A Single and Multiple Ascending Dose Study to Investigate Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of AZD2389 in Healthy Participants

A Phase I, Randomized, Single-blind, Placebo-controlled Study to Assess the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of AZD2389 After Single and Multiple Ascending Doses to Healthy Participants.

This study will assess the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of AZD2389 following single and multiple dose administration (SAD/MAD) to healthy participants.

Study Overview

• Status: Recruiting
• Conditions: Healthy Participants
• Intervention / Treatment: Drug: AZD2389; Drug: Placebo

Detailed Description

This is a Phase I, First In Human (FIH), randomized, single-blind, placebo-controlled, single and multiple ascending dose study in healthy male and/or female participants of non-childbearing potential including healthy participants of Chinese and Japanese ethnicity performed at a single center.

The study consists of 2 parts: Part A and Part B. 72 participants have been planned for Part A and 32 participants for Part B.

Each participant in Part A will be involved in the study for up to 6 weeks, and each participant in Part B will be involved in the study for up to 8 weeks.

• Study Type: Interventional
• Enrollment (Estimated): 104
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: AstraZeneca Clinical Study Information Center; Phone Number: 1-877-240-9479; Email: information.center@astrazeneca.com

Study Locations

• United States
  • California
    • Glendale, California, United States, 91206
      • Recruiting
      • Research Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• Healthy male and female (of non-childbearing potential) participants with suitable veins for cannulation or repeated venipuncture.
• Females must have a negative pregnancy test must not be lactating and must be non-childbearing potential, confirmed by post-menopausal defined as amenorrhea for at least 12 months; documentation of irreversible surgical sterilization.
• Sexually active fertile male participants and their female partners of childbearing potential must be willing to use highly effective contraception from the first day of dosing until 3 months after the last dose of IMP.
• Have a BMI between 18 and 32 kg/m2 inclusive and weigh at least 50 kg, at the Screening Visit.
• For the healthy Japanese cohorts (Parts A2 and B2): healthy participants are to beJapanese (eg, natives of Japan or Japanese Americans), defined as having both parents and 4 grandparents who are Japanese. This includes healthy second and third generation participants of Japanese descent whose parents or grandparents are living in a country other than Japan.
• For the healthy Chinese cohort (Part A3): healthy participants are to be Chinese defined as having both parents and 4 grandparents who are ethnically Chinese. This includes second and third generation Chinese whose parents or grandparents are living in a country other than China.

Exclusion Criteria:

• History or presence of gastrointestinal, hepatic, or renal disease or any other condition known to interfere with absorption, distribution, metabolism, or excretion of drugs.
• History of chronic haematologic disease.
• Any clinically important illness, medical/surgical procedure or trauma within 4 weeks of the first administration of IMP.
• Any clinically important abnormalities in clinical chemistry, haematology or urinalysis results
• Any positive result on Screening for serum Hepatitis B surface antigen (HBsAg), hepatitis C antibody and Human immunodeficiency virus (HIV).
• Any clinically important abnormalities in rhythm, conduction or morphology of the resting Electrocardiogram (ECG) and any clinically important abnormalities in the 12 lead ECG.
• Known or suspected history of alcohol or drug abuse or excessive intake of alcohol as judged by the investigator or any participant (male or female) who consumes more than one standard alcoholic drink per day on a regular basis in the 6 months prior to screening and as judged by the investigator (a standard drink is defined as 12 fl oz of beer, 5 fl oz of wine or 1.5 fl oz of distilled spirits), ), and/or a positive screen for alcohol at Screening or on each admission to the Clinical Unit.
• Current smokers or those who have smoked or used nicotine products (including e cigarettes) within the previous 3 months.
• History of severe allergy/hypersensitivity or ongoing clinically important allergy/hypersensitivity, or history of hypersensitivity to drugs with a similar chemical structure or class to AZD2389.
• Excessive intake of caffeine containing drinks or food
• Use of drugs with enzyme inducing properties such as St John's Wort within 3 weeks prior to the first administration of IMP.
• Use of any prescribed or nonprescribed medication including antacids, analgesics (other than paracetamol/acetaminophen [up to 2 g/day]), herbal remedies, mega dose vitamins (intake of > 20 times the recommended daily dose) and minerals during the 2 weeks prior to the first administration of IMP or longer if the medication has a long half life.
• Plasma donation within one month of the Screening Visit or any blood donation/blood loss > 500 mL during the 3 months prior to the Screening Visit.
• History of coagulation or bleeding disorders or use of anti-platelets/anti-coagulants during the 3 months prior to the Screening Visit, as judged by the investigator.
• History of hypersensitivity as judged by the investigator, to drugs with a similar chemical structure or class.
• History of severe dermatological disorders, eg, bullous pemphigoid or Stevens-Johnson syndrome, or clinically significant new or healing wounds in areas of the body not always covered by clothing such as face, forearm, and lower leg, as judged by the investigator.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Sequential Assignment
• Masking: Single

Number of Arms

13

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Cohort 1: Part A1 - AZD2389 dose 1/placebo oral administration; A total of 6 study participants will receive a single dose of AZD2389 and 2 will receive placebo.	Drug: AZD2389; Participants will receive AZD2389 orally as a single ascending dose or multiple ascending dose.; Drug: Placebo; Participants will receive placebo matching the AZD2389 dose orally as a single ascending dose or multiple ascending dose.
Experimental: Cohort 2: Part A1 - AZD2389 dose 2/placebo oral administration; A total of 6 study participants will receive a single dose of AZD2389 and 2 will receive placebo.	Drug: AZD2389; Participants will receive AZD2389 orally as a single ascending dose or multiple ascending dose.; Drug: Placebo; Participants will receive placebo matching the AZD2389 dose orally as a single ascending dose or multiple ascending dose.
Experimental: Cohort 3: Part A1 - AZD2389 dose 3 /placebo oral administration; A total of 6 study participants will receive a single dose of AZD2389 and 2 will receive placebo.	Drug: AZD2389; Participants will receive AZD2389 orally as a single ascending dose or multiple ascending dose.; Drug: Placebo; Participants will receive placebo matching the AZD2389 dose orally as a single ascending dose or multiple ascending dose.
Experimental: Cohort 4: Part A1 - AZD2389 dose 4 /placebo oral administration; A total of 6 study participants will receive a single dose of AZD2389 and 2 will receive placebo.	Drug: AZD2389; Participants will receive AZD2389 orally as a single ascending dose or multiple ascending dose.; Drug: Placebo; Participants will receive placebo matching the AZD2389 dose orally as a single ascending dose or multiple ascending dose.
Experimental: Cohort 5: Part A1 - AZD2389 dose 5 /placebo oral administration; A total of 6 study participants will receive a single dose of AZD2389 and 2 will receive placebo.	Drug: AZD2389; Participants will receive AZD2389 orally as a single ascending dose or multiple ascending dose.; Drug: Placebo; Participants will receive placebo matching the AZD2389 dose orally as a single ascending dose or multiple ascending dose.
Experimental: Cohort 6: Part A2 - AZD2389 dose 6 /placebo oral administration; A total of 6 study participants will receive a single dose of AZD2389 and 2 will receive placebo.	Drug: AZD2389; Participants will receive AZD2389 orally as a single ascending dose or multiple ascending dose.; Drug: Placebo; Participants will receive placebo matching the AZD2389 dose orally as a single ascending dose or multiple ascending dose.
Experimental: Cohort 7: Part A2 - AZD2389 dose 7 /placebo oral administration; A total of 6 study participants will receive a single dose of AZD2389 and 2 will receive placebo.	Drug: AZD2389; Participants will receive AZD2389 orally as a single ascending dose or multiple ascending dose.; Drug: Placebo; Participants will receive placebo matching the AZD2389 dose orally as a single ascending dose or multiple ascending dose.
Experimental: Cohort 8: Part A2 - AZD2389 dose 8 /placebo oral administration; A total of 6 study participants will receive a single dose of AZD2389 and 2 will receive placebo.	Drug: AZD2389; Participants will receive AZD2389 orally as a single ascending dose or multiple ascending dose.; Drug: Placebo; Participants will receive placebo matching the AZD2389 dose orally as a single ascending dose or multiple ascending dose.
Experimental: Cohort 9: Part A3 - AZD2389 dose 9 /placebo oral administration; A total of 6 study participants will receive a single dose of AZD2389 and 2 will receive placebo.	Drug: AZD2389; Participants will receive AZD2389 orally as a single ascending dose or multiple ascending dose.; Drug: Placebo; Participants will receive placebo matching the AZD2389 dose orally as a single ascending dose or multiple ascending dose.
Experimental: Cohort 10: Part B1 - AZD2389 dose 10 /placebo oral administration; A total of 6 study participants will receive multiple doses of AZD2389 and 2 will receive placebo.	Drug: AZD2389; Participants will receive AZD2389 orally as a single ascending dose or multiple ascending dose.; Drug: Placebo; Participants will receive placebo matching the AZD2389 dose orally as a single ascending dose or multiple ascending dose.
