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A Phase Ib, Dose-Finding Study of Multiple Doses of Remimazolam (CNS 7056) in Volunteers Undergoing Colonoscopy

Worthington, Mark T. MD*; Antonik, Laurie J. MD; Goldwater, D. Ronald MD; Lees, James P. BSc§; Wilhelm-Ogunbiyi, Karin MD; Borkett, Keith M. BSc§; Mitchell, Mack C. MD*

doi: 10.1213/ANE.0b013e3182a705ae
Anesthetic Pharmacology: Research Report
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BACKGROUND: We performed the first multiple dose study of remimazolam designed to assess both the feasibility of maintaining suitable sedation during colonoscopy and reversing the sedative effects of remimazolam with flumazenil.

METHODS: Healthy volunteers received fentanyl followed by remimazolam for sedation during colonoscopy. Three dose groups of 15 volunteers each received remimazolam in increasing initial doses, plus top-up doses to maintain sedation for a 30-minute period. In a separate double-blind crossover part of the trial, 6 volunteers were sedated with a single high dose of remimazolam, followed by flumazenil or placebo to reverse the sedation.

RESULTS: Successful sedation that was adequate for colonoscopy was achieved in >70% of subjects. After the procedure, subjects rapidly recovered to fully alert, with a median of <10 minutes overall. Failures were due to the inability to sedate or adverse events, with 1 subject failing due to hypotension (arterial blood pressure 80/40) and low SpO2 (<90%). There were no serious adverse events reported, and no events that were unexpected with the combination of a benzodiazepine and fentanyl. The study also showed that sedation was rapidly reversible (1.0 minutes flumazenil vs 10.5 minutes placebo) without resedation.

CONCLUSIONS: Remimazolam has the attributes of a sedative drug, with success rates comparable with recent studies of other drugs. Remimazolam provided adequate sedation in 33 of 44 subjects undergoing colonoscopy, and its sedative effects were easily reversed with flumazenil.

From the *Division of Digestive Diseases and Department of Anesthesiology, Johns Hopkins Hospital, and Early Phase Clinical Unit, PAREXEL, Baltimore, Maryland; §Clinical Development, PAION UK Ltd, Cambridge, United Kingdom; and Clinical Development, PAION Deutschland, GmbH, Aachen, Germany.

Accepted for publication July 1, 2013.

Funding: The study was funded by PAION UK Ltd.

Mack C. Mitchell, MD, is currently affiliated with Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas.

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, United Kingdom CB24 9ZR. Address e-mail to k.borkett@paion.com.

Painful medical procedures of limited duration generally require some form of analgesia and sedation to minimize patient discomfort and optimize operator performance. To minimize patient inconvenience and maximize efficiency in units conducting procedures like colonoscopies, there is an increasing emphasis on using sedative drugs that show both a rapid onset and resolution to allow a predictable patient onset, earlier patient recovery, faster discharge from the unit, and a rapid return to normal alertness.

Currently, either propofol or a benzodiazepine (sometimes in combination with an opioid) are used for sedation in endoscopic procedures.1,2 Both propofol and benzodiazepines are effective for obtaining sedation in such procedures.3,4 The principal disadvantages of benzodiazepines for sedation are 2-fold: first, they do not provide analgesia, and second, most benzodiazepines have long elimination half-lives. Even midazolam, which has the shortest elimination half-life of the benzodiazepines, has a half-life of approximately 1 to 3 hours. The need for analgesia is easily resolved through the concomitant use of an opioid such as fentanyl. Use of benzodiazepines for sedation procedures such as endoscopies can result in the patient being unable to function at their normal cognitive level for hours after what was a relatively short procedure.

