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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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

Conditions
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Hallux Valgus

Intervention / Treatment
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* Drug: TLC590
* Drug: Naropin®
* Drug: Normal Saline
* Drug: Bupivacaine


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Supportive Care
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: TLC590 dose 1 (152 mg)<br>TLC590 (Ropivacaine Liposome Injectable Suspension) is a sustained-release liposome formulation of ropivacaine, white aqueous suspension with ropivacaine concentration at approximately 19 mg/mL. | Drug: TLC590<br>* TLC590, a sustained-release formulation of the local anesthetics with lipid-based excipients<br>* Other names: TLC590 (Ropivacaine Liposome Injectable Suspension);|
| Experimental: TLC590 dose 2 (190 mg)<br>TLC590 (Ropivacaine Liposome Injectable Suspension) is a sustained-release liposome formulation of ropivacaine, white aqueous suspension with ropivacaine concentration at approximately 19 mg/mL. | Drug: TLC590<br>* TLC590, a sustained-release formulation of the local anesthetics with lipid-based excipients<br>* Other names: TLC590 (Ropivacaine Liposome Injectable Suspension);|
| Experimental: TLC590 dose 3 (228 mg)<br>TLC590 (Ropivacaine Liposome Injectable Suspension) is a sustained-release liposome formulation of ropivacaine, white aqueous suspension with ropivacaine concentration at approximately 19 mg/mL. | Drug: TLC590<br>* TLC590, a sustained-release formulation of the local anesthetics with lipid-based excipients<br>* Other names: TLC590 (Ropivacaine Liposome Injectable Suspension);|
| Active Comparator: Naropin®<br>Naronpin injection contains ropivacaine HCl 50 mg (0.5%, 10 mL) | Drug: Naropin®<br>* Local infiltration of Naropin to produce anesthesia for surgery and analgesia in postoperative pain management. 50 mg (0.5%, 10 mL)<br>* Other names: Naropin, 0.5% Injectable Solution;|
| Placebo Comparator: Placebo<br>Normal Saline (0.9% sodium chloride, 10 mL) | Drug: Normal Saline<br>* Normal Saline (0.9% sodium chloride, 10ml)<br>* Other names: Saline;|
| Active Comparator: Bupivacaine<br>Bupivacaine HCl 50 mg (0.5%, 10 mL) | Drug: Bupivacaine<br>* Bupivacaine 50 mg (0.5%, 10 mL)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| AUC of numerical pain rating scale | AUC of numerical pain rating scale (NPRS-R) following bunionectomy surgery | 0-24 hours, 0-72 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PK Cmax | Maximum blood concentration (Cmax) | 0-168 hours | 
| PK Tmax | Time to reach maximum blood concentration (Tmax) | 0-168 hours | 
| PK t½ | Terminal elimination half-life (t½) | 0-168 hours | 
| PK AUC | Area under the blood concentration-time curve (AUC) | 0-24, 0-48 , 0-72, 0-96 hours | 
| Number of treatment emergent adverse event (TEAE) | Number of treatment emergent adverse event (TEAE) occurred in the study | Screening through Day 43 | 
| Electrocardiogram (RR interval, QRS duration, QT duration, PR duration, QTcF interval) | The 12-lead electrocardiogram (ECG) result will be assessed including RR interval, QRS duration, QT duration, PR duration, and QTcF interval | Screening through Day 43 | 
| Wound assessment by Numerical Pain Rating Scale (NPRS) | The surgical site will be examined by the investigator using a 5-point numerical pain rating scale as follows: Normal healing Bruising, erythema, edema Clear or hemoserous drainage Evidence of cellulitis such as heat, spreading erythema, purulent discharge Tissue breakdown, wound dehiscence, hematoma requiring aspiration | Day 1 through Day 43 | 
| AUC of NPRS-R (0-10) | AUC of NPRS-R (0-10) | 0-36, 0-48, 0-72, 0-96, 0-120,24-48, 48-72, 72-96, 96-120, and 120-168 hours | 
| Proportion of pain-free (NPRS-R of 0 or 1) subjects | Proportion of pain-free (NPRS-R of 0 or 1) subjects | at 12, 24, 36, 48, 72, 96, 120, and 168 hours | 
| Proportion of subjects who used no rescue opioid analgesic | Proportion of subjects who used no rescue opioid analgesic | through 12, 24, 36, 48, 72, 96, 120, and 168 hours | 
| Time to the first postoperative use of rescue opioid analgesics | Time to the first postoperative use of rescue opioid analgesics | Day 1 to Day 43 | 
| Total postoperative consumption of rescue opioid analgesics used | Total postoperative consumption of rescue opioid analgesics used | through 24, 36, 48, 60, 72, 96, 120, and 168 hours |