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A Phase IIa, Randomized, Double-Blind Study of Remimazolam (CNS 7056) Versus Midazolam for Sedation in Upper Gastrointestinal Endoscopy

Borkett, Keith M. BSc*; Riff, Dennis S. MD; Schwartz, Howard I. MD; Winkle, Peter J. MD; Pambianco, Daniel J. MD§; Lees, James P. BSc*; Wilhelm-Ogunbiyi, Karin MD

doi: 10.1213/ANE.0000000000000548
Anesthetic Pharmacology: Research Report

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.

Published ahead of print December 11, 2014

From the *PAION UK Ltd., Cambridge, United Kingdom; Advanced Clinical Research Institute, Anaheim, California; Miami Research Institute, Miami, Florida; §Charlottesville Medical Research, Charlottesville, Virginia; and PAION Deutschland GmbH, Aachen, Germany.

Accepted for publication September 26, 2014.

Published ahead of print December 11, 2014

Funding: This study was funded by PAION UK Ltd.

Conflict of Interest: See Disclosures at the end of the article.

Reprints will not be available from the authors.

Address correspondence to Keith M. Borkett, BSc, PAION UK Ltd., Compass House, Vision Park, Histon, Cambridge CB24 9ZR, UK. Address e-mail to k.borkett@paion.com.

Remimazolam (CNS 7056) is a new benzodiazepine that is being developed as a short-acting drug for IV sedation for limited duration procedures, such as upper gastrointestinal (GI) endoscopy, colonoscopy, closed reductions of long-bone fractures, and reductions of dislocations. Currently, sedation for such procedures is obtained by primarily using either propofol or a benzodiazepine, sometimes in combination with an analgesic.1,2 Among benzodiazepines, midazolam is the most commonly used drug. However, despite the documented effectiveness of propofol and the benzodiazepines for inducing sedation, each drug has its disadvantages.3,4

Benzodiazepines currently used for sedation during limited duration procedures have 2 main disadvantages: they do not provide analgesia, and they typically have residual sedative effects that persist beyond the duration of the procedure. Patient responses from noxious stimuli can be managed by the administration of concomitant analgesics or increased doses of benzodiazepine, but both can lead to more complications. The offset of effect is related to both drug distribution and elimination. The half-life of midazolam, the shortest for any of the benzodiazepines, is approximately 1.8 to 6.4 hours.5 In addition, midazolam has an active metabolite, which has a profound contribution to its sedative profile6–9 and, in particular, to a longer and less predictable recovery from sedation.

Remimazolam, an ester-based drug, is designed to be rapidly hydrolyzed in the body by ubiquitous tissue esterases to an inactive carboxylic acid metabolite (CNS 7054).10 In a first-in-humans phase I trial in healthy volunteers, remimazolam was shown to safely and rapidly induce sedation after a single bolus administration.11 The depth and duration of sedation appeared to be sufficient to allow a short procedure requiring sedation at doses between 0.10 and 0.20 mg/kg. Offset of sedation with remimazolam was between 10 and 20 minutes at these doses compared with 40 minutes for midazolam, with no resedation observed.

We report the results of the first study in patients receiving remimazolam for procedural sedation. The objective of this exploratory study was to assess the safety and efficacy of 3 dose levels of remimazolam compared with midazolam in patients undergoing diagnostic upper GI endoscopy.a

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METHODS

Study Design and Procedures

The study was conducted in accordance with the Declaration of Helsinki and the International Conference on Harmonisation of Good Clinical Practice, at 7 sites across the United States and was registered with clinicaltrials.gov (NCT00869440).

