Clinical trial NCT04475848: A Study to Investigate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Food Effect of RO6953958 in Healthy Participants
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Autistic Disorder
Autism Spectrum Disorder
Child Development Disorders, Pervasive
Mental Disorders
Neurodevelopmental Disorders
Keywords: Autism Spectrum Disorder
Lead sponsor: Hoffmann-La Roche
Sponsor class: INDUSTRY
First posted: 2020-07-17
Enrollment: 88
Sex: MALE
Minimum age (years): 18
Maximum age (years): 55
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


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

Primary outcomes:
measure: Parts 1, 2 and 3: Percentage of Participants With Adverse Events
timeFrame: 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
measure: Part 2: Number of Participants With Post-baseline Suicide Risk, Assessed Using the Columbia Suicide Severity Rating Scale (C-SSRS)
timeFrame: From randomization up to 8 weeks
Secondary outcomes:
measure: Parts 1, 2 and 3: Maximum Observed Plasma Concentration (Cmax) of RO6953958 and Its Metabolites RO7021594 and RO7045755
timeFrame: Day 1-14
measure: Parts 2 and 3: Average Plasma Concentration (Cavg) of RO6953958 and Its Metabolites RO7021594 and RO7045755
timeFrame: Day 1-14
measure: Parts 1, 2 and 3: Time to Reach Maximum Observed Plasma Concentration (Tmax) of RO6953958 and Its Metabolites RO7021594 and RO7045755
timeFrame: Day 1-14
measure: Part 1: Last Quantifiable Concentration (Clast) of RO6953958 and Its Metabolites RO7021594 and RO7045755 in Fasted and Fed State
timeFrame: Day 1-10
measure: Part 1: Time To the Last Quantifiable Concentration (Tlast) of RO6953958 and Its Metabolites RO7021594 and RO7045755
timeFrame: Day 1-10
measure: Parts 1, 2 and 3: Terminal Elimination Phase Half-Life (t1/2) of RO6953958 and Its Metabolites RO7021594 and RO7045755
timeFrame: Day 1-14
measure: Parts 2 and 3: Area Under the Concentration-Time Curve (AUC(0-t)) of RO6953958 and Its Metabolites RO7021594 and RO7045755
timeFrame: Day 1-14
measure: Part 1: Area Under the Plasma Concentration Versus Time Curve From Zero to 24h Postdose (AUC(0-24h)) of RO6953958 and Its Metabolites RO7021594 and RO7045755
timeFrame: Day 1-5
measure: 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
timeFrame: Day 1-10
measure: Part 1: Area Under the Plasma Concentration Versus Time Curve Extrapolated to Infinity (AUC0-inf) of RO6953958 and Its Metabolites RO7021594 and RO7045755
timeFrame: Day 1-10
measure: Parts 1, 2 and 3: Apparent Clearance (CL/F) of RO6953958
timeFrame: Day 1-14
measure: Parts 1, 2 and 3: Apparent Volume of Distribution (V/F) of RO6953958
timeFrame: Day 1-14
measure: Parts 1 and 2: Cumulative Amount of Unchanged Drug Excreted Into the Urine (Ae) of RO6953958
timeFrame: Day 1 and 10
measure: Parts 1 and 2: Fraction of the Administered Drug Excreted Into the Urine (Fe) of RO6953958
timeFrame: Day 1 and 10
measure: Parts 1 and 2: Renal Clearance of the Drug From Urine (CLR) of RO6953958
timeFrame: Day 1 and 10
measure: Parts 2 and 3: Trough Plasma Concentration (Ctrough) of RO6953958 and Its Metabolites RO7021594 and RO7045755
timeFrame: Day 1, 3, 10, 12, 13
measure: Parts 2 and 3: Accumulation Ratio Based on AUC (RAUC) of RO6953958 and Its Metabolites RO7021594 and RO7045755
timeFrame: Day 1-14
measure: Parts 2 and 3: Accumulation Ratio Based on Cmax (RCmax) of RO6953958 and Its Metabolites RO7021594 and RO7045755
timeFrame: Day 1-14
measure: Parts 2 and 3: Accumulation Ratio Based on Ctrough (RCtrough) of RO6953958 and Its Metabolites RO7021594 and RO7045755
timeFrame: Day 1-14
measure: Parts 1, 2 and 3: Molecular Weight Adjusted Metabolite-to-Parent Ratio for Cmax of RO6953958 and Its Metabolites RO7021594 and RO7045755
timeFrame: Day 1-14
measure: 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
timeFrame: Day 1-14
measure: Part 3: Tmax of Midazolam
timeFrame: Day 1-14
measure: Part 3: Cmax of Midazolam
timeFrame: Day 1-14
measure: Part 3: T1/2 of Midazolam
timeFrame: Day 1-14
measure: Part 3: AUClast of Midazolam
timeFrame: Day 1-14
measure: Part 3: AUCinf of Midazolam
timeFrame: Day 1-14
measure: Part 3: VF of Oral Midazolam
timeFrame: Day 2-14
measure: Part 3: RAUC of Midazolam
timeFrame: Days 13 and 14
measure: Part 3: RCmax of Midazolam
timeFrame: Days 13 and 14
measure: Part 3: CL: Total Plasma Clearance of IV Midazolam
timeFrame: Days 1 and 13
measure: Part 3: Fraction Absorbed (F) of Midazolam
timeFrame: Days 2 and 14
measure: Part 3: Volume of Distribution Under Steady-state Conditions (Vss) of Midazolam
timeFrame: Days 3 and 14
Other outcomes:
Locations:
city: London
country: United Kingdom
facility: Hammersmith Medicines Research; Central Middlesex Hospital
Study officials:
affiliation: Hoffmann-La Roche
name: Clinical Trials
role: STUDY_DIRECTOR
References: