A phase IIb study comparing the safety and efficacy of remimazolam and midazolam in patients undergoing colonoscopy.

BACKGROUND AND AIMS: Remimazolam is an ultra-short-acting benzodiazepine currently being developed for procedural sedation and for induction and maintenance of anesthesia. This trial was the fourth study for procedural sedation. The aim was to compare the safety and efficacy profile of remimazolam and to refine suitable doses for subsequent phase III studies in this indication. METHODS: This was a randomized, double-blind, parallel group, active controlled clinical trial with 162 male and female patients, aged 18 to 70, scheduled to undergo a routine colonoscopy. Patients were randomized to receive 1 of 3 remimazolam doses or midazolam for sedation. Supplemental oxygen and 100 µg of fentanyl was given before procedures were started, and the colonoscopy commenced as soon as suitable sedation had been achieved (Modified Observer's Assessment of Alertness/Sedation score ≤3). Top-up doses of the study drug and/or fentanyl were allowed to maintain suitable sedation and/or analgesia. Response was defined as sufficient sedation, no rescue sedative, and no ventilation required. RESULTS: This study showed that a single dose of remimazolam or midazolam, followed by top-up doses to maintain suitable sedation, provided adequate sedation with a high success rate (>92%) for the remimazolam groups, compared with 75% for the midazolam group (P = .007). There was no requirement for mechanical ventilation in any group, and procedure failures were all due to use of rescue sedative. CONCLUSIONS: The high success rates and good safety profile of remimazolam observed in this study warrants further investigation and confirmation in phase III trials. ( CLINICAL TRIAL REGISTRATION NUMBER: NCT01145222.).

A Phase IIa, randomized, double-blind study of remimazolam (CNS 7056) versus midazolam for sedation in upper gastrointestinal endoscopy.

BACKGROUND: This exploratory study was the first study of remimazolam in patients to assess the safety and efficacy of different single doses for procedural sedation. METHODS: Patients scheduled to undergo a diagnostic upper gastrointestinal endoscopy were randomized to receive 1 of 3 doses of remimazolam or midazolam (25 per group) in a double-blind manner. After a single dose of study drug to achieve sedation, patients underwent gastroscopy. We assessed the success of the procedure, sedation levels, recovery from sedation, and safety. RESULTS: A single dose of remimazolam resulted in a successful procedure in 32%, 56%, and 64% of patients in the low (0.10), middle (0.15), and high (0.20 mg/kg) dose groups compared with 44% of patients in the midazolam (0.075 mg/kg) dose group. The onset of sedation was 1.5 to 2.5 minutes in the remimazolam dose groups compared with 5 minutes for midazolam. Because this was a single administration study, sedation could be maintained for as long as necessary to complete the procedure, using rescue midazolam or propofol. Recovery from sedation was rapid for all treatment groups but was influenced by the choice of rescue medication. There were no obvious differences in the safety profiles of remimazolam and midazolam. CONCLUSIONS: This exploratory dose-finding study showed that a single administration of remimazolam (0.10-0.20 mg/kg) was capable of inducing rapid sedation with a quick recovery profile in patients undergoing a diagnostic upper gastrointestinal endoscopy. The safety profile was favorable and appeared to be similar to that of midazolam, warranting further development of this short-acting compound.

The Food and Drug Administration advisory committees and panels: how they are applied to the drug regulatory process.

Food and Drug Administration (FDA) advisory panels and committees play a critical role in advising the FDA on the safety and efficacy of medical devices and drugs marketed in the US. Advisory panel recommendations are used by the FDA to make decisions regarding medical products. Currently, the FDA utilizes over 50 advisory panels that serve the three major FDA centers, including the Centers for Biologics, Drugs and Device Products. Members of an advisory panel typically include academicians, clinicians, consumers, patients, and industry representatives. The FDA establishes the schedules for advisory panel meetings on an annual basis and a panel usually meets several times a year for two consecutive days in Washington, DC. Typically, the advisory panel discusses issues highlighted by the FDA and is then asked to vote a response to the questions posed in advance by the FDA. Advisory panel recommendations have a strong influence on FDA's decision to approve a product, as evidenced by the 214 Advisory Panels FDA convened between January 2008 to November 2012, during which advisory panel members voted to approve the product (or use of the product) ∼74% of the time, with FDA ultimately approving the medical product (or use of the product) ∼79% of the time. The ACG membership are encouraged to consider serving the public's interest by participating in an FDA advisory panel utilizing their expertise for the evaluation of a new drug or medical device, and providing advice about whether the product should be sold in the US.

Computer-assisted personalized sedation for upper endoscopy and colonoscopy: a comparative, multicenter randomized study.

