A Study of RO5186582 Treatment on Cytochrome P450 (CYP) 3A4 Activity in Healthy Participants

This is a non-randomized, open-label, five treatment, fixed sequence cross-over study to investigate the effect of RO5186582 treatment on CYP3A activity using midazolam as a probe CYP3A substrate, and also to assess the pharmacodynamic measures of brain electrical activity and sedation to explore the pharmacodynamic interaction between the gama-amino butyric acid (GABA)A negative allosteric modulator RO5186582 and the prototypical GABAA positive allosteric modulator midazolam. The anticipated study duration is up to nine weeks.

Study Overview

• Status: Completed
• Conditions: Healthy Volunteer
• Intervention / Treatment: Drug: Midazolam, IV; Drug: Midazolam, oral; Drug: RO5186582

• Study Type: Interventional
• Enrollment (Actual): 12
• Phase: Phase 1

Contacts and Locations

Study Locations

• United Kingdom
  • Leeds, United Kingdom, LS2 9LH

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 60 years (Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Healthy participants with signed informed consent.

Exclusion Criteria:

• A history of epilepsy, convulsions or significant head injury
• Significant history of drug allergy, as determined by the Investigator, or a known hypersensitivity to any of the ingredients of any of the study treatments
• Use of any drugs or substances, including herbal treatments such as St John's Wort, that are known to be substrates, inducers or inhibitors of CYP3A4 within 30 days of the first dose administration
• Pregnant or lactating
• Any other clinically relevant abnormalities, concomitant diseases or ongoing medical conditions

Study Plan

How is the study designed?

Design Details

• Allocation: Non-Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: IV Midazolam Alone; A single 1 milligram (mg) dose of IV Midazolam on Day 1.	Drug: Midazolam, IV; 2 milligrams per milliliter (mg/mL) midazolam solution for IV administration. For a 1 mg dose, the midazolam solution (0.5 mL of 2 mg/mL) will be injected at 2 milligrams per minute (mg/min).
Other: Oral Midazolam Alone; A single 5 mg oral dose of midazolam on Day 2.	Drug: Midazolam, oral; 0.1 mg/mL midazolam for oral administration. For a 5 mg dose, participants will receive 50 mL of 0.1 mg/mL midazolam.
Experimental: RO5186582 Alone; RO5186582 240 mg oral tablet twice daily (BID) for 14 days from Days 3 to 16.	Drug: RO5186582; RO5186582 120 mg film-coated release tablet.
Experimental: RO5186582 Plus IV Midazolam; RO5186582 240 mg BID oral tablet in combination with a single 1 mg IV dose of midazolam on Day 17.	Drug: Midazolam, IV; 2 milligrams per milliliter (mg/mL) midazolam solution for IV administration. For a 1 mg dose, the midazolam solution (0.5 mL of 2 mg/mL) will be injected at 2 milligrams per minute (mg/min).; Drug: RO5186582; RO5186582 120 mg film-coated release tablet.
Experimental: RO5186582 Plus Oral Midazolam; RO5186582 240 mg BID in combination with a single 5 mg oral dose of midazolam on Day 18.	Drug: Midazolam, oral; 0.1 mg/mL midazolam for oral administration. For a 5 mg dose, participants will receive 50 mL of 0.1 mg/mL midazolam.; Drug: RO5186582; RO5186582 120 mg film-coated release tablet.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Bioavailability of Drug (F) for Oral Midazolam	Pre-dose [-0.5 hour (h)] and 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10 and 14 h post-dose (pd) on Day (D) 2 and 18, and 22 h pd on D3 and 19
Total Plasma Clearence (CL) for IV Midazolam	Pre-dose [-10 minutes (min)] and 0.08 (5 min), 0.25 (15 min), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10 and 14 h pd on D1 and D17, and 22 h pd on D2 and D18
Apparent Volume of Distribution at Steady-State (Vss) for IV Midazolam	Pre-dose (-10 min) and 0.08 (5 min), 0.25 (15 min), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10 and 14 h pd on D1 and D17, and 22 h pd on D2 and D18
Maximum Observed Plasma Concentration (Cmax) for Oral Midazolam	Pre-dose (-0.5 h) and 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10 and 14 h pd on D2 and 18, and 22 h pd on D3 and D19

