Multi-center (5 centers); United States and Canada. September 10, 1992 to April 9, 1993

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1 vi STUDY SYNOPSIS Study Number: Title: Investigator: GHBA-534 A Phase III, Randomized, Open-Label Study To Compare The Safety, Tolerability And Recovery Characteristics of Sevoflurane Versus Halothane Administered With Nitrous Oxide And Oxygen In ASA Class I And II Pediatric Patients Undergoing Ambulatory Surgery Multi-center (5 centers); United States and Canada Study Dates: Objective: Study Design: September 10, 1992 to April 9, 1993 The objective of this study was to evaluate the safety, tolerability and recovery characteristics of sevoflurane compared to halothane when administered with nitrous oxide and oxygen to ASA Class I or II pediatric patients (ages 1-12 years), scheduled for ambulatory surgical procedures. This Phase III, randomized (2:1), open-label, multi-center, clinical trial was designed to evaluate sevoflurane compared to halothane when both agents were administered with 60-70% nitrous oxide and 30-40% oxygen to ASA Class I or II pediatric patients 1-12 years of age. Surgical procedures were anticipated to be 0.5 to 2 hours in duration and to not require overnight hospitalization. The study anticipated 75 patients would be entered at each of 5 investigational centers for a total of 375 participants. Each treatment group's patient distribution was to have included patients throughout the age range of 1-12 years. Efficacy was evaluated based on time intervals for anesthesia and recovery events (e.g., time to induction, time to emergence, time to command response, time to first post-surgical analgesia, time to eligibility for discharge), clinical evaluations, recovery parameters and incidence of intraoperative recall. Inorganic fluoride concentrations were determined from samples collected prior to, and 1 hour post-anesthesia. Safety was evaluated throughout the study by adverse experience monitoring, and clinical laboratory and physical assessments.

2 vii Accountability: A total of 375 ASA Class I or II pediatric patients were enrolled in the study as follows: PATIENT ENROLLMENT Sevoflurane Halothane Total Male Female Total All enrolled patients were included in the safety analyses. Patient 17 discontinued the study during halothane induction due to a severe airway obstruction by a mucous plug resulting in hypoxia and was not included in the efficacy analyses. Study Drug Administration: Sevoflurane was administered using a SevoTec 3 vaporizer provided by Maruishi Pharmaceutical Co., Ltd. Four of the 5 investigational centers used a Mapleson D or F circuit (partial rebreathing circuits without a carbon dioxide absorbant). The fifth center used a circle system containing soda lime as the C02 absorbant. Sevoflurane and halothane were administered with nitrous oxide (60-70%) and oxygen (30-40%). The anesthetic concentrations were not to exceed maximum inspired concentrations of 7.0% for sevoflurane and 4.5% for halothane; concentrations greater than those stated were noted on the case report form. Maintenance concentrations of inhaled anesthetic were to be titrated to MAC, as clinically indicated. At a minimum of 10 minutes prior to the end of surgery, the anesthetic concentrations were to be titrated to 1 MAC (age adjusted MAC determined in 100% oxygen) of the inhalation agent in combination with nitrous oxide. Results: The sevoflurane and halothane groups were comparable in demographic and baseline characteristics. The most common primary diagnosis classification was the "digestive system" (17%, ), while the most common secondary diagnosis classification was "respiratory system" (24%, 88/375). Of the 62 patients with primary diagnoses in the "digestive system" category, the most common diagnoses were inguinal hernia (52 patients) and umbilical hernia (7 patients). Of the 88 patients with secondary diagnoses in the "respiratory system" category, the most common diagnoses were acute upper respiratory infection (26 patients), acute nasopharyngitis (26 patients), and asthma (22 patients). Primary and secondary diagnoses were comparable between treatment groups.

3 viii The most common types of surgical procedures were related to the "digestive system" (42%, 156/375) and the "male genital system" (39%, 145/375). There was no statistically significant difference between the 2 groups with regard to duration of surgery in minutes (mean ± standard error, p=0.446, sevoflurane: 30.1 ± 1.34; halothane: 28.3 ± 1.93). There was no statistically significant differences between groups with regard to duration of anesthetic administration. Significantly (p=0.024) fewer MAC hours of anesthesia were administered to sevoflurane patients (1.09 MAC hours) than halothane patients (1.23 MAC hours). The overall average end-tidal concentrations, and maximum and average end-tidal concentrations during induction to incision and incision to end of anesthesia phases (expressed in MAC multiples) were statistically lower for sevoflurane compared to halothane, as summarized in the following table: STATISTICALLY SIGNIFICANT TREATMENT DIFFERENCES IN ANESTHESIA CONCENTRATION (MAC) Anesthetic Phase Sevoflurane Halothane P-Value Induction to Incision: Maximum Average <0.001* <0.001* Incision to End of Anesthesia: Maximum Average <0.001* 0.003* Average 1.05 Concentration: * Statistically significant at p s <0.001* Efficacy. Patients anesthetized with sevoflurane had a more rapid induction and recovery than those anesthetized with halothane as evidenced by significantly shorter (p<0.001) times to induction, emergence, response to commands, and to eligibility for discharge in 2 of the 5 criteria (Le., Aldrete score of ~ 8, and orientation).

