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

NCT04475848 | Completed Phase 1 Results

• 2 other identifiers: BP416952019-004486-41
• Study Type: interventional
• Target: 88
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

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

Keywords

Autism Spectrum Disorder

Outcome Measures

Primary Outcomes (2)

• 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.

  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.

  From randomization up to 8 weeks

Secondary Outcomes (32)

• 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 1-10

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

  Day 1-10

Study Arms (5)

Part 1: SAD/FE

EXPERIMENTAL

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: SAD placebo

PLACEBO COMPARATOR

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 2: MAD

EXPERIMENTAL

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 2: MAD placebo

PLACEBO COMPARATOR

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.

Drug: Placebo

Part 3: DDI

EXPERIMENTAL

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; Drug: Midazolam

Interventions

RO6953958 DRUG

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).

Part 1: SAD/FE; Part 2: MAD; Part 3: DDI

Placebo DRUG

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.

Part 1: SAD placebo; Part 2: MAD placebo

Midazolam DRUG

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.

Part 3: DDI

Eligibility Criteria

• Age: 18 Years - 55 Years
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Hoffmann-La Roche: lead

Study Sites (1)

Hammersmith Medicines Research; Central Middlesex Hospital

London, NW10 7EW, United Kingdom

Location

MeSH Terms

Conditions

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

Interventions

Midazolam

Intervention Hierarchy (Ancestors)

Benzodiazepines; Benzazepines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Results Point of Contact

• Title: Medical Communications
• Organization: Hoffmann-La Roche

genentech@druginfo.com

800 821-8590

Study Officials

• Clinical Trials

  Hoffmann-La Roche

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 13, 2020
• First Posted: July 17, 2020
• Study Start: July 15, 2020
• Primary Completion: February 6, 2022
• Study Completion: February 6, 2022
• Last Updated: July 10, 2024
• Results First Posted: July 10, 2024

Record last verified: 2024-07

Data Sharing

• IPD Sharing: Will not share

Locations

GB (1)