Sevoflurane Protocol No. SEVO R&D/93/804 - Clinical/Statistical STUDY SYNOPSIS

Transcription

1 vi STUDY SYNOPSIS Protocol Number: Title: SEVO A Phase Ill, Multicenter, Open-Label, Randomized, Comparative Study Evaluating the Effect of Sevoflurane Versus Halothane in the Induction and Maintenance of Anesthesia in Pediatric ASA Class I and 11 Outpatients Investigators: Multicenter (13 centers); United Kingdom (1 center), France (2 centers), Germany (2 centers), Ireland (1 center), Spain (1 center), Sweden (1 center), and the United States (5 centers). Study Dates: January 26, October 8, 1993 Objective: Study Design: The objective of this study was to compare the use of two anesthetic agents, sevoflurane and halothane, for the induction and maintenance of anesthesia in ASA Class I or 11 pediatric outpatients who underwent surgical procedures of an anticipated duration of up to 3 hours. Comparisons were based on the following: - Rapidity and ease of induction, emergence and recovery. - Maintenance of anesthesia. This study was designed as a Phase Ill, multicenter, open-label, randomized (1:1), comparative trial of sevoflurane versus halothane in pediatric ASA Class I or 11 outpatients who underwent surgical procedures of an anticipated duration of up to 3 hours. The anticipated length of hospitalization was less than 24 hours postanesthesia. Patients who met all selection criteria were randomly assigned to receive either sevoflurane or halothane as their primary anesthetic agent, each administered with an inspired oxygen (02) concentration of 30 to 40% (up to 70% nitrous oxide [N 2 0]) during the scheduled surgical procedure. Efficacy was evaluated through the measurement of times to anesthesia and recovery events (induction, intubation, extubation, emergence, response to commands, orientation, first post-operative analgesia, eligibility for recovery area discharge, able to sit-up without nausea/dizziness, able to walk without dizziness, and eligibility for discharge from hospital); clinical evaluations (including induction, maintenance, emergence, and overall success rates); Objective Pain-Discomfort Scale; and Modified Aldrete Score. Safety was evaluated throughout the study by adverse experience monitoring, clinical laboratory and non-laboratory testing, and physical assessments. The protocol was modified by seven amendments; Amendment 1 (dated 10/27/92), Amendment 2 (dated 11/25/92), Amendment 3

2 vii (dated 2/22/93), Amendments 4, 5, and 6 (all dated 3/30/93), and Amendment 7 (dated 4/2/93). Patient Accountability: Demographics: Study Drug Administration: Five hundred-thirty (530) patients were enrolled in this study, all of whom were randomized; 525 (99%) of the randomized patients were treated. Five patients were randomized but not treated. Three patients randomized to sevoflurane were treated with halothane. Two hundred sixty-eight (51 %) of the 525 treated patients received sevoflurane and 257 (49%) received halothane. Of the 525 treated patients, 523 (99.6%) completed the study; one sevoflurane patient and one halothane patient were prematurely discontinued from the study during the intra-operative period due to adverse experiences. Data from all treated patients were included in both the efficacy and safety analyses. The sevoflurane group included 1 93 males and 75 females, of an average age of 4.1 years. Two hundred and forty-four (244) patients were ASA Class I and 24 patients were ASA Class 11. The halothane group included 1 95 males and 62 females, with the average age at 4.0 years. The ASA Class representation was 232 and 24 in ASA Classes I and 11, respectively. The mean maximum and average concentrations of anesthesia from induction to incision, the mean minimum, maximum, and average concentrations of anesthesia from incision to end of anesthesia, the concentration at the end of anesthesia, and the overall average concentration (expressed in MAC exposure) were statistically lower in the sevoflurane group compared to the halothane group. The average concentration (mean ± standard error: expressed in MAC exposure) of anesthesia during the anesthetic period was 1.04 ± in the sevoflurane group and 1.20 ± in the halothane group. The mean MAC hours of anesthesia was statistically lower (p<0.001) for sevoflurane patients (1.10 MAC hours) compared to patients in the halothane group (1.27 MAC hours). Results: Efficacy: The mean times to induction and intubation were statistically (p:50.05) shorter in the sevoflurane group compared to the halothane group. The mean times to extubation, emergence, response to commands, first post-operative analgesia, and able to sit-up without nausea/dizziness were statistically shorter in the sevoflurane group compared to the halothane group. No statistical differences were observed between the two treatment groups for any of the remaining post-anesthesia events, which included mean times to orientation (name, date of birth, age), eligibility for recovery area