After IRB approval of the protocol, all patients provided written informed consent at screening, before the start of any protocol-specified procedures or assessments. On the morning of their scheduled gastroscopy, eligible patients were randomly assigned to 1 of the 4 treatment groups: a single dose of remimazolam 0.10, 0.15, or 0.20 mg/kg; or midazolam 0.075 mg/kg. One hundred patients were planned to enter the trial, 25 patients per treatment group. Patients received their assigned treatment as a single IV injection by a syringe driver over a 1-minute period. The use of topical anesthetic was allowed at the discretion of the investigator. The protocol specified that the sedative was administered and monitored by an anesthesiologist. When the patient was sufficiently sedated (Modified Observer’s Assessment of Alertness/Sedation [MOAA/S] ≤3; Table 1),12 the procedure began. Patients were breathing room air throughout the procedure, so supplemental oxygen was not administered unless required for a decrease in oxygen saturation, at the investigator’s discretion. Because this was a single administration study, rescue with sedative medication (midazolam 1–2 mg) was permitted, if sedation was deemed to be inadequate, at the discretion of the administering physician. Flumazenil was also available as a reversal drug at the investigator’s discretion.

Table 1

Table 1

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Patient Eligibility

Male and female patients aged 18 to 65 years inclusive were eligible to enter the study if they were scheduled to undergo a diagnostic upper GI endoscopy. In addition, they had to have an ASA physical status score of I or II, with a weight range of 60 to 120 kg inclusive, and a body mass index (BMI) of 18 to 29 kg/m2.

Patients were excluded if they had a clinically significant abnormal 12-lead electrocardiogram at screening, were pregnant, had a positive drugs-of-abuse urine screening result, or a positive serum ethanol test at screening, or positive ethanol saliva test immediately before the procedure. In addition, patients were excluded if they had a suspected upper GI bleed; known sensitivity to benzodiazepines, flumazenil, or anesthetic drugs; had recently taken a cytochrome P450 3A4 inhibitor or investigational drug; or were using chronic benzodiazepines. Patients with a history of alcoholism or drug abuse were excluded, as were lactating female patients. Patients in whom the management of airways was judged to be difficult were also excluded, for example, thyromental distance ≤4 cm or Mallampati scores of 3 or 4.

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Efficacy and Safety Variables

The success of the endoscopy procedure was assessed using a composite end point that consisted of the following: (1) sufficient sedation as judged by MOAA/S ≤4 for 3 consecutive measurements; (2) completion of the endoscopy procedure (i.e., the procedure was not abandoned early for any reason); (3) no requirement for rescue sedative medication; and (4) no manual or mechanical ventilation.

Sedation levels were assessed using the MOAA/S score, which is a simple, and reliable instrument that can be administered quickly (Table 1). After the administration of study drug, sedation was assessed frequently (every 30 seconds for the first 3 minutes, then every 2 minutes for the next 12 minutes, then every 5 minutes) until the patient was fully alert (3 consecutive MOAA/S scores of 5).

Recall of the procedure was assessed using the Brice questionnaire13 after the fully alert criteria had been reached. The return to normal cognition and memory function was assessed by the Hopkins Verbal Learning Test-Revised (HVLT-R™),14 which was administered by asking the patient to remember a list of 12 words that are then read out by the investigator. The patient was then asked to recall as many of the 12 words as possible, immediately and at different times thereafter. A delayed recall trial was also conducted 20 to 25 minutes later, in which the patient read a longer list (24 words), which contained the original 12 target words, plus 6 semantically related, and 6 semantically unrelated new words. The patient was then asked to identify the 12 words from the original list. This whole test was performed at baseline before any study drug, and then within 5 minutes of becoming fully alert after the endoscopy procedure. The Total Recall Score shows the patient’s ability to learn new information, the Delayed Recall Score shows the patient’s ability to memorize new information, the Percentage Retention Score shows the patient’s ability to retain new information, and the Recognition Discrimination Index Score shows the patient’s ability to recognize and distinguish the original 12 test words from 12 false words, some of which were very similar to the original words. In all cases, the change from predose to postdose results is presented to ascertain the changes in these variables.15 A score of approximately 0 in each variable would be the best possible case, in that full recovery to baseline values would be indicated.

