A Single-Centre, Randomised, Double-Blind, Placebo-Controlled, 3-Period, Cross-Over Phase I Study to Investigate the Effect on the QTcF Interval of a Single Dose of 2 Different Doses of Verinurad, Each in Combination With Allopurinol 300 mg, Compared With Placebo In Healthy Volunteers
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 发起方
- AstraZeneca
- 入组人数
- 24
- 试验地点
- 1
- 主要终点
- Model Predicted Baseline-corrected and Placebo-corrected QT Interval Corrected for Heart Rate (HR) Using Fridericia's Formula (QTcF)(ΔΔQTcF) (Derived From Concentration-QTcF Analysis) at Geometric Mean of Cmax of Verinurad
研究概览
简要总结
This study will be conducted to investigate the safety of verinurad in healthy volunteers in combination with allopurinol 300 mg, compared with placebo in particular its effect on electrocardiogram (ECG), with focus on the QT/QTc interval
详细描述
This study will be conducted as a single-centre, randomised, placebo-controlled, double-blind, 3-period, crossover study to assess the effect on the QTcF interval of a single oral dose of verinurad 24 mg extended release (ER8) formulation (therapeutic exposure) or verinurad 40 mg immediate release (IR) formulation (supra-therapeutic exposure), each in combination with allopurinol 300 mg, compared to placebo in healthy subjects.
There are 3 study treatments:
- Treatment A: Verinurad 24 mg ER8 formulation co-administered with 300 mg allopurinol
- Treatment B: Verinurad 40 mg IR formulation co-administered with 300 mg allopurinol
- Treatment C: Matched placebos for both verinurad and allopurinol
All subjects will receive a single dose of all 3 treatments (A, B, and C) in a cross-over design with wash-out periods of at least 7 days between each study dose administration.
Subjects will be randomised to the treatment sequence (ABC, BCA, CAB, etc.) using William's Latin square. The treatments will be administered in a double-blind manner after an overnight fast of at least 10 hours.
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
- Triple (Participant, Investigator, Outcomes Assessor)
盲法说明
This study is double-blind with regards to treatment (verinurad and allopurinol or the matching placebos) at each dose level. Placebo will be matched with verinurad and allopurinol for appearance and amount. Subjects randomized to placebo will receive the same volume of oral suspension as subjects on active drug.
入排标准
- 年龄范围
- 18 Years 至 50 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 subjects aged 18 to 50 years (inclusive) with suitable veins for cannulation or repeated venipuncture.
- •Females must have a negative pregnancy test at Screening and on admission to the study centre must be:
- •(1) Not pregnant or currently lactating or breast-feeding. (2) Of non-childbearing potential confirmed at the Screening Visit by fulfilling one of the following criteria: (i) Post-menopausal defined as amenorrhea for at least 12 months or more following cessation of all exogenous hormonal treatments and follicle-stimulating hormone (FSH) levels in the post-menopausal range (FSH >40 IU/mL).
- •(ii) Documentation of irreversible surgical sterilization by hysterectomy, bilateral oophorectomy or bilateral salpingectomy but not tubal ligation.
- •(3) OR, if of childbearing potential, must be willing to use an acceptable method of contraception to avoid pregnancy for the entire study period and 3 months after the Follow-up Visit.
- •Have a body mass index (BMI) between 18 and 30 kg/m2 inclusive and weigh at least 50 kg and no more than 100 kg inclusive.
- •Serum uric acid (sUA) <300 μmol/L at Screening (Visit 1) and sUA <330 μmol/L on Day -1 in every treatment period (Visit 2 to 4). Note: Since sUA levels might vary on a daily basis, subjects with sUA ≥330 μmol/L on Day -1 will be retested. Treatment on Day 1 will only be administered when the sUA level on Day -1 is <330 μmol/L upon retesting. Subjects with sUA ≥330 μmol/L despite retesting, may conduct the treatment period at a later date when they have sUA <330 μmol/L.
- •Must be able to swallow multiple capsules/tablets.
- •Exclusion criteria:
- •History of any clinically significant disease or disorder which, in the opinion of the Investigator, may either put the subject at risk because of participation in the study, or influence the results or the subject's ability to participate in the study.
- •History or presence of gastrointestinal (GI), hepatic or renal disease, or any other condition known to interfere with absorption, distribution, metabolism, or excretion of drugs.
- •Any clinically significant illness, medical/surgical procedure, or trauma within 4 weeks of the first administration of investigational medicinal product (IMP).
- •Subject has a positive test result for SARS-CoV-2 RT-PCR before randomisation.
- •Subject has clinical signs and symptoms consistent with COVID-19, eg, fever, dry cough, dyspnoea, sore throat, fatigue or confirmed infection by appropriate laboratory test within the last 4 weeks prior to screening or on admission.
- •History of severe COVID-19 (hospitalization, extracorporeal membrane oxygenation, mechanically ventilated).
- •Any clinically significant abnormalities in clinical chemistry, haematology, or urinalysis results, at Screening (Visit 1) as judged by the Investigator, including:
- •(1) Alanine aminotransferase (ALT) >1.5 × upper limit of normal (ULN) (2) Aspartate aminotransferase (AST) >1.5 × ULN (3) Bilirubin (total) >1.5 × ULN (4) Gamma glutamyl transpeptidase (GGT) >1.5 × ULN
- •Any clinically significant abnormal findings in vital signs at Screening as judged by the Investigator, including:
- •(1) Systolic blood pressure <90 mmHg or >140 mmHg (2) Diastolic blood pressure <50 mmHg or >90 mmHg (3) Heart rate <50 or >90 bpm
- •Carrier of the HLA-B*58:01 allele.
- •Any clinically important abnormalities in rhythm, conduction or morphology of the 12 lead safety ECG and any clinically important abnormalities in the 12-lead safety ECG as considered by the Investigator that may interfere with the interpretation of QT interval corrected for heart rate using Fridericia's formula (QTcF), including abnormal ST T wave morphology, particularly in the Clinical Study Protocol (CSP)-defined primary lead for dECG analysis or left ventricular hypertrophy:
- •Prolonged QTcF >450 ms or shortened QTcF <340 ms or family history of long QT syndrome.
- •PR (PQ) interval shortening <120 ms (PR >110 ms but <120 ms is acceptable if there is no evidence of ventricular pre-excitation).
- •PR (PQ) interval prolongation (>220 ms) intermittent second (Wenckebach block while asleep is not exclusive) or third degree atrioventricular (AV) block, or AV dissociation.
- •Persistent or intermittent complete bundle branch block, incomplete bundle branch block, or intraventricular conduction delay with QRS >110 ms. Subjects with QRS >110 ms but <115 ms are acceptable if there is no evidence of ventricular hypertrophy or pre-excitation.
- •Any positive result on Screening for serum hepatitis B surface antigen OR anti-HBc antibody, hepatitis C antibody, and human immunodeficiency virus (HIV) antibody.
- •Suspected or known Gilbert's syndrome.
- •Current smokers or those who have smoked or used nicotine products (including e cigarettes) within the 3 months prior to Screening.
- •Known or suspected history of alcohol abuse or excessive intake of alcohol as judged by the Investigator. Excessive intake of alcohol defined as the regular consumption of more than 24 g of alcohol per day for men or 12 g per day for women.
- •Positive screen for drugs of abuse, cotinine (nicotine) or alcohol at the Screening Visit or on each admission to the study centre.
- •Excessive intake of caffeine-containing drinks or food (eg, coffee, tea, chocolate) as judged by the Investigator. Excessive intake of caffeine defined as the regular consumption of more than 600 mg of caffeine per day (eg, >5 cups of coffee) or would likely be unable to refrain from the use of caffeine-containing beverages during confinement at the study site.
- •Previous hypersensitivity reaction to allopurinol or any URAT1 inhibitor.
- •Subjects who are pregnant, breast-feeding or planning to become pregnant (pregnancy is to be avoided for the entire study period and 3 months after the Follow up Visit).
