Safety, Efficacy, and Pharmacokinetics of SKY0402 Administered as a Nerve Block in Subjects Undergoing Bunionectomy

This Phase 2, multicenter, randomized, double blind, dose escalating/de-escalating study evaluated the safety, efficacy, and pharmacokinetics of a single dose of SKY0402 compared to a single 125 mg dose of bupivacaine HCl for the treatment of postoperative pain in subjects undergoing bunionectomy.

Up to 88 subjects were to be randomized in five consecutive cohorts. The dose of bupivacaine HCl (125 mg) was to remain constant for all cohorts. After completion of Cohort 1, the decision to increase or decrease the dose of SKY0402 was made by a Cohort Data Review Committee following a review of pharmacokinetic, safety, and selected efficacy data from the previous cohort.

Study drug was to be administered as an ankle block, with or without a tourniquet, between 1 hour before the induction of general anesthesia and 20 minutes before the end of general anesthesia. The ankle block procedure consisted of five injections via three skin entries targeting the following nerves: posterior tibial, sural, deep peroneal, superficial peroneal, and saphenous.

The use of intravenous fentanyl during general anesthesia was permitted, but was not to exceed 250 micrograms. The intraoperative use of morphine was prohibited. Postoperatively, subjects had access to both opioid and non-opioid supplemental pain medication under general guidelines. Blood samples for the determination of plasma bupivacaine concentrations were obtained at Baseline and at specified time points through 96 hours.

Inclusion criteria

Subjects were eligible for enrollment if they met the following criteria:

• Males and females ≥18 years of age at the Screening Visit. NOTE: Eligible females were postmenopausal or surgically sterile, or, if of child bearing potential, were not pregnant or nursing, and they agreed to not become pregnant during the study by using acceptable means of contraception for at least 1 month before and 1 month after dosing, including any of the following: hormonal contraceptives (oral, injectable, implantable), effective barrier methods (e.g., condoms with spermicide), intrauterine device (IUD), lifestyle with a personal choice of abstinence, non-heterosexual lifestyle, or in a strictly monogamous relationship with a partner who has had a vasectomy.
• Scheduled to undergo a primary unilateral first metatarsal bunionectomy repair under general anesthesia, with or without internal fixation.

NOTE: For the purpose of this protocol, all surgical procedures involving osteotomy of the first metatarsal (significant bone resection, excision, surgical fracture, etc.) or fusion of the first metatarsal phalangeal joint were considered qualified procedures, whether or not performed specifically to repair a bunion (hallus valgus deformity). Surgical techniques accompanied by minimal bone excision (e.g. cheilectomy) or procedures limited to soft tissue repair were not eligible for this study.

• American Society of Anesthesiology (ASA) Physical Class 1 or 2.
• Able and willing to comply with all study visits and procedures.
• Capable of speaking and understanding the local language sufficiently to provide responses to pain assessment scales.
• Willing and capable of providing written informed consent.

Exclusion criteria

Subjects were excluded from the study if they met any of the following criteria:

• Clinically significant electrocardiogram (ECG) abnormalities at Screening or on Day 1 (before dosing).
• Albumin and/or alpha 1 acid glycoprotein (AAG) below normal levels.
• Current or historical evidence of any clinically significant disease or condition that, in the opinion of the Investigator, might have increased the risk of surgery or complicated the subject's postoperative course.
• Opioid medication usage during the 7 day period preceding the administration of study drug.
• Current medical conditions that could have required treatment with analgesic medications in the postoperative period for pain that was not surgically related (e.g., rheumatoid arthritis).
• Body mass index >30 kg/m^2.
• Body weight less than 60 kilograms.
• History of hypersensitivity or idiosyncratic reaction to amide type local anesthetic agents.
• History of hypersensitivity, idiosyncratic reactions, and other contraindications to the pain control agents (opioid or non-opioid) anticipated to be used postoperatively. These contraindications may have included the following: angioedema and bronchospastic reactivity to non-steroidal anti-inflammatory drug (NSAID), peptic ulcer (active within the last 3 months), or hepatic or renal insufficiency.
• Coagulation disorders or ongoing anticoagulation treatment.
• Administration of an investigational drug within 30 days or 5 half lives (of elimination), whichever was longer, prior to study drug administration.
• Suspected or known history of substance abuse and/or alcoholism.