Remimazolam (CNS 7056) is a benzodiazepine developed to provide sedative effects equivalent to those of drugs such as midazolam but with a shorter terminal half-life. This ester-based drug is rapidly hydrolyzed in the body by ubiquitous tissue esterases to an inactive carboxylic acid metabolite (CNS 7054).5 In healthy volunteers, remimazolam induced sedation rapidly after a single bolus administration,6 with no serious adverse events. The depth and duration of sedation appeared to be sufficient to allow short-term procedural sedation, and recovery was more rapid than with midazolam, with no resedation observed. These findings suggest that remimazolam would be suitable for use as a sedative during procedures such as colonoscopy.

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METHODS

Study Design and Procedures

This study was split into 2 distinct parts: flumazenil reversal and dose escalation. The objective of the flumazenil reversal part of the study was to assess the reversibility of remimazolam’s sedative effects with flumazenil. The objective of the dose escalation part of the study was to assess the feasibility of maintaining suitable sedation levels with remimazolam during colonoscopy. A schematic of the study design can be seen in Figure 1. The study was conducted in accordance with the Declaration of Helsinki and the International Conference on Harmonisation of Good Clinical Practice, at a single site in the United States.

Figure 1

Figure 1

After receiving IRB approval of the protocol, all volunteer study subjects provided written informed consent at screening, before the start of any protocol-specified procedures or assessments.

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Flumazenil Reversal

For this part of the study, which assessed the safety and efficacy of flumazenil in reversing the sedative effects of remimazolam (0.25 mg/kg), 6 subjects (3 men and 3 women) were randomized to 1 of 2 possible treatment sequences. This study was not powered statistically. Six subjects were empirically chosen as a standard group size in early studies. The sample size was considered sufficient to gain an impression of the ability of flumazenil to reverse the sedative effects of remimazolam. It was conducted in a double-blind, randomized manner, in which only the pharmacist and pharmacy staff were unblinded. They did not participate in any study procedures other than preparation of study medication. The identity of the study drug (flumazenil or placebo) was not revealed to study management or to anyone at the study site until this part of the study was completed.

The subjects were given 0.25 mg/kg remimazolam infused over 1 minute, a dose determined to be suitable to safely mimic oversedation requiring flumazenil rescue. Modified Observer’s Assessment of Alertness/Sedation7 (MOAA/S) scores were assessed at 1.5, 2.0, and 3.0 minutes after the start of remimazolam and then at 1-minute intervals until the time of dosing with flumazenil or placebo. Three minutes after the subject was successfully sedated (MOAA/S ≤3), either flumazenil (0.5 mg) or placebo was administered, and the subjects’ sedation was monitored at 1-minute intervals until they were fully alert (3 consecutive MOAA/S scores of 5). Sedation levels were also recorded at 30, 60, and 120 minutes after they were fully alert. The following day, the subject received the alternate treatment (flumazenil or placebo), and exactly the same procedures were followed.

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Dose Escalation for Sedation During Colonoscopy

Dose groups of 15 subjects (no more than 8 of either gender) each were enrolled into one of 3 initial dosing groups as part of an open-label initial dose escalation study. This study was not powered statistically. Fifteen subjects were chosen to gain an impression of the ability of remimazolam to maintain suitable sedation during colonoscopy. This sample size was considered sufficient to meet the study objectives. The initial doses of remimazolam were lower than the doses administered in the first-in-human study6 to account for the concomitant administration of fentanyl. An independent data monitoring committee met at the end of each dose group’s testing, to discuss the safety data, before permitting escalation to the next dose group.

On the day before the procedure, eligible subjects were admitted to the clinical unit and received HalfLytely® and Bisocodyl Tablets Bowel Prep Kit (Braintree Laboratories, Inc., Braintree, MA) to prepare for the colonoscopy. On the morning of the procedure, subjects received 50 µg fentanyl for analgesia and an initial dose of remimazolam (0.04, 0.075, or 0.10 mg/kg, depending on dose group) 5 to 10 minutes after the fentanyl. The initial dose of remimazolam was given as a 1-minute IV injection. As a result of hypotension being observed after the first 4 patients of dose group 2 that was thought to be due to the relative volume of fluid depletion after the bowel preparation, the data monitoring committee recommended the introduction of a saline infusion (500–1000 mL), along with the timing of the fentanyl administration being moved to 10 minutes before the initial remimazolam dosing. These changes were implemented during studying the second dose group and continued into the third dose group.