Experimental: Cohort 11: Part B1 - AZD2389 dose 11 /placebo oral administration; A total of 6 study participants will receive multiple doses of AZD2389 and 2 will receive placebo.	Drug: AZD2389; Participants will receive AZD2389 orally as a single ascending dose or multiple ascending dose.; Drug: Placebo; Participants will receive placebo matching the AZD2389 dose orally as a single ascending dose or multiple ascending dose.
Experimental: Cohort 12: Part B1 - AZD2389 dose 12 /placebo oral administration; A total of 6 study participants will receive multiple doses of AZD2389 and 2 will receive placebo.	Drug: AZD2389; Participants will receive AZD2389 orally as a single ascending dose or multiple ascending dose.; Drug: Placebo; Participants will receive placebo matching the AZD2389 dose orally as a single ascending dose or multiple ascending dose.
Experimental: Cohort 13: Part B2 - AZD2389 dose 13 /placebo oral administration; A total of 6 study participants will receive multiple doses of AZD2389 and 2 will receive placebo.	Drug: AZD2389; Participants will receive AZD2389 orally as a single ascending dose or multiple ascending dose.; Drug: Placebo; Participants will receive placebo matching the AZD2389 dose orally as a single ascending dose or multiple ascending dose.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Part A (SAD): Number of participants with adverse events (AE) and serious adverse events (SAE)	To assess the safety and tolerability of AZD2389 following oral administration of single ascending doses in healthy participants, including Japanese and Chinese participants.	Day ≤ -28 (Only SAE), Day -1 (Only SAE), Days 1 and 2, Day 8 Post-dose (± 1 day)
Part B (MAD): Number of participants with AE and SAE	To assess the safety and tolerability of AZD2389 following oral administration of multiple ascending doses in healthy participants, including Japanese participants.	Day ≤ -28 (Only SAE), Day -1 (Only SAE), Days 1 to 12, Day 17 (± 1 day)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Part A (SAD): Plasma concentrations of AZD2389	To characterize the plasma concentration of AZD2389 after single oral dosing in healthy participants, including Japanese and Chinese participants.	Day 1 and Day 2
Part A (SAD): Urine concentrations of AZD2389	To characterize the urine concentration of AZD2389 after single oral dosing in healthy participants, including Japanese and Chinese participants.	Day 1 and Day 2
Part A (SAD): Terminal rate constant (λz)	To characterize the λz of AZD2389 after single oral dosing in healthy participants, including Japanese and Chinese participants.	Day 1 and Day 2
Part A (SAD): Cumulative amount of unchanged drug excreted into urine from time t1 to time t2 [Ae(t1-t2)]	To characterize the Ae(t1-t2) of AZD2389 after single oral dosing in healthy participants, including Japanese and Chinese participants.	Day 1 and Day 2
Part A (SAD): Area under plasma concentration time curve from zero to infinity (AUCinf)	To characterize the AUCinf of AZD2389 after single oral dosing in healthy participants, including Japanese and Chinese participants.	Day 1 and Day 2
Part A (SAD): Dose normalized AUCinf (AUCinf/D)	To characterize the AUCinf/D of AZD2389 after single oral dosing in healthy participants, including Japanese and Chinese participants.	Day 1 and Day 2
Part A (SAD): Area under concentration curve from time 0 to the last quantifiable concentration (AUClast)	To characterize the AUClast of AZD2389 after single oral dosing in healthy participants, including Japanese and Chinese participants.	Day 1 and Day 2
Part A (SAD): Dose normalized AUClast (AUClast/D)	To characterize the AUClast/D of AZD2389 after single oral dosing in healthy participants, including Japanese and Chinese participants.	Day 1 and Day 2
Part A (SAD): Apparent total body clearance of drug (CL/F)	To characterize the CL/F of AZD2389 after single oral dosing in healthy participants, including Japanese and Chinese participants.	Day 1 and Day 2
