A Study to Investigate Safety, Tolerability, and Pharmacokinetics of Oral AZD0233 Compared With Placebo in Healthy Adult Participants.

Dilated Cardiomyopathy Clinical Trial

Official title:

A Phase I, Randomized, Single Blinded, Placebo-controlled Study to Assess the Safety, Tolerability, and Pharmacokinetics of AZD0233 Following Single and Multiple Ascending Dose Administration in Healthy Male and Female Participants 18 to 50 Years of Age.

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT06381466
• Other study ID #: D7250C00001
• Status: Recruiting
• Phase: Phase 1
• Start date: April 1, 2024
• Est. completion date: March 6, 2025

Study information

• Verified date: June 2024
• Source: AstraZeneca
• Contact: AstraZeneca Clinical Study Information Center
• Phone: 1-877-240-9479
• Email: information.center[@]astrazeneca.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The purpose of this study is to assess the safety, tolerability, and pharmacokinetics of AZD0233 following single and multiple ascending dose (SAD and MAD) administration in healthy participants.

Description:

This is a Phase I, first time in human, single-blinded, randomized, placebo-controlled study in healthy adult male and female (of non-childbearing potential) participants performed at a single Clinical Unit.

The study will be carried out in 2 parts: Part A and Part B. Eight participants will participate in each cohort. Within each cohort, 6 participants will be randomized to receive AZD0233, and 2 participants will be randomized to receive placebo.

Part A of the study will be a sequential SAD design. Five dose levels of AZD0233 are planned to be investigated (dose 1 to dose 5), 3 (dose 3, dose 4 and dose 5) of which will also be assessed in participants of Japanese descent.

Part A of the study will comprise:

• A Screening Period of maximum 26 days (Day -28 to Day -2).

• An inpatient Period of up to 7 days (Day -1 to Day 6):

• Cohorts 1A, 2A, 3A (including a Japanese sub-Cohort), 4A (including a Japanese sub-Cohort), and 5A (including a Japanese sub-Cohort): participants will be resident at the Clinical Unit from Day -1 before study intervention administration until Day 4 (72 hours after administration of the study intervention).

• Cohort 3A [food effect (FE)]: Participants will be resident at the Clinical Unit from Day -1 before study intervention administration and will check-out on Day 6 (72 hours after administration of the study intervention). The impact of food intake on the PK of AZD0233 will be evaluated in the same participants in Cohort 3A after a 24-hour washout period on Day 2.

Note: Japanese sub-Cohort from Cohort 3A will not be part of the FE study.

• A Follow-up Period of 7 days after the administration of the study intervention which will consist of 1 Follow-up Visit on Day 8 for Cohorts 1A, 2A, 3A (Japanese sub-Cohort only), 4A, and 5A (including their Japanese sub-Cohorts) and 1 Follow-up Visit on Day 10 for Cohort 3A, for which participants will return to the Clinical Unit for follow-up assessments.

Part B will be a sequential MAD study. Participants will be naïve to AZD0233, i.e., will not have participated in Part A of this study. There will be 3 dose levels in 4 cohorts, including a sub-cohort of participants of Japanese descent at the highest dose.

Part B will consist of:

• A Screening Period of maximum 26 days (Day -28 to Day -2).

• An Inpatient Period of 14 days (Day -1 to Day 13): Participants will be resident at the Clinical Unit from Day -1 before study intervention administration until Day 13 (>48 hours after administration of the last dose of study intervention in case of QD (once daily) dosing and >36 hours after the last dose for BID (twice a day) in case of dosing).

• A Follow-up Period of 7 days after the administration of the last dose of study intervention which will consist of 1 Follow-up Visit on Day 17.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 96
• Est. completion date: March 6, 2025
• Est. primary completion date: March 6, 2025
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years to 50 Years

Eligibility

Inclusion Criteria:

• Healthy male and/or female participants with suitable veins for cannulation or repeated venipuncture.

• All females must have a negative pregnancy test at the Screening Visit and on admission to the Clinical Unit.