Training investigator and site staff on the use of these assessments (MOAA/S, Brice, and HVLT-R) was performed during an initial investigator meeting, as well as at the sites during site initiation.

Pain on injection was assessed using a visual analog scale of 0 to 100 mm, where 0 is no pain and 100 mm is the worst imaginable. This assessment was made 1 and 15 minutes after the start of administration of study drug, or if the patient was still sedated, every 5 minutes thereafter until the patient was able to complete the scale.

In addition, safety was assessed by the monitoring of adverse events and clinical laboratory testing. Particular attention was paid to vital signs (heart rate, arterial blood pressure, respiratory rate), and events associated with decreased oxygen saturation with continuous pulse oximetry throughout the treatment period. The severity of adverse events was classified using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v3.0, where grade 1 to 4 events were classified as mild, moderate, severe, and life-threatening or disabling, respectively.

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Randomization and Statistical Considerations

Eligible patients were randomly assigned in a 1:1:1:1 ratio to 1 of the 4 treatment groups. Before the start of the study, a computer-generated randomization schedule was prepared using a permuted block algorithm with a block size of 4, and patients at each study site were randomly assigned by the central Interactive Voice Response System to 1 of the 4 treatment groups in chronological order in which they were enrolled.

All patients, investigators, and staff involved in the conduct of the study were blinded to treatment assignment with the exception of a specified unblinded statistician and programmer who had access to the randomization code, an unblinded pharmacist at each site, and an unblinded monitor with the specific remit of monitoring pharmacy-related data. The unblinded team members were not involved in any other study-related procedures.

The sample size was not statistically calculated but was expected to provide sufficient data to determine an appropriate dose level for further studies. Because sample size was not statistically calculated, power was not determined and the study did not aim to deliver confirmatory statistical conclusions. The safety and efficacy analyses were summarized descriptively by treatment group, where 95% confidence intervals for the comparison among treatment groups were used to yield information on the magnitude of effects and treatment differences. Continuous variables were analyzed by analysis of variance/analysis of covariance where treatment group was used as a factor and baseline value for a covariate, where applicable. Confidence intervals were derived for the resulting least squares means. For categorical variables, exact unconditional confidence intervals were calculated. Time to event variables were analyzed by Kaplan-Meier methods, and confidence intervals for the quartiles for the observed times are given.

The analysis was performed on an intent-to-treat (ITT) basis, which consisted of all randomized patients who received a dose of study drug, underwent the endoscopy procedure, and had at least 1 efficacy assessment. Where analyses were likely to be affected by the use of rescue medication, such as recovery times, a modified ITT analysis was used. This comprised all ITT patients but excluded those who received rescue sedative medication.

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RESULTS

Patient Disposition and Demography

One hundred patients were randomized into this trial between April and September 2009, when the planned enrollment target was reached with 25 patients per treatment group, as described in Figure 1.

Figure 1

Figure 1

Four hundred eighty-eight patients were screened, the majority of screen failures being due to BMI/weight being too high (37%) or being older than the maximum allowed age limit of 65 years (21%). Of the 100 patients randomized into the study, 3 withdrew before completion, as described in Figure 1. The 2 withdrawals in the remimazolam 0.10 mg/kg group were due to withdrawal of consent and an investigator’s decision due to extravasation at the infusion site, while the withdrawal in the remimazolam 0.15 mg/kg group was due to the investigator determining that sedation was inadequate to complete the procedure.

Across the 7 sites that participated in this trial, patient recruitment per site in descending order was 36, 24, 14, 9, 9, 7, and 1, which meant that the bulk of the patients (74%) were recruited from 3 of the sites. Analysis of the rates of rescue medication at each of these sites showed a range varying from 78.6% (the site with 14 patients) to 8.3% (the site with 24 patients). These percentages do not include the site with the single patient.

The site with 24 patients used topical anesthetics in each patient, and there was only 1 further patient (from a separate site) who received a topical anesthetic for the procedure. Only 2 of these 25 patients (8%) received rescue sedative (1 in each of the 0.15 mg/kg and midazolam groups) against an overall rate of 51%. The patients who received topical anesthetic were evenly distributed across all 4 treatment groups (6–7 patients each).