3 viii Statistically significant interactions between investigator and treatment were observed for the mean times to extubation, first post-operative analgesia, and able to sit-up without nausea/dizziness. Although the differences between sevoflurane and halothane were not consistent among investigators, sevoflurane generally had shorter times for all of these parameters. A summary of times to anesthesia and recovery events is presented by treatment group in the table below: TIMES TO ANESTHESIA AND RECOVERY EVENTS: ALL TREATED PATIENTS (N = 525) Time To (Min): Sevoflurane Halothane P-value* (N =268) (N =257) Treatment Investigator Interaction Inductiona N Mean ±SE 1.7 ± ± 0.06 <0.001 <0.001 NS Range Intubationb N Mean ±SE 9.5 ± ± <0.001 NS Range Extubation N Mean ±SE 7.5 ± ± 0.35 <0.001 < Range Emergencec N Mean ±SE 11.9 ± ± 0.59 <0.001 <0.001 NS Range Response to Commandsd N Mean ± SE 17.6 ± ± 0.97 <0.001 <0.001 NS Range Orientatione N Mean ± SE 32.0 ± ± 2.93 NS <0.001 NS Range First Post-Operative Analgesia N Mean ± SE 43.5 ± ± < Range SE = Standard Error (based on MSE of the model) Mean (least square, adjusted) Investigators with no data for a treatment group were excluded from that particular analysis. * Treatment group comparison based on a two-way ANOVA. NS = difference not statistically significant (p>0.05). a Time from the start of induction until loss of eyelash reflex. b Time from the start of induction until intubation. c Time from the end of anesthetic to the time the patient opened his/her eyes on command or moved in response to a non-painful stimuli. d Time from the end of anesthetic to the time the patient squeezed the Independent Observer's hand on command or demonstrated purposeful movement. e Time from the end of anesthetic to the time the patient stated name, date of birth, and age.

4 Protocol.No. SEVO ix TIMES TO ANESTHESIA AND RECOVERY EVENTS: ALL TREATED PATIENTS (N = 525) (CONTINUED) Time To (Min): Sevoflurane Halothane P-value* IN =268) (N =257) Treatment Investigator InteractionI Eligible for Recovery Area Discharge N Mean ± SE 67.0 ± ± 1.73 NS <0.001 NS Range Able to Sit-Up Without Nausea/Dizziness N <0.001 <0.001 <0.001 Mean ± SE 95.7 ± ± 5.57 Range Able to Walk Without Dizziness N Mean ± SE ± ± 5.32 NS <0.001 NS Range Eligible for Hospital Discharge N Mean ± SE 341.9± ± NS <0.001 NS Range SE =Standard Error (based on MSE of the model) Mean (least square, adjusted) Investigators with no data for a treatment group were excluded from that particular analysis. Treatment group comparison based on a two-way ANOVA. NS =Difference not statistically significant (p >0.05). for induction, maintenance, emergence, and overall success rates. For the Modified Aldrete Score, the distribution of times to best score statistically favored the sevoflurane group for best activity, consciousness, and total score. For these parameters, more sevoflurane patients achieved the best score at earlier timepoints than did halothane patients. No statistical differences were observed between the two treatment groups for the distribution of times to best score for respiration, circulation, and temperature. Safety: For all adverse experiences, no statistical difference was observed between the two treatment groups for the overall number of patients reporting one or more adverse experiences (sevoflurane: 77%, 206/268; halothane: 78%, 201/257). A significant difference (p:!90.05) was observed between the two treatment groups for the incidence of nervous system adverse experiences, with a statistically higher incidence noted in the sevoflurane group (41 %) compared to the halothane group (30%). Within the nervous

5 x system, agitation was observed in a statistically higher percentage of sevoflurane patients (31 %) compared to halothane patients (19%). Significant differences were observed between the two treatment groups for the following COSTART terms: within the body as a whole system, fever was observed in a statistically higher percentage of sevoflurane patients (9%) compared to halothane patients (4%) and chills was observed in a statistically higher percentage of halothane patients (4%) than sevoflurane patients (1 %); and within the cardiovascular system, hemorrhage was observed in a statistically higher percentage of sevoflurane patients (2%) compared to halothane (0%) patients, bradycardia was observed in a statistically higher percentage of halothane patients (5%) compared to sevoflurane patients (< 1%), and arrhythmia was observed in a statistically higher percentage of halothane patients (4%) compared to sevoflurane patients (< 1%). No other statistical differences were observed between the two treatment groups for the incidence of adverse experiences by body system or by COSTART term. For study drug-related adverse experiences, a significant difference was observed between the two treatment groups for the incidence of study drug-related nervous system adverse experiences, with a statistically higher incidence noted in the sevoflurane group (36%) compared to the halothane group (25%). Within the nervous system, agitation was observed in a statistically higher percentage of patients in the sevoflurane group (31 %) compared to the halothane group (18%). Significant differences were observed between the two treatment groups for the following COSTART terms: within the cardiovascular system, tachycardia was observed in a statistically higher percentage of sevoflurane patients (7%) compared to halothane patients (3%), arrhythmia was observed in a statistically higher percentage of halothane patients (4%) compared to sevoflurane patients (< 1 %), and bradycardia was observed in a statistically higher percentage of halothane patients (3%) compared to sevoflurane patients (< 1%); within the body as a whole system, chills were observed in a statistically higher percentage of the halothane patients (4%) compared to sevoflurane patients (11%). No other statistical differences were observed between the two treatment groups for the incidence of study drug-related adverse experiences by body system or by COSTART term. Overall, the most common study drug-related adverse experiences were those associated with the respiratory system (sevoflurane: 30%, 79/268; halothane: 34%, 86/257). The most common adverse experience within the respiratory system was increased cough (sevoflurane: 21 %, 57/268; halothane: 25%, 63/257). The majority of study drug-related adverse experiences in both treatment groups were mild in intensity. Eighteen (18) sevoflurane patients and 11 halothane patients had one or more severe study drug-related adverse experiences. The severe study drug-related adverse experiences in the sevoflurane group were as follows: agitation (13 patients), apnea (7 patients), somnolence (11 patient), headache (1 patient), and laryngismus (1