• Females of non-childbearing potential must be confirmed at the Screening Visit by fulfilling one of the following criteria:

1. Postmenopausal defined as amenorrhea for at least 12 months following cessation of all exogenous hormonal treatments and follicle-stimulating hormone (FSH) levels in the postmenopausal range.

2. Documentation of irreversible surgical sterilization by hysterectomy, bilateral oophorectomy, or bilateral salpingectomy but not tubal ligation.

• Sexually active fertile male participants with partners of childbearing potential must adhere to the specified contraception methods from the time of first administration of study intervention until 3 months after the study Follow-up Visit.

• Have a body mass index between 18 and 30 kg/m² inclusive and weigh at least 50 kg.

Note: For Japanese sub-Cohort minimum weight of 45 kg is acceptable.

• For the healthy Japanese sub-Cohorts: healthy Japanese participants (e.g., natives of Japan or Japanese Americans) are 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.

Exclusion Criteria:

• History of any clinically important disease or disorder which may either put the participant at risk because of participation in the study or influence the results or the participant's ability to participate in the study.

• History or presence of gastrointestinal, hepatic, or renal disease or any other condition known to interfere with absorption, distribution, metabolism, or excretion of drugs.

• Any clinically important illness, medical/surgical procedure, or trauma within 4 weeks of the first administration of study intervention.

• Any clinically important abnormalities in clinical chemistry, hematology, urinalysis, laboratory values or vital signs at Screening and/or first admission to the Clinical Unit.

• Any clinically important abnormalities in rhythm, conduction or morphology of the resting electrocardiogram (ECG) and any clinically important abnormalities in the 12-lead ECG that may interfere with the interpretation of corrected QT (QTc) interval changes in heart rate.

• Current smokers or those who have smoked or used nicotine products (including e-cigarettes) within the previous 3 months prior to Screening.

• Known or suspected history of alcohol or drug abuse or excessive intake of alcohol.

• Positive screen for drugs of abuse, or alcohol or cotinine at Screening or on each admission to the Clinical Unit.

• History of severe allergy/hypersensitivity or ongoing clinically important allergy/hypersensitivity, or history of hypersensitivity to drugs of a similar class to AZD0233.

• Use of drugs with enzyme [Cytochrome P450 3A (CYP3A)]/ transporter [breast cancer resistance protein (BCRP) and organic anion transporting polypeptide 1B (OATP1B)] inducing/ inhibiting properties such as St John's Wort within 3 weeks prior to the first administration of study intervention.

• Use of any prescribed or nonprescribed medication including antacids, analgesics (other than paracetamol/acetaminophen), herbal remedies, mega dose vitamins (intake of 20 to 600 times the recommended daily dose) and minerals during the 2 weeks prior to the first administration of study intervention or longer if the medication has a long half-life. Hormone replacement therapy medications are allowed for female participants.

• Has received another new chemical entity (defined as a compound which has not been approved for marketing) within 30 days or 5 half-lives (whichever is longest) of the first administration of investigational medicinal product (IMP) in this study. The period of exclusion begins one month after the final dose.

• Participants who have previously received AZD0233.

• Active systemic bacterial, viral, or fungal infection within 14 days prior to dosing or presence of fever (confirmed tympanic body temperature > 37.6 °C) within 14 days prior to dosing on Day 1 depending on experienced symptoms.

• Clinically significant serious active and chronic infections within 60 days prior to randomization.

• Known history of primary immunodeficiency (congenital or acquired) or an underlying condition that predisposes to infection.

• Concomitant immunosuppressive and/or steroid treatment.

• Any positive result on Screening for serum hepatitis B surface antigen (HBsAg), hepatitis B core antibody (anti-HBc), hepatitis C antibody, human immunodeficiency virus (HIV).

• Clinical signs and symptoms consistent with COVID-19.

• Participants who are vegans or have medical dietary restrictions.

• Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the Clinical Unit).

• Judgment by the investigator that the participant should not participate in the study if they have any ongoing or recent (ie, during the Screening period) minor medical complaints that may interfere with the interpretation of study data or are considered unlikely to comply with study procedures, restrictions, and requirements.

