Clinical trial NCT02254759: A Study of RO5186582 Treatment on Cytochrome P450 (CYP) 3A4 Activity in Healthy Participants
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Healthy Volunteer
Lead sponsor: Hoffmann-La Roche
Sponsor class: INDUSTRY
First posted: 2014-10-02
Enrollment: 12
Sex: ALL
Minimum age (years): 18
Maximum age (years): 60
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: NON_RANDOMIZED
Intervention model: CROSSOVER

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.


Eligibility criteria: 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

Primary outcomes:
measure: Bioavailability of Drug (F) for Oral Midazolam
timeFrame: 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
measure: Total Plasma Clearence (CL) for IV Midazolam
timeFrame: 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
measure: Apparent Volume of Distribution at Steady-State (Vss) for IV Midazolam
timeFrame: 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
measure: Maximum Observed Plasma Concentration (Cmax) for Oral Midazolam
timeFrame: 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:
measure: Apparent Volume of Distribution (V/F) for Oral Midazolam
timeFrame: 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
measure: 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)
timeFrame: 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
measure: Cmax for RO5186582 and RO5271857 (metabolite of RO5186582)
timeFrame: 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)
measure: Tmax for RO5186582 and RO5271857 (metabolite of RO5186582)
timeFrame: 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)
measure: Metabolic Ratio Based on AUC0-inf for IV Midazolam
timeFrame: 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
measure: Change From Baseline in Event-Related Potential (ERP) parameters Using Oddball Auditory
timeFrame: 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
measure: Change from Baseline in Electroencephalogram (EEG) Parameters
timeFrame: 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
measure: Change From Baseline in Saccadic Eye Movement (SEM) Parameters
timeFrame: D-1 (Baseline) and D16 at 1 h pd, time-matched to planned time, and D2 and D18 at 1 h pd
measure: Change From Baseline in Attention and Memory of Selected Domains of Repeatable Battery for the Assessment of Neuropyschological Status (RBANSTM)
timeFrame: 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
measure: Change from Baseline in Concentration of 4 Beta-Hydroxy Cholesterol
timeFrame: D1 (Baseline) and D17
measure: Area Under the Plasma Concentration Time Curve from Zero to Infinity (AUC0-inf) for Oral and IV Midazolam
timeFrame: 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
measure: Cmax for IV Midazolam
timeFrame: 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
measure: Area Under the Plasma Concentration Time Curve from Zero to Last Measurable Concentration (AUC[0-last]) for Oral and IV Midazolam
timeFrame: 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
measure: Time to Maximum Observed Concentration (Tmax) for Oral and IV Midazolam
timeFrame: 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
measure: Terminal Elimination Half-Life (t1/2) for Oral and IV Midazolam
timeFrame: 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
measure: Apparent Clearence (CL/F) for Oral Midazolam
timeFrame: 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
Other outcomes:
Locations:
city: Leeds
country: United Kingdom
Study officials:
affiliation: Hoffmann-La Roche
name: Clinical Trials
role: STUDY_DIRECTOR
References: