Safety and Efficacy of Bupivacaine HCl Collagen-Matrix Implant (INL-001) in Open Inguinal Hernia Repair: Results from Two Randomized Controlled Trials

Bupivacaine has been used to manage pain after surgery for many years. Surgical pain can last for days, but pain control only lasts for a few hours with bupivacaine. Therefore, opioid narcotics are often needed to decrease pain after surgery. There are risks of opioid use, including negative side effects and potential for abuse. INL-001 is an implant designed to provide extended delivery of bupivacaine to the area around the surgical wound. The effectiveness and safety of INL-001 were studied in two clinical trials involving patients undergoing hernia repair surgery. These two clinical trials were evaluated both separately and together (combined) to increase the number of patients studied. Patients who received INL-001 in both studies reported significantly lower pain intensity and opioid use through 24 h post-surgery versus those who received an implant without bupivacaine (placebo). When the data from these clinical trials were combined, patients who received INL-001 reported lower pain intensity through 72 h. In both studies, more of the patients receiving INL-001 did not use opioid medication up to 72 h post-surgery versus those administered a placebo. Most side effects seen with INL-001 were mild or moderate. These findings indicate that INL-001 is safe and effective at extending postsurgical pain control and decreasing opioid use for patients undergoing hernia repair surgery.

Achieving adequate pain control following surgery is a major concern for patients and physicians. Inadequate acute postsurgical pain control can result in increased patient morbidity or mortality and higher healthcare costs [1‐3]. Postsurgical pain is generally most severe during the first 1–3 days after surgery and improves over time [4, 5]. Historically, opioid medication has been the mainstay of postsurgical pain management; however, opioids are associated with well-known risks. Opioids are commonly associated with adverse events (AEs), such as constipation, nausea, and vomiting, and occasionally more serious effects, such as respiratory depression, all of which can negatively impact recovery from surgery [6‐8]. Furthermore, use of opioids for as few as 3 days, especially in opioid-naive patients, is associated with risk of long-term use, which can result in tolerance, dependence, and addiction [9, 10].

A desire to limit opioid use and improve postsurgical pain control has led to the development of multimodal approaches to postsurgical pain management [11, 12]. Infiltration of surgical wounds with local anesthetics, such as bupivacaine, has become a widely accepted component of multimodal approaches to the management of acute pain after soft tissue surgery [11‐16]. Bupivacaine, however, has a limited duration of effect (4–8 h), a duration that is not well aligned with the temporal profile of maximal postsurgical pain and is dependent primarily on contact with nerves in the surgical wound [17‐20]. Various attempts have been made to extend the delivery of bupivacaine to the tissues in the surgical site, such as administration through a catheter with a pump, the addition of epinephrine, and alternative formulations. However, all available bupivacaine formulations are liquid, and each approach presents limitations with respect to administration, analgesic duration, and/or safety [20‐24]. Bupivacaine’s most serious safety issue, local anesthetic systemic toxicity (LAST), is most often caused by inadvertent intravascular injection during administration of bupivacaine into the surgical wound and manifests with central nervous system (CNS) and cardiovascular signs and symptoms that can be serious or fatal [20, 21, 25]. Formulations that safely deliver bupivacaine over time into the surgical site for prolonged postsurgical pain are needed.

The bioresorbable bupivacaine HCl collagen-matrix implant (INL-001) is a single-application extended bupivacaine delivery technology designed for the management of acute postsurgical pain associated with soft tissue surgery [26‐29]. INL-001 is a combination product consisting of one active moiety, bupivacaine HCl, and a drug delivery component of type I bovine collagen designed to be placed in the surgical site. The type I collagen used in INL-001 is purified from bovine Achilles tendons, which are sourced from closed herds that have been certified as transmissible spongiform encephalopathy free and negligible for the risk of bovine spongiform encephalopathy. Degradation of INL-001 via chemical and enzymatic hydrolysis occurs within 2 months after implantation, as demonstrated in preclinical studies. Bovine type I collagen, which is used in numerous clinical applications, shares a common amino acid structure and surface epitopes with human type I collagen, presenting a negligible risk for an immune response [30‐33]. Each bupivacaine HCl collagen-matrix contains 100 mg bupivacaine HCl dispersed evenly within the matrix. INL-001 has been demonstrated to be compatible with common surgical materials, including mesh.

The extended bupivacaine delivery profile of INL-001 was demonstrated via postimplantation plasma concentrations [20]. Use of INL-001 300 mg results in bupivacaine blood levels that are quantifiable within 30 min after implantation and through 96 h (first and last time points measured) in patients undergoing open inguinal hernia repair with mesh [34]. The extended delivery of bupivacaine from INL-001 is further demonstrated by a longer time to maximum plasma concentration (T_max) and terminal elimination half-life (t_1/2) compared with 0.25% bupivacaine HCl 175 mg infiltration (3.0 h vs. 1.0 h and 19.0 h vs. 9.1 h, respectively), with a comparable C_max (663.4 ng/ml vs. 641.0 ng/ml) [34]. The highest individual plasma bupivacaine concentration reported in the INL-001 development program was 1230 ng/ml, a level well below the ≥ 2000 ng/ml that has been reported to be associated with bupivacaine systemic toxicity [34, 35]. Phase 1 and 2 clinical studies supported the safety and tolerability of INL-001 and found reductions in selected measures of pain intensity (PI) and opioid analgesia use in patients undergoing inguinal hernia repair or hysterectomy [26‐29]. Based on dose ranging in these studies, a dose of three implants (300 mg total) was identified to be evaluated in the phase 3 studies (MATRIX-1 and MATRIX-2).