• Participants who cannot communicate reliably with the investigator.

• Vulnerable participants, e.g., kept in detention, protected adults under guardianship, trusteeship, or committed to an institution by governmental or juridical order.

Related Conditions & MeSH terms

• Cardiomyopathies
• Cardiomyopathy, Dilated
• Dilated Cardiomyopathy

Intervention

Drug:
• AZD0233
Randomized participants will receive AZD0233 orally as a single ascending dose (dose 1, dose 2, dose 3, dose 4 or dose 5) or multiple ascending dose (dose 6, dose 7 or dose 8)
• AZD0233 Placebo
Randomized participants will receive matching placebo orally as a SAD or MAD.

Locations

Country	Name	City	State
United States	Research Site	Glendale	California

Sponsors (2)

Lead Sponsor	Collaborator
AstraZeneca	Parexel

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of participants with adverse events (AEs) and serious adverse events (SAEs)	To assess the safety and tolerability of AZD0233 following oral administration of single ascending doses (Part A) and multiple ascending doses (Part B) and to estimate the maximum tolerated dose (if within pre-defined exposure limits).	From screening (Day -28) to follow-up visit (Day 17)
Secondary	Maximum observed plasma (peak) drug concentration (Cmax) of AZD0233	To characterize the single-dose and steady state pharmacokinetics (PK) of AZD0233 following oral administration of AZD0233 and to assess the impact of food on the single-dose PK of AZD0233 (Dose 3 FE extended cohort in Cohort 3A of Part A).	Day 1 (Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16 hours), Day 2 (24 hours and 36 hours post-dose) and Day 3 (48 hours post-dose)
Secondary	Area under the plasma concentration-curve from zero to the last quantifiable concentration (AUClast) of AZD0233	To characterize the single-dose and steady state PK of AZD0233 following oral administration of AZD0233 and to assess the impact of food on the single-dose PK of AZD0233 (Dose 3 FE extended cohort in Cohort 3A of Part A).	Day 1 (Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16 hours), Day 2 (24 hours and 36 hours post-dose) and Day 3 (48 hours post-dose)
Secondary	Area under the concentration-time curve in the dose interval (AUCtau) of AZD0233	To characterize the single-dose and steady state PK of AZD0233 following oral administration of AZD0233 and to assess the impact of food on the single-dose PK of AZD0233 (Dose 3 FE extended cohort in Cohort 3A of Part A).	Day 1 (Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16 hours), Day 2 (24 hours and 36 hours post-dose) and Day 3 (48 hours post-dose)
Secondary	Area under plasma concentration time-curve from zero to infinity (AUCinf) of AZD0233	To characterize the single-dose and steady state PK of AZD0233 following oral administration of AZD0233 and to assess the impact of food on the single-dose PK of AZD0233 (Dose 3 FE extended cohort in Cohort 3A of Part A).	Day 1 (Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16 hours), Day 2 (24 hours and 36 hours post-dose) and Day 3 (48 hours post-dose)
Secondary	Time to reach peak or maximum observed concentration or response following drug administration (tmax) of AZD0233	To characterize the single-dose and steady state PK of AZD0233 following oral administration of AZD0233 and to assess the impact of food on the single-dose PK of AZD0233 (Dose 3 FE extended cohort in Cohort 3A of Part A).	Day 1 (Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16 hours), Day 2 (24 hours and 36 hours post-dose) and Day 3 (48 hours post-dose)
Secondary	Terminal elimination half-life (t1/2) of AZD0233	To characterize the single-dose and steady state PK of AZD0233 following oral administration of AZD0233 and to assess the impact of food on the single-dose PK of AZD0233 (Dose 3 FE extended cohort in Cohort 3A of Part A).	Day 1 (Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16 hours), Day 2 (24 hours and 36 hours post-dose) and Day 3 (48 hours post-dose)
