Phase I/II Dose-escalation Study to Evaluate Safety, PK and Efficacy of TLC590 for Postsurgical Pain Management

A Phase I/II, randomized, double-blind, comparator-controlled, dose-escalation study to assess the safety, PK, and efficacy of single postsurgical application of TLC590 compared with Naropin® via a single infiltrative local administration in adult subjects following inguinal hernia repair surgery.

Approximately 64 evaluable subjects across 4 cohorts. Dose escalation of a single postsurgical administration of TLC590 or Naropin® will be performed. Dose escalation will be determined by review of treatment-related adverse events and all serious adverse events (AEs) by a safety monitoring committee.

Inclusion criteria

• Able and willing to provide a written informed consent.
• Male or female between 18 and 65 years of age.
• Scheduled to undergo a primary, unilateral Lichtenstein inguinal hernia repair with mesh, and be able to use the anesthesia regimen.
• American society of anesthesiologists (ASA) Physical Status Classification of 1 or 2.
• Female subjects are eligible only if: not pregnant; not lactating; not planning to become pregnant during the study; commits to the use of an acceptable form of birth control.
• Male subjects must be sterile 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 blinded study medication.
• Body mass index ≤ 35 kg/m2.

Exclusion criteria

• Clinically significant abnormal clinical laboratory test value.
• Evidence of a clinically significant 12-lead ECG.
• 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.
• History of seizures or are currently taking anticonvulsants.
• History of hypersensitivity to ropivacaine, any other amide-type local anesthetic, propofol, hydromorphone or oxycodone (or other opioids).
• Persistent or recurrent nausea and/or vomiting due to other etiologies, including, but not limited to gastric outlet obstruction, hypercalcemia, or active peptic ulcer.
• History of severe or refractory post-operative nausea or vomiting deemed clinically significant.
• Concurrent painful condition that may require analgesic treatment during the study period.
• Have been receiving or have received chronic opioid therapy.
• Use of any of the following medications within 5 half-lives or as specified prior to the study surgical procedure:

Anti-platelet agents such as aspirin therapy within 7 days; clopidogrel within 5 days; Anticoagulants such as warfarin within 5 days; dabigatran etexilate mesylate within 2 days; factor Xa inhibitor within 24 hours; Class III antiarrhythmic drugs (e.g., amiodarone); Strong CYP1A2 inhibitors, such as cimetidine, ciprofloxacin, enoxacin, and fluvoxamine; CYP1A2 substrates, such as theophylline or imipramine; Strong CYP3A4 inhibitors such as voriconazole, erythromycin, ketoconazole, or ritonavir; CYP3A4 substrates, such as atazanavir, darunavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, or tipranavir; Corticosteroids, either systemically, inhaled, intranasally, orally, or by intra-articular injection within 14 days before the study surgical procedure (topical corticosteroid is allowed); Non-steroidal anti-inflammatory drugs (NSAIDs) within 14 days prior to the study surgical procedure; Any investigational product within 30 days prior to administration of blinded study medication.

• History of alcohol abuse or prescription and/or illicit drug abuse within 2 years.
• Current report of alcohol abuse within 6 months.
• Positive results on the urine drug screen or alcohol breath test indicative of illicit drug or alcohol abuse.
• History of human immunodeficiency virus (HIV), hepatitis C, or hepatitis B.
• Have had an inguinal hernia repair in the last 3 months before the study surgical procedure or presents with bilateral or recurrent inguinal hernia, other hernia presentations, or hernias with a large scrotal component that would be difficult to reduce surgically.