PMD-200

{0}------------------------------------------------ #### DE NOVO CLASSIFICATION REQUEST FOR MEDASENSE BIOMETRICS LTD. PMD-200 #### REGULATORY INFORMATION FDA identifies this generic type of device as: Adjunctive nociception index. An adjunctive nociception index is a prescription device that uses a software algorithm(s) to analyze physiological sensor data and provide a quantitative measure of nociceptive response to painful stimuli in patients under general anesthesia. This device type is intended for adjunctive use to personalize analgesic administration to a patient's actual response to painful stimuli and is not intended to independently direct therapy decisions. NEW REGULATION NUMBER: 21 CFR 868.2200 CLASSIFICATION: Class II PRODUCT CODE: QVE #### BACKGROUND DEVICE NAME: PMD-200 SUBMISSION NUMBER: DEN210022 DATE DE NOVO RECEIVED: June 04, 20212 #### SPONSOR INFORMATION: Medasense Biometrics, Ltd. 4 Hachilazon St., P.O. Box 3724 Ramat Gan 5213606 Israel #### INDICATIONS FOR USE The PMD-200 with the Nociception Level (NOL) Index is indicated for use in a clinical setting that requires assessment of changes in nociception levels in adult patients under general anesthesia receiving opioid or opioid-sparing analgesia as part of their care. The PMD-200 should be used as an adjunct to clinical judgment. Clinical judgment should always be used when interpreting the NOL index in conjunction with other available clinical and vital signs. {1}------------------------------------------------ ## LIMITATIONS The sale, distribution, and use of the PMD-200 are restricted to prescription use in accordance with 21 CFR 801.109. The PMD-200 should be used as an adjunct to clinical judgment. Clinical judgment should always be used when interpreting the NOL index and trend line in conjunction with other available clinical and vital signs. PLEASE REFER TO THE LABELING FOR A COMPLETE LIST OF WARNINGS, PRECAUTIONS AND CONTRAINDICATIONS. ## DEVICE DESCRIPTION The PMD-200 (device) is a nociception monitoring system which assists assessment of anaesthetized patient's physiological response to noxious stimuli and helps tailor analgesic administration to the patient's actual response to painful stimuli. The device provides quantification of the patient's response to noxious stimuli with the nociception level index (NOL). Image /page/1/Picture/6 description: The image shows a Medasense monitor displaying a graph and the number 58. The monitor is white with red accents and has a screen that displays various signals and trends. The graph on the screen shows a fluctuating line, and the number 58 is prominently displayed in the upper right corner of the screen. The PMD-200 system consists of 4 main components: - Monitor acquisition and display of physiological raw data signals and NOL . index and trend graph. - . Software includes two main components: - Calculation of the NOL index based on physiological parameters extracted from raw data signals. {2}------------------------------------------------ - O User interface displays physiological raw data signals, NOL index and trend graph. - Finger probe -includes the following sensors: . - Photoplethysmogram (PPG or Pleth) o - · Thermistor for peripheral temperature (TMP) - · A 3-axis accelerometer for movement (ACC or Movement). - Connectors for the Galvanic skin response sensor (GSR or Conductance) - Single use sensor (connected to the finger probe) includes the following sensor: . o Bio-impedance Galvanic skin response sensor (GSR or Conductance) The NOL index is a relative, non-linear measure with a range of 0-100, where 0 represents no pain /nociceptive response and 100 represents extreme pain/nociceptive response. The NOL index and trend are intended to support clinical decisions concerning the administration of analgesic medications. Clinical evidence 1-3.4 suggests the following guidelines for procedures under general anesthesia: - . NOL above 25 for more than one minute may indicate the patient requires additional analgesic therapy. Higher values indicate a stronger nociceptive response. However, the magnitude above the NOL threshold of 25 does not provide guidance on the magnitude of the dose of analgesic, but rather indicates timing as to when additional analgesic dosing may be necessary, following a nociceptive response. - NOL between 0-25 represents an appropriately suppressed physiological . response to noxious stimuli and suggests adequate analgesia. - . The NOL index cannot anticipate noxious stimuli and thus a minimal level of analgesics should always be maintained. ## SUMMARY OF NONCLINICAL/BENCH STUDIES ## BIOCOMPATIBILITY The PMD-200 includes components that are direct contact with patient skin during use. The finger probe and single-use sensor are categorized as surface contacting (intact skin) devices with prolonged contact in accordance with ISO 10993-1 referenced by the FDA guidance document, Use of International Standard ISO 10993-1, "Biological evaluation of medical devices - Part 1: Evaluation and testing within a risk management process". The components were subjected to biocompatibility testing in accordance ISO 10993-1. The following tests were conducted to assess biocompatibility of the device for the surface, intact skin contacting components for prolonged duration: ¹ Meijer, F et al/Reduced postoperative pain using Nocieption Level-guided fentany dosing during sevolurane anaesthesia: a randomised controlled trial/ British Journal of Anaesthesia 2020 September ² Meijer F et al Nociception-guided Care during Remifentanil-Propofol Anesthesia: A Randomized Controlled Trial/Anesthesiology 2019 Feb. ⁸ Ledowski, T., Schheter, P. & Hall, N. Nociception level inter-operative values allow the prediction of acute postoperative pain?. J Clin Monit Comput (2021). ⁴ Martini CH et al Ability of the Nociception Level (NOL), a multiparameter composite of autonomic signals, to detect noxious stimuli during propofol-remifentanil anesthesia Anesthesiology 2015 Sept. {3}------------------------------------------------ - . Cytotoxicity - Sensitization . - . Irritation All tests passed. The results demonstrated the biocompatibility of the device. #### SHELF LIFE/REPROCESSING/STERILITY The PMD-200 system is provided non-sterile and is not intended to be sterilized by the user. The monitor and finger probe components of the PMD-200 system are reusable and the single use sensor (disposable) has a three (3) year shelf-life. The labeling provides cleaning and disinfection procedures for the main unit and finger probe. The procedures for the reusable components were validated following the recommendations of the FDA Guidance Document "Reprocessing Medical Devices in Health Care Settings: Validation Methods and Labeling". The shelf-life of the single use sensor was assessed by visual and functional testing following accelerated and real-time aging of three (3) years. The expected service life of the PMD-200 finger probe is 2 years (24 months) which is reflected by 600 procedures (300 per year) based on usage data in other jurisdictions in which the device is already in routine use. Service life testing with 600 simulated use cycles followed by functional testing is provided to validate the service life. ## ELECTROMAGNETIC CAPABILITY & ELECTRICAL SAFETY Electrical safety and electromagnetic compatibility testing has been performed and complies with the following standards: - IEC 60601-1-2 Medical Electrical Equipment Part 1:2014+AMD1:2020: . General Requirements for Safety: Electromagnetic Compatibility Requirements and Tests (Edition 4.1). - AAMI / ANSI ES60601-1:2005/(R)2012 + AMD1:2012, C1:2009/(R)2012 And . A2:2010/(R)2012 (Consolidated Text) Medical Electrical Equipment - Part 1: General Requirements For Basic Safety And Essential Performance (IEC 60601-1:2005+ AMD1:2012+AMD2:2020, edition 3.2. - The device was also tested for requirements of IEC 60601-1-2:2014+AMD1:2020 . and AIM 7351731 for RFID to evaluate the effects of electrocautery and diathermy. ## SOFTWARE Software documentation including management of cybersecurity was provided in accordance with the FDA Guidance Document. "Guidance for the Content of Premarket Submissions for Software Contained in Medical Devices," (issued May 11, 2005) for a Moderate Level of Concern (LOC). A Moderate LOC is deemed appropriate as {4}------------------------------------------------ malfunction of the device software or a latent design flaw in the device software may lead to erroneous information or a delay in the delivery of appropriate medical care. which would likely result in minor injury but would likely not result in serious injury or death due to the current practice of medicine #### HUMAN FACTORS TESTING The PMD-200 has been evaluated in a comprehensive human factor validation process in compliance with IEC 62366 and ANSI/AAMI 60601-1-6. The summative validation study of 18 participants representative of intended users conducted in Ramban hospital (Haifa, Israel) and Carmel Medical Center (Haifa, Israel) was intended to validate usability aspects of the device including operational validation and display validation. The testing activities performed endured that the test tasks confirm to the ended use of the device and to patient safety and defined user needs. In the operational validation each task was completed at a success rate of 94%. In no case did two participants repeat the same use errors. In the display validation most questions were answered with 100% success rate and a few with 94% success rate. No wrong answer was repeated by more than one participant. Another summative validation study was conducted in a simulated use environment in Boulder, Colorado was intended to validate workflow and operational validation, clinical interpretation and troubleshooting validation, and knowledge tasks by US intended users . Fifteen (15) US licensed anesthesiologists and CRNAs were recruited to participate in this validation study. The study was conducted by testing the ability of the users to perform a set of real tasks and interpret various clinical conditions. Knowledge tasks were evaluated using questionnaires. Anesthesiologists and CRNAs are considered to be one user group, as their interactions with the device and the tasks they perform are identical. Both anesthesiologists and CRNAs are professional users, who underwent extensive clinical training qualifying them to manage anaesthetized patients including the routine use of patient monitors to inform clinical decision making. Both would use the device in the same manner, same use environment and for the same use population. Tasks evaluated during the study were categorized using task analysis technique, which systematically breaks down the device use process into discrete sequences of tasks. All critical tasks were identified. mitigated as far as possible, and evaluated in the human factor validation study. The participants received a short introduction and training to the system. This training was designed to approximate the training actual users are likely to receive. 45 minutes were allowed to elapse between the introductory & training session and the actual testing. Following the 45 minutes, participants were asked to perform a set of tasks for the operation of the device, interpret clinical conditions and troubleshooting scenarios and complete questionnaires. Data collection was followed by a debriefing interview, to enable the collection of users' perspectives of the device and its use. The results were scored by both the moderator and the observer, where primary data collection is performed by the moderator. The observer scoring was used as reference in case of any uncertainty regarding the result. No use errors were recorded in any of the test sessions. {5}------------------------------------------------ ### PERFORMANCE TESTING - BENCH #### Signal Acquisition The essential performance of the PMD-200 according to ANSI/AAMI 60601-1 is defined as the ability of the PMD-200 to continuously produce NOL values. This performance is evaluated in the electrical safety report where the PMD-200 demonstrates continuous performance under different constraints as defined by the standard. The PPG signal acquisition was validated by injecting a Sine wave into the PMD-200 using a signal generator, and then altering the signal frequency and viewing its effect on the Pleth signal displayed on the PMD-200 screen. The full range of the PPG signal acquisition was validated in the algorithm unit testing, The GSR signal acquisition is validated by using a resistor substitute to simulate a signal and reviewing the signal on the PMD-200 screen. The single-use sensor is then disconnected and the GSR alert 'Conductance' is verified. The full range of the GSR signal acquisition was validated in the algorithm unit testing. The temperature signal range was tested to verify the accuracy of the Finger Probe thermistor by comparing it to a reference calibrated thermometer, according to the requirements of ISO 80601-2-56, clause 201.101.2. All tests met the pre-defined acceptance criteria of the thermistor deviating < 2.5℃ from the reference thermometer measurement in compliance with the standard. The accelerometer performance was validated during software testing for movement detection and Trendelenburg detection in the algorithm unit testing. #### Algorithm Unit Testing A total of 604 different test points and test vectors were used for the unit testing. testing the main units of the algorithm. Four (4) additional bench tests were used for the unit testing: - Two (2) bench tests to validate algorithm model performance. . - . One (1) bench test to validate finger probe movement detection. - One (1) bench test to validate Trendelenburg detection. . - . One (1) bench test to validate the accuracy of detecting low quality of PPG signal (too low a quality for reliable calculation of physiological parameters). The sensitivity and specificity of the NOL Index in response to noxious stimulation should be above 75% for the low 95% CI, validated for nociception / no nociception levels. All tests included in the unit testing passed this pre-defined acceptance criteria. #### Algorithm Verification For the verification testing, a multinational, multi-center dataset, consisting of major abdominal/gynecological surgery recordings performed on adult patients under general {6}------------------------------------------------ anesthesia was used. None of the recordings used for verification were used in the training dataset or for validation activities. This dataset covers a wide range of patient demographics, such as age, sex, BMI, pre-existing conditions and ASA classification to ensure diversity. Anesthetic drugs included Remifentanil Fentanyl for analgesia and Propofol\volatile gas for anesthesia. The verification process includes 3 different types of tests, incorporating different methodology and procedures. The tests, acceptance criteria and results are provided in Table 1. | Test description | Test metrics | Acceptance criteria | Results | |-----------------------------------------------------|----------------------------------------------------------------------|-------------------------------------------------------------------|--------------------------------------------| | Algorithm overall<br>predictability | Estimated vs reference CISA:<br>mean +/- 95% CI | 95% CI < 1.0 CISA unit | Pass | | NOL algorithm decision<br>accuracy (binary testing) | Youden Index for NOL threshold<br>of 25 | 25 +/- 3 NOL units | Pass | | | AUC | 0.85 (0.8 for low 95% CI) | Pass | | | Specificity | 0.85 (0.75 for low 95% CI) | Pass | | | Sensitivity | 0.85 (0.75 for low 95% CI) | Pass | | | Accuracy | > 0.85 | Pass | | | Characterization of NOL<br>values at times of no<br>noxious stimulus | Mean NOL value during periods<br>where no nociception is reported | 97.7% of NOL samples<br>should be below 25 | Table 1: Algorithm verification results ## Algorithm Validation For validation, a multinational, multi-center dataset, consisting of major abdominal/gynecological surgeries surgery recordings, performed on adult patients under general anesthesia was used. All data is unique, i.e., was not used for training the algorithm or for verification purposes. This dataset covers a wide range of patient demographics, such as age. sex. BMI, pre-existing conditions and ASA score to ensure diversity. Validation was divided into two phases. Phase I repeated and expanded the verification activities on a separate dataset. Phase II included sub-group analysis. The purpose of the sub-group analysis is to validate the accuracy of the NOL algorithm for its intended use population, and to demonstrate that NOL performance is not affected by specific populations or anesthetic techniques: 1) Sex: Male/Female - 2) Age: 18-65/65+ - 3) BMI: 18-25/25-30/30+ - 4) Analgesic drug: Remifentanil/Fentanyl {7}------------------------------------------------ Each sub-group contained at least 40 patients. Phase I validation results are provided in Table 2. | Test description | Test metrics | Acceptance criteria | Result | |----------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------|--------| | Algorithm overall<br>predictability | Estimated vs reference<br>CISA: mean +/- 95%<br>CI | 95% CI < 1.0 CISA unit | Pass | | | NOL ability to correctly<br>grade various<br>nociceptive intensities<br><br>mean {NOL(POI)}<br>(-/+ 95% CI) by<br>stimulus groups:<br><br>TP1: intubation<br>TP2: incision/trocar<br>TNP: non-nociceptive<br>stimulus or no stimulus | mean {NOL(TP1)} > mean {NOL(TP2)} ><br>mean {NOL(TNP)}<br><br>Wilcoxon signed-rank test | Pass | | NOL algorithm<br>decision accuracy<br>(binary testing) | Youden Index for NOL<br>threshold of 25 | 25 +/- 3 NOL units | Pass | | | AUC | 0.85 (0.8 for low 95% CI) | Pass | | | Specificity | 0.85 (0.75 for low 95% CI) | Pass | | | Sensitivity | 0.85 (0.75 for low 95% CI) | Pass | | | Accuracy | > 0.85 | Pass | | | Clinical relevance score | > 0.8 | Pass | | Characterization of<br>NOL values at times of<br>no noxious stimulus | Mean NOL value<br>during periods where no<br>nociception is reported | 97.7% of NOL samples should be below<br>25 | Pass | Table 2: Phase I validation results Phase II validation results are provided in Table 3. For the subgroup analysis, both the verification and the