There were no obvious differences in baseline characteristics (age, sex, weight, and BMI) among the 4 treatment groups. The overall mean age was 41 years, with 46% male and 54% female patients.

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Efficacy Results

The primary end point of the study was the success of the procedure using only a single dose of the assigned drug, and it can be seen from Table 2 that the success rate was 32%, 56%, and 64% in the 0.10, 0.15, and 0.20 mg/kg groups, respectively, compared with a success rate of 44% in the midazolam treatment group.

Table 2

Table 2

When broken down to its individual components, it can be seen that the overall procedure success rate was due to the requirement for a rescue sedative (Table 2) because all the procedure failures were due to the need for rescue sedative.

Visual examination of the sedation profile (MOAA/S score; Figure 2) over time indicates that the onset of sedation (to a MOAA/S score ≤3, which allowed the procedure to start) was 1.5 to 2.5 minutes for the remimazolam dose groups compared with 5 minutes for midazolam.

Figure 2

Figure 2

Rescue propofol or propofol along with midazolam was used in 32 patients overall (12, 7, 7, and 6 patients in the lowest, middle and highest remimazolam, and midazolam groups, respectively; Table 3). Rescue midazolam or midazolam and propofol was used in 46 patients overall (16, 10, 8, and 12 patients in the lowest, middle and highest remimazolam, and midazolam groups, respectively). Of the patients who received rescue medication with propofol and midazolam, 11, 6, 6, and 4 patients received both in the lowest, middle, and highest remimazolam and midazolam dose groups, respectively.

Table 3

Table 3

Overall, the average procedure duration (time from scope in to scope out) was 4.4 and 4.3 minutes in the 0.10 and 0.15 mg/kg remimazolam groups, respectively, compared with the highest remimazolam dose group (3.4 minutes) and midazolam (3.3 minutes; Table 3).

The times to fully alert for those patients who did not receive any rescue sedative medication are presented in Table 4, along with confidence intervals. A scatter plot of individual recovery times is shown in Figure 3, which indicates the variability of recovery times for each treatment group.

Table 4

Table 4

Figure 3

Figure 3

Procedure recall was assessed by the Brice questionnaire. Approximately 80% of patients from all treatment groups could not recall the procedure, with very little difference among the treatment groups. Twenty patients (80%) in the midazolam group could not recall the procedure compared with 19 (76%), 21 (84%), and 20 (80%) patients in the each of the remimazolam groups (0.10, 0.15, and 0.20 mg/kg, respectively). Patients in all treatment groups were satisfied with their procedure (mean satisfaction of 9.6 to 9.7 on a scale of 0 to 10, with 10 = completely satisfied).

The results of the HVLT-R, assessing the return to normal cognition and memory function for those patients who did not receive any rescue sedative medication, are shown in Table 5. A smaller change from baseline represents a better cognitive recovery for the patient. As would be expected, there was a decline in cognitive function, as assessed by the 4 variables described above, after the administration of both midazolam and remimazolam, although the recovery for the remimazolam-treated patients was more pronounced in all the individual variables assessed.

Table 5

Table 5

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Safety Results

Overall, the adverse events observed during the study were as expected for this population and class of drug and occurred in 45% of patients with no obvious difference among the treatment groups. The adverse events are summarized in Table 6.

Table 6

Table 6

Most of the events were either mild or moderate. A severe event occurred in 1 patient (fatigue) 59 minutes after administration of remimazolam (0.15 mg/kg) and after the administration of various rescue sedative medications (midazolam, meperidine, propofol). There were no serious adverse events reported.

