Pain Management after Major Orthopedic Surgery with the Sufentanil Sublingual Microtablet System David W. Griffin, MD Vero Beach, FL
Disclosures/Acknowledgements Dr. Griffin received research funding and honorarium support from AcelRx Pharmaceuticals, the sponsor of the study Drs. Minkowitz, Jove, and Melson similarly received research funding for their participation in the trial Drs. Palmer and Royal are officers, employees and shareholders of AcelRx The authors and sponsor would like to thank the study subjects, investigators, research coordinators, and Pharmanet/I3, a subsidiary of Inventiv Health Clinical, for their participation in the trial
ZALVISO: Sufentanil sublingual microtablet system (currently under FDA review) Patient-activated bedside system to dispense sufentanil microtablets 15 mcg sublingually with a 20-minute lockout interval 40 microtablets per cartridge is approximately a two-day supply 3
Treatment of Pain after Major Orthopedic Surgery: Design features Randomized, Double-Blind, Placebo-Controlled Trial: Efficacy and safety of Zalviso (sufentanil sublingual microtablet system/15 mcg or SSMS) after elective unilateral knee or hip replacement ASA I-III male or female patients 18 years of age or older General or spinal anesthesia that did not include intrathecal opioids Excluded: opioid tolerance (more than 15 mg oral mophine equivalent per day) positive urine drug screen or history of opioid or alcohol dependence or illicit use of drugs of abuse documented sleep apnea use of perioperative regional anesthetic techniques, including neuraxial, intraarticular, peripheral nerve block and local anesthetic wound infiltration 4
SSMS and Rescue IV Morphine Dosing In the PACU, pain was first controlled to < 5 (NRS), and then when it was > 4, study drug dosing of SSMS could begin Patients were considered completers after 48 hours of SSMS dosing, however the study extended to 72 hours if needed A 2 mg IV morphine bolus was allowed no more than once an hour as supplemental/rescue analgesia Pain scores were obtained at prespecified timepoints after initial dosing and also prior to each administration of IV MS to allow pre-rescue imputation of pain scores 5
Primary and Key Secondary Endpoints 6 Primary endpoint: Weighted sum of pain intensity differences over 48 hours (SPID48) Pain intensity assessed using a numerical rating scale (0-10) Key secondary endpoints: Reasons for dropout Sum of pain relief scores (TOTPAR48) Patient and healthcare professional global assessment of method of pain control at 48 h (PGA48; HPGA48) Validated Patient and Nurse Ease of Care Questionnaires Adverse events
Demographics and Early Dropouts Baseline characteristics similar for treatment groups Enrolled 420 [201 knee/219 hip] randomized 3:1 (SSMS:Placebo) 419 randomized and received study drug (315:104) 258 (62%) completed the 48h study period: 215 (68%) in SSMS vs. 43 (41%) in placebo group Reasons for early dropout (most of the other category were early hospital discharges) Zalviso (%) n = 315 Placebo (%) n = 104 Adverse event 7.0 6.7 Lack of efficacy 14.3 48.1 Subject request 1.3 0 Other 8.9 3.8
Primary efficacy results Zalviso (SSMS) was superior to placebo for the SPID-48 primary endpoint (p ) Pain response was statistically significant by 60 min p for all time points from 2 to 72h Least Squares Mean of Time-Weighted Summed Pain Intensity Differences by Evaluation Time Point (ITT Population) 8
TOTPAR48; PGA48; HPGA48 Similar positive results in favor of Zalviso for the time-weighted summed pain relief over 48h (TOTPAR-48), PGA-48 and HPGA-48 Least Squares Mean of Time-Weighted Summed Pain Relief (TOTPAR) by Evaluation Time Point (ITT Population) % Patients Reporting Success on PGA/HPGA-48 Zalviso n=315 (%) Placebo n=104 (%) P value PGA24 65.7 32.7 PGA48 70.2 28.8 PGA72 71.4 31.7 HPGA24 70.2 33.7 HPGA48 69.8 27.9 HPGA72 70.8 28.8 9 PGA = Patient global assessment; HPGA = Healthcare professional global assessment
