A Randomized, Investigator- /Subject-blind, Single- and Multiple-ascending Dose, Placebo-controlled Study to Investigate Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Food Effect of RO6953958 (Including RO6953958 Effect on Midazolam) Following Oral Administration in Healthy Male Participants
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 88
- 试验地点
- 1
- 主要终点
- Parts 1, 2 and 3: Percentage of Participants With Adverse Events
研究概览
简要总结
This study will evaluate the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of single- and multiple-ascending doses (SAD (Part 1) and MAD (Part 2)) and food effect (FE) of RO6953958 following oral administration in healthy male participants. Part 3 (Drug-drug interaction (DDI)) will assess the safety, tolerability, and effect of RO6953958 on the PK of the cytochrome P450 (CYP) 3A substrate midazolam.
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 55 Years（Adult）
- 性别
- Male
- 接受健康志愿者
- 是
入选标准
- •Body mass index (BMI) within 18 to 31 kg/m2
- •During treatment and for at least 14 days after the last dose to remain abstinent
- •Refrain from donating sperm for at least 14 days after last dose
- •Part 2 (MAD) only - Participants must be prepared to collect a sleep log and wear an actigraphy device the week before participation in the study. Participants must also have scored 5 or less on the Pittsburgh Sleep Quality Index (PSQI), less than 13 on the Epworth sleepiness scale (ESS), and not be considered an extreme morning or evening type according to the morningness-eveningness questionnaire (MEQ) at screening to be eligible.
排除标准
- •History or evidence of any medical condition potentially altering the absorption, metabolism, or elimination of drugs
- •History of any clinically significant gastrointestinal, renal, hepatic, bronchopulmonary, neurological, psychiatric, cardiovascular, endocrinological, hematological, or allergic disease, sleep disorders (Part 2 [MAD] only), unexplained syncope (within 12 months prior to screening), metabolic disorder, cancer, or cirrhosis
- •Use of any psychoactive medication, or medications known to have effects on central nervous system (CNS), or blood flow
- •History of convulsions
- •History of clinically significant hypersensitivity (e.g., drugs, excipients) or allergic reactions
- •Abnormal blood pressure (BP) and pulse rate
- •Presence of orthostatic hypotension
- •History or presence of clinically significant ECG abnormalities or cardiovascular disease
- •Current or chronic history of liver disease or known hepatic or biliary abnormalities
- •Known active or any major episode of infection within 4 weeks prior to the start of drug administration
- •Participants who test positive for acute respiratory syndrome coronavirus 2 (SARS-CoV-2)
- •Have used or intend to use over-the-counter (OTC) or prescription medication including herbal medications within 30 days prior to dosing
- •Positive test for drugs, abuse of alcohol, human immunodeficiency virus (HIV), hepatitis B or hepatitis C virus (HCV), presence of hepatitis B surface antigen (HBsAg), or positive hepatitis C antibody test
- •Inability or unwillingness to fully consume standardized breakfast at Day 1
- •Part 2 (MAD) only - Participants who have issues sleeping or participants who have travelled across 2 or more time zones in the past month.
- •Part 2 (MAD) only - Participants who cannot produce sufficient saliva for study assessments
- •Participants who have donated more than 500 mL of blood or blood products or had significant blood loss within 3 months prior to screening
- •Have a history of clinically significant back pain, back pathology, and/or back injury that may predispose to complications from, or technical difficulty with, lumbar puncture
- •Complications that would lead to difficulty in obtaining a lumbar puncture
- •Part 3 (DDI) only - History of hypersensitivity to benzodiazepines (including midazolam) or its formulation ingredients
研究组 & 干预措施
Part 1: SAD placebo
There will be 7 cohorts in this study. In each cohort, participants will receive a single oral dose of a placebo while fasted/fed.
干预措施: Placebo (Drug)
Part 1: SAD/FE
There will be 7 cohorts in this study. In each cohort, participants will receive a single oral dose of RO6953958 while fasted. Participants in the fed (FE) cohort will return to receive the same single oral dose of RO6953958 repeated in the fed state.
干预措施: RO6953958 (Drug)
Part 2: MAD
A maximum of 5 dose levels are anticipated. For each dose level, a minimum of 8 and a maximum of 16 participants will receive a multiple oral dose of RO6953958 once daily (QD) for 10 days.
干预措施: RO6953958 (Drug)
Part 2: MAD placebo
A maximum of 5 dose levels are anticipated. For each dose level, a minimum of 8 and a maximum of 16 participants will receive a multiple oral dose of palcebo QD for 10 days.
干预措施: Placebo (Drug)
Part 3: DDI
RO6953958 will be administered at the maximum dose QD that was tested in the ongoing Part 2 (MAD).
Participants will also be administered midazolam.
干预措施: RO6953958 (Drug)
Part 3: DDI
RO6953958 will be administered at the maximum dose QD that was tested in the ongoing Part 2 (MAD).
Participants will also be administered midazolam.
干预措施: Midazolam (Drug)
结局指标
主要结局
Parts 1, 2 and 3: Percentage of Participants With Adverse Events
时间窗: Part 1: From randomization up to 7 weeks (or up to 14 weeks if the participant is part of the food effect cohort). Parts 2 and 3: From randomization up to 8 weeks
An adverse event (AE) is any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment.
