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

A Phase 2, Randomized, Double-blind, Comparator- and Placebo-controlled Study to Evaluate the Safety, Pharmacokinetics, and 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.

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:

1. Able and willing to provide a written informed consent.

2. Male or female between 18 and 65 years of age.

3. Body mass index ≤ 35 kg/m2.

4. Mild to moderate hallux valgus deformity.

5. Scheduled to undergo a primary, unilateral first metatarsal bunionectomy repair under local anesthesia.

6. American Society of Anesthesiology Physical Status Classification of 1 or 2 at screening.

7. 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.

8. 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:

1. Clinically significant abnormal clinical laboratory test value.

2. Evidence of a clinically significant 12-lead ECG abnormality.

3. History or evidence of orthostatic hypotension, syncope or other syncopal attacks.

4. History or clinical manifestations of significant renal, hepatic, gastrointestinal, cardiovascular, metabolic, neurologic, psychiatric, or other condition that would preclude participation in the study.

5. A history of seizure disorder or currently taking anticonvulsants.

6. History of hypersensitivity to ropivacaine, any other amide-type local anesthetic, propofol, lidocaine, midazolam, acetaminophen, naproxen, morphine or oxycodone (or other opioids).

7. Concurrent painful physical condition that may confound post-operative pain assessments.

8. Persistent or recurrent nausea and/or vomiting due to other etiologies.

9. History of severe or refractory post-operative nausea or vomiting (PONV) deemed clinically significant.

10. History of alcohol abuse or prescription/illicit drug abuse within 2 years.

11. Current evidence of alcohol abuse within 6 months.

12. Received opioid therapy for longer than 4 days per week within 2 months or opioid use within 2 weeks.

13. Use of concurrent therapy that could interfere with the evaluation of efficacy or safety.

14. 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.

15. 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.

16. Positive results on the urine drug screen or alcohol breath test indicative of illicit drug or alcohol abuse.

17. History or positive test results for HIV; active Hepatitis B or C.

18. Contralateral foot bunionectomy in the last 3 months or have collateral procedures.

19. 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.

20. History of rheumatoid disease, Type 1 or Type 2 diabetes or peripheral circulatory disorders.

21. Documented sleep apnea or are on home continuous positive airway pressure.