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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02254759
Recruitment Status : Completed
First Posted : October 2, 2014
Last Update Posted : November 2, 2016
Sponsor:
Information provided by (Responsible Party):
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.

Condition or disease Intervention/treatment Phase
Healthy Volunteer Drug: Midazolam, IV Drug: Midazolam, oral Drug: RO5186582 Phase 1

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 12 participants
Allocation: Non-Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)
Study Start Date : October 2014
Actual Primary Completion Date : November 2014
Actual Study Completion Date : November 2014

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
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).

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.




Primary Outcome Measures :
  1. Bioavailability of Drug (F) for Oral Midazolam [ Time Frame: 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 ]
  2. Total Plasma Clearence (CL) for IV Midazolam [ Time Frame: 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 ]
  3. Apparent Volume of Distribution at Steady-State (Vss) for IV Midazolam [ Time Frame: 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 ]
  4. Maximum Observed Plasma Concentration (Cmax) for Oral Midazolam [ Time Frame: 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 :
  1. Apparent Volume of Distribution (V/F) for Oral Midazolam [ Time Frame: 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 ]
  2. 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) [ Time Frame: 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 ]
  3. Cmax for RO5186582 and RO5271857 (metabolite of RO5186582) [ Time Frame: 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) ]
  4. Tmax for RO5186582 and RO5271857 (metabolite of RO5186582) [ Time Frame: 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) ]
  5. Metabolic Ratio Based on AUC0-inf for IV Midazolam [ Time Frame: 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 ]
  6. Change From Baseline in Event-Related Potential (ERP) parameters Using Oddball Auditory [ Time Frame: 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 ]
  7. Change from Baseline in Electroencephalogram (EEG) Parameters [ Time Frame: 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 ]
  8. Change From Baseline in Saccadic Eye Movement (SEM) Parameters [ Time Frame: D-1 (Baseline) and D16 at 1 h pd, time-matched to planned time, and D2 and D18 at 1 h pd ]
  9. Change From Baseline in Attention and Memory of Selected Domains of Repeatable Battery for the Assessment of Neuropyschological Status (RBANSTM) [ Time Frame: 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 ]
  10. Change from Baseline in Concentration of 4 Beta-Hydroxy Cholesterol [ Time Frame: D1 (Baseline) and D17 ]
  11. Area Under the Plasma Concentration Time Curve from Zero to Infinity (AUC0-inf) for Oral and IV Midazolam [ Time Frame: 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 ]
  12. Cmax for IV Midazolam [ Time Frame: 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 ]
  13. Area Under the Plasma Concentration Time Curve from Zero to Last Measurable Concentration (AUC[0-last]) for Oral and IV Midazolam [ Time Frame: 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 ]
  14. Time to Maximum Observed Concentration (Tmax) for Oral and IV Midazolam [ Time Frame: 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 ]
  15. Terminal Elimination Half-Life (t1/2) for Oral and IV Midazolam [ Time Frame: 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 ]
  16. Apparent Clearence (CL/F) for Oral Midazolam [ Time Frame: 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 ]


Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 60 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02254759


Locations
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United Kingdom
Leeds, United Kingdom, LS2 9LH
Sponsors and Collaborators
Hoffmann-La Roche
Investigators
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Study Director: Clinical Trials Hoffmann-La Roche
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Responsible Party: Hoffmann-La Roche
ClinicalTrials.gov Identifier: NCT02254759    
Other Study ID Numbers: WP29393
2014-001850-41 ( EudraCT Number )
First Posted: October 2, 2014    Key Record Dates
Last Update Posted: November 2, 2016
Last Verified: November 2016
Additional relevant MeSH terms:
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Midazolam
Adjuvants, Anesthesia
Hypnotics and Sedatives
Central Nervous System Depressants
Physiological Effects of Drugs
Anti-Anxiety Agents
Tranquilizing Agents
Psychotropic Drugs
Anesthetics, Intravenous
Anesthetics, General
Anesthetics
GABA Modulators
GABA Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action