A Randomized Double-Blind Placebo-Controlled Trial of AeroLEF™
(Aerosolized Free and Liposome-Encapsulated Fentanyl)
ASRA 2007 for Post-Operative Pain following Orthopedic Surgery
Richard Brull MD FRCPC1, Vincent Chan MD FRCPC 1, Sugantha Ganapathy FRCA FRCPC 2, Diana Pliura PhD 3
1Toronto Western Hospital, University of Toronto (Toronto, Ontario), 2London Health Sciences Centre, University of Western Ontario (London, Ontario), 4YM BioSciences Inc. (Mississauga, Ontario)
INTRODUCTION MAJOR INCLUSION CRITERIA EFFICACY (continued) SAFETY
Pain after orthopedic surgery can be severe, requiring rapid onset and Men and non-pregnant women ≥ 18 years of age with ASA Figure 2: Time to Effective Analgesia – Dosing Session 1 AeroLEF was generally safe and well-tolerated, with a safety
prolonged analgesia. The ideal analgesic is characterized by a simple Physical Status I-III scheduled for orthopedic surgery . profile similar to that of other fentanyl products.
and non-invasive route of administration, rapid onset of action, sustained Baseline post-surgery PI score ≥ 2 on a 4-point (0-3) VRS scale. AEs that were possibly or reasonably attributable to study drug
effect, self-titratable dosing, with minimal adverse effects. Inhalation of were consistent with typical opioid adverse effects seen in the
opioids is conceptually appealing as the alveolar surface permits rapid Patient alert and capable of self-administering an opioid;
immediate post-operative period. Most AEs were mild in severity.
drug absorption. respiratory rate >10 bpm.
Respiratory rate < 8 breaths per minute or SpO2 < 90% for > 20
We evaluated clinical efficacy and safety of a nebulized mixture of free Oxygen saturation >94% (supplemental O2 allowed).
seconds occurred in 13% of patients in the AeroLEF group and in
(rapid absorption) and liposome-encapsulated (extended-release) 5% of patients on placebo. One respiratory event was deemed
fentanyl (AeroLEF™) for treatment of post-operative pain following MAJOR EXCLUSION CRITERIA severe and attributable to study drug; supplemental oxygen was
orthopedic surgery in a two part study in opiate-naïve subjects. administered and the AE resolved without sequelae.
Patients with clinically significant illness and/or sleep apnea.
Part 1: Open-label lead-in study in which investigators acquired One SAE, atelectasis (mild), was deemed possibly related to study
experience with this new delivery system. Patients with hypersensitivity to opioids or to liposomes used to
drug in the AeroLEF group in Part 2.
formulate AeroLEF, including hypersensitivity to soya lecithin or
Part 2: Prospective randomized, double-blind, placebo controlled study. related food products (soya bean and peanuts). No patients received positive pressure ventilation or opioid
antagonists during the study. No deaths occurred.
This poster addresses the efficacy of only the first of three potential Patients currently receiving treatment with MAO inhibitors or CNS-
dosing sessions. The safety data refers to the entire set of doses. depressants drugs, or with a history of alcohol or drug abuse.
RESULTS Figure 3: Change in Pain Intensity (PI) at End of First Dosing CONCLUSIONS
PATIENT DEMOGRAPHICS AND BASELINE PAIN VALUES Results suggest that AeroLEF administered via inhalation
(1-2 nebulizers/dosing session) up to 3 times during an 8-hour
PRIMARY OBJECTIVE Part 1 AeroLEF
period demonstrated a safety and efficacy profile justifying
To evaluate efficacy of AeroLEF vs. placebo for treatment of acute Table 1: Intent-to-Treat (ITT) Population continued evaluation.
post-operative pain as measured by the summed pain intensity Part 2 AeroLEF
Part 1 Part 2 Part 2
difference/pain relief scores (SPID, SPRID) for 4 hours after the initial Variable AeroLEF AeroLEF Placebo
AeroLEF was well tolerated, with an incidence of treatment-
dose following orthopedic surgery. n=21 n=65 n=34 emergent adverse events similar to that of placebo.
Female 57% 40% 53% Part 2 Placebo
Male 43% 60% 47% The self-administration of AeroLEF shows an encouraging benefit /
SECONDARY OBJECTIVE Age, Mean (SD) 45.9 (17.8) 43.7 (16.3) 45.8 (17.1) risk profile in patients with post-operative pain, a population with
Range (Min - Max) 18 - 72 18 - 81 18 - 72
0% 20% 40% 60% 80% 100%
To assess safety and tolerability self-titration of AeroLEF for the limited options to self-titrate in a non-invasive manner.