- •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 non-prescribed medication including antacids, analgesics (other than paracetamol/acetaminophen), herbal remedies, megadose vitamins (intake of 20 to 600 × the recommended daily dose) and minerals during the 2 weeks prior to the first administration of IMP or within 5 half-lives (whichever is longer). Hormone replacement therapy is allowed for females.
- •Plasma donation within 1 month of Screening or any blood donation/blood loss >500 mL during the 3 months prior to Screening.
- •Has received another new chemical or biological entity (defined as a compound which has not been approved for marketing in the US) within 30 days or within 5 half lives (whichever is longer) of the first administration of IMP in this study.
- •Note: Subjects consented and screened, but not randomised in this study or a previous Phase I study, are not excluded.
- •Involvement of any AstraZeneca, Parexel or study site employee or their close relatives.
- •Subjects who have previously received verinurad.
- •Subjects who cannot communicate reliably with the Investigator and/or are not able to read, speak and understand the German language.
- •Judgment by the Investigator that the subject should not participate in the study if there are any ongoing or recent (ie, during the Screening Period) minor medical complaints that may interfere with the interpretation of the study data or are considered unlikely to comply with study procedures, restrictions and requirements.
- •Subjects who are vegans or have medical dietary restrictions.
- •Vulnerable subjects, eg, kept in detention, protected adults under guardianship, trusteeship, or committed to an institution by governmental or juridical order.
- •Subjects who are regularly exposed to COVID-19 (eg, health care professionals working in COVID-19 wards or at emergency departments) as part of their daily life.
排除标准
- 未提供
研究组 & 干预措施
Treatment ABC
Subjects will receive a single dose of all 3 treatments (A, B, and C) in a crossover design with wash-out periods of at least 7 days between each study dose administration.
干预措施: Allopurinol (Drug)
Treatment BCA
Subjects will receive a single dose of all 3 treatments (B, C, and A) in a crossover design with wash-out periods of at least 7 days between each study dose administration.
干预措施: Verinurad (Drug)
Treatment ABC
Subjects will receive a single dose of all 3 treatments (A, B, and C) in a crossover design with wash-out periods of at least 7 days between each study dose administration.
干预措施: Verinurad (Drug)
Treatment ABC
Subjects will receive a single dose of all 3 treatments (A, B, and C) in a crossover design with wash-out periods of at least 7 days between each study dose administration.
干预措施: Placebo (Drug)
Treatment BCA
Subjects will receive a single dose of all 3 treatments (B, C, and A) in a crossover design with wash-out periods of at least 7 days between each study dose administration.
干预措施: Placebo (Drug)
Treatment BCA
Subjects will receive a single dose of all 3 treatments (B, C, and A) in a crossover design with wash-out periods of at least 7 days between each study dose administration.
干预措施: Allopurinol (Drug)
Treatment CAB
Subjects will receive a single dose of all 3 treatments (C, A, and B) in a crossover design with wash-out periods of at least 7 days between each study dose administration.
干预措施: Verinurad (Drug)
Treatment CAB
Subjects will receive a single dose of all 3 treatments (C, A, and B) in a crossover design with wash-out periods of at least 7 days between each study dose administration.
干预措施: Placebo (Drug)
Treatment CAB
Subjects will receive a single dose of all 3 treatments (C, A, and B) in a crossover design with wash-out periods of at least 7 days between each study dose administration.
干预措施: Allopurinol (Drug)
Treatment ACB
Subjects will receive a single dose of all 3 treatments (A, C, and B) in a crossover design with wash-out periods of at least 7 days between each study dose administration.
干预措施: Verinurad (Drug)
Treatment ACB
Subjects will receive a single dose of all 3 treatments (A, C, and B) in a crossover design with wash-out periods of at least 7 days between each study dose administration.
干预措施: Placebo (Drug)
Treatment ACB
Subjects will receive a single dose of all 3 treatments (A, C, and B) in a crossover design with wash-out periods of at least 7 days between each study dose administration.
干预措施: Allopurinol (Drug)
Treatment BAC
Subjects will receive a single dose of all 3 treatments (B, A, and C) in a crossover design with wash-out periods of at least 7 days between each study dose administration.