Time to termination and time to first rescue Kaplan-Meier Cumulative Event Rate A: Time to Termination due to inadequate analgesia A B: Time to First Rescue B 10
Rescue consumption and inter-dosing interval Supplemental/rescue IV morphine consumption was significantly higher in the placebo group at all time points from 6 through 48h (p 0.002) Over 48h, the placebo group used 73% more morphine than the Zalviso group (p ) The mean inter-dosing interval was 84 min for Zalviso vs. 59 min for placebo (p ) 11
Adverse events Treatment-emergent AEs occurred in 83.8% and 61.5% of the Zalviso and placebo patients, respectively. No significant differences between the groups for any related AE except nausea and pruritus, both in favor of placebo. Zalviso (n = 315) Placebo (n = 104) p-value* Nausea 110 (34.9%) 23 (22.1%) 0.015 Vomiting 34 (10.8%) 6 (5.8%) ns Oxygen saturation decreased 22 (7.0%) 3 (2.9%) ns Dizziness 16 (5.1%) 1 (1.0%) ns Constipation 15 (4.8%) 1 (1.0%) ns Pruritus 15 (4.8%) 0 (0.0%) 0.028 Headache 13 (4.1%) 6 (5.8%) ns Insomnia 13 (4.1%) 3 (2.9%) ns Hypotension 12 (3.8%) 2 (1.9%) ns Based on a two-sided Fisher s exact test. NS = not significant 12
Conclusions Zalviso (Sufentanil Sublingual Microtablet System) is superior to placebo for treatment of major orthopedic pain Primary and key secondary endpoints were highly positive in favor of Zalviso The AEs were the type commonly seen after surgery and most were mild to moderate in severity Aside from itching and nausea, there were no statistically significant differences in the adverse event profile between treatment groups
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Abstract Pain Management after Major Orthopedic Surgery with the Sufentanil Sublingual Microtablet System David W. Griffin, MD 1 ; Harold S. Minkowitz, MD 2 ; Maurice Jove, MD 3 ; Timothy Melson, MD 4 ; Pamela P. Palmer, MD PhD 5,6 ; Mike A. Royal, MD JD 6 1 Orthopedic Center of Vero Beach, Vero Beach, FL; 2 MemorialHermann-Memorial City Medical Center, Houston, TX; 3 Southeaster Center for Clinical Trials/Atlanta Knee and Sports Medicine, Decatur, GA; 4 Helen Keller Hospital, Sheffield, AL; 5 University of California, San Francisco, San Francisco, CA; 6 AcelRx Pharmaceuticals, Redwood City, CA INTRODUCTION: The sufentanil sublingual microtablet system (SSMS; ZALVISO TM ) is a novel handheld, preprogrammed, noninvasive drug/device product which has completed Phase 3 development and is designed to allow patients to easily self-administer sublingual sufentanil 15 mcg microtablets with a 20-minute lockout period. While sufentanil has good cardiac stability, a high therapeutic index and minimal pharmacokinetic population differences, rapid redistribution from plasma and short duration of effect following IV administration limit its usefulness as an analgesic. When dosed sublingually, sufentanil s pharmacokinetic profile and non-invasive delivery makes it a useful alternative to IV PCA. MATERIALS/METHODS: This was a randomized, double-blind, placebo-controlled study in adult inpatients after total hip or knee arthroplasty. Patients expected to require parenteral opioid analgesia for at least 48 hours after surgery were randomized 3:1 (SSMS:placebo) and used identical System devices. The primary efficacy variable was the time-weighted summed pain intensity difference over the 48-hour study period (SPID48). Key secondary efficacy variables included pain intensity and pain relief scores, patient global assessments, patient and nurse ease of care scores and rescue medication consumption. Typical safety assessments were performed. RESULTS: A total of 426 patients were randomized (321 to SSMS and 105 to Placebo) and 315 and 105, respectively, received study drug and were included in the intent-to-treat