4 ix Time to anesthesia and recovery events (mean ± standard error) were as follows: TIME TO ANESTHESIA AND RECOVERY EVENTS IN MINUTES Time To:# n Seyoflurane n Halothane P-Value Induction ± ± 0.1 <0.001" Emergence ± ± 1.0 <0.001 " Recovery Times: Response to Commands ± ± 1.0 <0.001 " First Post-surgical ± ± Analgesia Discharge Criteria: Aldrete Score of ± ± 1.2 <0.001 " Stable Vitals (30 min) ± ± Orientation ± ± 1.5 <0.001 " Objective Pain - Discomfort Scale ~ ± ± Tolerates Clear Fluids ± ± Suitable for Discharge: Without Fluids ± ± With Fluids ± ± # Time from the end or start of anesthesia, as appropriate. + Emergence was noted in the protocol as the time from the end of anesthesia to when the patient opened their eyes or cried. " Statistically significant at p s Orientation is the time from the end of anesthesia to when the patient was oriented to name and place. There were no significant differences in induction, emergence or overall success rates (absence of complications during clinical evaluations) between treatment groups. Halothane patients had significantly (p<0.001) lower total score means for the Objective Pain - Discomfort Scale evaluations at 1, 10, 20 and 30 minutes after admission to the recovery room compared to sevoflurane patients. This likely reflects the more rapid recovery observed with sevoflurane patients. Sevoflurane patients demonstrated better recovery, as evidenced by statistically higher mean modified Aldrete scores across all time points in "activity", "consciousness" and total scores compared to halothane patients. Halothane patients had statistically higher mean scores across all time points in "circulation" than sevoflurane patients.

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6 xi No statistical differences were observed in mean changes from baseline to final evaluation between groups in hematology variables or in urine ph. Statistically significant differences in mean changes from baseline to final evaluation were observed between groups in two chemistry variables, as summarized in the following table: STATISTICALLY SIGNIFICANT MEAN CHANGES IN CHEMISTRY VARIABLES Chemistry Variable Sevoflurane Halothane P-value Calcium ± ± " (mmol/l) Inorganic Phosphorus ± ± " (mmol/l) " Statistically significant p os The changes from baseline to final evaluation in chemistry variables were small, remaining within normal limits and were not considered to be of clinical significance. One sevoflurane «1%,1/250) and 2 halothane (2%, 2/125) patients were noted to have clinically significant worsened changes at the final examination compared to the pre-study examination. One sevoflurane patient (Patient 446) had a worsened cough. Two halothane patients, had increased mucous drainage and worsened breathing (Patient 17), and congestion (Patient 437). There were no statistically significant differences between groups from preanesthesia to final examination for systolic or diastolic blood pressures, heart rate, respiration rate or temperature. Halothane patients had a statistically greater change (mean decrease ± standard error: ± 3.5) compared to sevoflurane patients (mean increase ± standard error: 5.6 ± 2.4) in mean arterial pressure from 1 minute prior to induction to final examination (admission to recovery). This change was not considered clinically significant. Seven patients had abnormal electrocardiograms which were reported as adverse experiences of possible or probable relation to study drug; <1% (21250) in the sevoflurane treated group and 4% (5/125) in the halothane treated group.

7 xii Conclusions: Sevoflurane compares to halothane as an effective and welltolerated inhalation agent for mask induction of anesthesia in pediatric patients. Sevoflurane provides faster induction and recovery from anesthesia than halothane, as evidenced by statistically significantly shorter times to induction, emergence, response to command, orientation and achievement of best Modified Aldrete Score. Sevoflurane patients «1%) had a lower incidence of abnormal electrocardiograms than did halothane patients (4%). Sevoflurane patients had a lower incidence of vomiting and bradycardia than halothane patients. Lower doses (expressed in MAC multiples) of sevoflurane compared to halothane were required for anesthesia, as evidenced by statistically lower sevoflurane overall average end-tidal concentrations, and maximum and average end-tidal concentrations (expressed in MAC multiples) during induction and maintenance. The inorganic fluoride concentrations measured at 1 hour postanesthesia were of the same magnitude as those obtained in a previous pediatric study conducted with similar dose and duration of sevoflurane administration.