A Phase I, Randomized, Open-label, 3 or 4-period, 7-treatment, Single-dose, Two Cohort, Crossover Study to Assess the Relative Bioavailability of Laroprovstat/Rosuvastatin Fixed Combination Drug Products to the Single Therapy Products in Healthy Adults
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 发起方
- AstraZeneca
- 入组人数
- 44
- 试验地点
- 2
- 主要终点
- Area under concentration time curve from time 0 to infinity (AUCinf)
研究概览
简要总结
The purpose of this study is to assess how well laroprovstat and rosuvastatin combined in a single tablet to be taken by mouth works compared with laroprovstat and rosuvastatin individual tablets taken by mouth (relative bioavailability) in healthy adults.
详细描述
This is a randomized, open-label, 3 or 4-period, single-dose, two-cohort, multi-center, crossover study. The study will comprise of a screening period (21 Days), 3 or 4 treatment periods (depending on cohort assignment) and washout period (14 Days, starting after dosing on Study Day 1 of a given treatment period). Each treatment period consists of dosing on Day 1; any subsequent treatment period will not start sooner than 14 days following dosing in the previous treatment period.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Crossover
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 55 Years（Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •Provision of signed and dated, written informed consent prior to any study-specific procedures.
- •Healthy male and female participants aged 18 to 55 years (inclusive) 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 childbearing potential must not be lactating and if heterosexually active must agree to use an approved method of highly effective contraception, in addition to a barrier method, to avoid pregnancy from the time of first administration of study intervention until 10 days after discharge from the study site.
- •Females of non-childbearing potential must be confirmed at the Screening Visit by checking if they are postmenopausal [amenorrhea for at least 12 months following cessation of all exogenous hormonal treatments and follicle stimulating hormone (FSH) levels in the postmenopausal range] or by documentation of irreversible surgical sterilization by hysterectomy, bilateral oophorectomy, or bilateral salpingectomy but not tubal ligation or tubal occlusion.
- •Have a body mass index between 18 and 30 kg/m2 inclusive and weigh at least 50 kg.
排除标准
- •History of any clinically important disease or disorder which, in the opinion of the investigator, 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 prior gastrointestinal surgery which may affect absorption, example (eg), gastric bypass or resection.
- •Any clinically important illness, medical/surgical procedure, or trauma within 4 weeks of the first administration of study intervention.
- •Asian origin.
- •Any laboratory values with the following deviations at the Screening Visit or on admission to the study site. Abnormal values may be repeated once at the discretion of the investigator:
- •ALT > upper limit of normal (ULN).
- •AST > ULN.
- •TBL > ULN.
- •Estimated glomerular filtration rate < 90 mL/min/1.73 m2 calculated using the Chronic Kidney Disease Epidemiology Collaboration equation.
- •Hemoglobin < lower limit normal (LLN).
- •Creatine kinase > 5 × ULN.
- •Inadequately treated hypothyroidism defined as TSH > 1.5 × ULN at screening or participants whose thyroid replacement therapy was initiated or modified within the last 3 months prior to screening.
- •Any clinically important abnormalities in clinical chemistry, hematology, or urinalysis results other than those listed above, at screening and/or admission to the study site, as judged by the investigator. Abnormal values may be repeated once at the discretion of the investigator.
- •Any positive result on screening for serum Hepatitis B surface antigen (HBsAg), Hepatitis B core antibody (HBcAb), Hepatitis C virus (HCV), or Human immunodeficiency virus (HIV).
- •Abnormal vital signs, after 10 minutes supine rest, at the Screening Visit and/or admission to the study site, defined as any of the following. Abnormal values may be repeated once (one triplicate measurement) at the discretion of the investigator:
- •Systolic Blood pressure (BP) < 90 mmHg or ≥ 140 mmHg.
- •Diastolic BP < 50 mmHg or ≥ 90 mmHg.
- •Pulse rate < 45 or > 90 beats per minute (bpm).
- •Any clinically significant abnormalities on 12-lead electrocardiogram (ECG) at screening and/or admission to the study site, as judged by the investigator. Abnormal values may be repeated once at the discretion of the investigator.
- •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 as judged by the investigator in the last one year.
- •Positive screen for drugs of abuse, alcohol, or cotinine at screening or on each admission to the study site.
- •History of severe allergy/hypersensitivity or ongoing clinically important allergy/hypersensitivity, as judged by the investigator or history of hypersensitivity to drugs with a similar chemical structure or class to laroprovastat or rosuvastatin.
- •Excessive intake of caffeine-containing drinks or food (eg, coffee, tea, chocolate) defined as the regular consumption of more than 500 mg of caffeine per day (eg, > 5 cups of coffee [one cup ~100 mg caffeine]; one cup of tea ~30 mg caffeine) or would likely be unable to refrain from the use of caffeine-containing beverages during confinement at the study site.
- •Use of drugs with enzyme inducing 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, intake of > 3 × daily recommended levels of vitamins and minerals during the 2 weeks prior to the first administration of study intervention or longer if the medication has a long half-life. Hormonal contraceptives (for females of childbearing potential) are allowed.
- •Treatment with any lipid lowering therapy or laroprovastat within the 3 months prior to the Screening Visit.