When adequate sedation (defined as a MOAA/S score of ≤3) was achieved, a flexible colonoscope was inserted, and a colonoscopy was performed according to standard clinical practice, to include visualization of the caecum and ileocecal valve. If additional fentanyl was required for analgesia during the procedure, a single supplemental dose of 25 µg was allowed at the investigator’s discretion, if at least 10 minutes had elapsed from the previous fentanyl dose. If adequate sedation to allow the start of the procedure could not be achieved with the initial dose of remimazolam, up to a maximum of 2 supplemental doses of 0.04 mg/kg were administered as IV boluses over approximately 15 seconds, not <2 minutes apart. If the initial bolus and the supplemental boluses were not sufficient to obtain adequate sedation for scope insertion, the colonoscopy was not performed.

Once the procedure was underway, supplemental doses of 0.04 mg/kg remimazolam were administered at the investigator’s discretion, at least 2 minutes apart (not to exceed a cumulative total of 6 supplemental boluses) to sustain a MOAA/S ≤4 for 30 minutes. If adequate sedation could not be maintained after all 6 supplemental doses had been administered, the scope was removed. Sedation was assessed using the MOAA/S score every minute until the subject was fully alert (the first of 3 consecutive MOAA/S scores of 5) and at 30, 60, and 120 minutes after fully alert.

The duration of the colonoscopy procedure was determined by normal clinical practice; however, the scope was removed after a maximum of 30 minutes. If the procedure was completed before 30 minutes had elapsed, the scope was removed, and the subject kept sedated until 30 minutes after the insertion of the scope to simulate a longer duration of the procedure. The intent of this study was to sustain sedation at a MOAA/S score of ≤4 for 30 minutes. Subjects did not routinely receive supplemental oxygen during the procedure. Subjects were discharged from the clinical unit after completion of the day 2 24-hour postdose assessments and returned to the clinical unit for a follow-up visit approximately 7 days later.

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Subject Eligibility

Men and women volunteers aged 18 to 75 years inclusive were eligible to enter the study if they had an ASA physical status of I, a weight range of 60 to 120 kg inclusive, and a body mass index of 18 to <30 kg/m2.

Subjects were excluded if they had a suspected or diagnosed pathology of the gastrointestinal tract that would add to the risk of endoscopy or could require acute treatment. In addition, subjects were excluded if they had a known sensitivity to benzodiazepines, flumazenil, opiates, naloxone, or a contraindication to receiving these medications. Subjects 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

In the dose escalation part of the study, the success of performing the colonoscopy 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 procedure (including 30 minutes of total sedation); (3) no requirement for rescue (alternate) sedative medication; and (4) no manual or mechanical ventilation.

In the dose escalation part of the study, in addition to the above, readiness for discharge was assessed by the Aldrete Criteria8 30 minutes after the first remimazolam dose and every 5 minutes thereafter until fully alert, plus also at 30, 60, and 120 minutes after fully alert. Safety was assessed by monitoring for adverse events and routine clinical laboratory testing. Heart rate, arterial blood pressure, respiratory rate, and oxygen saturation were monitored throughout the treatment period.

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RESULTS

Flumazenil Reversal

Six subjects entered the flumazenil reversal trial, and 45 subjects entered the colonoscopy trial between April and September 2009. All 6 subjects completed the flumazenil reversal. The median sedation scores (MOAA/S) over time for the flumazenil reversal are shown in Figure 2. After sedation with remimazolam, the median (range) time until subjects were fully alert was 1.0 (1–5) minutes after flumazenil and 10.5 (5–52) minutes after placebo.

