A Study to Evaluate Safety, PK, Efficacy of TLC590 for Postsurgical Pain Management Following Bunionectomy

This is a Phase 2, randomized, double-blind, 2-part comparator- and placebo-controlled study to evaluate the safety, PK, and efficacy of TLC590 via a single infiltrative local administration in adult subjects following bunionectomy.

The primary objective of this study is to evaluate the analgesic efficacy of TLC590 for post-surgical pain management in subjects following bunionectomy.

The secondary objectives of this study are:

• To evaluate the pharmacokinetic (PK) profile and dose-exposure relationship of TLC590, as well as the bioavailability as compared with Naropin®.
• To evaluate the safety and tolerability of TLC590 for post-surgical pain management in subjects following bunionectomy.
• To evaluate the exposure-response relationship between PK parameters and pain intensity.

The study will be divided into two parts:

Part 1: Blinded Pharmacokinetics of TLC590 and Naropin®. Approximately 48 subjects will be randomized to treatments.

Part 2: Efficacy and Safety of TLC590 versus bupivacaine and Placebo. Part 2 of the study will randomize approximately 150 evaluable subjects who meet all entry criteria.

Inclusion criteria

• Able and willing to provide a written informed consent.
• Male or female between 18 and 65 years of age.
• Body mass index ≤ 35 kg/m2.
• Mild to moderate hallux valgus deformity.
• Scheduled to undergo a primary, unilateral first metatarsal bunionectomy repair under local anesthesia.
• American Society of Anesthesiology Physical Status Classification of 1 or 2 at screening.
• Female subjects are eligible only if all of the following apply:

• Not pregnant;
• Not lactating;
• Not planning to become pregnant during the study;
• Commits to the use of an acceptable form of birth control for the duration of the study and for 42 days from administration of study drug.
• Male subjects must be surgically sterile (biologically or surgically) or commit to the use of a reliable method of birth control, for the duration of the study until at least 1 week after the administration of study medication.

Exclusion criteria

• Clinically significant abnormal clinical laboratory test value.
• Evidence of a clinically significant 12-lead ECG abnormality.
• History or evidence of orthostatic hypotension, syncope or other syncopal attacks.
• History or clinical manifestations of significant renal, hepatic, gastrointestinal, cardiovascular, metabolic, neurologic, psychiatric, or other condition that would preclude participation in the study.
• A history of seizure disorder or currently taking anticonvulsants.
• History of hypersensitivity to ropivacaine, any other amide-type local anesthetic, propofol, lidocaine, midazolam, acetaminophen, naproxen, morphine or oxycodone (or other opioids).
• Concurrent painful physical condition that may confound post-operative pain assessments.
• Persistent or recurrent nausea and/or vomiting due to other etiologies.
• History of severe or refractory post-operative nausea or vomiting (PONV) deemed clinically significant.
• History of alcohol abuse or prescription/illicit drug abuse within 2 years.
• Current evidence of alcohol abuse within 6 months.
• Received opioid therapy for longer than 4 days per week within 2 months or opioid use within 2 weeks.
• Use of concurrent therapy that could interfere with the evaluation of efficacy or safety.
• Unable to discontinue medications that have not been at a stable dose for at least 14 days prior to the study surgical procedure, within 5 half-lives of the specific prior medication.
• Use of any of the following medications within 5 half-lives or as specified prior to the study surgical procedure:

• Low-dose aspirin therapy for cardiovascular protection
• Class III antiarrhythmic drugs
• Strong CYP1A2 inhibitors
• CYP1A2 substrates
• Strong CYP3A4 inhibitors
• Corticosteroids, either systemically, inhaled either intranasally or orally, or by intra-articular injection, or NSAIDs within 14 days
• Any investigational product within 30 days.
• Positive results on the urine drug screen or alcohol breath test indicative of illicit drug or alcohol abuse.
• History or positive test results for HIV; active Hepatitis B or C.
• Contralateral foot bunionectomy in the last 3 months or have collateral procedures.
• Malignancy in the last 2 years, with the exception of non-metastatic basal cell or squamous cell carcinoma of the skin or localized carcinoma in situ of the cervix.
• History of rheumatoid disease, Type 1 or Type 2 diabetes or peripheral circulatory disorders.
• Documented sleep apnea or are on home continuous positive airway pressure.