4, 6, 8, 12 and 24 hours post dose)
Part 2: Area under plasma concentration time curve from zero to infinity (AUCinf)	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.	Day 1 through Day 3 of each treatment period
Part 2: Area under the plasma concentration curve from zero to the last quantifiable concentration (AUClast)	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.	Day 1 through Day 3 of each treatment period
Part 2: Maximum observed plasma drug concentration (Cmax)	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.	Day 1 through Day 3 of each treatment period
Part 2: Observed concentration at 24 hours post-dose (C24)	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.	Day 1 through Day 3 of each treatment period

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Part 2: Time to reach peak or maximum observed concentration (tmax)	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.	Day 1 through Day 3 of each treatment period
Part 2: Terminal rate constant (λz)	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.	Day 1 through Day 3 of each treatment period
Part 2: Half life associated with λz (t½λz)	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.	Day 1 through Day 3 of each treatment period
Part 2: Apparent total body clearance of drug from plasma after extravascular administration (CL/F)	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.	Day 1 through Day 3 of each treatment period
Part 2: Volume of distribution at steady state following extravascular administration (Vz/F)	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.	Day 1 through Day 3 of each treatment period
Part 1 and Part 2: Number of adverse events and serious adverse events	Safety and tolerability of zibotentan and dapagliflozin will be studied.	From Sceerning to Follow-up Visit approximately 40 days for Part 1 and 49 days for Part 2

Collaborators and Investigators

• Sponsor: AstraZeneca

Study record dates

Study Major Dates

• Study Start (Actual): July 29, 2021
• Primary Completion (Actual): October 22, 2021
• Study Completion (Actual): October 22, 2021

Study Registration Dates

• First Submitted: July 28, 2021
• First Submitted That Met QC Criteria: July 28, 2021
• First Posted (Actual): August 5, 2021

Study Record Updates

• Last Update Posted (Actual): November 23, 2021
• Last Update Submitted That Met QC Criteria: November 22, 2021
• Last Verified: November 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Urologic Diseases; Renal Insufficiency; Kidney Diseases; Renal Insufficiency, Chronic; Hypoglycemic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Sodium-Glucose Transporter 2 Inhibitors; Dapagliflozin
• Other Study ID Numbers: D4325C00003

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes

IPD Plan Description

Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal.

All request will be evaluated as per the AZ disclosure commitment: https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.

Yes, indicates that AZ are accepting requests for IPD, but this does not mean all requests will be shared.

• IPD Sharing Time Frame: AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA Pharma Data Sharing Principles. For details of our timelines, please rerefer to our disclosure commitment at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
• IPD Sharing Access Criteria: When a request has been approved AstraZeneca will provide access to the deidentified individual patient-level data in an approved sponsored tool . Signed Data Sharing Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information. Additionally, all users will need to accept the terms and conditions of the SAS MSE to gain access. For additional details, please review the Disclosure Statements at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No