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.

The study will enroll approximately 64 evaluable subjects who meet all entry criteria across
4 cohorts. Dose escalation of a single postsurgical administration of TLC590 will be
performed using sequential dose levels, as compared with Naropin®. Dose escalation will be
determined by review of treatment-related adverse events (TEAEs) and all serious AEs (SAEs)
by a safety monitoring committee (SMC).

Inclusion Criteria:

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

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

3. Scheduled to undergo a primary, unilateral Lichtenstein inguinal hernia repair with
mesh, and be able to use the anesthesia regimen.

4. Have an 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. Have a body mass index ≤ 35 kg/m2.

Exclusion Criteria:

1. Clinically significant abnormal clinical laboratory test value that would pose a
health risk to the subject should they participate in the trial.

2. Evidence of a clinically significant 12-lead ECG that would pose a health risk to the
subject should they participate in the trial.

3. History or evidence of orthostatic hypotension, syncope or other syncopal attacks,
that would pose a health risk to the subject should they participate in the trial.

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. 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. Have persistent or recurrent nausea and/or vomiting due to other etiologies,
including, but not limited to gastric outlet obstruction, hypercalcemia, or active
peptic ulcer, per the judgement of the investigator.

8. History of severe or refractory post-operative nausea or vomiting (PONV) deemed
clinically significant by the investigator.

9. Concurrent painful condition that may require analgesic treatment during the study
period, or, in the opinion of the investigator, may confound post-operative pain
assessments.

10. Have been receiving or have received chronic opioid therapy defined as greater than 15
oral morphine milligram equivalent units per day for greater than 3 out of 7 days per
week over a one-month period within 3 months of administration of blinded study
medication.

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
prior to Screening.

13. Current report of alcohol abuse within 6 months prior to Screening.

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

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.