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Efficacy and safety of remimazolam versus propofol for general anesthesia: a multicenter, single-blind, randomized, parallel-group, phase IIb/III trial

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Abstract

Purpose

This trial was conducted to confirm the non-inferiority of remimazolam versus propofol in the induction and maintenance of general anesthesia in surgical patients.

Methods

Surgical patients (n = 375) were randomized to remimazolam started at 6 or 12 mg/kg/h by continuous intravenous (IV) infusion until the loss of consciousness (LoC), followed by 1 mg/kg/h to be adjusted as appropriate until the end of surgery or IV propofol administered as a slow bolus of 2.0–2.5 mg/kg until LoC followed by 4–10 mg/kg/h until the end of surgery. Efficacy was measured via the combined primary endpoint of no intraoperative awakening/recall, no need for rescue sedatives, and no body movements. Adverse events and adverse drug reactions (ADRs) were monitored for safety.

Results

Efficacy rates were 100% in all treatment groups, and the non-inferiority of remimazolam was demonstrated [95% confidence interval (− 0.0487; 0.0250)]. The time to LoC was longer in the remimazolam 6 (p < 0.0001) and 12 mg/kg/h (p = 0.0149) groups versus propofol. The time to extubation was longer in both remimazolam groups versus the propofol group (p ≤ 0.0001). The incidence of ADRs was similar in the remimazolam groups (39.3% and 42.7%, respectively) compared with the propofol group (61.3%). Decreased blood pressure occurred in 20.0% and 24.0% of patients treated with 6 and 12 mg/kg/h remimazolam, respectively, compared with 49.3% of patients receiving propofol. Injection site pain was reported in 18.7% of propofol patients but not in those receiving remimazolam.

Conclusions

This trial demonstrated that remimazolam was well tolerated and non-inferior to propofol with regard to efficacy as a sedative hypnotics for general anesthesia.

Clinical trial registration

This trial is registered with the Japan Pharmaceutical Information Center - Clinical Trials Information (JapicCTI). JapicCTI number: 121973

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References

  1. Chitilian HV, Eckenhoff RG. Anesthetic drug development: novel drugs and new approaches. Surg Neurol Int. 2013;4(Suppl1):S2–S10.

    PubMed  PubMed Central  Google Scholar 

  2. Scott RP, Saunders DA. Propofol: clinical strategies for preventing the pain of injection. Anaesthesia. 1988;43:492–4.

    Article  CAS  Google Scholar 

  3. Sneyd JR, Rigby-Jones AE. New drugs and technologies, intravenous anaesthesia is on the move (again). Br J Anaesth. 2010;105:246–54.

    Article  CAS  Google Scholar 

  4. Tuk B, van Oostenbruggen MF. Characterization of the pharmacodynamic interaction between parent drug and active metabolite in vivo: midazolam and alpha-OH-midazolam. J Pharmacol Exp Ther. 1999;289:1067–74.

    CAS  PubMed  Google Scholar 

  5. Saari TI, Uusi-Oukari M. Enhancement of GABAergic activity: neuropharmacological effects of benzodiazepines and therapeutic use in anesthesiology. Pharmacol Rev. 2011;63:243–67.

    Article  CAS  Google Scholar 

  6. Kilpatrick GJ, McIntyre MS, Cox RF, Stafford JA, Pacofsky GJ, Lovell GG, Wiard RP, Feldman PL, Collins H, Waszczak BL, Tilbrook GS. CNS 7056: a novel ultra-short-acting benzodiazepine. Anesthesiology. 2007;107:60–6.

    Article  CAS  Google Scholar 

  7. Schnider T, Minto C. Context sensitive decrement times of remimazolam. Anesth Analg. 2013;117:285.

    Article  Google Scholar 

  8. Upton RN, Somogyi AA. Pharmacokinetics and pharmacodynamics of the short-acting sedative CNS 7056 in sheep. Br J Anaesth. 2010;105:798–809.

    Article  CAS  Google Scholar 

  9. Antonik LJ, Goldwater DR. A placebo- and midazolam-controlled phase I single ascending-dose study evaluating the safety, pharmacokinetics, and pharmacodynamics of remimazolam (CNS 7056): part I. Safety, efficacy, and basic pharmacokinetics. Anesth Analg. 2012;115:274–83.

    Article  CAS  Google Scholar 

  10. Ihmsen H, Eisenried A. Population pharmacokinetics of remimazolam after continuous infusion in volunteers. Poster 01AP14–1. Euroanaesthesia 2018. Copenhagen, Denmark 2018.

  11. Wiltshire HR, Kilpatrick GJ. A placebo- and midazolam-controlled phase I single ascending-dose study evaluating the safety, pharmacokinetics, and pharmacodynamics of remimazolam (CNS 7056): part II. Population pharmacokinetic and pharmacodynamic modeling and simulation. Anesth Analg. 2012;115:284–96.

    Article  CAS  Google Scholar 

  12. Worthington MT, Antonik LJ, Goldwater DR, Lees JP, Wilhelm-Ogunbiyi K, Borkett KM, Mitchell MC. A phase Ib, dose-finding study of multiple doses of remimazolam (CNS 7056) in volunteers undergoing colonoscopy. Anesth Analg. 2013;117:1093–100.

