Osteoarthritis (OA) of Knee

Primary: The primary objective is to evaluate the treatment efficacy of different test doses of TLC599 in patients with OA pain of knee. Secondary: The secondary objective is to evaluate the safety of different test doses of TLC599 in patients with OA of knee. Pharmacokinetics: The concentrations of dexamethasone and dexamethasone 21-phosphate in the synovial fluid at the end of study (EOS) or early termination (ET).

TLC599

Dexamethasone Sodium Phosphate (DSP)

Injection

13.2 mg/ml

Primary Endpoint:
The primary endpoint is to evaluate the change from baseline by Western Ontario and McMaster Universities
Osteoarthritis Index (WOMAC) pain subscale through Week 12.
Secondary Endpoints:
(1) Change from baseline to Weeks 1, 4, 8, 12, 16, 20, and 24 in the patient rated visual analogue scale
(VAS), and pain / function subscales of WOMAC.
(2) Change from baseline through Weeks 12, 16, 20 and 24 in VAS, and pain / function subscales of
WOMAC
(3) Area under the effect curve (AUEC) of the VAS from baseline to Week 12, 16, 20 and 24.
(4) Area under the effect curve of the WOMAC pain subscale from baseline to Week 12, 16, 20 and 24.
(5) Proportion of responders by a decrease of > 30% or > 50% in patient-rated VAS from baseline to
Weeks 1, 4, 8, 12, 16, 20, and 24.
(6) Proportion of responders by a decrease of > 30% or > 50% in WOMAC pain subscale from baseline to
Weeks 1, 4, 8, 12, 16, 20, and 24.
(7) Proportions of durable responders with persistent response since Week 1till Weeks 12, 16, 20, and 24,
respectively, by pain relief > 30% in VAS.
(8) Proportions of durable responders with persistent response since Week 1 till Weeks 12, 16, 20, and 24,
respectively, by pain relief > 30% in WOMAC pain subscales.
(9) Proportions of durable responders with persistent response since Week 1 till Weeks 12, 16, 20, and 24,
respectively, by outcome measured in rheumatology- Osteoarthritis Research Society International set
of responder criteria.
(10) Change from baseline to Weeks 1, 4, 8, 12, 16, 20, and 24 in EuroQol-5 Dimension questionnaire.
(11) Total consumption of acetaminophen at Weeks 1, 4, 8, 12, 16, 20, and 24.
(12) Safety and tolerability.
Pharmacokinetic Endpoints:
The concentrations of dexamethasone and dexamethasone 21-phosphate in synovial fluid of the study knee
joint at end of study or early termination.

Before the start of any screening procedure, all patients must have signed an informed consent form and be willing to follow the procedures as described in the protocol.
(1) Male or female patients, at least 50 years of age.
(2) Has any symptoms associated with OA of the knee for at least 6 months prior to the screening visit and confirmation of 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 2 to 3 severity based on the Kellgren Lawrence grades according to confirmatory X-ray result in inclusion criterion 2.
(4) Patients with patient related visual analogue scale (VAS) score of 5.0 to 9.0 of study knee prior to the study drug administration at baseline. The VAS score of study knee should be equal or higher than non-study knee.
Note: If the patient has been confirmed to have OA for one knee but the VAS score of this knee is lower than the other knee which was not diagnosed with OA, the patient should be excluded and screened failure.
(5) Willing and able to comply with study procedures and provide written informed consent.