- •Treatment with drugs for reduction or inhibition of Proprotein convertase subtilisin/kexin type 9 (PCSK9) within the last 12 months prior to the Screening Visit (approved or investigational and apart from laroprovstat).
- •Current or previous administration of inclisiran.
- •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.
- •Has received any Investigational Medicinal Product (IMP-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 study intervention in this study.
- •Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site).
- •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 have medical dietary restrictions or are unable/unwilling to comply with the meals provided in the unit during the stay at the study site.
- •Participants who cannot communicate reliably with the investigator.
- •Vulnerable participants, eg, kept in detention, protected adults under guardianship, trusteeship, or committed to an institution by governmental or juridical order.
研究组 & 干预措施
Cohort 1 Treatment B
Participants will receive a single oral FCDP test formulation 2 of Dose X laroprovstat/Dose 1 rosuvastatin following an overnight fast.
干预措施: Laroprovstat Dose X/Rosuvastatin Dose 1 FCDP test formulation 2 (Drug)
Cohort 1 Treatment C
Participants will receive a single oral Dose X laroprovstat and a single oral Dose 1 rosuvastatin as Single Therapy Product (STP) reference formulations following an overnight fast.
干预措施: Laroprovstat Dose X STP (Drug)
Cohort 1 Treatment A
Participants will receive a single oral Fixed Combination Drug Product (FCDP) test formulation 1 of Dose X laroprovstat/Dose 1 rosuvastatin following an overnight fast.
干预措施: Laroprovstat Dose X/Rosuvastatin Dose 1 FCDP test formulation 1 (Drug)
Cohort 2 Treatment D
Participants will receive a single oral FCDP test formulation 1 of Dose X laroprovstat/Dose 2 rosuvastatin following an overnight fast.
干预措施: Laroprovstat Dose X/Rosuvastatin Dose 2 FCDP test formulation 1 (Drug)
Cohort 2 Treatment E
Participants will receive a single oral FCDP test formulation 2 of Dose X laroprovstat/Dose 2 rosuvastatin following an overnight fast.
干预措施: Laroprovstat Dose X/Rosuvastatin Dose 2 FCDP test formulation 2 (Drug)
Cohort 1 Treatment C
Participants will receive a single oral Dose X laroprovstat and a single oral Dose 1 rosuvastatin as Single Therapy Product (STP) reference formulations following an overnight fast.
干预措施: Rosuvastatin Dose 1 STP (Drug)
Cohort 2 Treatment F
Participants will receive a single oral Dose X laroprovstat and a single oral Dose 2 rosuvastatin as STP reference formulations following an overnight fast.
干预措施: Rosuvastatin Dose 2 STP (Drug)
Cohort 2 Treatment F
Participants will receive a single oral Dose X laroprovstat and a single oral Dose 2 rosuvastatin as STP reference formulations following an overnight fast.
干预措施: Laroprovstat Dose X STP (Drug)
Cohort 2 Treatment G
Participants will receive a single oral FCDP test formulation 1 of Dose X laroprovstat/Dose 2 rosuvastatin in a fed state.
干预措施: Laroprovstat Dose X/Rosuvastatin Dose 2 FCDP test formulation 1 (Drug)
结局指标
主要结局
Area under concentration time curve from time 0 to infinity (AUCinf)
时间窗: At predefined intervals from Day 1 to Day 11
To evaluate the relative bioavailability between the FCDP test formulation 1 and the STPs of laroprovstat and rosuvastatin across the planned rosuvastatin dose range, Dose 1 (Cohort 1) to Dose 2 (Cohort 2)
Area under concentration curve from time 0 to the last quantifiable concentration (AUClast)
时间窗: At predefined intervals from Day 1 to Day 11
To evaluate the relative bioavailability between the FCDP test formulation 1 and the STPs of laroprovstat and rosuvastatin across the planned rosuvastatin dose range, Dose 1 (Cohort 1) to Dose 2 (Cohort 2).
Maximum observed drug concentration (Cmax)
时间窗: At predefined intervals from Day 1 to Day 11
To evaluate the relative bioavailability between the FCDP test formulation 1 and the STPs of laroprovstat and rosuvastatin across the planned rosuvastatin dose range, Dose 1 (Cohort 1) to Dose 2 (Cohort 2)
次要结局
- Terminal rate constant (λz)(At predefined intervals from Day 1 to Day 11)
- Time to reach maximum observed concentration (tmax)(At predefined intervals from Day 1 to Day 11)
- Terminal elimination half life (t1/2λz)(At predefined intervals from Day 1 to Day 11)
- Apparent total body clearance (CL/F)(At predefined intervals from Day 1 to Day 11)
- Apparent volume of distribution based on the terminal phase (V/F)(At predefined intervals from Day 1 to Day 11)
- AUCinf(At predefined intervals from Day 1 to Day 11)
- AUClast(At predefined intervals from Day 1 to Day 11.)
- Cmax(At predefined intervals form Day 1 to Day 11)
- tmax(At predefined intervals from Day 1 to Day 11)
- λz(At predefined intervals form Day 1 to Day 11)
- t1/2λz(At predefined intervals from Day 1 to Day 11.)
- CL/F(At predefined intervals form Day 1 to Day 11)
- V/F(At predefined intervals from Day 1 to Day 11)