This multicenter, randomized, single-blind, active comparator-controlled study (NCT03234374 posted on July 31, 2017, at https://clinicaltrials.gov/ct2/show/NCT03234374?term=inl-001&draw=2&rank=1) enrolled men and women aged ≥ 18 years that were undergoing elective unilateral inguinal hernioplasty via open laparotomy. The repair of multiple hernias through a single incision was permitted. This trial enrolled patients across five sites in the US from June through August 2017. Patients were randomized to receive either three INL-001 (Xaracoll®, Innocoll Pharmaceuticals Ltd., Athlone, Ireland) 100 mg bupivacaine HCl implants, for a total of 300 mg bupivacaine HCl (n = 35), or local infiltration of 0.25% bupivacaine HCl (Marcaine) 175 mg (n = 17).
The protocol and statement of informed consent were approved by an Institutional Review Board (IRB) prior to each center’s initiation (see Table S1 in Supplementary materials). All procedures were conducted in accordance with the Declaration of Helsinki, and the study was conducted in compliance with Good Clinical Practice guidelines. Informed consent was obtained from all participants. In addition, eligible individuals must have had the ability and willingness to comply with study procedures and to use only permitted medications (including opioids).
Patients were excluded from enrollment if they had a known hypersensitivity to amide local anesthetics, morphine, acetaminophen, or bovine products. Patients were also excluded if they were scheduled for bilateral inguinal hernia repair or another significant surgical procedure concomitantly. In addition, eligible patients could not have undergone major surgery within 3 months of initial treatment nor were they permitted to have another laparotomy procedure planned for within the 30-day postsurgical period. Also, patients with a known or suspected history of alcohol or drug abuse or misuse within 3 years of screening or a clinically significant unstable cardiac, neurologic, immunologic, renal, hepatic, or hematologic disease or any other significant condition were excluded.
Enrolled patients underwent elective unilateral inguinal hernioplasty via open laparotomy according to standard procedures. In the INL-001 group, three implants (each containing 100 mg of bupivacaine HCl) were cut in half; these six implants were placed in protocol-defined locations in the surgical site. After the hernia sac was reduced and the mesh was ready for insertion, three of the six implants 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 implants were placed between the fascia/muscle closure and skin closure. The subcutaneous tissue and skin were closed per the surgeon’s preferred method. If the surgeon encountered a significant surgical or medical complication, there was the option not to administer the study drug; this patient would be considered randomized, but not enrolled or treated. The comparator group was treated with 0.25% bupivacaine HCl 175 mg infiltrated into the muscular planes of the transverse abdominis and interior oblique muscles as well as the surrounding subcutaneous tissues. This dose of bupivacaine HCl (175 mg) was chosen because it represents a common clinically used dose per the prescribing information for bupivacaine HCl injection (Marcaine) and was the dose predicted to most closely result in a maximum concentration similar to that of INL-001 300 mg.
Following surgery, patients were transferred to a postanesthesia care unit (PACU) until stable and then moved to the clinic where they were allowed to receive parenteral morphine, if needed, as a rescue medication for breakthrough pain. Once patients were able to tolerate oral medication, they were started on a standardized oral analgesic regimen of acetaminophen 650 mg three times daily (TID). They were prescribed immediate-release morphine (15 mg) to manage breakthrough pain.
Patients remained at the clinic at least until the 72-h blood sample was collected. After discharge, patients returned to the clinic to complete the 96-h blood draw. For PK assessment, blood samples were collected before Time 0 (the time of implantation or infiltration) and 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 18, 24, 36, 48, 72, and 96 h after Time 0. The following PK parameters for bupivacaine were assessed when possible: maximum (peak) plasma concentration (Cmax), time to maximum (peak) plasma concentration (Tmax), lag-time (tlag), terminal elimination half-life (t1/2), terminal phase rate constant (λz), area under the plasma concentration-time curve (AUC) from Time 0 to time of last quantifiable plasma concentration (AUC0–last), AUC from Time 0 to infinity (AUC0–∞), and percentage extrapolation (AUCextrap%) (100 × [AUC0–∞ − AUC0–last]/AUC0–∞).
The λz was not presented for patients who did not exhibit a terminal elimination phase in their concentration-time profiles. To estimate λz, linear regression of the concentration in logarithm scale vs. time was performed using at least three data points. Uniform weighting was selected to perform the regression analysis to estimate λz.
Safety assessments included the following: physical examinations performed at screening; postsurgical assessment of vital signs through 72 h; 24-h continuous electrocardiogram (ECG) obtained at screening, prior to surgery, and 24 h following study drug administration; measurement of oxygen saturation levels prior to surgery and for at least 12 h after study drug administration; and adverse event (AE) reporting. Once discharged from the clinic, patients were instructed to return to the clinic on days 5, 7, 15, and 30 for follow-up safety assessments.
The number and percentage of patients who reported one or more treatment-emergent AEs (TEAEs), serious AEs, drug-related TEAEs, or TEAEs leading to removal of the implants were summarized for each treatment group. TEAEs were defined as any AE that occurred after implantation/infiltration. The Medical Dictionary for Regulatory Activities (MedDRA) version 18.0 was used to classify all AEs according to system organ class (SOC) and preferred term (PT). Patients reporting more than one AE for a given MedDRA PT or SOC were counted only once for that term or SOC using the most severe incident.
In addition, the safety endpoints included the following two specific assessments: one focused on the signs and symptoms typically associated with wound healing and the other focused on the signs and symptoms associated with potential bupivacaine toxicity. The number and percentage of patients with signs and symptoms related to impaired wound healing and potential bupivacaine toxicity were summarized descriptively at each scheduled time point for each treatment. Specific signs and symptoms potentially associated with wound healing were assessed during the 4-day inpatient observation period and through the 30-day outpatient period.
Systemic bupivacaine toxicity is generally identified by a constellation of central nervous system and cardiovascular AEs. Signs and symptoms reported as potentially indicative of bupivacaine toxicity (i.e., anxiety, blurred vision, change in the level of consciousness, depression, dizziness, drowsiness, incoherent speech, light-headedness, metallic taste, numbness and tingling of the mouth and lips, respiratory difficulty, restlessness, tinnitus, and tremors) were collected at the following time points after Time 0 (or more frequently if needed) in both treatment groups: 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12 h (± 15 min); and then 15, 18, 24, 36, 48, and 72 h (± 1 h).
The randomized population consisted of all patients, whether or not they received treatment. The safety population consisted of all patients who received INL-001 or 0.25% bupivacaine HCl infiltration. The PK population consisted of all patients who received INL-001 or 0.25% bupivacaine HCl infiltration and had at least one postimplantation/infiltration blood sample obtained. The per-protocol PK population consisted of all patients in the PK population who had no major PK-related protocol deviation and had sufficient data to calculate the Cmax, AUC0–∞, and AUC0–last.
Continuous data were summarized using descriptive statistics. Geometric mean and geometric mean percent coefficient of variation (CV%) were also provided for the summary of Cmax and AUC. Patients with 0 values were excluded from the calculation of geometric mean and geometric mean CV%.