    Article  CAS  Google Scholar 

  13. Borkett KM, Riff DS, Schwartz HI, Winkle PJ, Pambianco DJ, Lees JP, Wilhelm-Ogunbiyi K. A Phase IIa, randomized, double-blind study of remimazolam (CNS 7056) versus midazolam for sedation in upper gastrointestinal endoscopy. Anesth Analg. 2015;120:771–80.

    Article  CAS  Google Scholar 

  14. Pambianco DJ, Borkett KM, Riff DS, Winkle PJ, Schwartz HI, Melson TI, Wilhelm-Ogunbiyi K. A phase IIb study comparing the safety and efficacy of remimazolam and midazolam in patients undergoing colonoscopy. Gastrointest Endosc. 2016;83:984–92.

    Article  Google Scholar 

  15. Rex DK, Bhandari R, Desta T, DeMicco MP, Schaeffer C, Etzkorn K, Barish CF, Pruitt R, Cash BD, Quirk D, Tiongco F, Sullivan S, Bernstein D. A phase III study evaluating the efficacy and safety of remimazolam (CNS 7056) compared with placebo and midazolam in patients undergoing colonoscopy. Gastrointest Endosc. 2018;88(427–437):e6.

    Google Scholar 

  16. Pastis NJ, Yarmus LB, Schippers F, Ostroff R, Chen A, Akulian J, Wahidi M, Shojaee S, Tanner NT, Callahan SP, Feldman G, Lorch DG Jr, Ndukwu I, Pritchett MA, Silvestri GA, PAION Investigators. Safety and efficacy of remimazolam compared with placebo and midazolam for moderate sedation during bronchoscopy. Chest. 2019;155:137–46.

    Article  Google Scholar 

  17. Doi M. Remimazolam. J Jpn Soc Clin Anesthesia. 2014;34:860–6 (in Japanese, abstract in English).

    Article  Google Scholar 

  18. Probst S, Grossmann E (2014) Phase II study on ultra-short acting remimazolam vs. propofol / sevoflurane in cardiac surgery. Poster presentation. ASA 2014. New Orleans, USA.

  19. International Conference on Harmonisation. Guideline for Good Clinical Practice: E6(R1). International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use ICH Harmonised Tripartite Guideline. Geneva, Switzerland: ICH; 1996:1–59.

  20. World Medical Association. WMA declaration of helsinki—ethical principles for medical research involving human subjects. Fortaleza: WMA; 2013. p. 1–8.

    Google Scholar 

  21. American Society of Anesthesiologists. ASA Physical Status Classification System. 2014.

  22. Johansen JW. Update on bispectral index monitoring. Best Pract Res Clin Anaesthesiol. 2006;20:81–99.

    Article  Google Scholar 

  23. Brice DD, Hetherington RR. A simple study of awareness and dreaming during anaesthesia. Br J Anaesth. 1970;42:535–42.

    Article  CAS  Google Scholar 

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Acknowledgements

The authors thank Shigehito Sato, who served as the Lead Investigator of this clinical trial of remimazolam at the Hamamatsu University Hospital in Japan. They thank Ichiro Hatono, who provided overall trial monitoring as Director Clinical Research 1st Division, CMIC Co. They thank Kazunori Murakami, who provided data management services at Clinical Information Department, EPS Corporation. They acknowledge Shuya Kiyama, from Jikei University Hospital for serving as Medical Officer and providing advice on the overall conduct of the study and handling of individual subjects for analyses before unblinding. They acknowledge Creative Clinical Research GmbH, Berlin for providing medical writing support in drafting and finalizing this manuscript. They thank Melissa Crawford, PhD, from Edanz Group for editing a draft of this manuscript. This trial was conducted at 49 trial sites in Japan.

Funding

This study is supported by Ono Pharmaceutical Co.

Author information

Authors and Affiliations

  1. Department of Anesthesiology and Intensive Care, Hamamatsu University Hospital, 1-20-1 Handayama, Higashi-Ku, Hamamatsu-Shi, 431-3192, Japan

    Matsuyuki Doi

  2. Okayama University, Okayama, Japan

    Kiyoshi Morita

  3. Keio University, Tokyo, Japan

    Junzo Takeda

  4. Department of Anesthesiology, Nippon Medical School, Tokyo, Japan

    Atsuhiro Sakamoto

  5. Department of Anesthesiology, Sapporo Medical University School of Medicine, Sapporo, Japan

    Michiaki Yamakage

  6. Department of Anesthesiology, Tokai University of Medicine, Isehara, Kanagawa, Japan

    Toshiyasu Suzuki

Authors
  1. Matsuyuki Doi
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  2. Kiyoshi Morita
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  3. Junzo Takeda
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  4. Atsuhiro Sakamoto
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  5. Michiaki Yamakage
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  6. Toshiyasu Suzuki
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Corresponding author

Correspondence to Matsuyuki Doi.

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Conflict of interests

M. Doi is a consultant of PAION UK and Mundipharma. All others authors have no interests to declare.

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Doi, M., Morita, K., Takeda, J. et al. Efficacy and safety of remimazolam versus propofol for general anesthesia: a multicenter, single-blind, randomized, parallel-group, phase IIb/III trial. J Anesth 34, 543–553 (2020). https://doi.org/10.1007/s00540-020-02788-6

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  • DOI: https://doi.org/10.1007/s00540-020-02788-6

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