6 Ai patient). The severe study drug-related adverse experiences in the halothane group were as follows: agitation (5 patients), vomiting (3 patients), cough increased (2 patients), nausea (2 patients), bigeminy (1 patient), ventricular extrasystoles (1 patient), and somnolence (1 patient). There were no patient deaths. Two patients were discontinued from the study due to adverse experiences. Patient 1 603, (sevoflurane) experienced a respiratory disorder which was considered to have an unlikely relationship to study drug; Patient 212, (halothane) experienced bigeminy and ventricular extrasystoles, which were considered to have a highly probable relationship to study drug. Nine patients had serious adverse experiences (sevoflurane: 3%, 7/268; halothane: < 1 %, 2/257). Three patients in the sevoflurane group (Patients 1 702, 1 704, and 1 722) and both patients in the halothane group (Patients 335 and 11 02) had serious adverse experiences considered by the investigator to be related to study drug. The serious adverse experiences in the sevoflurane group were as follows: Patient (increased operative bleeding); Patient 1426 (hemorrhage); Patient (ear hematoma); Patient 1633 (tonsillitis); Patient (apnea); Patient 1704 (apnea); and Patient 1722 (laryngospasm). The serious adverse experiences in the halothane group were as follows: Patient 335 (drowsiness); and Patient 1102 (epistaxis). Statistical differences were observed between the two treatment groups in mean changes from baseline to the first post-anesthesia assessment for platelet count, with a greater mean decrease noted in the sevoflurane group compared to the halothane group; white blood cells, with a mean decrease noted in the sevoflurane group and a mean increase noted in the halothane group; and eosinophils, with a mean increase noted in the sevoflurane group and a mean decrease noted in the halothane group. These statistical differences were not considered to be clinically meaningful. for the frequency summary of changes from baseline to the first postanesthesia assessment for any of the hematology variables. Three patients (two sevoflurane and one halothane) had hematology values considered possibly clinically significant per criteria developed by the sponsor. None of these laboratory values were considered by the investigator to be adverse experiences.

7 R&D193/804 - Clinical/Statistical xii Statistical differences were observed between the two treatment groups in mean changes from baseline to the first post-anesthesia assessment for uric acid, blood urea nitrogen (BUN), and creatinine, with greater mean increases for each of these variables noted in the halothane group compared to the sevoflurane group; and inorganic phosphorus, with a mean decrease noted in the sevoflurane group and a mean increase noted in the halothane group. These statistical differences were not considered to be clinically meaningful. for the frequency summary of changes from baseline to the first postanesthesia assessment for any chemistry variable. No patients in either the sevoflurane group or halothane group had chemistry laboratory values considered by the sponsor to be possibly clinically significant. for mean changes or in the frequency summary of changes from baseline to the first post-anesthesia assessment for either of the urinalysis variables, which included urine ph and specific gravity. Statistical differences were observed between the two treatment groups in the mean change from baseline to admission to the recovery area for systolic blood pressure (a mean increase of 3.2 mmhg was observed in the sevoflurane group compared to a mean decrease of 1.7 mmhg observed in the halothane group) and pulse (a mean increase of 20.3 beats/minute was observed in the sevoflurane group compared to a mean increase of beats/minute observed in the halothane group). No other statistical differences were observed between the two treatment groups for mean changes from baseline to any other timepoint for vital sign parameters, which included temperature, respiration rate, and diastolic blood pressure. No statistical difference was observed between the two treatment groups for response to the question of whether the patient or parent/guardian would request the same anesthetic agent, with the majority of patients responding yes. Conclusion: 0 Sevoflurane was as safe as halothane for the conduct of anesthesia in pediatric outpatients. However, there was a higher incidence of bradycardia and arrhythmia in halothane patients. 0 Sevoflurane patients had statistically significantly shorter times to extubation, emergence, response to commands, first post-operative analgesia, and able to sit-up without nausea/dizziness compared to halothane patients.