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.
概览
- 阶段
- 1 期
- 干预措施
- AZD0233
- 疾病 / 适应症
- Dilated Cardiomyopathy
- 发起方
- AstraZeneca
- 入组人数
- 84
- 试验地点
- 1
- 主要终点
- Number of participants with adverse events (AEs) and serious adverse events (SAEs)
- 状态
- 终止
- 最后更新
- 3个月前
概览
简要总结
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.
详细描述
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), 2 (dose 3 and dose 4) 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 (Japanese sub-Cohort only), 4A (including a Japanese sub-Cohort), and 5A: 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 (including a Japanese sub-Cohort), and 5A and one 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 2 Follow-up Visits on Day 15 and Day 17.
研究者
入排标准
入选标准
- •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:
- •Post-menopausal defined as amenorrhea for at least 12 months following cessation of all exogenous hormonal treatments and follicle-stimulating hormone (FSH) levels in the post-menopausal range.
- •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.
排除标准
- •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 AZD
- •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.
研究组 & 干预措施
Part A (SAD): Cohort 1A - AZD0233 (dose 1)
Healthy participants will receive AZD0233 (dose 1) orally as a single ascending dose.
干预措施: AZD0233
Part A (SAD): Cohort 2A - AZD0233 (dose 2)
Healthy participants will receive AZD0233 (dose 2) orally as a single ascending dose.
干预措施: AZD0233
Part A (SAD): Cohort 3A - AZD0233 (dose 3)
Healthy participants will receive AZD0233 (dose 3) orally as a single ascending dose.
干预措施: AZD0233
Part A (SAD): Cohort 4A - AZD0233 (dose 4)
Healthy participants will receive AZD0233 (dose 4) orally as a single ascending dose.
干预措施: AZD0233
Part A (SAD): Cohort 5A - AZD0233 (dose 5)
Healthy participants will receive AZD0233 (dose 5) orally as a single ascending dose.
干预措施: AZD0233
Part B (MAD): Cohort 1B - AZD0233 (dose 6)
Healthy participants will receive AZD0233 (dose 6) orally as a multiple ascending dose.
干预措施: AZD0233
Part B (MAD): Cohort 2B - AZD0233 (dose 7)
Healthy participants will receive AZD0233 (dose 7) orally as a multiple ascending dose.
干预措施: AZD0233
Part B (MAD): Cohort 3B - AZD0233 (dose 8)
Healthy participants will receive AZD0233 (dose 8) orally as a multiple ascending dose.
干预措施: AZD0233
Part A (SAD): Placebo cohort
Healthy participants will receive placebo orally as a single ascending dose.
干预措施: AZD0233 Placebo
Part B (MAD): Placebo cohort
Healthy participants will receive placebo orally as a multiple ascending dose.
干预措施: AZD0233 Placebo
Part A (SAD): Food Effect (FE) extended Cohort 3A
Healthy participants from Cohort 3A will participate in this extended cohort after a washout period of 24 hours.
干预措施: AZD0233
结局指标
主要结局
Number of participants with adverse events (AEs) and serious adverse events (SAEs)
时间窗: From screening (Day -28) to follow-up visit (Day 17)
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).
次要结局
- Maximum observed plasma (peak) drug concentration (Cmax) of AZD0233(Day 1 (Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 16 hours), Day 2 (24 hours and 36 hours post-dose) and Day 3 (48 hours post-dose))
- Area under the plasma concentration-curve from zero to the last quantifiable concentration (AUClast) of AZD0233(Day 1 (Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 16 hours), Day 2 (24 hours and 36 hours post-dose) and Day 3 (48 hours post-dose))
- Area under the concentration-time curve in the dose interval (AUCtau) of AZD0233(Day 1 (Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 16 hours), Day 2 (24 hours and 36 hours post-dose) and Day 3 (48 hours post-dose))
- Area under plasma concentration time-curve from zero to infinity (AUCinf) of AZD0233(Day 1 (Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 16 hours), Day 2 (24 hours and 36 hours post-dose) and Day 3 (48 hours post-dose))
- Time to reach peak or maximum observed concentration or response following drug administration (tmax) of AZD0233(Day 1 (Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 16 hours), Day 2 (24 hours and 36 hours post-dose) and Day 3 (48 hours post-dose))
- Terminal elimination half-life (t1/2) of AZD0233(Day 1 (Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 16 hours), Day 2 (24 hours and 36 hours post-dose) and Day 3 (48 hours post-dose))
- Apparent total body clearance of drug from plasma after extravascular administration (CL/F) of AZD0233(Day 1 (Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 16 hours), Day 2 (24 hours and 36 hours post-dose) and Day 3 (48 hours post-dose))
- Apparent volume of distribution at steady state following extravascular administration (Vz/F) of AZD0233(Day 1 (Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 16 hours), Day 2 (24 hours and 36 hours post-dose) and Day 3 (48 hours post-dose))
- Terminal rate constant (λz) of AZD0233(Day 1 (Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 16 hours), Day 2 (24 hours and 36 hours post-dose) and Day 3 (48 hours post-dose))
- Accumulation ratio for Cmax (Rac Cmax) of AZD0233(Day 1 (Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 16 hours), Day 2 (24 hours and 36 hours post-dose) and Day 3 (48 hours post-dose))
- Accumulation ratio for AUC (Rac AUC) of AZD0233(Day 1 (Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 16 hours), Day 2 (24 hours and 36 hours post-dose) and Day 3 (48 hours post-dose))
- Renal clearance (CLR) of AZD0233(Spot sample at pre-dose and pooled urine at Day 1 (0-3, 3-6, 6-9, 9-12, and 12-24 hours post-dose), Day 2 (24-36 hours post dose) and Day 3 (36-48 hours post-dose).)
- Cumulative amount of unchanged drug excreted into urine from time t1 to time t2 [Ae(t1-t2)] of AZD0233(Spot sample at pre-dose and pooled urine at Day 1 (0-3, 3-6, 6-9, 9-12, and 12-24 hours post-dose), Day 2 (24-36 hours post dose) and Day 3 (36-48 hours post-dose).)
- Percentage of dose excreted unchanged in urine from time t1 to t2 [Fe(t1-t2)] of AZD0233(Spot sample at pre-dose and pooled urine at Day 1 (0-3, 3-6, 6-9, 9-12, and 12-24 hours post-dose), Day 2 (24-36 hours post dose) and Day 3 (36-48 hours post-dose).)