A prospective dose escalation, nine period cross-over trial assessing the safety, pharmacokinetics, bioavailability and pharmacodynamics of escalating doses of Remimazolam when administered intranasally as powder and solution in healthy subjects and compared to an intravenous control
The design will be a randomized, double-blind, comparative, placebo- and active-controlled nine-period crossover study in healthy male volunteers. Subjects will be randomized and will receive each of the 9 treatments which will be separated by a minimum of 48 hours.The first treatment arm will always be the intravenous remimazolam. Eligible subjects will then be randomized to treatment sequence prior to study drug administration in treatment period 2. Each subject will participate in the study for up to 51 days, from Screening until Follow-up.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
QUADRUPLE
Enrollment
12
For induction and maintenance of sedation
Control arm
PRA Health Sciences
Salt Lake City, Utah, United States
Number of Participants with Treatment-related Adverse Events
Adverse events assessment will include: change in clinical laboratory assessments from baseline, change in vital signs from baseline, change in 12-lead electrocardiograms from baseline, drop in oxygen saturation measured using continuous pulse oximetry, nasal effect using the Nasal Effect Questionnaire (NEQ) and nose and throat examination. Adverse events with a respiratory or cardiovascular focus and adverse events related to effects seen with medications known to be associated with abuse will be analysed separately. The intensity, causality, outcome, seriousness and expectedness of adverse events will be assessed
Time frame: Predose until 180 minutes postdose
Alertness/Drowsiness using a bipolar 100-point Visual Analogue Scale (VAS)
maximum effect (Emax), time to Emax (TEmax), minimum effect (Emin) and area under the effect curve (AUEC) determined pre-dose, 5, 10, 30, 60 and 180 minutes post dose
Time frame: Predose until 180 minutes postdose
Agitation/Relaxation using a bipolar 100-point Visual Analogue Scale (VAS)
maximum effect (Emax), time to Emax (TEmax), minimum effect (Emin) and area under the effect curve (AUEC) determined pre-dose, 5, 10, 30, 60 and 180 minutes post dose
Time frame: Predose until 180 minutes postdose
Any Drug Effects using a unipolar 100-point Visual Analogue Scale (VAS)
maximum effect (Emax), time to Emax (TEmax), minimum effect (Emin) and area under the effect curve (AUEC) determined pre-dose, 5, 10, 30, 60 and 180 minutes post dose
Time frame: Predose until 180 minutes postdose
Memory/Amnestic Effects using the Paired Associates Learning (PALs) test
maximum effect (Emax), time to Emax (TEmax), minimum effect (Emin) and area under the effect curve (AUEC) determined pre-dose,10, 30, 60 and 180 minutes post dose
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Time frame: Predose until 180 minutes postdose
Reaction Time using the Reaction Time Test
maximum effect (Emax), time to Emax (TEmax), minimum effect (Emin) and area under the effect curve (AUEC) determined pre-dose, 20, 30, 60, 90, 120, 150 and 180 post dose
Time frame: Predose until 180 minutes postdose
Time to Maximum Observed Plasma Concentration (Tmax)
Time frame: From first dose of study drug until 240 minutes postdose
Maximum Observed Plasma Concentration (Cmax)
Time frame: From first dose of study drug until 240 minutes postdose
Area Under the Plasma Concentration-time Curve from Zero to the last Measurable Concentration (AUC0-last)
Time frame: From first dose of study drug until 240 minutes postdose
Area Under the Plasma Concentration-time Curve from Zero to Infinity (AUC0-∞)
Time frame: From first dose of study drug until 240 minutes postdose
Terminal Elimination Half-life (t1/2) for Remimazolam and its Metabolite (CNS7054)
Time frame: From first dose of study drug until 240 minutes postdose
Concentration at Time Zero (C0) for Intravenous Remimazolam and its Metabolite (CNS7054) Only
Time frame: From first dose of study drug until 240 minutes postdose
The Fraction in Percent as a Measurement of the Rate and Extent to Which a Drug Reaches the Site of Action (F%)
F% will be calculated for the highest dose level (40 mg) and dose-proportionality will be evaluated across the dose range of 10 - 40 mg for each formulation (powder and solution) as available. Dose proportionality is AUC0-∞ and Cmax based. Bioavailability will be dose adjusted.
Time frame: From first dose of study drug until 240 minutes postdose