A Single-Center, Randomized, Investigator/Subject-Blind, Adaptive Single-Ascending-Dose(SAD), Placebo-Controlled, Parallel Study to Investigate the Safety, Tolerability, Pharmacokinetics (Including the Effect of Food and the Effect of Itraconazole on the Pharmacokinetics of a Single Oral Dose of RO7034067), and Pharmacodynamics of RO7034067 Following Oral Administration in Healthy Subjects
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 33
- 试验地点
- 1
- 主要终点
- Percentage of Participants with Clinically Significant Changes in Safety Measurements, Including Vital Signs and Electrocardiograms (ECGs)
研究概览
简要总结
The objective of this study is to assess the safety and tolerability of Risdiplam (RO7034067) in healthy people. The study will assess what the body does to Risdiplam (RO7034067) and what Risdiplam (RO7034067) does to the body. Risdiplam (RO7034067) will be given by mouth in gradually increasing doses. The data from this study will help to define the dose to further explore Risdiplam (RO7034067) in patients with Spinal Muscular Atrophy.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Double (Participant, Investigator)
入排标准
- 年龄范围
- 18 Years 至 45 Years（Adult）
- 性别
- Male
- 接受健康志愿者
- 是
入选标准
- •Healthy men, aged 18 to 45 years of age, inclusive
- •Body Mass Index (BMI) of 18 to 30 kilograms/meter square, inclusive
排除标准
- •History or evidence of any medical condition potentially altering the absorption, metabolism or elimination of drugs
- •History of malignancy in the past 5 years
- •A history of clinically significant hypersensitivity (e.g. drugs, excipients) or allergic reactions
- •Any major illness within one month before the screening examination or any febrile illness within one week prior to screening and up to first study drug administration
- •History or presence of clinically significant electrocardiogram (ECG) abnormalities or cardiovascular disease
- •Clinically significant abnormalities in laboratory test results
- •Confirmed resting pulse rate (PR) greater than 100 or less than 40 bpm
- •Confirmed systolic blood pressure (SBP) greater than 140 or less than 90 mm Hg, and diastolic blood pressure (DBP) greater than 90 or less than 50 mm Hg
- •Positive result on HIV1 and HIV2, hepatitis C (HCV) or hepatitis B (HBV)
- •History of any clinically significant gastrointestinal, renal, hepatic, broncho-pulmonary, neurological, psychiatric, cardio-vascular, endocrinological, ophthalmological, dermatological, hematological or allergic disease, metabolic disorder, hypofertility, cancer or cirrhosis
- •History or evidence of (neuro)muscular disorders
- •Hypersensitivity to itraconazole, to any of the other ingredients, or to any other triazole antifungal
- •Any other known contraindications to itraconazole
研究组 & 干预措施
Part 1: Single Ascending Dose: Placebo
Participants will receive a single dose of matching placebo orally on Day 1 of Part 1.
干预措施: Placebo (Other)
Part 1: Single Ascending Dose: Risdiplam
Participants will receive a single ascending dose (SAD) of Risdiplam orally on Day 1 of Part 1.
干预措施: Risdiplam (Drug)
Part 2: Food Effect: Fed-Fasted
This arm consists of two periods. In Period 1 participants will receive one oral dose of Risdiplam in the fed state on Day 1. In Period 2 participants will receive one oral dose of Risdiplam in the fasted state on Day 1.
干预措施: Risdiplam (Drug)
Part 2: Food Effect: Fasted-Fed
This arm consists of two periods. In Period 1 participants will receive one oral dose of Risdiplam in the fasted state on Day 1. In Period 2 participants will receive one oral dose of Risdiplam in the fed state on Day 1.
干预措施: Risdiplam (Drug)
Part 3: Itraconazole Interaction
In Period 1 a single oral dose of Risdiplam will be administered. After a wash-out period in Period 2 participants will be administered oral doses of itraconazole twice daily from Day 1 to Day 8. On Day 4 participants will receive a single oral dose of Risdiplam in the fed state in combination with itraconazole.
干预措施: Itraconazole (Drug)
Part 3: Itraconazole Interaction
In Period 1 a single oral dose of Risdiplam will be administered. After a wash-out period in Period 2 participants will be administered oral doses of itraconazole twice daily from Day 1 to Day 8. On Day 4 participants will receive a single oral dose of Risdiplam in the fed state in combination with itraconazole.
干预措施: Risdiplam (Drug)
结局指标
主要结局
Percentage of Participants with Clinically Significant Changes in Safety Measurements, Including Vital Signs and Electrocardiograms (ECGs)
时间窗: Parts 1 and 2: Up to 21 days after last dose of study drug. Part 3: Up to 28 days after last dose of study drug.
Percentage of Participants with Clinically Significant Changes in Ophthalmological Assessments
时间窗: Part 1: Up to 26 weeks; Part 2 (Treatment Period [TP] 1 and 2): Up to 29 weeks; Part 3 (TP 1, 2): Up to 30 weeks
Percentage of Participants with Adverse Events (AEs)
时间窗: Parts 1 and 2: Up to 21 days after last dose of study drug. Part 3: Up to 28 days after last dose of study drug.
Percentage of Participants with Laboratory Test Abnormalities
时间窗: Parts 1 and 2: Up to 21 days after last dose of study drug. Part 3: Up to 28 days after last dose of study drug.
次要结局
- Area Under the Plasma Concentration-Time Curve up to Time t (AUC0-t)(Parts 1 and 2: Up to Day 21; Part 3: Up to Day 28)
- Change from In Vivo Baseline in Splicing Modifications of SMN mRNAs, Including SMN1, SMN2 FL, and SMNdelta7 mRNA in Blood Ex Vivo(Part 1: Day 1)
- Change from Baseline in Splicing Modifications of Survival of Motor Neuron (SMN) Messenger Ribonucleic Acids (mRNAs), Including SMN1, SMN2 FL, and SMNdelta7 mRNA in Blood In Vivo(Part 1: Day -1, 1, 2, 3, 4, 5)
- Maximum Observed Plasma Concentration (Cmax)(Parts 1 and 2: Up to Day 21; Part 3: Up to Day 28)
- Time to Maximum Plasma Concentration (Tmax)(Parts 1 and 2: Up to Day 21; Part 3: Up to Day 28)
- Metabolite-to-Parent Ratio (AUCm/AUCp) Corrected for Molecular Weight for AUCInf, AUClast or AUC0-t(Parts 1 and 2: Up to Day 21; Part 3: Up to Day 28)
- Area Under the Plasma Concentration-Time Curve up to the Last Measurable Concentration (AUClast)(Parts 1 and 2: Up to Day 21; Part 3: Up to Day 28)
- Area Under the Plasma Concentration-Time Curve Extrapolated to Infinity (AUC0-inf)(Parts 1 and 2: Up to Day 21; Part 3: Up to Day 28)
- Apparent Terminal Half-Life (t1/2)(Parts 1 and 2: Up to Day 21; Part 3: Up to Day 28)
- Apparent Oral Clearance (CL/F)(Parts 1 and 2: Up to Day 21; Part 3: Up to Day 28)
- Apparent Oral Volume of Distribution (Vz/F)(Parts 1 and 2: Up to Day 21; Part 3: Up to Day 28)
- Cumulative Amount Excreted Unchanged into Urine (Ae)(Part 1: Day 1, 2, 3, 4)
- Renal Clearance (CLR)(Part 1: Day 1, 2, 3, 4)
- Fraction of Dose Excreted Unchanged Renally (Fe)(Part 1: Day 1, 2, 3, 4)
- Change from Baseline in SMN Protein Levels in Blood(Part 1: Day -1, 1, 2, 3, 4, 5, 7)
- Metabolite-to-Parent Ratio (Cmax_m/Cmax_p) for Cmax, Corrected for Molecular Weight(Parts 1 and 2: Up to Day 21; Part 3: Up to Day 28)
- Predose Trough Plasma Concentration (Ctrough) of Itraconazole(Parts 1 and 2: Up to Day 21; Part 3: Up to Day 28)