Secondary Outcome Measures

Outcome Measure	Time Frame
Apparent Volume of Distribution (V/F) for Oral Midazolam	Pre-dose (-0.5 h) and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10 and 14 h pd on D2 and D18, and 22 h pd on D3 and D19
Area Under the Plasma Concentration Time Curve from Time Zero to Time Tau, Where Tau is the Dosing Interval (AUC0-tau) for RO5186582 and RO5271857 (metabolite of RO5186582)	D18: Pre-dose -0.17 h (10 min) and 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10 and 12 h pd
Cmax for RO5186582 and RO5271857 (metabolite of RO5186582)	Pre-dose (10 min) and 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10 and 12 h pd on D18 (timepoints relative to oral midazolam dosing are (- 2 h 10 min), -1.5, -1, -0.5, 0 h pre-dose and 1, 2, 3, 4, 6, 8, and 10 h pd)
Tmax for RO5186582 and RO5271857 (metabolite of RO5186582)	Pre-dose (10 min) and 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10 and 12 h pd on D18 (timepoints relative to oral midazolam dosing are (- 2 h 10 min), -1.5, -1, -0.5, 0 h pre-dose and 1, 2, 3, 4, 6, 8, and 10 h pd)
Metabolic Ratio Based on AUC0-inf for IV Midazolam	Pre-dose (-10 min) and 0.08 (5 min), 0.25 (15 min), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10 and 14 h pd on D1 and D17, and 22 h pd on D2 and D18
Change From Baseline in Event-Related Potential (ERP) parameters Using Oddball Auditory	D-1 (Baseline) and D16 at 1 and 4 h pd, time-matched to planned time, and D2 and D8 at 1 and 4 h pd
Change from Baseline in Electroencephalogram (EEG) Parameters	D-1 (Baseline) and D16 at 1 and 4 h pd, time-matched to planned time, and D2 and D8 at 1 and 4 h pd
Change From Baseline in Saccadic Eye Movement (SEM) Parameters	D-1 (Baseline) and D16 at 1 h pd, time-matched to planned time, and D2 and D18 at 1 h pd
Change From Baseline in Attention and Memory of Selected Domains of Repeatable Battery for the Assessment of Neuropyschological Status (RBANSTM)	D-1 (Baseline) and D16 at 2 and 5 h pd, time-matched to planned time, and D2 and D18 at 2 and 5 h pd
Change from Baseline in Concentration of 4 Beta-Hydroxy Cholesterol	D1 (Baseline) and D17
Area Under the Plasma Concentration Time Curve from Zero to Infinity (AUC0-inf) for Oral and IV Midazolam	Midazolam (MDZ)-oral: pre-dose (-0.5 h) and 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10 and 14 h pd on D2 and 18, and 22 h pd on D3 and 19; MDZ-IV: Pre-dose (-10 min) and 5, 15 min, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10 and 14 h pd on D1 and 17, and 22 h pd on D2 and 18
Cmax for IV Midazolam	Pre-dose (-10 min) and 5, 15 min, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10 and 14 h pd on D1 and 17, and 22 h pd on D2 and 18
Area Under the Plasma Concentration Time Curve from Zero to Last Measurable Concentration (AUC[0-last]) for Oral and IV Midazolam	MDZ-oral: pre-dose (-0.5 h) and 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10 and 14 h pd on D2 and 18, and 22 h pd on D3 and 19; MDZ-IV: Pre-dose (-10 min) and 5, 15 min, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10 and 14 h pd on D1 and 17, and 22 h pd on D2 and 18
Time to Maximum Observed Concentration (Tmax) for Oral and IV Midazolam	MDZ-oral: pre-dose (-0.5 h) and 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10 and 14 h pd on D2 and 18, and 22 h pd on D3 and 19; MDZ-IV: Pre-dose (-10 min) and 5, 15 min, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10 and 14 h pd on D1 and 17, and 22 h pd on D2 and 18
Terminal Elimination Half-Life (t1/2) for Oral and IV Midazolam	MDZ-oral: pre-dose (-0.5 h) and 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10 and 14 h pd on D2 and 18, and 22 h pd on D3 and 19; MDZ-IV: Pre-dose (-10 min) and 5, 15 min, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10 and 14 h pd on D1 and 17, and 22 h pd on D2 and 18
Apparent Clearence (CL/F) for Oral Midazolam	Pre-dose (-0.5 h) and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10 and 14 h pd on D2 and D18, and 22 h pd on D3 and D19

Collaborators and Investigators

• Sponsor: Hoffmann-La Roche

Study record dates

Study Major Dates

• Study Start: October 1, 2014
• Primary Completion (Actual): November 1, 2014
• Study Completion (Actual): November 1, 2014

Study Registration Dates

• First Submitted: September 23, 2014
• First Submitted That Met QC Criteria: September 29, 2014
• First Posted (Estimate): October 2, 2014

Study Record Updates

• Last Update Posted (Estimate): November 2, 2016
• Last Update Submitted That Met QC Criteria: November 1, 2016
• Last Verified: November 1, 2016

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Anesthetics, Intravenous; Anesthetics, General; Anesthetics; Tranquilizing Agents; Psychotropic Drugs; Hypnotics and Sedatives; Adjuvants, Anesthesia; Anti-Anxiety Agents; GABA Modulators; GABA Agents; Midazolam
• Other Study ID Numbers: WP29393; 2014-001850-41 (EudraCT Number)