NCT04475848 - A Study to Investigate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Food Effect of RO6953958 in Healthy Participants | Crick

Eligibility

Sex: MALEMin age: 18 YearsMax age: 55 YearsHealthy volunteers:

Medical Language ↔ Plain English

Inclusion Criteria: * 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. Exclusion Criteria: * 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

Outcomes

Primary Outcomes

Parts 1, 2 and 3: Percentage of Participants With Adverse Events

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.

Time frame: 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

Part 2: Number of Participants With Post-baseline Suicide Risk, Assessed Using the Columbia Suicide Severity Rating Scale (C-SSRS)

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.

Time frame: From randomization up to 8 weeks

Secondary Outcomes

Parts 1, 2 and 3: Maximum Observed Plasma Concentration (Cmax) of RO6953958 and Its Metabolites RO7021594 and RO7045755

Time frame: Day 1-14

Parts 2 and 3: Average Plasma Concentration (Cavg) of RO6953958 and Its Metabolites RO7021594 and RO7045755

Time frame: Day 1-14

Parts 1, 2 and 3: Time to Reach Maximum Observed Plasma Concentration (Tmax) of RO6953958 and Its Metabolites RO7021594 and RO7045755

Time frame: Day 1-14

Part 1: Last Quantifiable Concentration (Clast) of RO6953958 and Its Metabolites RO7021594 and RO7045755 in Fasted and Fed State

Time frame: Day 1-10

Part 1: Time To the Last Quantifiable Concentration (Tlast) of RO6953958 and Its Metabolites RO7021594 and RO7045755

Time frame: Day 1-10

Parts 1, 2 and 3: Terminal Elimination Phase Half-Life (t1/2) of RO6953958 and Its Metabolites RO7021594 and RO7045755

Time frame: Day 1-14

Parts 2 and 3: Area Under the Concentration-Time Curve (AUC(0-t)) of RO6953958 and Its Metabolites RO7021594 and RO7045755

Time frame: 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

Time frame: Day 1-5

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

Time frame: 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

Time frame: Day 1-10

Parts 1, 2 and 3: Apparent Clearance (CL/F) of RO6953958

Time frame: Day 1-14

Parts 1, 2 and 3: Apparent Volume of Distribution (V/F) of RO6953958

Time frame: Day 1-14

Parts 1 and 2: Cumulative Amount of Unchanged Drug Excreted Into the Urine (Ae) of RO6953958

Time frame: Day 1 and 10

Parts 1 and 2: Fraction of the Administered Drug Excreted Into the Urine (Fe) of RO6953958

Time frame: Day 1 and 10

Parts 1 and 2: Renal Clearance of the Drug From Urine (CLR) of RO6953958

Time frame: Day 1 and 10

Parts 2 and 3: Trough Plasma Concentration (Ctrough) of RO6953958 and Its Metabolites RO7021594 and RO7045755

Time frame: Day 1, 3, 10, 12, 13

Parts 2 and 3: Accumulation Ratio Based on AUC (RAUC) of RO6953958 and Its Metabolites RO7021594 and RO7045755

Time frame: Day 1-14

Parts 2 and 3: Accumulation Ratio Based on Cmax (RCmax) of RO6953958 and Its Metabolites RO7021594 and RO7045755

Time frame: Day 1-14

Parts 2 and 3: Accumulation Ratio Based on Ctrough (RCtrough) of RO6953958 and Its Metabolites RO7021594 and RO7045755

Time frame: 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

Time frame: Day 1-14

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

Time frame: Day 1-14

Part 3: Tmax of Midazolam

A single IV dose of 100 ug midazolam was administered on Day 1 and Day 13. A single oral dose 300 ug of midazolam was administered on Day 2 and Day 14. RO6953958 was administrated once daily at 210 mg from Day 3 up to Day 14 so concomitantly with IV dose of midazolam on Day 13 and with oral dose of midazolam on Day 14.

Time frame: Day 1-14

Part 3: Cmax of Midazolam

Time frame: Day 1-14

Part 3: T1/2 of Midazolam

Time frame: Day 1-14

Part 3: AUClast of Midazolam

Time frame: Day 1-14

Part 3: AUCinf of Midazolam

Time frame: Day 1-14

Part 3: VF of Oral Midazolam

Time frame: Day 2-14

Part 3: RAUC of Midazolam

Time frame: Days 13 and 14

Part 3: RCmax of Midazolam

Time frame: Days 13 and 14

Part 3: CL: Total Plasma Clearance of IV Midazolam

Time frame: Days 1 and 13

Part 3: Fraction Absorbed (F) of Midazolam

F is stated as a fraction of 1.

Time frame: Days 2 and 14

Part 3: Volume of Distribution Under Steady-state Conditions (Vss) of Midazolam

Time frame: Days 3 and 14

A Study to Investigate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Food Effect of RO6953958 in Healthy Participants

Overview

Conditions

Interventions

Eligibility

Locations (1)

Outcomes

Primary Outcomes

Secondary Outcomes