BMI, Mean (SD) 27.5 (3.4) 28.7 (4.8) 28.3 (4.8) % Patients (ITT Population)
treatment of acute post-operative pain. Range (Min - Max) 19.4 – 32.0 20.1 – 42.2 19.8 – 38.6
Decreased PI No Change Increased PI
Type of Surgery
ACL 33% 31% 35%
Total Hip 19% 15% 24%
Total Knee 19% 12% 12% Table 2: Summary of Primary and Secondary Endpoints REFERENCES
METHODS Other 29% 42% 29% for First Dosing Session
Pain Intensity 1. Ganapathy S, Choi PT, Chisholm KC, Sutton I, Chan VWS. Inhaled Liposome-Encapsulated
STUDY DESIGN (Treatment Initiation)
Moderate 67% 74% 71% Part 1 AeroLEF Part 2 AeroLEF Part 2 Placebo Fentanyl (AeroLEF) for Post-Operative Pain after Orthopedic Surgery. Proceedings of the 2006
Endpoint P value American Society of Anesthesiologists Annual Meeting, Abstract #A1191.
(n=21) (n=65) (n=34)
Phase II, eight center, double-blind study with patients undergoing Severe 33% 26% 29%
elective orthopedic surgery with institutional IRB/REB approval and >2 52% 54% 47%
SPRID4, Mean (SD) 10.15 (6.36) 8.32 (7.60) 4.49 (6.48) < 0.02 Principal Investigators and Study Coordinators by Study Site
informed written consent. 3 38% 19% 3% Dartmouth General Hospital Alex Finlayson, MB, ChB
TOTPAR4, Mean (SD) 16.02 (10.48) 13.58 (10.34) 8.51 (8.99) < 0.02
* Dose was defined as 1-2 nebulizers/dosing session; each nebulizer charged with 3 mL of (Dartmouth, Nova Scotia) Maria Forbes, RN
The treatment phase of the study began in the PACU after completion AeroLEF (500 g fentanyl/mL); administered up to 3 times during an 8-hour period. London Health Sciences Centre, Sugantha Ganapathy, FRCA, FRCPC
SPID4, Mean (SD) 5.85 (3.60) 4.30 (6.17) 1.22 (5.88) < 0.02
of surgery when the patient reported a pain intensity (PI) score of at University of Western Ontario (London, Ontario) Deenaz Zaidi, MBBS, MSc
least 2 (moderate pain) on a 4-point verbal rating scale (0 [none] to Time to Effective Analgesia:
Kaplan-Meier Estimates 15.3 11.2 28.3 < 0.005 Queen Elizabeth II Health Sciences Centre Kenneth C. Chisholm, MD, FRCPC
3 [severe]). (minutes) 25th percentile (Halifax, Nova Scotia) Maggie Rossiter-Rooney, RN
EFFICACY Pain Intensity of Mild or None at St. Paul’s Hospital C. Brian Warriner, MD, FRCPC
Patients were allowed to self-titrate blinded study drug (1-2 nebulizers End of Dose 71% 59% 27% 0.005 (Vancouver, British Columbia) Stephanie Taylor, RN
per dosing session, up to 3 times during an 8-hour period) using a Figure 1: Reason for Stopping First Treatment Session (%ITT population)
Toronto Western Hospital, Vincent Chan, MD, FRCPC
breath actuated nebulizer (AeroEclipse® - Trudell Medical, London, Pain Relief of Moderate or University of Toronto (Toronto, Ontario) Filomena Valle-Leutri, BSc
Greater at End of Dose (%ITT 86% 66% 32% < 0.02
Ontario) charged with 3 mL (of which 2 mL can be emitted from the Part 1 AeroLEF population) Winnipeg Health Sciences Centre Ian Sutton, MD, FRCPC
nebulizer) of AeroLEF (500 g fentanyl/mL). If required, a second (Winnipeg, Manitoba) Teralyne Wilson, RN
nebulizer was available for each dosing session. University of Alberta Hospital Barry Finegan, MB, ChB
Part 2 AeroLEF RESULTS (Edmonton, Alberta) Courtney Bryden, BSc
Patients were instructed to continue inhalation of AeroLEF until one of AeroLEF produced effective analgesia more frequently (Figure 1)
Vancouver General Hospital Peter Choi, MD, FRCPC, MSc(Epid)
(Vancouver, British Columbia) Marion Eng, RN, BSN
the following endpoints was reached: and earlier (Figure 2) than placebo.
Part 2 Placebo
1) achievement of effective analgesia, Research supported by YM BioSciences Inc., manufacturer of AeroLEF™.
AeroLEF decreased pain intensity more frequently than placebo
2) onset of dose-limiting side effects, (Figure 3).
AeroLEF™ is a proprietary formulation comprised of 65% liposome encapsulated and 35% free
0% 20% 40% 60% 80% 100% fentanyl, and as a result cannot be referred to by generic name.
3) upper limit (6 mL) of study drug was completed, or
% Patients (ITT population) Pain relief scores and pain intensity scores improved more with
4) patient fell asleep and was not able to continue dosing. AeroLEF compared to placebo (Table 2).
Effective Analgesia Rescue Fell Asleep Not Reported
YM BioSciences Inc.
Subjects were allowed to withdraw and be treated with an alternative Approximately one-third of AeroLEF patients used a second 5045 Orbitor Drive, Bldg 11, Suite 400
Mississauga, Ontario, CANADA, L4W 4Y4
opioid at any time. nebulizer during the first dosing session in Part 2. www.ymbiosciences.com