Secondary	Apparent total body clearance of drug from plasma after extravascular administration (CL/F) of AZD0233	To characterize the single-dose and steady state PK of AZD0233 following oral administration of AZD0233 and to assess the impact of food on the single-dose PK of AZD0233 (Dose 3 FE extended cohort in Cohort 3A of Part A).	Day 1 (Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16 hours), Day 2 (24 hours and 36 hours post-dose) and Day 3 (48 hours post-dose)
Secondary	Apparent volume of distribution at steady state following extravascular administration (Vz/F) of AZD0233	To characterize the single-dose and steady state PK of AZD0233 following oral administration of AZD0233 and to assess the impact of food on the single-dose PK of AZD0233 (Dose 3 FE extended cohort in Cohort 3A of Part A).	Day 1 (Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16 hours), Day 2 (24 hours and 36 hours post-dose) and Day 3 (48 hours post-dose)
Secondary	Terminal rate constant (?z) of AZD0233	To characterize the single-dose and steady state PK of AZD0233 following oral administration of AZD0233 and to assess the impact of food on the single-dose PK of AZD0233 (Dose 3 FE extended cohort in Cohort 3A of Part A).	Day 1 (Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16 hours), Day 2 (24 hours and 36 hours post-dose) and Day 3 (48 hours post-dose)
Secondary	Accumulation ratio for Cmax (Rac Cmax) of AZD0233	To characterize the single-dose and steady state PK of AZD0233 following oral administration of AZD0233 and to assess the impact of food on the single-dose PK of AZD0233 (Dose 3 FE extended cohort in Cohort 3A of Part A).	Day 1 (Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16 hours), Day 2 (24 hours and 36 hours post-dose) and Day 3 (48 hours post-dose)
Secondary	Accumulation ratio for AUC (Rac AUC) of AZD0233	To characterize the single-dose and steady state PK of AZD0233 following oral administration of AZD0233 and to assess the impact of food on the single-dose PK of AZD0233 (Dose 3 FE extended cohort in Cohort 3A of Part A).	Day 1 (Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16 hours), Day 2 (24 hours and 36 hours post-dose) and Day 3 (48 hours post-dose)
Secondary	Renal clearance (CLR) of AZD0233	To characterize the single-dose and steady state PK of AZD0233 following oral administration of AZD0233 and to assess the impact of food on the single-dose PK of AZD0233 (Dose 3 FE extended cohort in Cohort 3A of Part A).	Spot sample at pre-dose and pooled urine at Day 1 (0-3, 3-6, 6-9, 9-12, 12-24 hours post-dose), Day 2 (24-36 hours post dose) and Day 3 (36-48 hours post-dose).
Secondary	Cumulative amount of unchanged drug excreted into urine from time t1 to time t2 [Ae(t1-t2)] of AZD0233	To characterize the single-dose and steady state PK of AZD0233 following oral administration of AZD0233 and to assess the impact of food on the single-dose PK of AZD0233 (Dose 3 FE extended cohort in Cohort 3A of Part A).	Spot sample at pre-dose and pooled urine at Day 1 (0-3, 3-6, 6-9, 9-12, 12-24 hours post-dose), Day 2 (24-36 hours post dose) and Day 3 (36-48 hours post-dose).
Secondary	Cumulative amount of unchanged drug excreted into urine (Aeinf) of AZD0233	To characterize the single-dose and steady state PK of AZD0233 following oral administration of AZD0233 and to assess the impact of food on the single-dose PK of AZD0233 (Dose 3 FE extended cohort in Cohort 3A of Part A).	Spot sample at pre-dose and pooled urine at Day 1 (0-3, 3-6, 6-9, 9-12, 12-24 hours post-dose), Day 2 (24-36 hours post dose) and Day 3 (36-48 hours post-dose).
Secondary	Percentage of dose excreted unchanged in urine from time t1 to t2 [Fe(t1-t2)] of AZD0233	To characterize the single-dose and steady state PK of AZD0233 following oral administration of AZD0233 and to assess the impact of food on the single-dose PK of AZD0233 (Dose 3 FE extended cohort in Cohort 3A of Part A).	Spot sample at pre-dose and pooled urine at Day 1 (0-3, 3-6, 6-9, 9-12, 12-24 hours post-dose), Day 2 (24-36 hours post dose) and Day 3 (36-48 hours post-dose).