Particular attention was paid to events of special interest when considering the development of a sedative for procedural sedation, such as arterial blood pressure, oxygen saturation levels, and respiratory depression. Arterial blood pressure and heart rate were stable in the remimazolam treatment groups, 1 case of hypotension occurred in the midazolam treatment group. There were 2 reports of respiratory depression/obstruction (respiratory rate <8 bpm) during the study. The first event was in a patient in the remimazolam 0.15 mg/kg treatment group, whose respiratory rate decreased to 8 breaths per minute, 3 minutes after receiving study drug. No action was taken, and the respiratory rate increased to 10 breaths per minute, 2 minutes after the onset of the event. The second event was in a patient in the midazolam treatment group. Five minutes after receiving midazolam, the patient received propofol due to insufficient sedation, and 1 minute after this the SpO2 had decreased to 85% and the patient experienced respiratory depression/obstruction. A chin lift was performed to relieve the airway obstruction and the event resolved rapidly (<1 minute). There were no other reports of respiratory depression or obstruction. No patients required supported ventilation. Four patients received supplemental oxygen for a transient decrease in oxygen saturation, 3 in the remimazolam 0.10 mg/kg group, and 1 in the remimazolam 0.20 mg/kg group.

In general, no treatment-related pattern could be discerned in the mean pulse oximetry readings over time. Because the use of rescue sedative medication could obscure the interpretation of these data, individual plots of oxygen saturation over time for those patients who did not receive rescue sedative are presented for each dose group in Figure 4. Of the patients who did not receive rescue sedative, there were 0 of 8 (0%), 1 of 14 (7%), 2 of 16 (13%), and 0 of 11 (0%) patients in the remimazolam 0.10, 0.15, and 0.20 mg/kg and midazolam groups, respectively, with an oxygen saturation level which decreased <90% on at least 1 occasion. This compares with 4 of 25 (16%), 5 of 25 (20%), 6 of 25 (24%), and 5 of 25 (20%) patients from the same treatment groups, respectively, when those who received rescue sedative are added. When patients both receiving and not receiving rescue sedative were combined, there were 2, 3, 2, and 0 patients in the same respective treatment groups whose oxygen saturation also decreased <85%. Two of these were classified as moderate by the investigators, the remainder being classified as mild. However, of the 15 remimazolam patients with an SpO2 of <90%, 11 had received propofol before the decrease in SpO2, and 1 of the remaining patients had received midazolam as rescue medication. This is in comparison with the midazolam group, where 2 of the 5 patients with an SpO2 of <90% had received propofol, and the remaining 3 had received additional midazolam doses as rescue medication. The majority of patients remained above an oxygen saturation level of 90% throughout the procedure for all treatment groups.

Figure 4

Figure 4

Airway interventions occurred in 1, 3, 3, and 2 subjects in the remimazolam 0.10, 0.15, and 0.20 mg/kg and midazolam groups, respectively. The overall requirement for airway intervention seemed low, considering the patients were not receiving supplemental oxygen.

There was no particular pattern that emerged for mean respiratory rate over time, other than a similar profile between each treatment group (Fig. 5).

Figure 5

Figure 5

There were also no discernable differences in vital signs among all 4 treatment groups with respect to the mean, systolic, and diastolic blood pressures. Overall, there was a slight increase in arterial blood pressure (up to approximately 10 mm Hg) within 2 to 6 minutes after drug administration, which then slowly decreased to baseline approximately 20 minutes later (Fig. 5).

A similar picture emerged for heart rate, in which an initial increase was observed over the first 4 to 8 minutes, which then recovered to baseline after approximately 20 minutes. Again, there were no discernable differences among the treatment groups (Fig. 5).

Pain on injection was also assessed using a visual analog scale. The mean pain scores were 17.6, 14.1, 14.0, and 12.4 for the remimazolam 0.10, 0.15, 0.20, and midazolam groups, respectively, on a 0- to 100-mm pain scale where 0 is no pain.

