OSTEOARTHRITIS OF THE KNEE

The primary objective of this study is to characterize the pharmacokinetic (PK) profiles of TLC599 and dexamethasone sodium phosphate (DSP) in the knee joint synovial fluid (SF) and plasma of subjects with mild to moderate knee OA The secondary objectives are:  To evaluate the safety and tolerability of TLC599 and DSP in subjects with knee OA;  To evaluate the pharmacodynamic (PD) effect on the hypothalamicpituitary-adrenal (HPA) axis function by assessment of the serum cortisol levels.

TLC599

Dexamethasone Sodium Phosphate

Injection

12 mg/mL

Blood samples will be collected prior to drug injection (pre-dose) and 0.5, 1, 2, 4, 6, 8, 12, 24,
48, 72, 96, 120 and 168 hours post-dose (8 mL for each sampling time, a total of 14 blood
samples) for all cohorts.
For Cohort G2(b), additional blood samples will be collected at every scheduled return visit
through EOPK (i.e., 2, 4, 8, 12 and 16 weeks post-injection). A total of 19 blood samples will be
collected.

1. Male or female subjects, non-smokers or moderate smokers (no more than 25 cigarettes or equivalent daily), 45 years or older, with BMI ≤ 40.0 kg/m2.
2. Has any symptoms associated with OA of the knee for at least 6 months prior to the Screening Visit including regular pain (defined as more than 15 days of pain over one month period) in one or both knees due to OA over the month prior to the Screening Visit, and confirmation of mild to moderate OA based on the clinical and radiological criteria of American College of Rheumatology Criteria for Classification of Idiopathic OA of the knee (standing fixed-flexion posteroanterior X-ray of the knee of approximately 20 degrees) within 6 months prior to the Screening Visit or during the screening period.
3. The study knee has OA with grade 1-3 in severity based on the Kellgren-Lawrence grades according to confirmatory X-ray result in Inclusion Criterion 2.
4. Females of childbearing potential (defined as all the female subjects after puberty, unless they have been post-menopausal for at least 2 years, are sterile based on a documented ovarian failure, or are surgically sterile, such as after hysterectomy, bilateral oophorectomy, or bilateral tubal ligation) must use a highly effective method of avoiding pregnancy until at least 25 weeks after the study drug administration. Acceptable and effective methods of birth control for this study include:
• Absolute sexual abstinence (no sexual intercourse or genital contact with a male partner)
• Monogamous partner who is vasectomized
• Use of double-barrier contraception in the event of sexual activity
• Use of an approved insertable, injectable, transdermal, or combination oral contraceptive for greater than 2 months prior to Screening.
5. Male subjects who are not vasectomized for at least 6 months, and who are sexually active with a non-sterile female partner (sterile female partners include post-menopausal females for at least 2 years and surgically sterile females) must be willing to use a highly effective method of avoiding pregnancy until at least 25 weeks after the study drug administration. Acceptable and effective methods of birth control for this study include:
• Absolute sexual abstinence (no sexual intercourse or genital contact with a female partner)
• Use of double-barrier contraception with partner in the event of sexual activity
6. Willing and able to comply with study procedures and provide written informed consent.