(1) Patients who received systemic corticosteroids within the last 30 days prior to study drug administration.
(2) Patients who start new rehabilitation or exercise program during screening period.
(3) Patients using glucosamine or chondroitin or dietary supplement with unstable dose or frequency within 4 weeks before screening visit.
(4) Patients who use prohibited medications within 7 days prior to study drug administration or any pain control medication including acetaminophen within 48 hours prior to study drug administration.
(5) Patients who use prohibited medications other than acetaminophen and oral NSAIDs from screening visit to 7 days prior to study drug administration.
(6) Documented history and confirmed 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.
(7) Evidence of intra-articular bleeding of the study knee at baseline prior to study drug administration.
(8) History of infective arthritis in the study knee, or suspected /concurrent infection in the study knee at baseline prior to study drug administration.
(9) Documented gout attack in study knee within 6 months, evidence of tophi formulation, or active gouty arthritis attack prior to the baseline.
(10) Patient with any amputation in any lower limb.
(11) Any condition that could possibly confound the patient's assessment of study knee pain in judgement of the investigator (i.e., ipsilateral hip OA, radicular low back pain, and hip pain refer to the study knee).
(12) Unstable study knee joint as determined by the investigator based on physical examination (with or without buckling or giving way) due to an acute injury (defined as injury within 6 months, eg. anterior cruciate ligament injury or tear); OR any surgery or arthroscopy in the study knee within the 12 months prior to the screening visit.
(13) Clinical symptoms and signs of acute infection or infection-related inflammation in the other knee before study drug administration.
(14) Use of IA corticosteroid, hyaluronic acid, or other IA injection in the study knee within 3 months prior to the screening visit.
(15) Any skin lesion / breakdown at the anticipated injection site or any condition that impairs penetration of the study knee joint space.
(16) Patient with body mass index > 40 kg/m2 at the screening visit.
(17) Platelet count < 80,000/µL, or blood coagulation disorders, including patients with hemophilia, decompensated liver cirrhosis or uremia at the screening visit.
(18) History of acquired or congenital immunodeficiency diseases.
(19) Concurrent systemic active or uncontrolled infectious disease.
(20) A history of treated malignancy which is disease free for ≤ 5 years prior to the screening visit, except basal-cell carcinoma of skin or carcinoma-in-situ of the uterine cervix.
(21) Stroke or myocardial infarction within 3 months prior to the screening visit.
(22) Uncontrolled and unstable concurrent medical or psychiatric illness, including but not limited to, poorly controlled diabetes (defined as HbA1c > 9.0%), poorly controlled hypertension (mean arterial pressure [2/3 diastolic blood pressure + 1/3 systolic blood pressure] > 110mmHg), severe dementia, schizophrenia, or bipolar disorder, that will jeopardize the safety of the patient, interfere with the objectives of the protocol, or affect the patient compliance with study requirements, as determined by the investigator.
(23) Patients with a condition or in a situation which, in the assessment of the investigators, will interfere with the patient’s ability to comply or cooperate with the dosing and visit schedules and the protocol evaluations or may not be suitable for this study (e.g. illiterate).
(24) Use of any chemotherapeutic or systemic immunosuppressant agents for inflammatory diseases within 6 months prior to the screening visit.
(25) Current use of anticoagulants, including warfarin, heparin, low molecular weight heparin, or dabigatran.
(26) Use of any investigational agent within 4 weeks prior to study drug administration or within 5 half lives of the product, whichever is longer.
(27) Known allergy or hypersensitivity to the study drug or its components.
(28) Female patients who are pregnant, nursing, planning to become pregnant, or who are of childbearing potential (defined as all the female patients 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) and not using reliable means of contraception (e.g. established use of oral, transdermal, injected or implanted hormonal methods of contraception, placement of an intrauterine device or intrauterine system, barrier methods of contraception, male sterilization, total abstinence, etc.).
(29) Abnormalities of laboratory parameters as described below will qualify for exclusion at the screening visit:
 hemoglobin < 8 g/dL;
 total white blood cell count < 4000/ μL;
 serum bilirubin/ alanine aminotransferase/ aspartate aminotransferase > 2 times upper limit of normal (ULN) for the laboratory reference ranges;
 eGFR < 30 ml/min;
 prothrombin time / International Normalized Ratio > ULN for the laboratory reference range.
(30) Contraindication to undergoing magnetic resonance imaging (MRI) for both knees including but not limited to pacemaker, metal sutures, presence of shrapnel or iron filings.