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

Autism Spectrum Disorder Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04475848
• Other study ID #: BP41695
• Secondary ID: 2019-004486-41
• Status: Completed
• Phase: Phase 1
• Start date: July 15, 2020
• Est. completion date: February 6, 2022

Study information

• Verified date: February 2022
• Source: Hoffmann-La Roche
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 88
• Est. completion date: February 6, 2022
• Est. primary completion date: February 6, 2022
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Male
• Age group: 18 Years to 55 Years

Eligibility

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

Related Conditions & MeSH terms

• Autism Spectrum Disorder
• Autistic Disorder
• Child Development Disorders, Pervasive
• Developmental Disabilities
• Disease
• Mental Disorders
• Neurodevelopmental Disorders

Intervention

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
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.
• 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.

Locations

Country	Name	City	State
United Kingdom	Hammersmith Medicines Research; Central Middlesex Hospital	London

Sponsors (1)

Lead Sponsor	Collaborator
Hoffmann-La Roche

Country where clinical trial is conducted

United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	Part 2: Change in suicide risk assessed using the Columbia Suicide Severity Rating Scale (C-SSRS)		From randomization up to 8 weeks
Secondary	Parts 1, 2 and 3: Maximum Observed Plasma Concentration (Cmax) of RO6953958 and its Metabolites RO7021594 and RO7045755		Day 1-14
Secondary	Parts 2 and 3: Average Plasma Concentration (Cavg) of RO6953958 and its Metabolites RO7021594 and RO7045755		Day 1-14
Secondary	Parts 1, 2 and 3: Time to Reach Maximum Observed Plasma Concentration (Tmax) of RO6953958 and its Metabolites RO7021594 and RO7045755		Day 1-14
Secondary	Part 1: Last Quantifiable Concentration (Clast) of RO6953958 and its Metabolites RO7021594 and RO7045755 in Fasted and Fed state		Day 1-5
Secondary	Part 1: Time To the Last Quantifiable Concentration (Tlast) of RO6953958 and its Metabolites RO7021594 and RO7045755		Day 1-5
Secondary	Parts 1, 2 and 3: Terminal Elimination Phase Half-Life (t1/2) of RO6953958 and its Metabolites RO7021594 and RO7045755		Day 1-14
Secondary	Parts 2 and 3: Area Under the Concentration-Time Curve (AUC(0-t)) of RO6953958 and its Metabolites RO7021594 and RO7045755		Day 1-14
Secondary	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
Secondary	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
Secondary	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
Secondary	Parts 1, 2 and 3: Apparent Clearance (CL/F) of RO6953958		Day 1-14
Secondary	Parts 1, 2 and 3: Apparent Volume of Distribution (V/F) of RO6953958		Day 1-14
Secondary	Parts 1 and 2: Cumulative Amount of Unchanged Drug Excreted into the Urine (Ae) of RO6953958		Day 1-14
Secondary	Parts 1 and 2: Fraction of the Administered Drug Excreted into the Urine (Fe) of RO6953958		Day 1-14
Secondary	Parts 1 and 2: Renal Clearance of the Drug from Urine (CLR) of RO6953958		Day 1-14
Secondary	Parts 1, 2 and 3: Trough Plasma Concentration (Ctrough) of RO6953958 and its Metabolites RO7021594 and RO7045755		Day 1-14
Secondary	Parts 2 and 3: Accumulation Ratio based on AUC (RAUC) of RO6953958 and its Metabolites RO7021594 and RO7045755		Day 1-14
Secondary	Parts 2 and 3: Accumulation Ratio Based on Cmax (RCmax) of RO6953958 and its Metabolites RO7021594 and RO7045755		Day 1-14
Secondary	Parts 1, 2 and 3: Accumulation Ratio based on Ctrough (RCtrough) of RO6953958 and its Metabolites RO7021594 and RO7045755		Day 1-14
Secondary	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
Secondary	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
Secondary	Part 3: Tmax of Midazolam		Day 1-14
Secondary	Part 3: Cmax of Midazolam		Day 1-14
Secondary	Part 3: T1/2 of Midazolam		Day 1-14
Secondary	Part 3: AUClast of Midazolam		Day 1-14
Secondary	Part 3: AUCinf of Midazolam		Day 1-14
Secondary	Part 3: VF of oral Midazolam		Day 1-14
Secondary	Part 3: RAUC of Midazolam		Days 13 and 14
Secondary	Part 3: RCmax of Midazolam		Days 13 and 14
Secondary	Part 3: CL: Total Plasma Clearance of IV Midazolam		Days 1 and 13
Secondary	Part 3: Fraction Absorbed (F) of Midazolam		Day 1-14
Secondary	Part 3: Volume of Distribution under Steady-state Conditions (Vss) of Midazolam		Days 1 and 13