validation data sets were used Table 3: Phase II validation results | Sub-group | Numbe<br>r<br>of | Test #1<br>CISA | Test #2 | Test #3<br>Youde<br>n | Test #4 | Test #5<br>Specificit<br>y | Test #6<br>Sensitivit<br>y | Test #7<br>Accurac<br>y | |-----------|------------------|-----------------|---------|-----------------------|---------|----------------------------|----------------------------|-------------------------| |-----------|------------------|-----------------|---------|-----------------------|---------|----------------------------|----------------------------|-------------------------| {8}------------------------------------------------ | | patients | err<br>95%C<br>I | TP1/TP2/TN<br>P | index | AU<br>C | | | | |------------------|----------|------------------|-----------------|-------|---------|------|------|------| | Female | 75 | Pass | Pass | Pass | Pass | Pass | Pass | Pass | | Male | 75 | Pass | Pass | Pass | Pass | Pass | Pass | Pass | | Age < 65 | 81 | Pass | Pass | Pass | Pass | Pass | Pass | Pass | | Age > 65 | 48 | Pass | Pass | Pass | Pass | Pass | Pass | Pass | | BMI<br>18-25 | 39 | Pass | Pass | Pass | Pass | Pass | Pass | Pass | | BMI<br>25-30 | 45 | Pass | Pass | Pass | Pass | Pass | Pass | Pass | | BMI > 30 | 45 | Pass | Pass | Pass | Pass | Pass | Pass | Pass | | Remifentani<br>1 | 55 | Pass | Pass | Pass | Pass | Pass | Pass | Pass | | Fentanyl | 67 | Pass | Pass | Pass | Pass | Pass | Pass | Pass | #### SUMMARY OF CLINICAL INFORMATION #### Clinical Outcome Studies Two outcome studies (SOLAR & Abdomi-NOL) demonstrate clinically meaningful reduction of pain scores in the NOL guided groups vs. the standard of clinical care group. These studies were conducted with patients receiving a sevoflurane / fentanyl anesthesia regimen, which is broadly used in US practice. The studies were designed as singleblinded, two-group randomized, superiority studies. In order to evaluate the adjunctive intended use of the PMD-200, patients were randomized to either NOL-guided analgesia (NOL groups) or standard of care monitoring only (SOC group). The instructions and guidance on how to use the output from the PMD-200 were pre-specified and provided to investigators, prior to patient enrollment. Subjects underwent common, elective, noncardiac procedures as would normally be conducted in routine clinical practice. Both outcome studies compared the effect of NOL-guided fentanyl dosing versus standard clinical care in patients undergoing major abdominal surgery under sevoflurane/fentany] anesthesia on postoperative pain scores. The study hypothesis was that objective NOLguided fentanyl dosing during surgery would result in superior pain scores compared to standard of care fentanyl dosing based on the hemodynamic indices, blood pressure and heart rate. A clinically meaningful reduction in post-operative pain scores was demonstrated in both the SOLAR study and the Abdomi-NOL study. In the SOLAR study a clinically meaningful reduction of 1.6 in the median pain score was reported throughout the 90 minutes. The Abdomi-NOL study was designed as a confirmatory study to confirm and support the results of the SOLAR study and a clinically meaningful reduction of 1.5 was maintained up to 90 minutes from PACU entrance. These reductions represent 30-33% improvement on the 11-point NRS scale in comparison to the standard of care control groups. ## Table 1: Abdomi-NOL Clinical Study | Title of Study | Impact of Nociceptive-Level (NOL) Intraoperative Guided<br>Fentanyl Analgesia versus Standard Clinical Care (SOC) for<br>Elective Major Abdominal Surgery | |----------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------| |----------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------| {9}------------------------------------------------ | Investigators | Dr. Rivka Fuica | | | | | |---------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--|--|--|--| | Study center | Shaare Zedek Medical Center, Jerusalem, Israel | | | | | | Patient Enrollment Period | November 2019 - March 2021 | | | | | | Objective | To guide intraoperative fentanyl dosing using Nociception Level<br>(NOL) index and assess the effect of this guidance on the<br>postoperative pain scores in the post-anesthesia care unit (PACU) | | | | | | Primary Endpoint | Reduction of pain score in the PACU. (Time points: at arrival;<br>every 15min; at discharge or following 3 hours, whichever comes<br>first) | | | | | | Secondary Endpoints | 1. Reduction in the frequency of inadequate analgesia/anesthesia<br>events (MAP $< 55$ mmHg (severe hypotension) and/or $< 60$<br>mmHg (hypotension); Systolic blood pressure $>140$ mmHg;<br>Heart rate $<45$ min-1; Heart rate $>90$ min-1) during the<br>maintenance period until reversal in the NOL-guided group.