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

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Autistic Disorder, Autism Spectrum Disorder, Child Development Disorders, Pervasive, Mental Disorders, Neurodevelopmental Disorders

Intervention / Treatment
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* Drug: RO6953958
* Drug: Placebo
* Drug: Midazolam


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part 1: SAD/FE<br>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. | Drug: RO6953958<br>* Part 1: RO6953958 will be administered in an adaptive manner. The starting dose is planned to be 5 milligrams (mg). Part 2: The starting dose is planned to be 45 mg. Part 3: RO6953958 will be administered QD following a standardized breakfast on Day 3 to Day 14 at the maximum dose QD that was tested in the ongoing Part 2 (MAD).<br>|
| Placebo Comparator: Part 1: SAD placebo<br>There will be 7 cohorts in this study. In each cohort, participants will receive a single oral dose of a placebo while fasted/fed. | Drug: Placebo<br>* Part 1: A placebo will be administered in an adaptive manner. The starting dose is planned to be 5 mg. Part 2: The starting dose is planned to be 45 mg.<br>|
| Experimental: Part 2: MAD<br>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. | Drug: RO6953958<br>* Part 1: RO6953958 will be administered in an adaptive manner. The starting dose is planned to be 5 milligrams (mg). Part 2: The starting dose is planned to be 45 mg. Part 3: RO6953958 will be administered QD following a standardized breakfast on Day 3 to Day 14 at the maximum dose QD that was tested in the ongoing Part 2 (MAD).<br>|
| Placebo Comparator: Part 2: MAD placebo<br>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 QD for 10 days. | Drug: Placebo<br>* Part 1: A placebo will be administered in an adaptive manner. The starting dose is planned to be 5 mg. Part 2: The starting dose is planned to be 45 mg.<br>|
| Experimental: Part 3: DDI<br>RO6953958 will be administered at the maximum dose QD that was tested in the ongoing Part 2 (MAD). Participants will also be administered midazolam. | Drug: RO6953958<br>* Part 1: RO6953958 will be administered in an adaptive manner. The starting dose is planned to be 5 milligrams (mg). Part 2: The starting dose is planned to be 45 mg. Part 3: RO6953958 will be administered QD following a standardized breakfast on Day 3 to Day 14 at the maximum dose QD that was tested in the ongoing Part 2 (MAD).<br>Drug: Midazolam<br>* Midazolam will be administered as single intervenous (IV) bolus injection of 100 micrograms (ug) on Day 1 and Day 13, and as single oral dose of 300 ug on Day 2 and Day 14.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Parts 1, 2 and 3: Percentage of Participants with Adverse Events |  | 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: Change in suicide risk assessed using the Columbia Suicide Severity Rating Scale (C-SSRS) |  | From randomization up to 8 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 
| 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: Last Quantifiable Concentration (Clast) of RO6953958 and its Metabolites RO7021594 and RO7045755 in Fasted and Fed state |  | Day 1-5 | 
| Part 1: Time To the Last Quantifiable Concentration (Tlast) of RO6953958 and its Metabolites RO7021594 and RO7045755 |  | Day 1-5 | 
| 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 | 
| Part 1: Area Under the Plasma Concentration Versus Time Curve From Zero to 12h Postdose (AUC(0-12h)) of RO6953958 and its Metabolites RO7021594 and RO7045755 |  | 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 |  | Day 1-5 | 
| Part 1: Area Under the Plasma Concentration Versus Time Curve Extrapolated to Infinity (AUC0-inf) of RO6953958 and its Metabolites RO7021594 and RO7045755 |  | Day 1-5 | 
| Parts 1, 2 and 3: Apparent Clearance (CL/F) of RO6953958 |  | Day 1-14 | 
| Parts 1, 2 and 3: Apparent Volume of Distribution (V/F) of RO6953958 |  | Day 1-14 | 
| Parts 1 and 2: Cumulative Amount of Unchanged Drug Excreted into the Urine (Ae) of RO6953958 |  | Day 1-14 | 
| Parts 1 and 2: Fraction of the Administered Drug Excreted into the Urine (Fe) of RO6953958 |  | Day 1-14 | 
| Parts 1 and 2: Renal Clearance of the Drug from Urine (CLR) of RO6953958 |  | Day 1-14 | 
| Parts 1, 2 and 3: Trough Plasma Concentration (Ctrough) of RO6953958 and its Metabolites RO7021594 and RO7045755 |  | Day 1-14 | 
| Parts 2 and 3: Accumulation Ratio based on AUC (RAUC) of RO6953958 and its Metabolites RO7021594 and RO7045755 |  | Day 1-14 | 
| Parts 2 and 3: Accumulation Ratio Based on Cmax (RCmax) of RO6953958 and its Metabolites RO7021594 and RO7045755 |  | Day 1-14 | 
| Parts 1, 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 | 
| 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 | 
| Part 3: Tmax of Midazolam |  | Day 1-14 | 
| Part 3: Cmax of Midazolam |  | Day 1-14 | 
| Part 3: T1/2 of Midazolam |  | Day 1-14 | 
| Part 3: AUClast of Midazolam |  | Day 1-14 | 
| Part 3: AUCinf of Midazolam |  | Day 1-14 | 
| Part 3: VF of oral Midazolam |  | Day 1-14 | 
| Part 3: RAUC of Midazolam |  | Days 13 and 14 | 
| Part 3: RCmax of Midazolam |  | Days 13 and 14 | 
| Part 3: CL: Total Plasma Clearance of IV Midazolam |  | Days 1 and 13 | 
| Part 3: Fraction Absorbed (F) of Midazolam |  | Day 1-14 | 
| Part 3: Volume of Distribution under Steady-state Conditions (Vss) of Midazolam |  | Days 1 and 13 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Autism Spectrum Disorder