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

NCT02254759 | Completed Phase 1

• 2 other identifiers: WP293932014-001850-41
• Study Type: interventional
• Target: 12
• Locations: 1 country
• Sites: 1

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.

Conditions

Healthy Volunteer

Outcome Measures

Primary Outcomes (4)

• 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 Outcomes (16)

• 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

Study Arms (5)

IV Midazolam Alone

OTHER

A single 1 milligram (mg) dose of IV Midazolam on Day 1.

Drug: Midazolam, IV

Oral Midazolam Alone

OTHER

A single 5 mg oral dose of midazolam on Day 2.

Drug: Midazolam, oral

RO5186582 Alone

EXPERIMENTAL

RO5186582 240 mg oral tablet twice daily (BID) for 14 days from Days 3 to 16.

Drug: RO5186582

RO5186582 Plus IV Midazolam

EXPERIMENTAL

RO5186582 240 mg BID oral tablet in combination with a single 1 mg IV dose of midazolam on Day 17.

Drug: Midazolam, IV; Drug: RO5186582

RO5186582 Plus Oral Midazolam

EXPERIMENTAL

RO5186582 240 mg BID in combination with a single 5 mg oral dose of midazolam on Day 18.

Drug: Midazolam, oral; Drug: RO5186582

Interventions

Midazolam, IV DRUG

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).

IV Midazolam Alone; RO5186582 Plus IV Midazolam

Midazolam, oral DRUG

0.1 mg/mL midazolam for oral administration. For a 5 mg dose, participants will receive 50 mL of 0.1 mg/mL midazolam.

Oral Midazolam Alone; RO5186582 Plus Oral Midazolam

RO5186582 DRUG

RO5186582 120 mg film-coated release tablet.

RO5186582 Alone; RO5186582 Plus IV Midazolam; RO5186582 Plus Oral Midazolam

Eligibility Criteria

• Age: 18 Years - 60 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Healthy participants with signed informed consent.

You may not qualify if:

• 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

Sponsors & Collaborators

• Hoffmann-La Roche: lead

Study Sites (1)

Unknown Facility

Leeds, LS2 9LH, United Kingdom

Location

MeSH Terms

Interventions

Midazolam

Intervention Hierarchy (Ancestors)

Benzodiazepines; Benzazepines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Study Officials

• Clinical Trials

  Hoffmann-La Roche

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Intervention Model: CROSSOVER
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 23, 2014
• First Posted: October 2, 2014
• Study Start: October 1, 2014
• Primary Completion: November 1, 2014
• Study Completion: November 1, 2014
• Last Updated: November 2, 2016

Record last verified: 2016-11

Locations

GB (1)