SAFETY AND EFFICACY OF THE BUPIVACAINE HCL COLLAGEN-MATRIX IMPLANT (INL-001) IN OPEN INGUINAL HERNIA REPAIR
David Leiman, MD1,2; Harold S. Minkowitz, MD2; Nigel Jones, BSc3; Lesley Russell, MBChB, MRCP3
1University of Texas Health Science Center, Houston, TX, USA; 2HD Research Corp, Houston, TX, USA; 3Innocoll Pharmaceuticals, Newtown Square, PA, USA
•Despite efforts to improve pain management, inadequate postsurgical pain control continues to be a clinical concern1-3
•For multimodal pain strategies to effectively reduce postsurgical pain and adverse effects associated with opioid analgesics, longer-acting formulations of local anesthetics are needed1,4-6
•The bioresorbable bupivacaine HCl collagen-matrix implant (INL-001) is currently in development for postsurgical pain management7,8
•Previous studies of INL-001 have supported its safety, tolerability, and efficacy in reducing selected measures of pain intensity (PI) and opioid analgesia use7-9
•Two Phase 3 studies, MATRIX-1 and MATRIX-2, examined the safety and efficacy of INL-001 for postsurgical analgesia in patients undergoing open inguinal hernia repair with mesh
•In 2 identical Phase 3, multicenter, randomized, double-blind, placebo-controlled studies (MATRIX-1 and -2), subjects undergoing elective open mesh tension-free inguinal hernia repair under general anesthesia were stratified by gender and history of ipsilateral hernia repair and randomized 2:1 to receive either
–3 INL-001 100-mg bupivacaine HCl collagen-matrix implants (300 mg bupivacaine HCl total) or
–3 collagen-matrix implants without bupivacaine (placebo)
•In the immediate postsurgical period, parenteral morphine was available as needed as rescue medication for breakthrough pain
•Once subjects were able to tolerate oral medication, they began oral acetaminophen (650 mg tid) and were prescribed immediate-release morphine for breakthrough pain if it occurred
•At predefined timepoints and immediately prior to receiving parenteral or oral analgesia, subjects assessed postsurgical PI via an electronic diary using an 11-point numerical rating scale (NRS), where 0 = “no pain,” and 10 = “worst pain possible”
•The primary efficacy endpoint was the sum of pain intensity (SPI) from 0-24 hours (defined as the area under the curve of NRS PI; SPI24)
•Secondary efficacy endpoints included
–SPI from 0-48 and 0-72 hours (SPI48, SPI72)
–Total use of opioid analgesia (TOpA) in mg intravenous (IV) morphine equivalents calculated from the time the matrix was implanted (Time 0) to 24, 48, and 72 hours
•Because both studies were powered to evaluate only the primary endpoint, data were pooled from the 2 studies, yielding more statistical power
•Safety assessments included wound healing assessments, bupivacaine toxicity assessments, adverse events (AEs) recording, and vital sign measurements evaluated throughout the 30-day study period
•All study sites received institutional review board approval prior to study initiation
•A total of 624 subjects were randomized (INL-001=417; placebo=207), comprising the intent-to-treat (ITT) population. The modified ITT population, used for efficacy assessments, contained 610 subjects (Figure 1). The safety population included all subjects who received any dose of INL-001 or placebo
•Demographics and baseline characteristics were similar between the pooled analysis groups (Table 1) and between both studies
•For the primary endpoint, SPI24, subjects treated with INL-001 reported significantly less pain through the first 24 hours after surgery vs placebo in MATRIX-1, MATRIX-2, and the pooled analysis (P=0.0004, P<0.0001, and P<0.0001, respectively) (Table 2). These reductions in PI were coupled with significantly less TOpA in subjects treated with INL-001 vs placebo throughout the first 24 hours (TOpA24) in both studies and the pooled analysis (P<0.0001 for all) (Table 2)
•In the pooled analysis, subjects treated with INL-001 reported significantly less pain and used significantly less total opioid analgesia at all timepoints vs placebo subjects (Table 2, Figure 2, Figure 3)
•In addition, throughout the 72-hour postsurgical period, approximately one third of INL-001 subjects did not use any rescue opioid medication vs 17% of placebo subjects
•At least 1 AE was reported in 62.3% of subjects given INL-001 and 68.8% of those given the placebo collagen-matrix implant (Table 3)
•Most AEs were mild or moderate in intensity, did not indicate bupivacaine toxicity or deleterious effects on wound healing, and were judged unrelated to study treatment
–One death occurred in the placebo group due to a myocardial infarction not considered related to the study drug
–No serious AEs were considered related to the study drug in the Phase 3 studies
•Subjects treated with INL-001 experienced significantly fewer opioid-related AEs (ie, nausea, constipation, and vomiting) over the postsurgical period vs the placebo group (n [%], 68 [16.6] vs 59 [28.4], P=0.0007)
•Subjects in the INL-001 300 mg group reported significantly less PI from 0-24 hours vs placebo in both studies and in the pooled analysis
–Reductions in pain intensity were coupled with less TOpA in the INL-001 treatment group vs placebo
•Over the 72-hour postsurgical period, approximately one-third of INL-001 subjects did not require opioid medication vs 17% of placebo subjects
–INL-001 subjects also used significantly less opioid rescue medication and experienced significantly fewer opioid-related AEs over the postsurgical period than placebo subjects
•The AEs observed were largely mild or moderate, with no serious AEs considered related to study drug
–Observed AEs were not indicative of bupivacaine toxicity
–No evidence of deleterious effects on wound healing was observed with use of the collagen matrix
•These findings support the use of INL-001 as a long-acting, opioid-sparing local anesthetic implant for management of postsurgical pain in patients undergoing open, tension-free mesh inguinal hernia repair
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DL, HSM: Have received research funding and consultant fees from Innocoll, Inc., Heron, Durect, and Pacira.
NJ: Former employee of Innocoll.
LR: Current employee of Innocoll.
This study was funded by Innocoll Pharmaceuticals (Athlone, Ireland). Development, editorial, design, and production support was provided by MedVal Scientific Information Services, LLC (Princeton, NJ) and funded by Innocoll.