Phase 1
Completed N=88
A Study to Investigate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Food Effect of RO6953958 in Healthy Participants
Autistic Disorder · Autism Spectrum Disorder · Child Development Disorders, Pervasive · Mental Disorders
Source: ClinicalTrials.gov NCT04475848 ↗
Enrolled (actual)
88
Serious AEs
0.0%
Results posted
Jul 2024
Primary outcomePrimary: Parts 1, 2 and 3: Percentage of Participants With Adverse Events — 2; 2; 2; 4 Participants
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.
Outcome Measures
| Outcome | Result | p-value |
|---|---|---|
| PRIMARY Parts 1, 2 and 3: Percentage of Participants With Adverse Events |
2; 2; 2; 4; 2; 3 | — |
| PRIMARY Part 2: Number of Participants With Post-baseline Suicide Risk, Assessed Using the Columbia Suicide Severity Rating Scale (C-SSRS) |
0; 0; 0; 0; 0; 0 | — |
| SECONDARY Parts 1, 2 and 3: Maximum Observed Plasma Concentration (Cmax) of RO6953958 and Its Metabolites RO7021594 and RO7045755 |
70.3; 150; 299; 451; 932; 618 | — |
| SECONDARY Parts 2 and 3: Average Plasma Concentration (Cavg) of RO6953958 and Its Metabolites RO7021594 and RO7045755 |
81.47; 279.87; 496.48; 531.60; 87.96; 283.22 | — |
| SECONDARY Parts 1, 2 and 3: Time to Reach Maximum Observed Plasma Concentration (Tmax) of RO6953958 and Its Metabolites RO7021594 and RO7045755 |
1.00; 1.00; 2.00; 2.00; 4.00; 2.00 | — |
| SECONDARY Part 1: Last Quantifiable Concentration (Clast) of RO6953958 and Its Metabolites RO7021594 and RO7045755 in Fasted and Fed State |
3.88; 4.42; 5.98; 6.75; 11.1; 8.99 | — |
| SECONDARY Part 1: Time To the Last Quantifiable Concentration (Tlast) of RO6953958 and Its Metabolites RO7021594 and RO7045755 |
9.44; 16.47; 21.40; 51.37; 24.00; 70.14 | — |
| SECONDARY Parts 1, 2 and 3: Terminal Elimination Phase Half-Life (t1/2) of RO6953958 and Its Metabolites RO7021594 and RO7045755 |
1.75; 3.43; 3.98; 9.54; 3.57; 13.1 | — |
| SECONDARY Parts 2 and 3: Area Under the Concentration-Time Curve (AUC(0-t)) of RO6953958 and Its Metabolites RO7021594 and RO7045755 |
1830; 5820; 11600; 11400; 2010; 6060 | — |
| SECONDARY 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 |
204; 665; 1740; 4140; 5330; 6170 | — |
| 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 |
188; 651; 1730; 4990; 5330; 9470 | — |
| SECONDARY Part 1: Area Under the Plasma Concentration Versus Time Curve Extrapolated to Infinity (AUC0-inf) of RO6953958 and Its Metabolites RO7021594 and RO7045755 |
206; 676; 1780; 5120; 5410; 9710 | — |
| SECONDARY Parts 1, 2 and 3: Apparent Clearance (CL/F) of RO6953958 |
24.3; 22.2; 25.2; 17.6; 16.6; 18.5 | — |
| SECONDARY Parts 1, 2 and 3: Apparent Volume of Distribution (V/F) of RO6953958 |
89.1; 110; 145; 242; 85.8; 45.5 | — |
| SECONDARY Parts 1 and 2: Cumulative Amount of Unchanged Drug Excreted Into the Urine (Ae) of RO6953958 |
0.0322; 0.133; 0.266; 0.612; 0.321; 0.675 | — |
| SECONDARY Parts 1 and 2: Fraction of the Administered Drug Excreted Into the Urine (Fe) of RO6953958 |
0.644; 0.888; 0.592; 0.679; 0.356; 0.375 | — |
| SECONDARY Parts 1 and 2: Renal Clearance of the Drug From Urine (CLR) of RO6953958 |
115; 142; 123; 116; 49.9; 56.2 | — |
| SECONDARY Parts 2 and 3: Trough Plasma Concentration (Ctrough) of RO6953958 and Its Metabolites RO7021594 and RO7045755 |
0.473; 31.0; 82.4; 60.78; 1.20; 24.2 | — |
| SECONDARY Parts 2 and 3: Accumulation Ratio Based on AUC (RAUC) of RO6953958 and Its Metabolites RO7021594 and RO7045755 |
1.10; 1.04; 0.794; 1.25; 1.81; 1.87 | — |
| SECONDARY Parts 2 and 3: Accumulation Ratio Based on Cmax (RCmax) of RO6953958 and Its Metabolites RO7021594 and RO7045755 |
1.05; 1.05; 0.856; 1.14; 1.63; 1.77 | — |
| SECONDARY Parts 2 and 3: Accumulation Ratio Based on Ctrough (RCtrough) of RO6953958 and Its Metabolites RO7021594 and RO7045755 |
— | — |
| SECONDARY Parts 1, 2 and 3: Molecular Weight Adjusted Metabolite-to-Parent Ratio for Cmax of RO6953958 and Its Metabolites RO7021594 and RO7045755 |
0.839; 1.20; 1.54; 1.05; 0.846; 1.91 | — |
| 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 |
6.98; 7.30; 6.81; 3.97; 3.84; 7.39 | — |
| SECONDARY Part 3: Tmax of Midazolam |
0.08; 0.75; 0.08; 0.63 | — |
| SECONDARY Part 3: Cmax of Midazolam |
2410; 1200; 2030; 1250 | — |
| SECONDARY Part 3: T1/2 of Midazolam |
4.38; 4.44; 4.69; 4.55 | — |
| SECONDARY Part 3: AUClast of Midazolam |
3550; 4140; 3790; 4470 | — |
| SECONDARY Part 3: AUCinf of Midazolam |
3630; 4270; 3910; 4630 | — |
| SECONDARY Part 3: VF of Oral Midazolam |
450; 426 | — |
| SECONDARY Part 3: RAUC of Midazolam |
1.07; 1.08 | — |
| SECONDARY Part 3: RCmax of Midazolam |
0.844; 1.05 | — |
| SECONDARY Part 3: CL: Total Plasma Clearance of IV Midazolam |
27.6; 25.6 | — |
| SECONDARY Part 3: Fraction Absorbed (F) of Midazolam |
0.391; 0.396 | — |
| SECONDARY Part 3: Volume of Distribution Under Steady-state Conditions (Vss) of Midazolam |
161; 142 | — |
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
Data sourced from ClinicalTrials.gov (NCT04475848). Outcome figures and adverse-event rates are extracted automatically from the registry's posted results and are provided for clinician reference, not as a substitute for the primary publication. Informational only — not medical advice.