A phase III randomised, triple-blind controlled superiority trial of remimazolam (CNS 7056), compared to midazolam, in adults having lower third molar wisdom tooth extraction under intravenous conscious sedation to assess cognitive and motor recovery at normal discharge times

INTERVENTION: Participants will be randomised in a 1:1 ratio (remimazolam: midazolam). Randomisation will use permuted blocks of varying sizes and will be undertaken via a bespoke online randomisation service. In the remimazolam arm, patients will be given an initial dose of 5 mg (2 ml) over 60 seconds, pausing for 90 seconds, followed by 2.5 mg (1 ml) over 30 seconds and waiting 30 seconds will be titrated to the response endpoint. Subsequent doses of 2.5 mg (1 ml) increments can be administered if required should the procedure take longer, or the patient recovers more quickly than expected, to maintain the sedation level. Top‐up doses will be administered slowly, at least 2 minutes apart. Top‐up doses will be limited to a maximum of 5 doses in a 15‐minute window. Additionally, a maximum dose of 40 mg of remimazolam (16 ml) will be set. In the midazolam arm, dosing of midazolam was based on local formulary and standard of care/local guidance. An initial dose of 2 mg (2 ml) over 60 seconds, pausing for 90 seconds, followed by 1 mg (1 ml) over 30 seconds and waiting 30 seconds will be titrated to the response endpoint. Subsequent doses of 1 mg (1 ml) increments can be administered if required should the procedure take longer, or the patient recovers more quickly than expected, to maintain the sedation level. Top‐up doses will be administered slowly at least 2 minutes apart. Top‐up doses will be limited to a maximum of 5 doses in a 15‐minute window. Additionally, a maximum dose of 16 mg of midazolam (16 ml) will be set. The patient will have the treatment on the day of their procedure only. Prior to their procedure, each patient will undergo memory and balance testing, which will be repeated again once the procedure is CONDITION: Low risk mandibular third molar wisdom tooth extraction ; Oral Health PRIMARY OUTCOME: Verbal learning measured using the Hopkins Verbal Learning Test Revised (HVLT(R)) at baseline and 60 min from last dose of Investigational Medicinal Product (IMP) vs midazolam (T60) INCLUSION CRITERIA: 1. Healthy adult male and female patients aged between 18 and 59 years old 2. Scheduled to have low risk mandibular third molar wisdom tooth extraction with intravenous conscious sedation SECONDARY OUTCOME: ; 1. Recovery measured using the proportion of patients returning to within 1 standard error (SE) of pre‐dose cognitive and motor testing, measured using HVLT(R), Digit Symbol Substitution Test (DSST), Multi‐Operational Apparatus for Reaction Time (MOART) and sway scores at baseline and 60 min from last IMP dose (T60); 2. Cognitive operation measured using the Digit Symbol Substitution Test (DSST) at baseline and 60 min from last IMP dose (T60); 3. Sway measured using the scales for assessment and rating of ataxia (balance board) at baseline and T60; 4. Reaction time measured using MOART device by choice reaction time (with Go/No Go) at baseline and last dose of IMP (T60); 5. The times to fully alert (first of three Modified Observer's Assessment of Alertness/Sedation (MOAA/S) scores of 5) after the end of the procedure (surgical “time out”) and after the last IMP dose (T60); 6. The times to ready for discharge after the end of the procedure (surgical “time out”) measured using Clinical Walk and orientation test; 7. The overall co‐operation score given by the surgical team (Dental Sedation Teacher Groups (DSTG) score) at end of the procedure; 8. Occurrence of pain on injection at the application of study medication measured using the visual analogue score (VAS) at dosing; 9. The procedure failure rate due to inadequate sedation at the maximum dose/top‐up rate measured using the number of failures at the end of the trial; 10. Comparative safety measures of adverse events measured using the number of adverse events at the end of the trial;