Figure 2

Figure 2

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Dose Escalation

Subject Disposition and Demography

Of the 45 subjects randomized into the colonoscopy groups, 4 were discontinued (Fig. 3). Two subjects (0.075 mg/kg and 0.10 mg/kg group) completed the procedure but were lost to follow-up. One subject (204, 0.04 mg/kg group) was discontinued because of mild hypotension considered unrelated to study drug (as it occurred before study drug administration and was thought to be probably related to fentanyl administration), and the remaining subject (411, 0.10 mg/kg group) was discontinued due to moderate hypotension and mild oxygen desaturation, both considered related to study drug. Severity was assessed using the Common Terminology Criteria for Adverse Events.

Figure 3

Figure 3

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Success of Colonoscopy

In this part of the study, remimazolam was titrated to effect. The number of supplemental doses and total amount of remimazolam (cumulative dose 0.21, 0.29, and 0.27 mg/kg for the 0.04, 0.075, and 0.10 mg/kg groups, respectively) are shown in Table 1.

Table 1

Table 1

Supplemental fentanyl was also administered for additional analgesia in 5, 15, and 10 subjects in each of the 0.04, 0.075, and 0.10 mg/kg groups, respectively, with mean cumulative doses per subject of 58, 75, and 67 µg for each group, respectively. Colonoscopy was performed successfully in 10 of 15 subjects in dose group 1 (0.04 mg/kg), 15 of 15 subjects in dose group 2 (0.075 mg/kg), and 9 of 14 subjects in dose group 3 (0.10 mg/kg). One subject could not be assessed in dose group 3 due to poor bowel preparation (subject 404). In the successful subjects, the mean number of remimazolam top-up doses was 5.4, 5.4, and 5.2 (mean cumulative dose of 0.26, 0.29, and 0.31 mg/kg) for the 0.04, 0.075, and 0.10 mg/kg groups, respectively.

Of the 10 subjects who did not have a successful procedure, 8 failed to achieve a sufficient level of sedation for insertion of the colonoscope (5 in the 0.04 mg/kg group [subjects 201, 202, 204, 205, 208], and 3 in the 0.10 mg/kg group [subjects 405, 408, 409]). Subject 204 was withdrawn before remimazolam administration. The remaining 2 subjects failed due to not being able to maintain the target level of sedation long enough to complete the procedure (subject 410) and also an adverse event (hypotension and oxygen desaturation) before initiation of colonoscopy as described above (subject 411).

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Efficacy of Sedation During Colonoscopy

The sedation profile for each treatment group can be seen in Figure 4.

Figure 4

Figure 4

Onset of sedation was <1 minute in each treatment group. The levels of sedation in all 3 groups after administration of supplemental doses (0.04 mg/kg) of remimazolam are shown in Figure 4. The proportion of subjects reaching loss of consciousness (MOAA/S 0 or 1) at some point during the procedure was 100% in the 0.075 mg/kg group, compared with 67% and 87% in the 0.04 and 0.10 groups, respectively. For these subjects, the duration of loss of consciousness was a median of 13 minutes in the 0.075 group compared with 9 and 8 minutes in the 0.04 and 0.10 groups, respectively.

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Recovery from Sedation After Colonoscopy

The median time to fully alert (3 consecutive MOAA/S scores of 5) varied between approximately 7 to 9 minutes (Table 2), and subjects were ready for discharge (Aldrete Criteria)8 <25 minutes from the last dose of remimazolam in all groups.

Table 2

Table 2

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Sedation Safety Results

Overall, the adverse events that were observed during the study were those expected after administration of a benzodiazepine and fentanyl during colonoscopy. There were no serious adverse events. Because remimazolam is in the early phase of development, attention was paid to oxygen saturation levels, respiratory depression, airway interventions, hypotension, bradycardia, and prolonged sedation.

Treatment-related hypotension (systolic blood pressure ≤80 mm Hg) was observed in 24% of subjects in all treatment groups. All of these episodes were easily managed with normal saline infusion (saline preload was introduced for all subjects during the second dose group) and resolved quickly. The details of these events can be seen in Table 3. Hypotension was reported in 3, 5, and 3 subjects in the 0.04, 0.075, and 0.10 mg/kg groups, respectively.

