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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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.

Conditions
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Healthy Participants

Intervention / Treatment
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* Drug: AZD2389
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: Placebo-controlled
Masking: Single


Arms and Interventions

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

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Liver disease, Single ascending dose, Multiple ascending dose