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

NCT ID: NCT04475848

Last Updated: 2024-07-10

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1
• Total Enrollment: 88 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2020-07-15
• Study Completion Date: 2022-02-06

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

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: DOUBLE

Study Groups

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.

Group Type: EXPERIMENTAL

RO6953958

Intervention Type: 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 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.

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: 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 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.

Group Type: EXPERIMENTAL

RO6953958

Intervention Type: 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 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.

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: 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 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.

Group Type: EXPERIMENTAL

RO6953958

Intervention Type: 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).

Midazolam

Intervention Type: 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.

Interventions

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).

Intervention Type: 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.

Intervention Type: 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.

Intervention Type: DRUG

Eligibility Criteria

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

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 55 Years
• Eligible Sex: MALE
• Accepts Healthy Volunteers: Yes

Sponsors

Hoffmann-La Roche

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Clinical Trials

Role: STUDY_DIRECTOR

Hoffmann-La Roche

Locations

Hammersmith Medicines Research; Central Middlesex Hospital

London, , United Kingdom

Countries

United Kingdom

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Other Identifiers

2019-004486-41

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

BP41695

Identifier Type: -

Identifier Source: org_study_id