Damian McNamara

October 21, 2016

LAS VEGAS — For patients undergoing outpatient colonoscopy, remimazolam was more likely than midazolam or placebo to provide adequate sedation, reduce the need for rescue medication, and speed recovery, results from a new study show.

"Remimazolam given under the supervision of an endoscopist is a safe and effective sedative for use in colonoscopy patients, with a shorter recovery time and fast recovery of neuropsychiatric function," said Douglas Rex, MD, from Indiana University Hospital in Indianapolis.

"Propofol is increasingly popular for endoscopic sedation and allows rapid recovery, but it is targeted primarily for deep sedation, and administration usually requires an anesthetist," he explained. "Midazolam is the cornerstone of moderate sedation," but it has a mean half-life of 4.3 hours, so recovery can be prolonged. In contrast, remimazolam, a new benzodiazepine that is metabolized differently from midazolam, has an elimination half-life of 45 minutes.

Results from the phase 3 trial were presented here at the American College of Gastroenterology (ACG) 2016 Annual Scientific Meeting.

All 461 study participants underwent diagnostic or therapeutic colonoscopy at one of 13 facilities in the United States, and all met class I to III criteria on the American Society of Anesthesiologists (ASA) Physical Status Classification System.

All patients received fentanyl 50 µg to 75 µg before the procedure. In addition, 298 patients were randomly assigned to receive remimazolam, 103 to open-label midazolam, and 60 to placebo.

In the remimazolam group, an initial dose of 5 mg was followed by 2.5-mg top-up doses. Midazolam was administered in accordance with the label, and rescue doses were permitted at the clinician's discretion. Additional doses of fentanyl 25 µg to 200 µg were allowed only for pain.

"All agents were given by the endoscopist or under their supervision with no involvement of anesthesia specialists," Dr Rex reported.

The level of sedation was monitored with the Modified Observer's Assessment of Alertness/Sedation (MOAA/S) scale.

The composite endpoint was completion of colonoscopy; no need for an alternative sedative; and no need for more than five doses of remimazolam or placebo in any 15-minute interval or more than three doses of midazolam in any 12-minute interval.

More than 98% of patients completed colonoscopy, so "the differences were really in the other two components of the composite outcome," Dr Rex explained.

Table. Outcomes in the Three Sedation Groups

Outcome Remimazolam Group, % Midazolam Group, % Placebo Group, %
Procedure success 91 25 2
Adequate sedation achieved 94 46 27
No rescue medication needed 97 35 5

 

Time from the end of the procedure to full alertness — defined as three successive MOAA/S scores of 5 taken at least 5 minutes apart — was 7 minutes for remimazolam, 21 minutes for placebo, and 26 minutes for midazolam (P < .0001). Patients also recovered neuropsychiatric function faster with remimazolam than with midazolam.

The rate of any treatment-emergent adverse event was 19% lower with remimazolam than with midazolam. This is largely a reflection of the significantly lower rates of hypotension with remimazolam (44% vs 67%; P = .0003).

Is Remimazolam Ready for Prime Time Use?

"Having something that wears off that quickly would be nice," said session comoderator Colleen Kelly, MD, from Miriam Hospital in Providence, Rhode Island. The relatively short half-life of remimazolam could be beneficial in terms of improving recovery time and allowing physicians to schedule patients more efficiently, she explained.

It is not surprising that remimazolam and midazolam provided better sedation than placebo. A placebo group in a colonoscopy study "seems kind of cruel," she told Medscape Medical News, but she pointed out that rescue medications were available and that the placebo group might have been a requirement for approval by the US Food and Drug Administration (FDA).

When asked by an audience member if remimazolam is ready for prime time use, Dr Rex noted that two other phase 3 studies are underway: one in patients of ASA classifications III to IV who are undergoing colonoscopy, and the other in patients undergoing bronchoscopy. "When completed, the drug will be submitted to the FDA for approval," he reported. "But I can't tell you the exact time frame."

There was big difference in intraprocedural sedation between remimazolam and midazolam, said session comoderator David Greenwald, MD, from the Mount Sinai Medical Center in New York City. He asked whether that was reflective of FDA dosing recommendations or the real-world use of midazolam.

"The MOAA/S scores tended to be lower in the remimazolam than in the midazolam arm, which was a function of giving midazolam according to labeling, which is a slower rate than we use in clinical practice," Dr Rex explained.

"Some of the most important information we get from this study has to do with recovery. If you are using midazolam as we commonly use it in clinical practice, those differences would be magnified, because you would give more drug and get deeper sedation and longer recovery times with midazolam."

This study was sponsored by Paion. Dr Rex, Dr Kelly, and Dr Greenwald have disclosed no relevant financial relationships . Two study coauthors are consultants for Paion.

American College of Gastroenterology (ACG) 2016 Annual Scientific Meeting. Abstract 45. Presented October 18, 2016.

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