A Study to Investigate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Food Effect of RO6953958 in Healthy Participants
- Conditions
- Autistic DisorderChild Development Disorders, PervasiveNeurodevelopmental DisordersMental DisordersAutism Spectrum Disorder
- Interventions
- Registration Number
- NCT04475848
- Lead Sponsor
- Hoffmann-La Roche
- 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.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- Male
- Target Recruitment
- 88
- 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.
- 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
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Part 1: SAD placebo 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. Part 2: MAD placebo 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. Part 1: SAD/FE RO6953958 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. Part 2: MAD RO6953958 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. Part 3: DDI Midazolam RO6953958 will be administered at the maximum dose QD that was tested in the ongoing Part 2 (MAD). Participants will also be administered midazolam. Part 3: DDI RO6953958 RO6953958 will be administered at the maximum dose QD that was tested in the ongoing Part 2 (MAD). Participants will also be administered midazolam.
- Primary Outcome Measures
Name Time Method 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 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 2: Number of Participants With Post-baseline Suicide Risk, Assessed Using the Columbia Suicide Severity Rating Scale (C-SSRS) From randomization up to 8 weeks 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.
- Secondary Outcome Measures
Name Time Method Part 3: Fraction Absorbed (F) of Midazolam Days 2 and 14 F is stated as a fraction of 1.
Parts 2 and 3: Average Plasma Concentration (Cavg) of RO6953958 and Its Metabolites RO7021594 and RO7045755 Day 1-14 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 Day 1-5 Parts 1 and 2: Cumulative Amount of Unchanged Drug Excreted Into the Urine (Ae) of RO6953958 Day 1 and 10 Parts 1 and 2: Fraction of the Administered Drug Excreted Into the Urine (Fe) of RO6953958 Day 1 and 10 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 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: 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 1-10 Parts 2 and 3: Accumulation Ratio Based on Ctrough (RCtrough) of RO6953958 and Its Metabolites RO7021594 and RO7045755 Day 1-14 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 Parts 1, 2 and 3: Maximum Observed Plasma Concentration (Cmax) of RO6953958 and Its Metabolites RO7021594 and RO7045755 Day 1-14 Part 1: Time To the Last Quantifiable Concentration (Tlast) of RO6953958 and Its Metabolites RO7021594 and RO7045755 Day 1-10 Parts 1, 2 and 3: Terminal Elimination Phase Half-Life (t1/2) of RO6953958 and Its Metabolites RO7021594 and RO7045755 Day 1-14 Parts 2 and 3: Area Under the Concentration-Time Curve (AUC(0-t)) of RO6953958 and Its Metabolites RO7021594 and RO7045755 Day 1-14 Parts 2 and 3: Trough Plasma Concentration (Ctrough) of RO6953958 and Its Metabolites RO7021594 and RO7045755 Day 1, 3, 10, 12, 13 Part 3: T1/2 of Midazolam Day 1-14 A single IV dose of 100 ug midazolam was administered on Day 1 and Day 13. A single oral dose 300 ug of midazolam was administered on Day 2 and Day 14. RO6953958 was administrated once daily at 210 mg from Day 3 up to Day 14 so concomitantly with IV dose of midazolam on Day 13 and with oral dose of midazolam on Day 14.
Part 3: VF of Oral Midazolam Day 2-14 Part 1: Last Quantifiable Concentration (Clast) of RO6953958 and Its Metabolites RO7021594 and RO7045755 in Fasted and Fed State Day 1-10 Part 1: Area Under the Plasma Concentration Versus Time Curve Extrapolated to Infinity (AUC0-inf) of RO6953958 and Its Metabolites RO7021594 and RO7045755 Day 1-10 Parts 1, 2 and 3: Apparent Volume of Distribution (V/F) of RO6953958 Day 1-14 Parts 1 and 2: Renal Clearance of the Drug From Urine (CLR) of RO6953958 Day 1 and 10 Parts 2 and 3: Accumulation Ratio Based on Cmax (RCmax) of RO6953958 and Its Metabolites RO7021594 and RO7045755 Day 1-14 Part 3: Cmax of Midazolam Day 1-14 A single IV dose of 100 ug midazolam was administered on Day 1 and Day 13. A single oral dose 300 ug of midazolam was administered on Day 2 and Day 14. RO6953958 was administrated once daily at 210 mg from Day 3 up to Day 14 so concomitantly with IV dose of midazolam on Day 13 and with oral dose of midazolam on Day 14.
Part 3: RAUC of Midazolam Days 13 and 14 Part 3: RCmax of Midazolam Days 13 and 14 Parts 1, 2 and 3: Apparent Clearance (CL/F) of RO6953958 Day 1-14 Parts 2 and 3: Accumulation Ratio Based on AUC (RAUC) of RO6953958 and Its Metabolites RO7021594 and RO7045755 Day 1-14 Part 3: Tmax of Midazolam Day 1-14 A single IV dose of 100 ug midazolam was administered on Day 1 and Day 13. A single oral dose 300 ug of midazolam was administered on Day 2 and Day 14. RO6953958 was administrated once daily at 210 mg from Day 3 up to Day 14 so concomitantly with IV dose of midazolam on Day 13 and with oral dose of midazolam on Day 14.
Part 3: AUClast of Midazolam Day 1-14 A single IV dose of 100 ug midazolam was administered on Day 1 and Day 13. A single oral dose 300 ug of midazolam was administered on Day 2 and Day 14. RO6953958 was administrated once daily at 210 mg from Day 3 up to Day 14 so concomitantly with IV dose of midazolam on Day 13 and with oral dose of midazolam on Day 14.
Part 3: AUCinf of Midazolam Day 1-14 A single IV dose of 100 ug midazolam was administered on Day 1 and Day 13. A single oral dose 300 ug of midazolam was administered on Day 2 and Day 14. RO6953958 was administrated once daily at 210 mg from Day 3 up to Day 14 so concomitantly with IV dose of midazolam on Day 13 and with oral dose of midazolam on Day 14.
Part 3: CL: Total Plasma Clearance of IV Midazolam Days 1 and 13 Part 3: Volume of Distribution Under Steady-state Conditions (Vss) of Midazolam Days 3 and 14
Trial Locations
- Locations (1)
Hammersmith Medicines Research; Central Middlesex Hospital
🇬🇧London, United Kingdom