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

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

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.

Study Overview

• Status: Completed
• Conditions: Mental Disorders; Neurodevelopmental Disorders; Autism Spectrum Disorder; Autistic Disorder; Child Development Disorders, Pervasive
• Intervention / Treatment: Drug: RO6953958; Drug: Placebo; Drug: Midazolam

• Study Type: Interventional
• Enrollment (Actual): 88
• Phase: Phase 1

Contacts and Locations

Study Locations

• United Kingdom
  • London, United Kingdom, NW10 7EW
    • Hammersmith Medicines Research; Central Middlesex Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 55 years (ADULT)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: Male

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: DOUBLE

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: 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.	Drug: RO6953958; 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).
PLACEBO_COMPARATOR: 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.	Drug: Placebo; 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.
EXPERIMENTAL: 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.	Drug: RO6953958; 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).
PLACEBO_COMPARATOR: 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 RO6953958 QD for 10 days.	Drug: Placebo; 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.
EXPERIMENTAL: 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.	Drug: RO6953958; 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).; Drug: Midazolam; 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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	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

Collaborators and Investigators

• Sponsor: Hoffmann-La Roche

Study record dates

Study Major Dates

• Study Start (ACTUAL): July 15, 2020
• Primary Completion (ACTUAL): February 6, 2022
• Study Completion (ACTUAL): February 6, 2022

Study Registration Dates

• First Submitted: July 13, 2020
• First Submitted That Met QC Criteria: July 15, 2020
• First Posted (ACTUAL): July 17, 2020

Study Record Updates

• Last Update Posted (ACTUAL): February 16, 2022
• Last Update Submitted That Met QC Criteria: February 15, 2022
• Last Verified: February 1, 2022

More Information

Terms related to this study

• Keywords: Autism Spectrum Disorder
• Additional Relevant MeSH Terms: Pathologic Processes; Disease; Mental Disorders; Autistic Disorder; Autism Spectrum Disorder; Child Development Disorders, Pervasive; Developmental Disabilities; Neurodevelopmental Disorders; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Anesthetics, Intravenous; Anesthetics, General; Anesthetics; Tranquilizing Agents; Psychotropic Drugs; Hypnotics and Sedatives; Adjuvants, Anesthesia; Anti-Anxiety Agents; GABA Modulators; GABA Agents; Midazolam
• Other Study ID Numbers: BP41695; 2019-004486-41 (EUDRACT_NUMBER)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: Qualified researchers may request access to individual patient level data through the clinical study data request platform (www.vivli.org). Further details on Roche's criteria for eligible studies are available here (https://vivli.org/members/ourmembers/). For further details on Roche's Global Policy on the Sharing of Clinical Information and how to request access to related clinical study documents, see here (https://www.roche.com/research_and_development/who_we_are_how_we_work/clinical_trials/our_commitment_to_data_sharing.htm).

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No