Part A (SAD): Maximum observed plasma (peak) drug concentration (Cmax)	To characterize the Cmax of AZD2389 after single oral dosing in healthy participants, including Japanese and Chinese participants.	Day 1 and Day 2
Part A (SAD): Dose normalized Cmax (Cmax/D)	To characterize the Cmax/D of AZD2389 after single oral dosing in healthy participants, including Japanese and Chinese participants.	Day 1 and Day 2
Part A (SAD): Renal clearance (CLR)	To characterize the CLR of AZD2389 after single oral dosing in healthy participants, including Japanese and Chinese participants.	Day 1 and Day 2
Part A (SAD): Individual and cumulative percentage of dose excreted unchanged in urine from time t1 to time t2 [fe(t1-t2)]	To characterize the fe(t1-t2) of AZD2389 after single oral dosing in healthy participants, including Japanese and Chinese participants.	Day 1 and Day 2
Part A (SAD): Mean residence time (MRTinf)	To characterize the MRTinf of AZD2389 after single oral dosing in healthy participants, including Japanese and Chinese participants.	Day 1 and Day 2
Part A (SAD): Apparent terminal elimination half-life (t½λz)	To characterize the t½λz of AZD2389 after single oral dosing in healthy participants, including Japanese and Chinese participants.	Day 1 and Day 2
Part A (SAD): Time of last quantifiable concentration (tlast)	To characterize the tlast of AZD2389 after single oral dosing in healthy participants, including Japanese and Chinese participants.	Day 1 and Day 2
Part A (SAD): Time to reach peak or maximum observed concentration (tmax)	To characterize the tmax of AZD2389 after single oral dosing in healthy participants, including Japanese and Chinese participants.	Day 1 and Day 2
Part A (SAD): Apparent volume of distribution based on the terminal phase (Vz/F)	To characterize the Vz/F of AZD2389 after single oral dosing in healthy participants, including Japanese and Chinese participants.	Day 1 and Day 2
Part A (SAD): Change in PD biomarkers over time	To characterize the percentage change in PD biomarkers over time compared to baseline of AZD2389 after single oral dosing in healthy participants, including Japanese and Chinese participants.	Day 1 and Day 2
Part B (MAD): Plasma concentrations of AZD2389	To characterize the plasma concentration of AZD2389 following oral administration of multiple ascending doses in healthy participants, including Japanese participants.	Day 1 to Day 12
Part B (MAD): Urine concentrations of AZD2389	To characterize the urine concentration of AZD2389 following oral administration of multiple ascending doses in healthy participants, including Japanese participants.	Day 1 and Days 10 to 12
Part B (MAD): Terminal rate constant (λz)	To characterize the λz of AZD2389 following oral administration of multiple ascending doses in healthy participants, including Japanese participants.	Day 1 to Day 12
Part B (MAD): Cumulative amount of unchanged drug excreted into urine from time t1 to time t2 [Ae(t1-t2)]	To characterize the Ae(t1-t2) of AZD2389 following oral administration of multiple ascending doses in healthy participants, including Japanese participants.	Day 1 and Days 10 to 12
Part B (MAD): Area under concentration curve from time 0 to the last quantifiable concentration (AUClast)	To characterize the AUClast of AZD2389 following oral administration of multiple ascending doses in healthy participants, including Japanese participants.	Day 1 to Day 12
Part B (MAD): Area under the concentration-time curve in the dose interval (AUCtau)	To characterize the AUCtau of AZD2389 following oral administration of multiple ascending doses in healthy participants, including Japanese participants.	Day 1 to Day 12
Part B (MAD): Dose normalized AUCtau (AUCtau/D)	To characterize the AUCtau/D of AZD2389 following oral administration of multiple ascending doses in healthy participants, including Japanese participants.	Day 1 to Day 12
Part B (MAD): Dose normalized AUClast (AUClast/D)	To characterize the AUClast/D of AZD2389 following oral administration of multiple ascending doses in healthy participants, including Japanese participants.	Day 1 to Day 12