<br>2. Total intraoperative fentanyl consumption (in mcg). | | | | | | Exploratory Endpoints | Intraoperative Use of vasoactive medication (ephedrine, phenylephrine,<br>norepinephrine, atropine) In the PACU Time to the first administration of morphine and/or non-opioid<br>systematically administered analgesics Post-operative opioid consumption from arrival to discharge Readiness to discharge from PACU (Aldrete score measured at<br>arrival, every hour and at discharge) Post-operative sedation scores with Ramsay Sedation Score<br>(Time points: at arrival; every 15 min) Respiratory Depression- defined as respiratory rate (RR) below<br>8 respirations per minute (RPM) for 1 minute. Saturation of less<br>than 90% for 1 minute under continuous monitoring. Nausea and vomiting incidence (PONV Score) Pruritis requiring treatment WARD - up to 24 hours post-surgery Pain scores (VAS or NRS Scale; Time points: ~every 8 hours<br>or according to the SOC)) 24 hours post-operative opioid consumption PONV medication consumption | | | | | {10}------------------------------------------------ | Methodology | Patients were randomized to receive NOL-guided anesthesia or<br>standard of care. In both groups, a NOL device was connected, but<br>in the standard care group, the anesthesia team was blinded to the<br>device. The anesthetic technique was identical in the two groups<br>and consisted of induction with a single dose of 1-2µg/kg fentanyl<br>(analgesia), followed by maintenance boluses of 0.5 µg/kg,<br>sevoflurane (anesthesia maintenance targeted at MAC 0.8-1.2) and<br>rocuronium (muscle relaxant). In the standard clinical care (SOC)<br>arm, fentanyl boluses were given based on hemodynamic variables<br>such as blood pressure and heart rate. In the NOL-guided analgesia<br>arm, fentanyl dosing was based on NOL values. | |--------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------| | Number of Patients | 75 patients (ASA 1-3 patients undergoing elective major<br>laparoscopic abdominal, urologic or gynecologic procedures under<br>general anesthesia) were enrolled and completed all study<br>procedures. | | Main Criteria for<br>Inclusion | 1. Age: 18 years and older;<br>2. ASA I-III<br>3. Elective major laparoscopic abdominal, urologic or<br>gynecologic procedures under general anesthesia.<br>4. Patient able to provide informed consent | | Main Criteria for<br>Exclusion | 1. Use of any type of anesthesia other than general anesthesia<br>(neuraxial, epidural analgesia or local regional anesthesia, e.g.<br>transversus abdominal plane block).<br>2. Non-sinus heart rate.<br>3. Pregnancy/lactation.<br>4. Central nervous system disorder (neurologic/head<br>trauma/uncontrolled epileptic seizures).<br>5. Abuse of alcohol or illicit drugs within the last 6 months.<br>6. Chronic pain conditions - pain in 1 or more anatomic regions<br>that persists or recurs for longer than 3 months and is<br>associated with significant emotional distress or significant<br>functional disability.<br>7. Opioid tolerant - if for at least 1 week the patient has been<br>receiving oral morphine 60 mg/day; transdermal fentanyl 25<br>mcg/hour; oral hydromorphone 8 mg/day; oral oxymorphone<br>25 mg/day; or an equianalgesic dose of any other opioids.<br>8. Chronic use of psychoactive drugs within 90 days prior to<br>surgery.<br>9. Allergy or intolerance to any of the study drugs.<br>10. History of severe cardiac arrhythmias within the last 12<br>months.<br>11. Surgeries less than one hour (from incision to<br>extubation).<br>12. Current participation in another clinical study | {11}------------------------------------------------ | Statistical Methods | Confidence intervals for median values were obtained using<br>generalized linear models with the cluster bootstrap and bias<br>corrected and accelerated (Bca) 95% confidence intervals (CI).