Clinical Trials

Date: 2016-10-19

Type of information: Presentation of results at a congress

phase: 3

Announcement: presentation of results at the 2016 American College of Gastroenterology (ACG) Annual Scientific Meeting

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: procedural sedation in patients undergoing colonoscopy

Therapeutic area: CNS diseases

Country: USA

Trial details:

• This Phase III clinical trial is a prospective, double-blind, randomized, placebo and midazolam-controlled, U.S. multicenter study in 460 patients undergoing colonoscopies for diagnostic or therapeutic reasons. Patients will be randomized to receive Remimazolam, midazolam or placebo in addition to fentanyl to achieve moderate sedation. The primary objective of this study is to investigate the short-term sedation, and hence the success of a colonoscopy compared to placebo and midazolam. The primary endpoint is the successful completion of the colonoscopy procedure with no requirement for alternative sedative. The completion of patient recruitment is expected before the end of 2015. (NCT02290873)

Latest news:

• • On October 19, 2016, Paion announced that data on the clinical results of remimazolam’s U.S. Phase III colonoscopy trial were presented in the Colon/Stomach oral session at the 2016 American College of Gastroenterology (ACG) Annual Scientific Meeting in Las Vegas. Douglas Rex (Indiana University,) principal investigator of the trial, presented the results. The Phase III trial enrolled a total of 461 patients at 13 U.S. sites and was designed to evaluate the efficacy and safety of remimazolam compared to placebo (with midazolam rescue) in patients undergoing proceduralistadministered sedation for colonoscopy. The primary outcome measure was a composite endpoint defined as: no need for rescue medication, completion of the procedure and no more than 5 top-up doses within any 15-minute window. The primary endpoint was reached in 91.3% of the patients in the remimazolam arm and 1.7% in the placebo (including midazolam rescue) arm.
• Important secondary endpoints in the remimazolam arm showed a median time from start of medication to start of procedure of 4.0 minutes (placebo 19.5 minutes) and a mean time from end of procedure to return to full alertness of 7.2 minutes (placebo 21.3 minutes). Additionally, time to “back to normal” as reported by patients on remimazolam was 331 minutes (placebo 572 minutes). There were no treatment-emergent serious adverse events in the trial. Hypotension was 44.3% with remimazolam and 47.5% with placebo and accounted for most of the adverse events in all study arms. Hypoxia occurred in 1.0% of patients given remimazolam, 3.4% in the placebo arm. On the Hopkins Verbal Learning Test administered five minutes after reaching the fully alert status, the total raw score, delayed recall, memory retention, and recognition discrimination scores were all better with remimazolam compared to placebo. Patient satisfaction was similar in all arms of the study. In addition to the detailed analysis of the primary and secondary endpoints of the Phase III trial (comparison to placebo), Dr. Rex also presented data for the open label midazolam arm. These results will not be part of the label claims. They will however serve as valuable data to plan future studies and perform pharmacoeconomic modelling. Midazolam patients showed a median time from start of medication to start of procedure of 19.0 minutes and a mean time from end of procedure to return to full alertness of 15.7 minutes. Midazolam patients took 553 minutes to be back to normal. Hypotension was 67.3% with midazolam and hypoxia occurred in 1.0% of patients given midazolam.
• • On March 31, 2015, Paion announced the initiation of a U.S. Phase III clinical trial of remimazolam for procedural sedation in patients undergoing colonoscopy. During Phase II clinical trials, remimazolam displayed faster onset of sedation and greater procedural success compared to midazolam. Remimazolam showed a benign safety profile and patients experienced rapid recovery from sedation including faster recovery of cognitive function as compared to midazolam. The initiation of the Phase III trial in patients undergoing colonoscopies marks the start of Paion's Phase III clinical program, which includes a second pivotal Phase III trial in patients undergoing bronchoscopies and a third smaller safety trial in high-risk patients undergoing colonoscopies. In parallel, Paion will conduct three Phase I studies. This Phase III clinical trial is a prospective, double-blind, randomized, placebo and midazolam-controlled, U.S. multicenter study in 460 patients undergoing colonoscopies for diagnostic or therapeutic reasons. Patients will be randomized to receive Remimazolam, midazolam or placebo in addition to fentanyl to achieve moderate sedation. The primary objective of this study is to investigate the short-term sedation, and hence the success of a colonoscopy compared to placebo and midazolam. The primary endpoint is the successful completion of the colonoscopy procedure with no requirement for alternative sedative. The completion of patient recruitment is expected before the end of 2015.
• • On November 25, 2013, Paion has announced that it held an End-of-Phase II meeting with the FDA to discuss remimazolam for the US lead indication \'procedural sedation\' and now received the final meeting minutes. At that meeting, the FDA laid out its expectations for the remaining development program up to NDA filing and offered a dialogue to finalise the necessary study designs together with Paion. A pivotal Phase III program evaluating the safety and efficacy of remimazolam is planned to start in H2/2014 depending on successful completion of current funding and/or partnering discussions. The cost for completion of the procedural sedation development program is currently estimated at approximately € 20 million and is depending on the final requirements of the FDA.
• Labelling comparable to midazolam may be achieved if the Phase III studies are designed and the safety data continue to support such claim. FDA has agreed to work with Paion on the design of the Phase III studies to support the desired labelling. Paion aims at a label similar to that for midazolam.
• Midazolam is a very safe agent for induction of conscious sedation, but long recovery times for the patient reduce the numbers of procedures that can be performed by GI docs who therefore often use propofol to double the number of patients that can be screened. The high numbers of patients are necessary to achieve the goal to screen as many patients as possible, as it is the only proven preventive colon cancer intervention. Remimazolam is expected to be as safe as midazolam and Paion hopes to demonstrate in Phase III studies designed with FDA input that significantly more patients can be screened without the additional costs for the healthcare system of having an anaesthesiologist present to administer the sedative (like with propofol). Both, remimazolam and midazolam, share the advantage of having a reversal agent which enhances the safety profile of the compounds.
• With this safety profile, supported by collection of positive safety results from the Phase III studies Remimazolam could offer savings to the healthcare system if approved for administration by persons trained in airway management. As this could result in a savings potential of > $1 billion per year for simple procedures such as colonoscopies, Paion sees a very attractive business case for conscious sedation in the US market.

Is general: Yes