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

Phase 1

Completed

• Conditions: Healthy Volunteer
• Interventions: Drug: RO5186582; Drug: Midazolam, oral; Drug: Midazolam, IV

• Registration Number: NCT02254759
• Lead Sponsor: Hoffmann-La Roche

Brief Summary

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.

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2014-09-23
• Study First Submitted QC: 2014-09-29
• Study Start: 2014-10
• Study First Posted: 2014-10-02
• Primary Completion: 2014-11
• Study Completion: 2014-11
• Status Verified: 2016-11
• Last Update Submitted: 2016-11-01
• Last Update Posted: 2016-11-02

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 12

Inclusion Criteria

• Healthy participants with signed informed consent.

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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

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
RO5186582 Alone	RO5186582	RO5186582 240 mg oral tablet twice daily (BID) for 14 days from Days 3 to 16.
RO5186582 Plus Oral Midazolam	Midazolam, oral	RO5186582 240 mg BID in combination with a single 5 mg oral dose of midazolam on Day 18.
IV Midazolam Alone	Midazolam, IV	A single 1 milligram (mg) dose of IV Midazolam on Day 1.
RO5186582 Plus IV Midazolam	Midazolam, IV	RO5186582 240 mg BID oral tablet in combination with a single 1 mg IV dose of midazolam on Day 17.
RO5186582 Plus IV Midazolam	RO5186582	RO5186582 240 mg BID oral tablet in combination with a single 1 mg IV dose of midazolam on Day 17.
Oral Midazolam Alone	Midazolam, oral	A single 5 mg oral dose of midazolam on Day 2.
RO5186582 Plus Oral Midazolam	RO5186582	RO5186582 240 mg BID in combination with a single 5 mg oral dose of midazolam on Day 18.

Primary Outcome Measures

Name	Time	Method
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

Name	Time	Method
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