population. Of those, 258 patients (62%) completed the 48h study period (68% in the SSMS group and 41% in the Placebo group). The most common reason for early termination was lack of efficacy (14% - SSMS and 48% - Placebo). The primary efficacy variable, time-weighted SPID48 was statistically significant in favor of the SSMS over Placebo (LS mean 77.17 vs. -15.27; p ). Key secondary variables were similarly positive in favor of the SSMS group over placebo. The most frequently reported AEs were nausea (48.0%), pyrexia (17.2%), and vomiting (11.0%). A significantly higher proportion of patients in the SSMS group had nausea (52.7% vs. 33.7%; p < 0.001), dizziness (6.0% vs. 1.0%; p = 0.034), and pruritus (6.0% vs. 0%; p = 0.006) compared with the placebo group. Most AEs were mild or moderate in severity. CONCLUSION: SSMS provides an attractive alternative to traditional IV PCA analgesia, is easy for healthcare professionals to set-up and for patients to use. Introduction The sufentanil sublingual microtablet system (SSMS; ZALVISO TM, AcelRx Pharmaceuticals, Redwood City, USA) is a novel preprogrammed noninvasive product candidate currently under review at the Food and Drug Administration that dispenses small (3 mm diameter) sufentanil 15 mcg microtablets sublingually with a 20-minute lockout period (Figure 1). Sufentanil possesses a high therapeutic index (26,716 compared to 71 for morphine) 1 and rapid equilibration between plasma and CNS (t ½keo = 6min compared to 2.8 hrs for morphine) 2,3 (Table 1), however, rapid redistribution from plasma following IV administration and short duration of action make it less than ideal for intravenous patient-controlled analgesia (IV PCA). IV PCA, particularly with morphine, is commonly used for the management of moderate-to-severe post-operative pain. However, its use is associated with limitations, including the use of low therapeutic index opioids, the risk of pump programming errors and reduced patient mobility due to IV tethering. Figure 1. ZALVISO (sufentanil sublingual microtablet system) Methods Table 1. Comparisons of Therapeutic Index and t ½ke0 Therapeutic index t ½ke0 (min) Morphine 71 1 168 2 Hydromorphone 232 4 46 5 Meperidine 5 1 10 5 Fentanyl 277 1 6.6 3 Sufentanil 26,716 1 6.2 3 Note that M6G (morphine-6-glucuronide) has a t ½ke0 of 384 minutes (6.4 h) 6 The study objectives were to compare the safety and efficacy of SSMS to placebo delivered via the SSMS device for the management of moderate-to-severe post-operative pain after major orthopedic surgery. After IEC/IRB approval and patient informed consent, 440 post-operative inpatients (18 years and older) were to be randomized (3:1 to SSMS 15 mcg or placebo using identical devices to deliver study drug sublingually) to ensure at least 400 total patients (300 in the SSMS group and 100 in the placebo group) would receive study drug and provide primary efficacy data (90% power) for analysis. The primary efficacy variable was time-weighted summed pain intensity difference over the 48h study period (SPID48) using an 11-point numerical rating scale. Key secondary efficacy variables included pain intensity and pain relief scores (5-point categorical scale) over the study period, % of patients reporting success ( good or excellent rating) on the patient or healthcare professional global assessments of method of pain control over 48h using a 4- point categorical scale (PGA48/HPGA48), patient and nurse ease of care (EOC) scores (using a validated EOC questionnaire), and rescue medication consumption. Safety assessments included spontaneous adverse event (AE) reports, vital signs, medical history, physical examinations, oxygen saturation measurements, and concomitant medication usage. Results The study was conducted at 34 US sites from August 2012 to April 2013. A total of 533 patients were screened and 426 were randomized, with 321 and 105 allocated to the SSMS and placebo groups, respectively, and 315 and 104 who received study drug. Average patient age (years) was 66.6 and 65.0 in the SSMS and placebo groups, respectively. Most patients in the SSMS and placebo groups were female (70% and 84%, respectively). 