Clinical Trials

Date: 2016-02-09

Type of information: Halting of the trial

phase: 3

Announcement: halting of the trial

Company: Paion (Germany)

Product: remimazolam

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: general anesthesia

Therapeutic area: CNS diseases

Country: Germany

Trial details:

• This randomized, single-blind, propofol-controlled study investigates the use of remimazolam as a sedative/hypnotic in general anesthesia. Remimazolam or propofol will be administered together with fentanyl/sufentanil/remifentanil as opioid analgesics and a neuromuscular blocker. In total, 530 patients will be randomized. This group of 530 patients will be split randomly into 2 groups as follows:
• • 106 patients will be randomized to induction with propofol plus fentanyl or sufentanil or remifentanil and a neuromuscular blocker. Throughout maintenance, the patients will receive propofol and remifentanil until weaning from the mechanical ventilation on the ICU or PACU within 24 hours after induction. Afterwards, sedation with propofol as study medication has to be ended. If necessary, the sedation is to be continued with the hospital\'s own supplies (propofol or other sedative).
• • 424 patients will be randomized to induction with remimazolam 6.0 mg/kg/hr together with fentanyl or sufentanil or remifentanil and a neuromuscular blocker. Throughout maintenance, the patients will receive remimazolam and remifentanil until weaning from the mechanical ventilation on the ICU or PACU within 24 hours after induction.
• The primary endpoint is successful sedation is defined as a Narcotrend index of 60 or less during at least 85% of the maintenance time and no rescue sedative medication administered. The maintenance starts at arrival at the operation theater and ends with the completion of the last skin suture. (NCT02523859)

 

Latest news:

• • On February 9, 2016, Paion announced its decision to discontinue the European remimazolam Phase III trial in cardiac surgery. The European Phase III Remimazolam clinical trial in cardiac surgery faced recruitment challenges due to the complex study design. Despite intensive efforts to enhance study recruitment, the trial proved to be difficult to implement in practice. Paion decided to discontinue the trial in order to avoid a long and expensive study with the existing design. No drug-related serious adverse events have been observed. Accordingly, Paion will work together with recognized experts on setting up an alternative design in general surgery patients. The EU decision will have no impact on the U.S. program. The company will now focus on the ongoing U.S. development program in procedural sedation with highest priority. The Phase III colonoscopy trial is on track and completion of patient recruitment is still expected in the first quarter 2016. Patient recruitment in the Phase III bronchoscopy trial remains moderate which could possibly extend the completion into 2017. Conditional on successful implementation of ongoing counter measures, Paion expects filing for approval in 2017.
• • On August 11, 2015, Paion announced the initiation of an EU Phase III clinical trial of remimazolam, an ultra-short-acting sedative/anesthetic in the indication "general anesthesia". The objective of the now starting confirmatory EU phase III study is to repeat the current results in a broader, multi-national Phase III study with patients undergoing cardiac surgery. Secondary endpoints are, amongst others, hemodynamic stability and controllability of anesthesia. Improved hemodynamic stability of patients under general anesthesia becomes more and more important due to the increasing patient age. In addition, the complexity of anesthesia procedures increases due to the growing number of relevant concomitant diseases in this patient population. Based on the existing clinical data we are convinced that Remimazolam can significantly contribute to address these requirements."
• The now starting phase III study is a multi-national, multicenter, randomized, single-blind, propofol-controlled, confirmatory study in patients undergoing major cardiac surgery. The objective is to receive further data to evaluate efficacy, safety and pharmacokinetics of Remimazolam. The primary endpoint is successful anesthesia as measured by meeting a pre-defined level of sedation depth without the use of rescue medication. After end of surgery, patients will be transferred to the post anesthesia care unit (PACU) or the intensive care unit (ICU), with the option to continue Remimazolam treatment for up to 24 hours if required. A total of 530 patients will be treated in several European study centers. Results of the study are expected in 2016. The study is designed to provide further information about the cardiovascular tolerability profile of Remimazolam. Furthermore, it is expected that further insights on the predictable offset of effect as well as the easy control of sedation in the postoperative phase can be gained. Remimazolam will be evaluated against propofol during induction and maintenance of general anesthesia with respect to efficacy and tolerability. Data in the postoperative phase will also be obtained for further exploration of the ICU sedation indication. The study was designed such that the data can be combined with data collected in previous anesthesia studies, including data obtained from trials conducted in Japan.
• During the Phase II clinical trial in general anesthesia for cardiac surgery, remimazolam showed an excellent efficacy rate across both treatment groups. As expected, the onset and offset profile of remimazolam was comparable to propofol/sevoflurane, showing that Remimazolam indeed shares the same fast acting properties. In addition, both the Japanese and the European study demonstrated an improved hemodynamic profile over propofol and the combination propofol/sevoflurane. In the Phase III program in Europe, hemodynamic stability will therefore be the key secondary parameter for profiling Remimazolam. Hemodynamic stability (intraoperative drop of blood pressure and vasopressor usage) is an increasing area of special attention as it is linked to clinical outcomes and patient safety. If remimazolam\'s Phase III program confirms its positive hemodynamic profile, the drug may offer anesthesists a valuable therapeutic alternative.

Is general: Yes