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

Healthy Volunteer Clinical Trial

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02254759
• Other study ID #: WP29393
• Secondary ID: 2014-001850-41
• Status: Completed
• Phase: Phase 1
• First received: September 23, 2014
• Last updated: November 1, 2016
• Start date: October 2014
• Est. completion date: November 2014

Study information

• Verified date: November 2016
• Source: Hoffmann-La Roche
• Contact: n/a
• Is FDA regulated: No
• Health authority: United Kingdom: Medicines and Healthcare Products Regulatory Agency
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 12
• Est. completion date: November 2014
• Est. primary completion date: November 2014
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Both
• Age group: 18 Years to 60 Years

Eligibility

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 Design

Allocation: Non-Randomized, Endpoint Classification: Pharmacokinetics/Dynamics Study, Intervention Model: Crossover Assignment, Masking: Open Label

Related Conditions & MeSH terms

• Healthy Volunteer

Intervention

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).
• 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.
• RO5186582
RO5186582 120 mg film-coated release tablet.

Locations

Country	Name	City	State
n/a

Sponsors (1)

Lead Sponsor	Collaborator
Hoffmann-La Roche

Country where clinical trial is conducted

United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	No
Primary	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	No
Primary	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	No
Primary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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)	No
Secondary	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)	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	Change from Baseline in Concentration of 4 Beta-Hydroxy Cholesterol		D1 (Baseline) and D17	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No