215 patients (68.3%) in the SSMS group completed the 48h study period compared to 43 (41.3%) in the placebo group. Early drop-outs in the SSMS and placebo groups, respectively, were due to adverse events (7.0% vs. 6.7%), lack of efficacy (14.3% vs. 48.1%), and other (8.9% vs. 3.8%) (Table 2). Results (cont.) SSMS was superior to placebo for the SPID48 primary endpoint (least squares [LS] means 76.2 vs. -15.3, p ). Key secondary variables were similarly positive in favor of the SSMS group over placebo (Table 3). Figure 2 shows the Kaplan-Meier cumulative event rate for time to termination from the study due to inadequate analgesia. LS mean SPID values by evaluation timepoint are shown in Figure 3. Secondary endpoint data showed that SPID24 and SPID72 were better in the SSMS group than placebo (p for both; not shown). SSMS was superior to placebo for timeweighted summed pain relief over 48h (TOTPAR48) (Table 3) and PGA/HPGA (Table 3). The mean inter-dose interval was 83.7 and 58.9 minutes for SSMS and placebo, respectively (p ). Rescue or supplemental morphine consumption was significantly higher in the placebo group at all timepoints from 6 through 48h (p 0.002). Both groups expressed high satisfaction with System use on the EOC questionnaire, not surprising since identical Systems were used to deliver sufentanil or placebo microtablets, however the mean pain control subscale score and patient satisfaction with level of pain control were significantly higher in the SSMS group (p for both; not shown). Table 2. Patient Disposition and Reasons for Early Discontinuation Randomized SSMS Placebo Total n=321 (%) n=105 (%) n=426 (%) Did not receive treatment 6 1 7 Received non-randomized treatment 1 0 1 Safety and efficacy ITT population 315 (100%) 104 (100%) 419 (100%) Study Completer (48-h period) 215 (68.3%) 43 (41.3%) 258 (61.6%) Discontinued study prior to 48h 100 (31.7%) 61 (58.7%) 161 (38.4%) Reason for discontinuation before 48h Adverse event 22 (7.0%) 7 (6.7%) 29 (6.9%) Lack of efficacy 45 (14.3%) 50 (48.1%) 95 (22.7%) Subject request 4 (1.3%) 0 (0%) 4 (1.0%) Other a 28 (8.9%) 4 (3.8%) 32 (7.6%) a Other reasons included: patient discharged from hospital prior to 48 hours (19 SSMS group, 3 Placebo group); patient no longer needed narcotic or opioid pain medication (3 SSMS group); System technical error or malfunction (4 SSMS group); insufficient drug at study site (1 Placebo group); patient switched to oral medications (2 SSMS group). Table 3. Key Secondary Variables (ITT Population) Key Secondary Endpoints Time-weighted SPID24 and SPID72 (LS mean) Time-weighted TOTPAR24, TOTPAR48, and TOTPAR72 (LS mean) Cumulative event rate for time to discontinuation due to inadequate analgesia (hrs) Proportion of patients who discontinued due to inadequate analgesia Note: HPGA## = healthcare professional global assessment of method of pain control over 24, 48, or 72 hours; ITT = intent-to-treat; LS = least squares; PGA## = patient global assessment of method of pain control over 24, 48, or 72 hours; SPID## = summed pain intensity differences over 24, 48 or 72 hours; SSMS = sufentanil sublingual microtablet system, success = a good or excellent response on the PGA/HPGA using a 4-point categorical scale; TOTPAR## = summed pain relief scores over 24, 48 or 72 hours Figure 2. Kaplan-Meier Cumulative Event Rates for Time to Termination due to inadequate analgesia SSMS n=315 (%) 32.02 134.58 42.77 91.29 145.67 Placebo n=104 (%) -8.98-2.84 25.80 53.45 81.91 P-value N/A 66.6 14.3% 48.1% Time to first rescue opioid use (hrs) 