We hypothesized that the INL-001 implant would lead to less pain and less opioid consumption than a control placebo collagen-matrix implant. Two phase 3 studies, MATRIX-1 (ClinicalTrials.gov identifier, NCT02523599) and MATRIX-2 (ClinicalTrials.gov identifier, NCT02525133), were conducted as part of a regulatory strategy to examine the efficacy and safety of INL-001 300 mg in the treatment of postsurgical pain in the surgical model of open inguinal hernia repair with mesh.

Two similar phase 3, multicenter, randomized, double-blind, placebo-controlled studies (MATRIX-1 and MATRIX-2) were performed in patients scheduled for unilateral inguinal hernia repair. MATRIX-1 was conducted from August 2015 to April 2016 and MATRIX-2 from September 2015 to April 2016 in the USA. Thirty-nine unique centers participated across the two studies.

Eligible patients were ≥ 18 years of age and undergoing elective open mesh tension-free inguinal hernia repair under general anesthesia. Operations were performed according to standard surgical technique. Randomization was stratified by sex and history of previous ipsilateral hernia repair using mesh. Patients were randomized just prior to surgery in a 2:1 ratio to either INL-001 or placebo collagen-matrix implants to ensure the required number of INL-001 300 mg patient exposures for the regulatory approval process. A centralized block randomization was performed using an electronic randomization system.

The protocol and statement of informed consent were approved by an Institutional Review Board (IRB) prior to each center’s initiation. All procedures were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. The studies were also conducted in compliance with the International Council for Harmonisation (ICH) principles of Good Clinical Practice (GCP; including archiving of essential study documents) and other applicable local regulations and guidelines. Informed consent was obtained from all individual participants included in the study.

Patients in the INL-001 group received a total of three INL-001 100-mg bupivacaine HCl collagen-matrix implants for a total dose of 300-mg bupivacaine HCl. The placebo collagen-matrix group received three collagen-matrix implants without bupivacaine (placebo collagen-matrix implants). Both the INL-001 bupivacaine HCl and placebo collagen-matrix implants were approximately 5 × 5 cm, off-white to white, lyophilized, porous matrices of type I bovine collagen. Investigators and patients were blinded as to whether a patient received INL-001 or matched placebo collagen-matrix implants, and the investigators were not aware of the size of the randomization block. When a patient had an AE that required the investigator to be unblinded, the investigator was able to obtain the treatment assignment.

For both groups, the three collagen-matrix implants were placed at specific protocol-prescribed locations in the surgical site prior to incision closure. After the hernia sac was reduced and the mesh was ready for insertion, each of the three 5 × 5-cm test article matrices were cut in half for a total of six half matrices measuring approximately 2.5 × 5 cm in size. Three half matrices were placed into the hernia repair site below the site of mesh placement. The mesh placement was completed per the surgeon’s typical technique. The external oblique aponeurosis was closed, and the remaining three half matrices were placed between the fascia/muscle closure and skin closure. The subcutaneous tissue and skin were closed per the surgeon’s preference.

In the immediate postsurgical period, parenteral morphine was available, as needed, for the treatment of pain. When able to tolerate oral medication, patients were required to take oral acetaminophen 650 mg three times daily for 3 days and were also prescribed immediate-release (IR) morphine to manage pain to be taken on an as-needed basis only. All use of acetaminophen and rescue opioid analgesia was recorded.

Demographics and baseline characteristics were similar between groups in MATRIX-1 and MATRIX-2 (Table 1). Patients’ sex ratios and percentages of patients with a history of previous ipsilateral hernia repair were comparable across treatment groups in both studies, reflecting the stratified randomization method. In MATRIX-1, 305 patients were randomized (INL-001 = 204; placebo collagen-matrix = 101), and in MATRIX-2, 319 patients were randomized (INL-001 = 213; placebo collagen-matrix = 106) and therefore comprised the ITT population (Fig. 1). The mITT (analysis) population included 297 MATRIX-1 patients and 312 MATRIX-2 patients.

INL-001 is a bupivacaine delivery technology designed to be implanted in the surgical site at the time of soft tissue surgery to produce extended postoperative analgesia and result in reduced opioid use. In both MATRIX-1 and MATRIX-2, treatment with INL-001 was associated with significant reductions in postsurgical PI over the first 24 h compared with the placebo collagen-matrix, thus meeting the primary end point in both studies conducted with patients undergoing unilateral open inguinal hernioplasty. In addition, INL-001 treatment resulted in significantly less total opioid analgesic usage during the first 24 h compared with the placebo collagen-matrix in both studies.