干预措施: Verinurad (Drug)
Treatment BAC
Subjects will receive a single dose of all 3 treatments (B, A, and C) in a crossover design with wash-out periods of at least 7 days between each study dose administration.
干预措施: Placebo (Drug)
Treatment BAC
Subjects will receive a single dose of all 3 treatments (B, A, and C) in a crossover design with wash-out periods of at least 7 days between each study dose administration.
干预措施: Allopurinol (Drug)
Treatment CBA
Subjects will receive a single dose of all 3 treatments (C, B and A) in a crossover design with wash-out periods of at least 7 days between each study dose administration.
干预措施: Verinurad (Drug)
Treatment CBA
Subjects will receive a single dose of all 3 treatments (C, B and A) in a crossover design with wash-out periods of at least 7 days between each study dose administration.
干预措施: Placebo (Drug)
Treatment CBA
Subjects will receive a single dose of all 3 treatments (C, B and A) in a crossover design with wash-out periods of at least 7 days between each study dose administration.
干预措施: Allopurinol (Drug)
结局指标
主要结局
Model Predicted Baseline-corrected and Placebo-corrected QT Interval Corrected for Heart Rate (HR) Using Fridericia's Formula (QTcF)(ΔΔQTcF) (Derived From Concentration-QTcF Analysis) at Geometric Mean of Cmax of Verinurad
时间窗: Baseline; Day 1: 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8 and 12 h post-dose; Day 2: 24 and 36 h post-dose; Day 3: 48 h post-dose
Assessment of the effect of a single dose of verinurad given as either a 24 mg ER8 formulation (clinical exposure) or a 40 mg IR formulation (exposure needed to waive positive control as per question 5.1 of International Council for Harmonisation Guideline E14 and associated Questions and Answers \[ICH E14 Q\&A\]), both in combination with allopurinol 300 mg, on the QTcF interval compared to placebo using a concentration-QTcF analysis. A linear mixed-effect concentration-QTcF model was used as the primary analysis. This is a result of the statistical model so it does not have values for every timepoint, it is just one set of numbers - summarizes data across all timepoints. No non-placebo-corrected QTcF data values were collected or could be obtained for each Arm/Group at Cmax of Verinurad.
次要结局
- Baseline-corrected RR Interval (ΔRR Interval)(Baseline; Day 1: 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8 and 12 h post-dose; Day 2: 24 and 36 h post-dose; Day 3: 48 h post-dose)
- Baseline-corrected and Placebo-adjusted RR Interval (ΔΔRR Interval)(Baseline; Day 1: 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8 and 12 h post-dose; Day 2: 24 and 36 h post-dose; Day 3: 48 h post-dose)
- Baseline-corrected PR Interval (ΔPR Interval)(Baseline; Day 1: 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8 and 12 h post-dose; Day 2: 24 and 36 h post-dose; Day 3: 48 h post-dose)
- Baseline-corrected and Placebo-corrected QRS Interval (ΔΔQRS Interval)(Baseline; Day 1: 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8 and 12 h post-dose; Day 2: 24 and 36 h post-dose; Day 3: 48 h post-dose)
- Baseline-corrected and Placebo-corrected QTcF Interval (ΔΔQTcF Interval)(Baseline; Day 1: 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8 and 12 h post-dose; Day 2: 24 and 36 h post-dose; Day 3: 48 h post-dose)
- Maximum Observed Plasma Concentration (Cmax) for Verinurad, M1, M8, Allopurinol, and Oxypurinol(Day 1: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, and 12 hours post-dose; Day 2: 24 and 36 hours post-dose; Day 3: 48 hours post-dose)
- Baseline-corrected Heart Rate (ΔHR)(Baseline; Day 1: 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8 and 12 hour (h) post-dose; Day 2: 24 and 36 h post-dose; Day 3: 48 h post-dose)
- Baseline-corrected and Placebo-adjusted Heart Rate (ΔΔHR)(Baseline; Day 1: 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8 and 12 h post-dose; Day 2: 24 and 36 h post-dose; Day 3: 48 h post-dose)