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DISCUSSION

A volunteer study has previously been published,11 but this is the first patient study to be reported with remimazolam, which is a new short-acting benzodiazepine currently in clinical development for procedural sedation. Due to the early stage of clinical development of the compound, there were some protocol-specific restrictions in the way the patients were managed in this trial, to understand the profile of the characteristics of remimazolam for this indication. To this end, supplemental oxygen was not administered unless specifically required by the patient, and patients were restricted to a single dose of study medication to cover the entire procedure. If further sedative medication was necessary due to insufficient sedation (as determined by the investigator) to complete the procedure, then rescue sedative medication was allowed, but the patients would be categorized as a failure as far as the primary end point of treatment success was concerned. While this is somewhat artificial, because in practice additional top-ups of the sedative medication would be used, it is nevertheless useful in being able to determine the comparative abilities of single doses of remimazolam or midazolam to maintain sedation for a short procedure, and the necessity for additional medication. In addition, it allows a cleaner look at the potential for remimazolam to cause adverse events related to respiratory complications, in comparison with midazolam, because the patients were breathing room air. However, one of the drawbacks of this approach is that it clouds any comparative results when rescue sedative medication is given, because this would clearly affect any recovery times being assessed. Attempts to rectify this using a modified ITT analysis, which would exclude any subjects who received rescue sedative medication, resulted in smaller numbers of patients being available for analysis, and hence, results with these patients are more difficult to interpret.

The efficacy results showed that procedure success was achieved with a single administration of remimazolam, varying from 32% to 64%, compared with a success rate in the midazolam treatment group of 44%. Considering the restrictions of the trial design in the determination of success, this shows the potential of a single administration of remimazolam for the conduct of short procedures (<10 minutes) such as upper GI endoscopies.

The success rate was driven largely by the number of patients requiring rescue medication. There was an overall variation among the sites in the number of patients requiring rescue medication, ranging from 8.3% to 78.6%, suggesting that some sites were waiting longer than others before administering rescue medication. In addition, 1 site used topical anesthetics for the procedure in every patient they recruited (n = 24). There was only 1 further patient, from a separate site, who received a topical anesthetic. Only 2 of these 25 patients (8%) received rescue sedative (1 in each of the 0.15 mg/kg and midazolam groups) against an overall rate of 51%. The patients who received topical anesthetic were evenly distributed across all 4 treatment groups.

These effects had an impact on the overall interpretation of these results although any influence of this effect applied equally across the treatment groups, and a randomization block size of 4 helped to spread any individual site influence across all treatment groups but could not prevent that local practice differed with respect to providing topical anesthetics. In future upper GI endoscopy studies, the use of topical anesthetics should be standardized across all sites.

One of the potential benefits of this drug over midazolam comes from the design of the molecule, resulting in its rapid breakdown to an inactive metabolite by ubiquitous tissue esterases. This should result in a more rapid and predictable recovery of patients from their sedation, and hence not only benefit the patients in that they are potentially able to leave the unit quickly and perform everyday tasks more rapidly but should also result in a more rapid and consistent throughput of patients in the gastroenterology suite. The results of this small, single-dose study showed times to fully alert varying from 7.0 to 10.0 minutes with remimazolam for those patients who did not receive a rescue sedative compared with 7.0 minutes for midazolam, but these median times do not reflect the lack of outliers seen in the remimazolam groups in comparison with midazolam, where the variability was greater. The relatively short duration of recovery in the midazolam group can be attributed to the single-dose study design, when compared with midazolam recovery times reported in the literature, which varies from as short as 4 minutes16 to as long as 70 minutes,17 and the variability of midazolam recovery times (22–82 minutes) is summarized in the review by McQuaid and Laine18 of 11 other articles. As described above, the study design only allowed for 1 administration of study drug, and any additional top-ups were given as rescue sedative medication, which resulted in 2 points for consideration when interpreting these results. First, in normal practice, additional top-ups of the same sedative medication would be given routinely, which will increase the low response rates, and this would be expected to be the case for remimazolam patients as well. Second, by excluding these patients from any recovery analyses, one is excluding the poorer responders from this analysis, who are the very patients who are likely to receive larger doses of the sedatives, and hence take longer to recover. The study design itself has therefore biased any recovery analyses against remimazolam, but because it was planned to study the effect of single remimazolam doses this goal has been achieved. Multiple doses will be used in future studies, which is more in-line with standard practice. In addition, topical anesthesia should be used in all patients.