Part 2: Number of Participants With Post-baseline Suicide Risk, Assessed Using the Columbia Suicide Severity Rating Scale (C-SSRS)
时间窗: From randomization up to 8 weeks
The C-SSRS is a questionnaire that is used to assess a participant's suicidal ideation and behaviors. The categories in the questionnaire have binary responses (yes/no) and include: Wish to be Dead; Non-specific Active Suicidal Thoughts; Active Suicidal Ideation with Any Methods (Not Plan) without Intent to Act; Active Suicidal Ideation with Some Intent to Act, without Specific Plan; Active Suicidal Ideation with Specific Plan and Intent, Preparatory Acts and Behavior; Aborted Attempt; Interrupted Attempt; Actual Attempt (non-fatal); Completed Suicide. Suicidal ideation or behavior is indicated by a "yes" answer to any of the listed categories. A score of 0 is assigned if no suicide risk is present. Categories with non-zero values are reported here.
次要结局
- Part 3: Fraction Absorbed (F) of Midazolam(Days 2 and 14)
- Parts 1, 2 and 3: Maximum Observed Plasma Concentration (Cmax) of RO6953958 and Its Metabolites RO7021594 and RO7045755(Day 1-14)
- Parts 2 and 3: Average Plasma Concentration (Cavg) of RO6953958 and Its Metabolites RO7021594 and RO7045755(Day 1-14)
- Part 1: Area Under the Plasma Concentration Versus Time Curve From Zero to 24h Postdose (AUC(0-24h)) of RO6953958 and Its Metabolites RO7021594 and RO7045755(Day 1-5)
- Parts 1 and 2: Cumulative Amount of Unchanged Drug Excreted Into the Urine (Ae) of RO6953958(Day 1 and 10)
- Parts 1 and 2: Fraction of the Administered Drug Excreted Into the Urine (Fe) of RO6953958(Day 1 and 10)
- Parts 1, 2 and 3: Molecular Weight Adjusted Metabolite-to-Parent Ratio for Area Under the Concentration-Time Curve (AUC(0-t)) of RO6953958 and Its Metabolites RO7021594 and RO7045755(Day 1-14)
- Parts 1, 2 and 3: Time to Reach Maximum Observed Plasma Concentration (Tmax) of RO6953958 and Its Metabolites RO7021594 and RO7045755(Day 1-14)
- Part 1: Area Under the Plasma Concentration Versus Time Curve From Zero to the Last Measurable Concentration (AUC0-last) of RO6953958 and Its Metabolites RO7021594 and RO7045755(Day 1-10)
- Parts 2 and 3: Accumulation Ratio Based on Ctrough (RCtrough) of RO6953958 and Its Metabolites RO7021594 and RO7045755(Day 1-14)
- Parts 1, 2 and 3: Molecular Weight Adjusted Metabolite-to-Parent Ratio for Cmax of RO6953958 and Its Metabolites RO7021594 and RO7045755(Day 1-14)
- Part 1: Time To the Last Quantifiable Concentration (Tlast) of RO6953958 and Its Metabolites RO7021594 and RO7045755(Day 1-10)
- Parts 1, 2 and 3: Terminal Elimination Phase Half-Life (t1/2) of RO6953958 and Its Metabolites RO7021594 and RO7045755(Day 1-14)
- Parts 2 and 3: Area Under the Concentration-Time Curve (AUC(0-t)) of RO6953958 and Its Metabolites RO7021594 and RO7045755(Day 1-14)
- Parts 2 and 3: Trough Plasma Concentration (Ctrough) of RO6953958 and Its Metabolites RO7021594 and RO7045755(Day 1, 3, 10, 12, 13)
- Part 3: T1/2 of Midazolam(Day 1-14)
- Part 3: VF of Oral Midazolam(Day 2-14)
- Part 1: Last Quantifiable Concentration (Clast) of RO6953958 and Its Metabolites RO7021594 and RO7045755 in Fasted and Fed State(Day 1-10)
- Part 1: Area Under the Plasma Concentration Versus Time Curve Extrapolated to Infinity (AUC0-inf) of RO6953958 and Its Metabolites RO7021594 and RO7045755(Day 1-10)
- Parts 1, 2 and 3: Apparent Volume of Distribution (V/F) of RO6953958(Day 1-14)
- Parts 1 and 2: Renal Clearance of the Drug From Urine (CLR) of RO6953958(Day 1 and 10)
- Parts 2 and 3: Accumulation Ratio Based on Cmax (RCmax) of RO6953958 and Its Metabolites RO7021594 and RO7045755(Day 1-14)
- Part 3: Cmax of Midazolam(Day 1-14)
- Part 3: RAUC of Midazolam(Days 13 and 14)
- Part 3: RCmax of Midazolam(Days 13 and 14)
- Parts 1, 2 and 3: Apparent Clearance (CL/F) of RO6953958(Day 1-14)
- Parts 2 and 3: Accumulation Ratio Based on AUC (RAUC) of RO6953958 and Its Metabolites RO7021594 and RO7045755(Day 1-14)
- Part 3: Tmax of Midazolam(Day 1-14)
- Part 3: AUClast of Midazolam(Day 1-14)
- Part 3: AUCinf of Midazolam(Day 1-14)
- Part 3: CL: Total Plasma Clearance of IV Midazolam(Days 1 and 13)
- Part 3: Volume of Distribution Under Steady-state Conditions (Vss) of Midazolam(Days 3 and 14)