A Phase IIb Study Comparing the Safety and Efficacy of Remimazolam and Midazolam in Colonoscopy Patients

Abstract

Introduction: This study compared the safety and efficacy profiles of remimazolam, a new ultra short acting benzodiazepine, with midazolam in patients undergoing routine colonoscopy. Methods: Patients ages 18 to 70, ASA I-III, BMI > 33 were randomized 1:1:1:1 to receive 1 of 3 doses of remimazolam (R), or midazolam(M), in this double-blind, parallel, multicenter study. For sedation induction, patients received an initial dose of either remimazolam (8.0, 7.0, or 5.0 mg) or midazolam (2.5 mg) by IV bolus and the sedation level was maintained throughout the procedure by bolus top-up doses of 3.0, 2.0, or 3.0 mg for the remimazolam groups respectively, or 1.0 mg of midazolam. All patients received 100 ug of IV fentanyl pre-treatment and supplemental oxygen at 2-4 LPM via nasal cannula. The protocol and informed consent form were IRB approved. The colonoscopy started when adequate sedation (MOAA/S ≤ 3) had been reached, and sedation was kept at a maintenance level (MOAA/S ≤ 4) by administration of appropriate top-up doses of study drug (R or M). Up to two top-up doses of (R or M) were allowed to induce sedation, and up to 6 top-up doses were allowed to maintain sedation (a maximum limit of 6 top-up doses were allowed). Sedative rescue was allowed if there was insufficient sedation to start or continue the procedure, which included sedation as per each sites usual protocol. The primary efficacy endpoint was success of the colonoscopy, defined as: 1.) MOAA/S ≤ 4 on 3 consecutive measurements taken every minute, 2.) Procedure completion, 3.) No requirement for alternative sedative, 4.) No manual or mechanical ventilation. Results: One hundred sixty patients, mean age 55, 88F, 72M, BMI avg 27 were randomized. R groups combined met the primary endpoint compared with M, with a success rate of > 92% for each of the R groups (R 8.0 mg- 92.5%, R 7.0 mg- 95%, R 6. 0mg - 97.5%), compared with 75% for M (p = 0.007). (R 8.0mg- N37/40, R 7.0mg- N38/40, R 6.0mg- N39/40, M 2.5mg- N30/40) There was no requirement for manual or mechanical ventilation in any group, and procedure failures were all due to use of rescue sedative. Recovery from sedation was rapid for R (means 11.3 - 13.6 mins) and unexpectedly short in the M group (15.2 mins), which may have been due to the limited top-ups allowed in the study. Conclusion: In this dose-finding study, the R 5/3 mg dose group demonstrated the highest efficacy rate and at the same time the best safety profile, indicating that this initial dose, combined with top up doses of up to 3 mg should be pursued in future studies. This study’s success in documenting both efficacy and safety warrants further investigation through confirmatory Phase 3 studies. Disclosure - Dr. Pambianco- Consultant: Paion. Mr. Borkett- Employee: Paion. Dr. Wilhelm-Ogunbiyi-Employee: Paion. This research was supported by an industry grant from Paion.