The cognitive assessments performed pointed toward the potential for an earlier return to full cognition in the remimazolam-treated patients, as indicated by all the individual variables assessed using HVLT-R. These effects will be studied again in larger, later stage trials.

Because the subjects were breathing room air during this trial, it afforded the opportunity to show an indication of any concerns relating to oxygen desaturation. While there were 15 (20%) remimazolam patients overall with an SpO2 of <90% at some point during the procedure, any assessment would need to consider the use of rescue propofol, which was given to 11 of these 15 patients. This is in comparison with 5 (20%) midazolam patients with an SpO2 <90%, 2 of whom also received propofol as rescue sedation. The use of rescue propofol clearly had a major impact on the oxygen saturation levels observed in this study, as would be expected, but this does make it difficult to draw any conclusions in a study of this size. The majority of patients remained at an SpO2 of >90% throughout the procedure, and there were no obvious differences in the treatment groups.

From a safety perspective, there were no obvious differences between remimazolam and midazolam, with a stable vital sign profile, and both compounds had a low potential for respiratory complications. Remimazolam would appear to have a safety profile typical of benzodiazepines, but this remains to be confirmed.

While the results of this study are very encouraging, further work needs to be done to establish remimazolam’s efficacy and safety profile including a multiple-dose setting, and its ability to induce and maintain appropriate levels of sedation for both short procedures such as this, as well as longer procedures such as colonoscopy. The results from this study indicate that initial loading doses starting from at least 0.15 mg/kg of remimazolam should be sufficient to warrant further investigation in multiple administration trials. To date, >920 subjects have been treated with remimazolam, and a phase III program, taking into consideration the outcomes of this study, is in active preparation.

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DISCLOSURES

Name: Keith M. Borkett, BSc.

Contribution: This author helped design the study, conduct the study, analyze the data, and write the manuscript.

Attestation: Keith M. Borkett has seen the original study data, reviewed the analysis of the data, approved the final manuscript, and is the author responsible for archiving the study files.

Conflicts of Interest: Keith M. Borkett worked for PAION UK Ltd.

Name: Dennis S. Riff, MD.

Contribution: This author helped conduct the study.

Attestation: Dennis S. Riff has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.

Conflicts of Interest: Dennis S. Riff acted in an advisory capacity to PAION as part of an expert panel.

Name: Howard I. Schwartz, MD.

Contribution: This author helped conduct the study.

Attestation: Howard I. Schwartz has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.

Conflicts of Interest: The author has no conflicts of interest to declare.

Name: Peter J. Winkle, MD.

Contribution: This author helped conduct the study.

Attestation: Peter J. Winkle has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.

Conflicts of Interest: The author has no conflicts of interest to declare.

Name: Daniel J. Pambianco, MD.

Contribution: This author helped conduct the study.

Attestation: Daniel J. Pambianco has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.

Conflicts of Interest: This author has no conflicts of interest to declare.

Name: James P. Lees, BSc.

Contribution: This author helped design the study, conduct the study, and analyze the data.

Attestation: James P. Lees has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.

Conflicts of Interest: James P. Lees worked for PAION UK Ltd.

Name: Karin Wilhelm-Ogunbiyi, MD.

Contribution: This author helped design the study, conduct the study, and analyze the data.

Attestation: Karin Wilhelm-Ogunbiyi has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.

Conflicts of Interest: Karin Wilhelm-Ogunbiyi worked for PAION GmbH.

This manuscript was handled by: Tony Gin, MD, FRCA, FANZCA.

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FOOTNOTE

a Data from this study were presented as a poster at Digestive Disease Week (DDW) 2010.19
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