- Baseline-corrected and Placebo-corrected QT Interval (ΔΔQT Interval)(Baseline; Day 1: 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8 and 12 h post-dose; Day 2: 24 and 36 h post-dose; Day 3: 48 h post-dose)
- Baseline-corrected QTcF Interval (ΔQTcF Interval)(Baseline; Day 1: 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8 and 12 h post-dose; Day 2: 24 and 36 h post-dose; Day 3: 48 h post-dose)
- Area Under the Plasma Concentration-time Curve From Time Zero to Time of Last Quantifiable Concentration (AUC[0-t]) for Verinurad, M1, M8, Allopurinol, and Oxypurinol(Day 1: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, and 12 hours post-dose; Day 2: 24 and 36 hours post-dose; Day 3: 48 hours post-dose)
- Time to Reach Maximum Plasma Concentration (Tmax) for Verinurad, M1, M8, Allopurinol, and Oxypurinol(Day 1: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, and 12 hours post-dose; Day 2: 24 and 36 hours post-dose; Day 3: 48 hours post-dose)
- Time Delay Between Drug Administration and the First Observed Concentration in Plasma (Tlag) for Verinurad, M1, M8, Allopurinol, and Oxypurinol(Day 1: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, and 12 hours post-dose; Day 2: 24 and 36 hours post-dose; Day 3: 48 hours post-dose)
- Terminal Half-life (t½λz) for Verinurad, M1, M8, Allopurinol, and Oxypurinol(Day 1: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, and 12 hours post-dose; Day 2: 24 and 36 hours post-dose; Day 3: 48 hours post-dose)
- Time of Last Quantifiable Plasma Concentration (Tlast) for Verinurad, M1, M8, Allopurinol, and Oxypurinol(Day 1: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, and 12 hours post-dose; Day 2: 24 and 36 hours post-dose; Day 3: 48 hours post-dose)
- Apparent Total Body Clearance of Drug From Plasma After Extravascular Administration (Parent Drug Only) (CL/F) for Verinurad and Allopurinol(Day 1: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, and 12 hours post-dose; Day 2: 24 and 36 hours post-dose; Day 3: 48 hours post-dose)
- Apparent Volume of Distribution at Steady State Following Extravascular Administration (Parent Drug Only) (Vss/F) for Verinurad and Allopurinol(Day 1: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, and 12 hours post-dose; Day 2: 24 and 36 hours post-dose; Day 3: 48 hours post-dose)
- Number of Participants With Adverse Events (AEs)(From Screening (Day -28 to Day -2) until the Follow-up visit (7 to 10 Days After the Last Dose))
- Baseline-corrected QRS Interval (ΔQRS Interval)(Baseline; Day 1: 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8 and 12 h post-dose; Day 2: 24 and 36 h post-dose; Day 3: 48 h post-dose)
- Baseline-corrected and Placebo-adjusted PR Interval (ΔΔPR Interval)(Baseline; Day 1: 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8 and 12 h post-dose; Day 2: 24 and 36 h post-dose; Day 3: 48 h post-dose)
- Baseline-corrected QT Interval (ΔQT Interval)(Baseline; Day 1: 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8 and 12 h post-dose; Day 2: 24 and 36 h post-dose; Day 3: 48 h post-dose)
- Area Under Plasma Concentration-time Curve From Time Zero Extrapolated to Infinity (AUC) for Verinurad, M1, M8, Allopurinol, and Oxypurinol(Day 1: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, and 12 hours post-dose; Day 2: 24 and 36 hours post-dose; Day 3: 48 hours post-dose)
- Apparent Volume of Distribution During the Terminal Phase After Extravascular Administration (Parent Drug Only) (Vz/F) for Verinurad and Allopurinol(Day 1: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, and 12 hours post-dose; Day 2: 24 and 36 hours post-dose; Day 3: 48 hours post-dose)
- Mean Residence Time of the Unchanged Drug in the Systemic Circulation From Zero to Infinity (MRT) for Verinurad and Oxypurinol(Day 1: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, and 12 hours post-dose; Day 2: 24 and 36 hours post-dose; Day 3: 48 hours post-dose)