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®

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:

1. Able and willing to provide a written informed consent.
2. Male or female between 18 and 65 years of age.
3. Scheduled to undergo a primary, unilateral Lichtenstein inguinal hernia repair with mesh, and be able to use the anesthesia regimen.
4. American society of anesthesiologists (ASA) Physical Status Classification of 1 or 2.
5. 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.
6. 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.
7. Body mass index ≤ 35 kg/m2.

Exclusion Criteria:

1. Clinically significant abnormal clinical laboratory test value.

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

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.

5. History of seizures or are currently taking anticonvulsants.

6. History of hypersensitivity to ropivacaine, any other amide-type local anesthetic, propofol, hydromorphone or oxycodone (or other opioids).

7. Persistent or recurrent nausea and/or vomiting due to other etiologies, including, but not limited to gastric outlet obstruction, hypercalcemia, or active peptic ulcer.

8. History of severe or refractory post-operative nausea or vomiting deemed clinically significant.

9. Concurrent painful condition that may require analgesic treatment during the study period.

10. Have been receiving or have received chronic opioid therapy.

11. 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.

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

13. Current report of alcohol abuse within 6 months.

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

15. History of human immunodeficiency virus (HIV), hepatitis C, or hepatitis B.

16. 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.

One subject who was randomized (period 2, Naropin group) did not receive any treatment (withdraw by subject), and was replaced. This subject was not included in any analysis population.

58 days

Total 64 subjects were enrolled in the study, 12 subjects in each TLC590 group and 16 subjects in Naropin group.

To maintain objectiveness, the study drug will be managed and administered by an independent unblinded team. Subjects, investigators, and all other site staff who directly interact with subjects, evaluate safety and efficacy, and collect subject data, will remain blinded and must not communicate or discuss any study information with the unblinded team.