<br>Continuous variables showing normality such as age, height,<br>weight, and BMI were analyzed using Student's t-test and<br>expressed as mean ± SD. | |-----------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------| | | Continuous variables not showing normality such as frequency of<br>inadequate analgesia/ anesthesia events and total intraoperative<br>fentanyl consumption were analyzed using the Mann-Whitney test<br>and expressed as median (IQR). | | | For the secondary outcomes, according to the study protocol, the p<br>value 0.05, normally considered as the threshold for statistical<br>significance, should have been corrected using the Holm step-<br>down procedure. | | | As none of the secondary outcomes were found to be statistically<br>significant even before the correction, actual application of the<br>Holm step-down procedure was deemed unnecessary. | | | SUMMARY AND CONCLUSIONS | | Safety Results | No adverse events associated with the use of the device were<br>reported. Three (3) non-device related adverse events were reported<br>during the study. | | Effectiveness Results | Primary Endpoint: | | | Median postoperative pain scores following 60 minutes in the<br>PACU were 3 (inter-quartile range 0-5) and 5 (3-7) in NOL-guided<br>and SOC groups, respectively. | | | Bootstrap analysis actual difference 1.6, 95% confidence interval<br>0.5-2.7 or 1.9 corrected for differences in sex distribution, 95%<br>confidence interval 0.7-3.0 | | | Median postoperative pain scores following 90 minutes in the<br>PACU were 3 (inter-quartile range 0-5) and 5 (3-6) in NOL-guided<br>and SOC groups, respectively. | | | Bootstrap analysis actual difference 1.3, 95% confidence interval<br>0.3-2.3 or 1.5 corrected for differences in sex distribution, 95%<br>confidence interval 0.5-2.6. | | | Secondary Endpoints: | | | Mean intraoperative fentanyl dosing was not different between<br>groups 351 mcg in the NOL group vs. 338 mcg in the SOC. (Mann-<br>Whitney p=0.22). There were no differences in the prevalence of | | | inadequate analgesia/anesthesia events between the NOL and the<br>SOC groups. | | | <b>Exploratory Endpoints:</b><br>There were no significant differences between groups in any of the<br>exploratory endpoints. | | Conclusion | Despite absence of differences in fentanyl and morphine<br>consumption during and after surgery, a 1.5-1.9-point<br>improvement in postoperative pain scores was observed in the<br>NOL-guided group. This was attributed to NOL-guided rather<br>than BP- and HR driven fentanyl dosing during anesthesia. | {12}------------------------------------------------ # Table 2: SOLAR Clinical Study | Title of Study | Sevoflurane/fentanyl anesthesia guided by Nociceptive-Level index<br>during abdominal surgery in ASA 1-3 patients - a randomized<br>controlled trial on the effect of NOL-guidance on postoperative pain<br>scores | |----------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------| | Investigators | Monique van Velzen PhD, Martijn Boon MD PhD, Chris Martini<br>MD, PhD, Maarten Honing MD, Paul Calis MD, Emre Almac MD,<br>Albert<br>Dahan MD PhD | | Study centers | 1. Leiden University Medical Center, Leiden<br>2. Alrijne Hospital, Leiderdorp | | Study period | From: May 2019<br>To: December 2019 | | Objective | To guide the analgesic component of anesthesia using the NOL<br>index in ASA 1-3 patients under general anesthesia for elective<br>abdominal surgery | {13}------------------------------------------------ | Endpoints | Primary Endpoints | |---------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------| | | Postoperative pain scores in the post anesthetic care unit (PACU). | | | Secondary Endpoints | | | 1. Postoperative opioid consumption; | | | 2. Fentanyl use during anesthesia; | | | 3. Sevoflurane consumption during anesthesia; | | | 4. Inadequate hemodynamic events; | | | 5. Time between reversal of neuromuscular block and extubation<br>/eyes open; | | | 6. Occurrence of awareness; | | | 7. Anesthesia and surgery times/PACU stay time. | | | 8. Blood ACTH and cortisol levels during and following the<br>procedure. | | Methodology | Patients were randomized to receive NOL-guided anesthesia or<br>standard of clinical care. In both groups, a NOL device was<br>connected, but in the standard of clinical care group, the anesthesia<br>team was blinded to the device. The anesthetic technique was<br>identical in the two studies and consisted of 25-50 or 50-100 $ μ $ g<br>fentanyl boluses (analgesia), sevoflurane (anesthesia maintenance<br>aimed at BIS values 50 ± 5) and rocuronium (muscle relaxant). In<br>the standard of clinical care (SOC) arm, fentanyl boluses were<br>given based on hemodynamic variables such as blood pressure and<br>heart rate. In the NOL-guided analgesia arm, fentanyl dosing<br>was based on NOL values. | | Number of patients | 50 ASA 1-3 patients undergoing elective open abdominal surgery<br>or laparoscopic/ robot-assisted abdominal surgery at two centers. | | Main criteria for | 1. Age: 18 years and older; | | inclusion | 2. ASA 1-3 | | | 3. Elective open abdominal surgery or robotic/laparoscopic<br>abdominal surgery. | | Main criteria for | 1. Unable to give written informed consent; | | exclusion | 2. Use of epidural analgesia or local anesthesia (e.g. transversus | | | abdominal plane block-TAP block) | | | 3. Non-elective surgery | | | 4. Pregnancy/lactation. | | | 5. Uncontrolled preoperative hypo- or hypertension (Mean | | | arterial pressure < 60 mmHg or systolic blood pressure > 160<br>mmHg) | | | 6. Preoperative Heart rate < 45/min or > 90/min; | | | 7. Central nervous system disorder (neurologic/head trauma/<br>uncontrolled epileptic seizures). | | Statistical Methods | The primary endpoint, PACU pain scores over time, was compared<br>between the two treatment groups using generalized linear model<br>with the cluster bootstrap and bias corrected and accelerated (Bca)<br>95% confidence intervals (CI) (Deen 2000). Analyses were<br>implemented using R Cluster Bootstrap package v1.1.2. Models<br>included group, time center and demographic characteristics. | | | For secondary endpoints, since statistical testing was exploratory<br>rather than confirmatory, power calculations were not performed.<br>Data analysis of these data was performed using independent two-<br>tailed-t-test, Mann-Whitney test, $\chi^2$ -test for continuous &<br>categorical measurements respectively, for measurements<br>evaluated over time (morphine & stress hormones) Cluster<br>Bootstrap with Bca 95% confidence intervals were applied. | | | Data are presented as mean ± SD, mean ± 95% confidence<br>interval, median and interquartile range and counts & percentages<br>unless otherwise stated. | | | Corrections for type one error were not performed as: | | | The study included a single primary endpoint | | | Sample size was not powered for secondary endpoints,<br>and they are therefore considered as exploratory and<br>not confirmatory | | | For assessment of the reproducibility of the study endpoints at the<br>two hospitals (Leiden University Medical Center, Leiden and<br>Alrijne Hospital, Leiderdorp), descriptive analysis was performed<br>as well graphical representation using boxplots. | {14}------------------------------------------------ # SUMMARY AND CONCLUSIONS {15}------------------------------------------------ | Safety Results | 4 of 50 (8%) of patients experienced serious adverse events<br>(SAEs) not related to the study device. In the SOC group, two SAEs<br>(one event of postoperative nausea/vomiting and constipation and<br>the other of bile leakage) were judged as unrelated to the study<br>device. In addition, in the NOL-guided group, two SAEs (one<br>event of anastomotic leak and one episode of postoperative<br>bleeding) were judged to be also, unrelated to the study device.<br><br>No adverse events (AE), or device related adverse events (ADE) or<br>serious adverse device events (SADEs) were recorded throughout<br>the study. | |-----------------------|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------| | Effectiveness Results | During the first 90 minutes of PACU stay, the median<br>postoperative pain scores were 3.2 [interquartile range 1.3 – 4.3]<br>and 4.8 [3.0 – 5.3] in NOL-guided and control groups, respectively<br>(actual difference 1.6, 95% confidence interval 0.5-2.7). As two<br>independent centers were included in this study, center was added<br>to the Bootstrap model as a covariate, this addition did not impact<br>the results (actual difference 1.7, 95% confidence interval 0.8-2.8).<br><br>Postoperative morphine consumption was 0.06 ± 0.07 mg/kg<br>(NOL-guided group) and 0.09 ± 0.09 mg/kg (p=0.3) During<br>surgery, fentanyl dosing was not different between groups.<br><br>ACTH and cortisol levels were analyzed using bias corrected and<br>accelerated cluster bootstrap intervals with time, center, sex, age<br>and BMI as covariates. Relative to baseline, the increase of ACTH<br>and cortisol was 1.5 to 2-fold greater in the group that received<br>standard care compared to those that received Nociception Level<br>index guided fentanyl dosing”. Mean difference 40.6 and 242.6 for<br>cortisol and ACTH respectively (95% confidence interval 7.1 to -<br>85.1 for cortisol and 39.4 to 513.5 for ACTH).<br><br>The results demonstrated for morphine consumption and stress<br>hormone levels are considered exploratory, representing a trend<br>towards reduction of morphine consumption in the PACU and<br>reduced levels of stress hormones in the NOL guided group.<br>Further confirmatory studies are required in order to assess the<br>reproducibility and clinical relevance of these results.<br><br>The remaining secondary endpoints did not demonstrate any | | | meaningful results.…