Clinical Trials

Date: 2013-11-14

Type of information: Results

phase: 2-3

Announcement: results

Company: Paion (Germany) Ono Pharmaceutical (Japan)

Product: remimazolam (ONO-2745)

Action mechanism:

• benzodiazepine derivative. Remimazolam is a short-acting general anaesthetic/sedative. Sedatives are used, for example, in endoscopic procedures such as colonoscopies. After intravenous administration remimazolam rapidly induces the desired sedation. Importantly, this sedative effect quickly disappears. This rapid offset of the effect of the substance is due to its metabolism by tissue esterase enzymes that are widely distributed throughout the body. Remimazolam is being developed as a sedative agent for day case procedures (procedural sedation) as well as for the induction and maintenance of anaesthesia. It could also be used as a sedative for patients in the Intensive Care Unit (ICU).

Disease: sedation
general anaesthesia

Therapeutic area: CNS diseases

Country: Japan

Trial details:

• The study was conducted in Japan as a multi-centre randomized parallel-group study with propofol as a control in surgery patients undergoing general anaesthesia in combination with analgesics. Remimazolam and propofol were intravenously administered to 375 patients (2 Remimazolam groups with induction doses of 6 mg/kg/h or 12 mg/kg/h and started at the rate of 1 mg/kg/h for maintenance, 150 subjects per group) and 75 patients received a standard dose of propofol, respectively, to compare success rates of induction and maintenance of general anaesthesia.

Latest news:

• • On November 14, 2013,  Paion has announced that its Japanese development partner, Ono Pharmaceutical has informed that it has completed a phase II/III clinical study of remimazolam in its lead indication of General Anaesthesia successfully met the primary endpoint.
• All 375 patients achieved loss of consciousness and underwent successful intubation. The primary efficacy endpoint of effectiveness as a general anaesthetic (defined as no intraoperative awakening/memory, no body motion and no rescue therapy for sedative effect necessary) was achieved by 100% of patients in all groups. Typically for an anaesthesia study the study was designed as non-inferiority study vs. standard of care, in this case i.v. propofol.
• No adverse events of concern were observed. The incidence rates of adverse events were 84.7%, 80.7% and 84.0% in 6 mg/kg/h and 12 mg/kg/h of Remimazolam and propofol groups, respectively. Common adverse events included decrease of blood pressure, primary wound complication, abnormal laboratory test results, nausea/vomiting and injection site pain (observed only in the propofol group) etc, which corresponded with relatively common events typically observed in perioperative patients. The incidence rates of decrease in blood pressure were 35.3%, 34.7% and 60.0% in 6 mg/kg/h and 12 mg/kg/h of Remimazolam and propofol groups, respectively. This suggests that Remimazolam has a clinically meaningfully less cardio depressive effect as compared to propofol. The incidence rate was significantly lower in each Remimazolam group as compared to the propofol group (p=0.0004 and p=0.0003 for the 6 and 12 mg/kg/h doses vs. propofol).
• Pharmacokinetic and pharmacodynamic modelling is still ongoing.
• • On October 30, 2013, Paion has announced that its Japanese development partner, Ono Pharmaceutical, has completed the recruitment of a study in patients with chronic hepatic impairment using remimazolam. This was the study required to complete the Japanese development program for the indication of induction and maintenance of general anesthesia.
• This study was conducted in the USA as an open-label study with sequential parts to compare the pharmacokinetics and safety of Remimazolam in subjects with chronic hepatic impairment with their respectively matching healthy volunteers. No adverse events of concern were observed in this study. • On August 1, 2013,  Paion has announced that it was informed by its partner Ono Pharmaceutical that it has decided to stop the dose finding explorative Phase II trial in ICU sedation. Due to an unclear pharmacokinetic result in long-term administration in the study, Ono has decided the discontinuation of the study. Overall all patients were sedated successfully and no significant adverse events were reported. The next step will be to perform a batch of pre-clinical experiments, perform PK modelling based on the plasma samples and consider if dose adjustment (reduced or changed) is necessary for new studies. Ono furthermore confirmed that clinical trials in general anaesthesia are on track. The recruitment of the second study in the Phase III program (American Society of Anesthesiologists classification III or higher) in more severely sick patients has been completed. No significant adverse events has been reported so far. • On May 8, 2013, Paion has announced that its partner, Ono Pharmaceutical has published, that the recruitment of the Phase II/III study with remimazolam for general anaesthesia is completed. Remimazolam was administered during anaesthesia to 375 surgery patients. The objective of this study was to investigate efficacy and safety of Remimazolam in induction and maintenance of general anaesthesia in a multicenter randomized parallel-group study compared to propofol in surgery patients requiring general anaesthesia. Ono Pharmaceutical entered into the license agreement with Paion UK (former CeNeS Limited) in 2007 to develop and commercialize remimazolam in Japan and is developing the substance for the Japanese market for both 'induction and maintenance of anaesthesia' and 'ICU sedation'. Remimazolam is available for licensing outside Japan and China, where the compound is partnered with Ono Pharmaceutical and Yichang Humanwell, respectively. • On December 18, 2012, Paion has announced that its partner Ono Pharmaceutical has paid $ 3 million (€2.3 million) after enrolment of the first patient into the initiated Phase II/III study with remimazolam in Japan which was announced on 5th November 2012. Ono entered into the license agreement with Paion UK (former CeNeS Limited) in 2007 to develop and commercialize remimazolam in Japan and is developing the substance for the Japanese market for both 'induction and maintenance of anaesthesia' and 'ICU sedation'. • On November 5, 2012, Paion has initiated a Phase II/III study with remimazolam for general anaesthesia in September 2012 as the next step after the announcement of a successful completion of a Phase II study in anaesthesia in May 2012. The enrolment of the first patient will trigger a milestone payment of $ 3 million from Ono Pharmaceutical which is expected by the end of this year. The objective of this study is to investigate efficacy and safety of remimazolam in induction and maintenance of general anaesthesia in a multicenter randomized parallel-group study compared to propofol in surgery patients requiring general anaesthesia. In addition a Phase II study for ICU sedation was initiated.
• Ono Pharmaceutical entered into a license agreement with Paion in August 2007, acquiring the exclusive rights to develop and market remimazolam in Japan.

Is general: Yes