Part B (MAD): Apparent total body clearance of drug (CL/F)	To characterize the CL/F of AZD2389 following oral administration of multiple ascending doses in healthy participants, including Japanese participants.	Day 1 and Days 10 to 12
Part B (MAD): Renal clearance (CLR)	To characterize the CLR of AZD2389 following oral administration of multiple ascending doses in healthy participants, including Japanese participants.	Day 1 and Days 10 to 12
Part B (MAD): Maximum observed plasma (peak) drug concentration (Cmax)	To characterize the Cmax of AZD2389 following oral administration of multiple ascending doses in healthy participants, including Japanese participants.	Day 1 to Day 12
Part B (MAD): Dose normalized Cmax (Cmax/D)	To characterize the Cmax/D of AZD2389 following oral administration of multiple ascending doses in healthy participants, including Japanese participants.	Day 1 to Day 12
Part B (MAD): Observed lowest concentration before the next dose is administered(Ctrough)	To characterize the Ctrough of AZD2389 following oral administration of multiple ascending doses in healthy participants, including Japanese participants.	Day 1 to Day 12
Part B (MAD): Individual and cumulative percentage of dose excreted unchanged in urine from time t1 to time t2 [fe(t1-t2)]	To characterize the fe(t1-t2) of AZD2389 following oral administration of multiple ascending doses in healthy participants, including Japanese participants.	Day 1 and Days 10 to 12
Part B (MAD): Accumulation ratio for AUC (Rac AUC)	To characterize the Rac AUC of AZD2389 following oral administration of multiple ascending doses in healthy participants, including Japanese participants.	Day 1 to Day 12
Part B (MAD): Accumulation ratio for Cmax (Rac Cmax)	To characterize the Rac Cmax of AZD2389 following oral administration of multiple ascending doses in healthy participants, including Japanese participants.	Day 1 to Day 12
Part B (MAD): Time to reach peak or maximum observed concentration (tmax)	To characterize the tmax of AZD2389 following oral administration of multiple ascending doses in healthy participants, including Japanese participants.	Day 1 to Day 12
Part B (MAD): Apparent terminal elimination half-life (t½λz)	To characterize the t½λz of AZD2389 following oral administration of multiple ascending doses in healthy participants, including Japanese participants.	Day 1 to Day 12
Part B (MAD): Apparent volume of distribution based on the terminal phase (Vz/F)	To characterize the Vz/F of AZD2389 following oral administration of multiple ascending doses in healthy participants, including Japanese participants.	Day 1 to Day 12
Part B (MAD): Change in PD biomarkers over time	To characterize the percentage change in PD biomarkers over time compared to baseline of AZD2389 following oral administration of multiple ascending doses in healthy participants, including Japanese participants.	Days 1, 2, 4, 8, and 10

Collaborators and Investigators

• Sponsor: AstraZeneca

Study record dates

Study Major Dates

• Study Start (Actual): November 20, 2023
• Primary Completion (Estimated): August 7, 2024
• Study Completion (Estimated): August 7, 2024

Study Registration Dates

• First Submitted: November 14, 2023
• First Submitted That Met QC Criteria: November 14, 2023
• First Posted (Actual): November 18, 2023

Study Record Updates

• Last Update Posted (Estimated): February 6, 2024
• Last Update Submitted That Met QC Criteria: February 5, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Keywords: Multiple ascending dose; Liver disease; Single ascending dose
• Other Study ID Numbers: D7930C00001

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 Vivli.org. All requests 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 approved.

• IPD Sharing Time Frame: AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA/PhRMA Data-Sharing Principles. For details of our timelines, please refer 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 anonymized individual patient-level data via secure research environment Vivli.org. A Signed Data Usage Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No