Table 3

Table 3

Oxygen saturation was monitored continuously throughout the trials, and individual subject profiles can be seen in Figure 5. The mean oxygen saturation level (SpO2) decreased slightly (<5%) in the first 10 minutes after the initial dose of fentanyl and remimazolam in the 0.075 and 0.10 mg/kg groups and recovered to baseline by 60 minutes. There were individual decreases in oxygen saturation below 90%, with the lowest value observed being 84% in 1 subject in the 0.075 mg/kg group, and the overall number of subjects with a level below 90% being 1, 5, and 3 in the 0.04, 0.075, and 0.10 mg/kg groups, respectively.

Figure 5

Figure 5

Oxygen desaturation (oxygen saturation <90% on room air) was observed in 2 of 6 subjects after administration of a single large dose (0.25 mg/kg) as part of the flumazenil reversal study and in 9 of 45 subjects during the colonoscopy phase of the study (Table 4). All oxygen desaturation events were transient.

Table 4

Table 4

One subject in the 0.075 mg/kg group received oxygen via a facemask for treatment of oxygen desaturation. No subject required manual or mechanical ventilation, and 1 subject received airway management (a chin lift) for a brief period of oxygen desaturation. The mean respiratory rates were 14 to 17 breaths per minute, with individual rates changing from 10 to 24 breaths per minute. Respiratory depression was not observed.

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DISCUSSION

A previous study with remimazolam demonstrated that a single dose of 0.25 mg/kg induces significant sedation within a short period of time.6 Most benzodiazepines are both sedative and anxiolytic when given IV, and their effects can be rapidly reversed by the administration of flumazenil. The flumazenil reversal part of the current study demonstrated that the effect of remimazolam could be reversed by the addition of flumazenil.

The dose escalation part of the study assessed the feasibility of inducing and maintaining a suitable level of sedation in subjects undergoing routine colonoscopy. Because it was conducted in healthy volunteers, a slight departure from normal colonoscopy practice was made. After completion of a standard screening colonoscopy, the scope was withdrawn, but the subjects were kept sedated for a total of 30 minutes from the start of the procedure. As this was the first multiple administration study of remimazolam in humans, the 30-minute sedation was undertaken to evaluate a longer maintenance of sedation by remimazolam, a benzodiazepine with a very short terminal plasma half-life.

The subjects received a bowel preparation the evening before and were fasted overnight. In the first dose group, fentanyl (50 µg) was administered for analgesia 5 minutes before receiving remimazolam. Hypotension was observed in some subjects, a finding that had not been observed in the first human study with single doses of remimazolam6 or after a single higher dose of remimazolam in the first phase of this study. The hypotension was thought likely to be due to dehydration after the bowel preparation, in combination with the vasodilatory effects of fentanyl given at the start of the procedure. After the first 4 subjects of the second dose group were studied, the protocol was amended to include infusion of 500 to 1000 mL saline before administration of fentanyl, and the dose of fentanyl was moved to 10 minutes before the initial remimazolam dose. Because the study called for titration of remimazolam doses to achieve and maintain a particular sedative effect, the amount of remimazolam administered during the trial was similar among the 3 groups. Consequently, an overall dose response could not be observed across the treatment groups, except with regard to the initial dose of remimazolam. Higher initial doses resulted in a deeper initial sedation.

Overall, 34 of 44 subjects (77%) completed a colonoscopy and continued sedation for 30 minutes (1 subject is not included in the denominator because an assessment could not be made due to poor bowel preparation). This result is encouraging, particularly since this study is the first to use a multiple dose paradigm for a clinical procedure at an early stage of drug development. The onset of sedation was very rapid, and the recovery from sedation was short (7–9 minutes to fully alert), irrespective of the treatment group. Readiness for discharge (Aldrete Score) was also very quick, approximately 24 minutes from the last dose of study drug. These findings indicate that, in combination with a very low dose of fentanyl, repeated dosing with remimazolam provided effective sedation that wore off quickly after dosing was stopped.