BACKGROUND: The SEDASYS System is an investigational computer-assisted personalized sedation system integrating propofol delivery with patient monitoring to enable endoscopist/nurse teams to safely administer propofol. OBJECTIVE: To compare the safety and effectiveness of the SEDASYS System to the current standard of care for sedation during routine endoscopic procedures. DESIGN: Nonblinded multicenter randomized comparative study. SETTING: Four ambulatory surgery centers, 3 endoscopy centers, and 1 academic center in the United States. PATIENTS: One thousand American Society of Anesthesiologists physical status class I to III adults undergoing routine colonoscopy or EGD. INTERVENTIONS: Sedation with the SEDASYS System (SED) and sedation with each site's current standard of care (CSC; benzodiazepine/opioid combination). MAIN OUTCOME MEASUREMENTS: Area under the curve of oxygen desaturation was the primary endpoint. Secondary endpoints included patient satisfaction, clinician satisfaction, level of sedation, and patient recovery time. RESULTS: Four hundred ninety-six patients were randomized to SED and 504 to CSC. Area under the curve of oxygen desaturation was significantly lower for SED (23.6 s·%) than for CSC (88.0 s·%; P = .028). Patients were predominately minimally to moderately sedated in both groups. SED patients were significantly more satisfied than CSC patients (P = .007). Clinician satisfaction was greater with SED than with CSC (P < .001). SED patients recovered faster than CSC patients (P < .001). The incidence of adverse events was 5.8% in the SED group and 8.7% in the CSC group. LIMITATIONS: Nonblinded. CONCLUSIONS: The SEDASYS System could provide endoscopist/nurse teams a safe and effective on-label means to administer propofol to effect minimal to moderate sedation during routine colonoscopy and EGD.

Future directions in endoscopic sedation.

The role of sedation in endoscopic procedures has increased and so has the demand for advances in its administration. The pursuit of new agents or administration techniques and their study specific to endoscopic nonsurgical procedures is necessary to improve patient comfort and safety.The science of moderate and deep sedation specific to endoscopy is fledgling but approaching new horizons.

An assessment of computer-assisted personalized sedation: a sedation delivery system to administer propofol for gastrointestinal endoscopy.

BACKGROUND: Demand for colonoscopy and EGD procedures is increasing. Impediments to performing these examinations persist. Patients perceive these procedures as unpleasant and painful. The use of suboptimal sedatives results in inefficiency in endoscopy practices. Improving sedation methods utilizing precise control of preferred sedatives may increase patient satisfaction and practice efficiency. OBJECTIVE: Our purpose was to demonstrate the feasibility of computer-assisted personalized sedation (CAPS) for facilitating the precise administration of propofol by endoscopist/nurse teams, achieving minimal to moderate sedation in subjects undergoing routine endoscopies. DESIGN: Open label, single-center studies. SETTING: Endoscopy clinics in Charlottesville, Virginia, and Gent, Belgium. SUBJECTS: Twenty-four adults per center; 12 colonoscopies, 12 EGDs. INTERVENTIONS: Propofol sedation with CAPS by endoscopist/registered nurse care teams. MAIN OUTCOME MEASUREMENTS: Sedation level measured by modified observer's assessment of alertness/sedation (MOAA/S), recovery time measured from endoscope removal until Aldrete >/= 12, dosage of propofol, oxygen saturation, and safety assessments. RESULTS: Subjects responded to mild tactile and verbal stimuli MOAA/S = 5, 4, 3, or 2) 99% of the time. Mean propofol doses in the United States and Belgium were 65.4 and 72.1 mg, respectively. Mean recovery times were 29 and 10 seconds, respectively. Oxygen desaturation occurred in only 6% of subjects. No device-related adverse events occurred. LIMITATION: Open-label design. CONCLUSIONS: Using CAPS, the endoscopist/nurse teams precisely controlled the administration of propofol achieving minimal to moderate sedation in subjects undergoing colonoscopy and EGD procedures. Mean propofol dosage was low and post-procedure recovery times were rapid. The device performed well when operated by the endoscopist/nurse team, with no device-related adverse events.

Low volume bowel preparation for colonoscopy: randomized, endoscopist-blinded trial of liquid sodium phosphate versus tablet sodium phosphate.

OBJECTIVE: The aim of this study was to compare the colon-cleansing effectiveness, ease of consumption, and side effect profiles of two commercially available preparations of sodium phosphate: liquid Fleet Phospho-soda and Visicol tablets. METHODS: Outpatients undergoing elective colonoscopy were sequentially randomized to one of two preparation groups: liquid: 45 ml at 7:00 PM, 45 ml 3 h before colonoscopy; or tablet: 20 tablets at 7:00 PM, 20 tablets 3-5 h before colonoscopy. Subjects rated preparation tolerability on a 5-point Likert scale. A Residual Stool Score was calculated for each subject based on the amount of stool, consistency of residual stool, and percent of bowel visualized (range 0-11, 0 = best). The endoscopists were blinded to the preparation used. RESULTS: A total of 101 subjects were enrolled (43 male, 58 female, mean age 58.2 yr). The groups were similar in age and indications for colonoscopy. Overall, bowel cleansing was rated "Excellent" or "Good" in 92% of liquid preparation subjects, compared with 74% of tablet preparation subjects (p = 0.03). Subjects in the liquid group demonstrated significantly less residual stool than did tablet subjects (Residual Stool Scores: liquid 1.3 +/- 1.2 vs tablet 1.9 +/- 1.5, p < 0.05). Subjects rated the liquid preparation easier to swallow (p < 0.005) and more convenient to take (p < 0.005) than tablets. Among liquid subjects, 45 of 50 reported a willingness to take their preparation for future colonoscopies, compared with 36 of 49 who took tablet sodium phosphate (p < 0.04). CONCLUSIONS: Liquid sodium phosphate is better tolerated and more effective at colon cleansing when compared with sodium phosphate in tablet form.