26.5 6.1 Proportion of patients requiring rescue opioid 50.8% 73.1% Mean cumulative rescue/supplemental opioid doses consumed over 48h Proportion of patients reporting success on PGA24, PGA48, and PGA72 Proportion of HCPs reporting success on HPGA24, HPGA48 and HPGA72 2.2 3.8 65.7% 70.2% 71.4% 70.2% 69.8% 70.8% 32.7% 28.8% 31.7% 33.7% 27.9% 28.8% Figure 3. LS Mean of SPID by Evaluation Timepoint Results (cont.) 351 Galveston Drive Redwood City, CA 94063 Safety Results: Table 4 shows the treatment-emergent adverse event summary. Related adverse events with an occurrence greater than 3% in either the sufentanil group or the placebo group are shown in Table 5. The most frequently reported related AEs were nausea and vomiting. All reported cases of itching in the trial were mild in nature. One placebo patient and 7 SSMS patients experienced severe AEs (oxygen saturation decreased [2], nausea [1], and chills [1] were deemed related). All other AEs were mild to moderate. Six SAEs were reported in the SSMS group - events of oxygen saturation decreased, sinus tachycardia, confusional state, and pneumonia aspiration were deemed possibly related. Table 4. Adverse Event Summary Patients SSMS Placebo Received treatment 315 (100%) 104 (100%) with at least one AE 264 (83.8%) 64 (61.5%) with at least one severe AE 7 (2.2%) 1 (1.0%) with at least one related AE 171 (54.3%) 35 (33.7%) with an SAE 6 (1.9%) 1 (1.0%) Table 5. Frequent Possibly or Probably Related Adverse Events (at least 3% in either group) SSMS (n = 315) Placebo (n = 104) p-value* Nausea 110 (34.9%) 23 (22.1%) 0.015 Vomiting 34 (10.8%) 6 (5.8%) ns Oxygen saturation decreased 22 (7.0%) 3 (2.9%) ns Dizziness 16 (5.1%) 1 (1.0%) ns Constipation 15 (4.8%) 1 (1.0%) ns Pruritus 15 (4.8%) 0 (0.0%) 0.028 Headache 13 (4.1%) 6 (5.8%) ns Insomnia 13 (4.1%) 3 (2.9%) ns Hypotension 12 (3.8%) 2 (1.9%) ns *Based on a two-sided Fisher s exact test. Note: ns = not significant; p > 0.05. Continuous pulse oximetry was used during the study. An inability to maintain saturation above 95% despite oxygen supplementation resulted in an early discontinuation. Conclusions Patients receiving active SSMS demonstrated a significantly better SPID48 compared to placebo SSMS-treated patients during the study period (p ). The SSMS was effective and well-tolerated in the management of moderate-to-severe post-operative pain after major orthopedic surgery. Related adverse events were similar to placebo with the exception of nausea and itching SSMS provides an alternative to traditional IV PCA which is easy for healthcare professionals to set up and patients to use. References 1. Mather LE. Opioids: a pharmacologist s delight! Clin Exp Pharmacol Physiol 1995; 22:833-6. 2. Lotsch J. Pharmacokinetic-pharmacodynamic modeling of opioids. J Pain Symptom Manage 2005; 29(5 Suppl):S90-S103. 3. Scott JC et al. Electroencephalographic quantitation of opioid effect: comparative pharmacodynamics of fentanyl and sufentanil. Anesthesiol 1991; 74:34 42. 4. Kumar P et al. Hydromorphone efficacy and treatment protocol impact on tolerance and μ-opioid receptor regulation. Eur. J. Pharmacol; 597: 39, 2008 (re: ED 50 ) and Purdue Pharma MSDS, 2009 (re: LD 50 ). 5. Shafer SL, Flood P. The Pharmacology of Opioids. In Geriatric Anesthesiology 2007; Ch. 15, Table 15-1; Springer Verlag, New York. 6. Lotsch et al. The transfer half-life of morphine-6-glucuronide from plasma to effect site assessed by pupil size measurement in healthy volunteers. Anesthesiol 2001; 95:1329 38. Poster presentation at the Orthopedics Today Hawaii 2014, January 19-23, 2014 at the Grand Wailea, Maui, HI. Acknowledgements: AcelRx Pharmaceuticals (Redwood City, CA), the study sponsor, wishes to thank the study subjects, PharmaNet/i3, a subsidiary of Inventiv Health Clinical, the research coordinators and the investigators for their contribution.