When used in combination with fentanyl, treatment-related hypotension was experienced by 24% of subjects, easily managed with normal saline infusions and resolved quickly. Dehydration after bowel preparation and an overnight fast may have predisposed some subjects to hypotension, since only 4 of 25 subjects who were given saline before the procedure developed hypotension compared with 7 of 20 subjects who were not rehydrated before receiving remimazolam and fentanyl. Fentanyl, a known vasodilator, complicated the assignment of causality of hypotension. Of the 11 subjects with hypotension, 7 had received a 25 µg supplemental dose of fentanyl in addition to their initial 50 µg dose. Of note, hypotension was not observed in the subjects receiving remimazolam as a single dose in the first-in-human clinical study, at higher doses. For all of these reasons, while hypotension was observed after the combination of fentanyl and remimazolam, it is difficult to ascribe this directly to remimazolam. However, this will have to be assessed in future trials, against a background of an anticipated hypotension rate of approximately 7% with midazolam plus an opiate.9

Respiratory depression and oxygen desaturation are clearly an area of prime interest or concern when considering the development of a new benzodiazepine. In the flumazenil reversal part of the study, oxygen desaturation was experienced by 2 of 6 subjects, after a high dose of remimazolam (0.25 mg/kg) was used to induce a deeper level of sedation than typically desired for procedural sedation. During the dose escalation part of the trial, transient oxygen desaturation to below 90% was observed in 20% of the subjects overall. Most of these events resolved spontaneously within 1 to 2 minutes. Our study was performed without routine administration of supplemental oxygen, which is a more stringent test than current clinical practice, as all subjects were breathing room air. The study was designed in this way to determine the potential for remimazolam to induce oxygen desaturation. The degree of oxygen desaturation observed seemed to be very low, even at higher levels of sedation. Indeed, examination of the pulse oximetry data over time reveals a steady profile, with an initial decrease (to a median SpO2 of, at worst, 94%) during the first 10 minutes, which then slowly recovered to baseline. In clinical practice, supplemental oxygen is routinely administered during colonoscopy,1 and hence, it is difficult to compare the levels of oxygen desaturation here against an expected background rate of approximately 6% for midazolam plus an opiate.9 On the basis of the degree of oxygen desaturation observed on room air, it is likely that fewer events would have been observed in this study if supplemental oxygen had been administered. Only 1 subject (0.075 mg/kg group) required the use of oxygen during the study, which was administered via a facemask. One further subject (0.10 mg/kg group) required a chin lift after a brief period of oxygen desaturation. No subject required manual or mechanical ventilation. Overall, there was nothing of concern observed with respect to the airway safety profile of remimazolam in this study.

In summary, remimazolam has the attributes of a sedative drug, with success rates that are very encouraging. It was easily reversible and provided adequate sedation in 77% of subjects undergoing colonoscopy. Further studies are needed in colonoscopy patients under standard conditions to refine the optimal dosing regimen before widespread clinical use. E

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DISCLOSURES

Name: Mark T. Worthington, MD.

Contribution: This author helped conduct the study.

Attestation: Mark T. Worthington 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: Laurie J. Antonik, MD.

Contribution: This author helped conduct the study.

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

Conflicts of Interest: Laurie J. Antonik consulted for PAION UK Ltd and attended an expert panel meeting.

Name: D. Ronald Goldwater, MD.

Contribution: This author helped conduct the study.

Attestation: D. Ronald Goldwater 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: James P. Lees, BSc.

Contribution: This author helped design 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 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 Deutschland GmbH.

Name: Keith M. Borkett, BSc.

Contribution: This author helped design 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: Mack C. Mitchell, MD.

Contribution: This author helped conduct the study.

Attestation: Mack C. Mitchell 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.

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

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