1. Abnormalities of the following laboratory parameters at Screening visit or Visit 1 (Day -1):
a. HbA1c >9.0%
b. platelet count <80,000/µL
c. hemoglobin <8.0 g/dL
d. serum bilirubin/alanine aminotransferase/ aspartate aminotransferase >2 times upper limit of normal (ULN) for the laboratory reference ranges
e. serum creatinine level >1.5X ULN
f. prothrombin time/International Normalized Ratio and activated partial thromboplastin time (aPTT) > ULN for the laboratory reference range
g. positive test for hepatitis B, hepatitis C, or HIV.
2. Positive urine drug screen (amphetamines, methamphetamines, barbiturates, benzodiazepines, tetrahydrocannabinol, cocaine, opiates, PCP, MDMA, methadone) at Screening or Visit 1 (Day -1).
3. History of allergic reactions to TLC599, its components or other related drugs.
4. Clinically significant and unstable illness, including:
a) neurological, endocrinal, cardiovascular, pulmonary, hematological, immunologic, psychiatric, gastrointestinal, renal, hepatic, and metabolic disease with the exception of findings that in the opinion of the Investigator are consistent with the normal condition as of OA subjects and would not affect the study drug absorption and metabolism;
b) systemic fungal infection during screening;
5. History of clinically significant autoimmune disease including but not limited to secondary OA, Reiter’s syndrome, systemic lupus erythematosus, Sjögren’s syndrome, systemic sclerosis, inflammatory myositis, mixed connective tissue disease, palindromic rheumatism, reactive arthritis, rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, Bechet’s disease, arthritis associated with inflammatory bowel disease, sarcoidosis, vasculitis, cryoglobulinemia, or amyloidosis.
6. Evidence of intra articular bleeding of the study knee at baseline prior to study drug administration.
7. History of infective arthritis in the study knee, or suspected / concurrent infection in the study knee at baseline prior to study drug administration; clinical symptoms and signs of acute infection or infection-related inflammation in the non-study knee before study drug administration.
8. Any skin lesion/breakdown at the anticipated injection site or any condition that would impair penetration of the study knee joint space.
9. Blood coagulation disorders, including subjects with hemophilia, decompensated liver cirrhosis or uremia at the Screening Visit.
10. Total white blood cell count <4000/ µL or >13000/ µL.
11. History of acquired or congenital immunodeficiency diseases.
12. A history of treated malignancy which is disease free for ≤ 5 years prior to the Screening Visit, except for basal cell carcinoma and squamous cell carcinoma of skin or carcinoma in situ of the uterine cervix.
13. Stroke or myocardial infarction within 3 months prior to the Screening Visit.
14. Subjects with a condition or in a situation which, in the assessment of the investigators, will interfere with the subject’s ability to comply or cooperate with the dosing and visit schedules and the protocol evaluations or may not be suitable for this study.
15. Clinically significant ECG abnormalities at Screening visit
16. Vital sign abnormalities (systolic blood pressure lower than 90 or over 150 mmHg, diastolic blood pressure lower than 50 or over 95 mmHg, or heart rate less than 45 or over 100 bpm) at Screening visit or Day 1.
17. History of significant alcohol abuse within one year prior to the Screening Visit or regular use of alcohol within six months prior to the Screening Visit (more than 14 units of alcohol per week [1 unit = 150 mL of wine, 360 mL of beer, or 45 mL of 40% alcohol]). A positive alcohol test on Day -1 will exclude the subject from the study.
18. History of significant drug abuse within one year prior to the Screening Visit or use of soft drugs (such as marijuana) within 3 months prior to the Screening Visit or hard drugs (such as cocaine, PCP, crack, opioid derivatives including heroin, and amphetamine derivatives) within 1 year prior to the Screening Visit.
19. Participation in a clinical research study involving the administration of an investigational or marketed drug or device within 30 days prior to dosing, administration of a biological product in the context of a clinical research study within 90 days prior to dosing.
20. Any use of the following medications:
a) any drugs known to induce or inhibit hepatic CYP 3A4 metabolism (examples of inducers: St. John’s Wort, barbiturates, carbamazepine, phenytoin, glucocorticoids, dexamethasone, etc., examples of inhibitors: HIV antivirals, clarithromycin, ciprofloxacin, gestodene, etc.) within 30 days prior to dosing;
b) prescription medication within 14 days prior to dosing except for: i) hormonal contraceptives; ii) topical products without significant systemic absorption [except on the knees]; iii) any stable treatment taken from at least 1 month prior to the Screening Visit, with no change in dosage for at least 14 days before dosing and with no expected change throughout the study, and that will not interfere in the PK or the assay of the study drug;
c) over-the-counter products and natural health products (including herbal remedies, homeopathic and traditional medicines, probiotics, food supplements such as vitamins, minerals, amino acids, essential fatty acids, and protein supplements used in sports) within 7 days prior to dosing, (with the exception of the use of acetaminophen [up to 3 g daily], ibuprofen [up to 2.4 g/day] or other NSAIDs with no known PK and assay interaction), unless such products are deemed medically necessary for standard of care for OA subjects and there is no known PK or assay interaction.
d) any prescription medication known to affect platelet function within 14 days prior to dosing (stable low-dose aspirin use allowed [up to 100 mg/day]);
e) a depot injection or an implant of any drug (other than hormonal contraceptives) within 3 months prior to dosing;
f) use of IA corticosteroid, hyaluronic acid, or other IA injection in the study knee within 6 months prior to dosing;
g) any IA injection drug that could impact endogenous steroid levels within 6 months prior to dosing;
h) systemic corticosteroids within 30 days prior to dosing;
i) Use of any chemotherapeutic or systemic immunosuppressant agents for inflammatory diseases within 6 months prior to dosing.
21. Donation of plasma within 7 days prior to dosing. Donation or loss of blood (excluding volume drawn at screening) of 50 mL to 499 mL of blood within 30 days, or more than 499 mL within 56 days prior to dosing.
22. Female subjects who are pregnant, breast-feeding, or plan to become pregnant/breast-feeding.
23. History of latent or active tuberculosis (TB) or exposure to endemic areas with pulmonary tuberculosis within 8 weeks prior to the Screening Visit.
24. Positive TB test indicating possible tuberculosis infection at the Screening.
25. Immunization with a live attenuated vaccine 1 month prior to dosing or planned during the course of the study.
26. History of clinically significant opportunistic infection (e.g., invasive candidiasis or pneumocystis pneumonia).
27. Serious local infection (e.g., cellulitis, abscess) or systemic infection (e.g., septicemia) within the 3 months prior to the Screening Visit.
28. Presence of a symptomatic viral or bacterial infection within 2 weeks prior to dosing.
29. Subjects with current diagnosis of severe OA with grade 4 classification in the non-study knee based on the Kellgren-Lawrence grades at Screening.
30. Subject who had a surgery within 4 weeks prior to dosing or expected to have knee replacement surgury scheduled during his/her study duration.
31. Subjects with known history of adrenal insufficiency or with potential risk of adrenal insufficiency at Screening visit as shown by either:
a) Morning serum cortisol levels <5 mcg/dL;
b) ACTH stimulation test at Screening with post-stimulation cortisol level ≤ 18 mcg/dL (or ≤ 497 nmol/L)
Subjects found to have a screening cortisol level <5 mcg/dL or who are suspected of having adrenal insufficiency should be referred to their primary care physician for further evaluation.
32. History of allergic reactions to cosyntropin, natural ACTH, or other related drugs.
33. Patient with any lower limb amputation.
34. Inadequate synovial fluid collection of the study knee joint (less than 0.2 ml) prior to dosing on Day 1.