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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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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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