Both PI and opioid use were statistically significantly reduced during the first 48 h with INL-001 compared with placebo collagen-matrix in MATRIX-2. The magnitude of effect on the mean SPI48 score was similar in MATRIX-1 to that seen in MATRIX-2, but there was a slightly higher variability in the score, and statistical significance on this end point was barely missed in MATRIX-1. Assessment of PI is inherently variable given its subjective nature. There is also the likelihood of increasing variability in PI assessment among patients further from the surgical event, because patients recover at different rates. In addition, it is recognized that the use of opioid rescue medication can make assessment of PI challenging in clinical trials. Given this, it is useful to consider the reductions in PI in the context of reductions in opioid use.

A statistical test for median TOpA48 was not performed for the MATRIX-1 study due to the fixed hierarchical testing order of the key secondary end points; however, the numerical reduction in opioid use (median mg IV morphine equivalents) in favor of INL-001 compared with the placebo collagen-matrix was actually greater in MATRIX-1 compared with MATRIX-2 48 h post-surgery. In addition, the percentage of opioid-free patients treated with INL-001 was approximately double that of patients receiving the placebo collagen-matrix at 48 h, with similar results seen at 72 h.

Pooling the data from the two studies limited the statistical impact of increasing variability over time post-surgery in the mean SPI score, and analysis of this data set demonstrated that patients treated with INL-001 showed a significant reduction in mean SPI through 24, 48, and 72 h compared with those receiving a placebo collagen-matrix, with the same result seen for the median TOpA.

INL-001 was well tolerated in these studies. The most common TEAEs were those that would be expected after anesthesia or with opioid use, and treatment-related TEAEs occurred at a low rate. Because both the placebo and treatment groups received a collagen-matrix implant, to assess the true risk of the collagen-matrix implant, it is useful to consider the rate of complications frequently reported after inguinal hernia repair. Patients in a national hernia registry reported via questionnaire that the most common AEs experienced after inguinal or femoral hernia repair were hematoma (14%), severe pain (12%), testicular pain (8%), postoperative infections (7%), wound rupture (4%), and constipation (4%) [37]. Postsurgical AEs required 12% of patients to visit a healthcare provider [37]. A systematic review of open inguinal hernia repair studies found infection rates ranging from 3 to 5% [38]. In another study, 6% of patients undergoing open mesh inguinal hernia repair developed a wound hematoma, 5% developed a scrotal hematoma, and 2% developed seroma [39]. When the types and rates of AEs commonly associated with open inguinal hernia repair are compared with the AE profiles seen in the studies for both INL-001 and the placebo collagen-matrix, it would appear that delivery of bupivacaine in the surgical site via a collagen-matrix is well tolerated. The pooled analysis also demonstrated a statistically significant reduction in AEs associated with opioid medication.

The reductions in opioid use and opioid-related adverse drug events (ORADEs) seen with INL-001 are clinically meaningful findings. One study of surgical inpatients found that ORADEs following surgery increased median hospitalization costs by 7% and the median length of stay by 10% [8]. A recent report suggests that, among opioid-naive patients, opioid use for as short as 3 days may increase the likelihood of long-term use and that an increased length of initial exposure (higher total dose, longer duration of first use) is associated with an increased risk of long-term use [9]. A review of a nationwide data set of insurance claims, which included 36,177 patients, found that new persistent opioid use (i.e., opioid prescriptions filled) between 90 and 180 days after major surgical procedures, such as hernia repair, occurred at a rate of 7% in patients who were opioid-naive at the time of surgery [36].

While a limitation of this study is that it did not include a comparison with bupivacaine infiltration, the use of INL-001 collagen technology to deliver bupivacaine avoids the greatest risk of bupivacaine use in a surgical wound, that of unintended intravascular injection, which can lead to serious systemic bupivacaine toxicity [20, 21, 25]. No injection technique is known to eliminate this risk [20]. There was no evidence that any patient experienced systemic bupivacaine toxicity in either study.

The generalizability of these findings may be limited by the fact that the study population was almost entirely male and predominantly white. However, the large number of patients across both studies and the number of unique study centers support the potential clinical efficacy, utility, and safety of INL-001.

Two pivotal phase 3 studies of INL-001 met their primary end points, both demonstrating statistically significant reductions in acute postsurgical pain during the first 24 h after open inguinal hernia repair compared with the placebo collagen-matrix. The analgesic efficacy of INL-001 was further supported by a significantly lower use of opioid analgesics in the INL-001 group compared with the placebo collagen-matrix group through 24 h. One of the studies also demonstrated statistically significant and clinically meaningful reductions in mean SPI and median opioid use through 48 h with INL-001, with the other study demonstrating a similar magnitude of effect with INL-001 treatment, almost reaching statistical significance. When the data from the two studies were pooled, statistically significant differences were seen in reductions in mean SPI and median opioid use through 24, 48, and 72 h. INL-001 was well tolerated, and no safety issues emerged during these studies that were related to the use of the collagen-matrix. These results support the use of INL-001 as an alternative treatment for the management of acute postsurgical pain following open inguinal hernia repair.