A Phase 2, Open Label, PK Study of TLC599 in Subject With Osteoarthritis of the Knee

Study Overview
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Brief Summary
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This study is a multi-center, Phase 2, open-label, 1-period, parallel study with 9 cohorts of subjects with OA of the knee enrolled to receive single-dose of TLC599 or DSP via IA injection and 1 cohort of healthy subjects to receive single-dose of DSP via IV injection.

Detailed Description
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This Phase 2, open-label, 1 period, parallel study will enroll approximately 90 subjects to receive a single dose of TLC599 or DSP via IA injection, followed by a PK evaluation period up to 24 weeks and an additional follow-up period of 1 to 5 weeks. Additional subjects may be recruited as needed to achieve at least 10 subjects completing the 1-week blood collection period for each treatment. approximately 12 healthy subjects to recieve a single dose of DSP via IV injection, followed by a PK evaluation period up to 1 week and an additional follow-up period of 1 week. Additional subjects may be recruited as needed to achieve at least 12 subjects completing the 48-hour blood collection period for IV DSP.

Official Title
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A Phase 2, Open-label, Pharmacokinetic Study of a Single Intra-articular Administration of TLC599 in Subjects With Mild to Moderate Osteoarthritis of the Knee

Conditions
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OSTEOARTHRITIS OF THE KNEE

Intervention / Treatment
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* Drug: TLC599
* Drug: DSP


Participation Criteria
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Eligibility Criteria
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Cohort G1-G9 Study Criteria Inclusion Criteria: Age 45 or older, non or moderate smokers, BMI ≤ 40.0 kg/m2. Knee OA symptoms with confirmed mild to moderate OA. Study knee OA severity grade 1-3 (Kellgren-Lawrence). Agree to use contraception Exclusion Criteria: CS abnormalities (physical, lab, hepatitis B/C, HIV, ECG, vital sign or unstable illness). Positive urine drug screen, TB test; significant alcohol/drug abuse Allergic reactions to TLC599, its components, related drugs or cosyntropin. History of autoimmune disease, immunodeficiency diseases, treated malignancy, CS opportunistic infection, tuberculosis, infective arthritis or concurrent knee infection Intra-articular bleeding in study knee. Skin issues at injection site or hindrance to knee joint penetration. Blood coagulation disorders. Stroke or myocardial infarction Poorly controlled hypertension or vital sign abnormalities. Interfering conditions with dosing, visits, or compliance or refusal of synovial fluid collection. Medication: Strong/moderate CYP 3A/3A4 inhibitors/inducers, prescription meds, OTC/natural health products, meds affecting platelet function, depot injection/implant, IA corticosteroid, hyaluronic acid, or other injection in study knee, impact on endogenous steroid levels, systemic corticosteroids, live attenuated vaccine, chemotherapeutic/immunosuppressant use for inflammatory diseases. Plasma donation or significant blood loss. Pregnancy, breastfeeding, or planning to be pregnant/breastfeed Serious local/systemic infection or symptomatic viral/bacterial infection Severe OA (grade 4) in non-study knee (Kellgren-Lawrence). Recent surgery, scheduled knee replacement or lower limb amputation. Known/adrenal insufficiency risk. Recent participation in other study research Cohort G10 (Healthy Subjects) Study Criteria Inclusion Criteria: Age 18-45, non-smokers, BMI 18.5-25 kg/m2, body weight ≥ 50.0 kg (males) or ≥ 45.0 kg (females). Healthy with no CS illness/surgery within 4 weeks or CS medical history. Agree to use contraception No new tattoos/body piercings at the injection site until the study ends. Exclusion Criteria: CS abnormal physical, ECG or vital sign findings. Known/adrenal insufficiency risk. Abnormal lab results (HBV, HCV, HIV, TB). Positive pregnancy test or lactating; positive urine drug screen or cotinine test. Significant alcohol/drug abuse or positive alcohol test. Significant drug allergies or allergic reactions to DSP, dexamethasone, cosyntropin, natural ACTH, or other related drugs. History/presence of conditions including CS opportunistic infection, serious local/systemic infection, autoimmune, blood, heart, vascular, respiratory, lung, skin, liver, gallbladder, retinopathy, neuromuscular, cancer, kidney, diabetes, severe allergic reactions, or others that would preclude participation. Fever Active/latent tuberculosis or symptomatic viral/bacterial infection Medication: Depot injection/implant, vaccine, drug known to induce or inhibit CYP3A4 metabolism, prescription meds, OTC/natural health products. Consumption of specified fruits. Recent participation in other study research Plasma donation or significant blood loss. Reasons preventing study participation

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: TLC599 12 mg<br>12 mg DSP with 100 μmol phospholipid via IA injection; | Drug: TLC599<br>* TLC599 is manufactured with the proprietary lipid formulation in lyophilized form (BioSeizer) for the reconstitution with the aqueous DSP (active ingredient).<br>* Other names: TLC599 Injection;|
| Experimental: TLC599 6 mg<br>6 mg DSP with 50 μmol phospholipid via IA injection. | Drug: TLC599<br>* TLC599 is manufactured with the proprietary lipid formulation in lyophilized form (BioSeizer) for the reconstitution with the aqueous DSP (active ingredient).<br>* Other names: TLC599 Injection;|
| Active Comparator: DSP 4mg<br>Dexamethasone Sodium Phosphate (DSP): 4 mg/mL, 1 mL via IA injection. | Drug: DSP<br>* Dexamethasone sodium phosphate (DSP) is a glucocorticoid widely used in the treatment of joint pain such as gout, osteoarthritis and rheumatoid arthritis via IA injection.<br>* Other names: Dexamethasone Sodium Phosphate;|
| Active Comparator: DSP 10mg<br>Dexamethasone Sodium Phosphate (DSP): 4 mg/mL, 2.5 mL via IV injection. | Drug: DSP<br>* Dexamethasone sodium phosphate (DSP) is a glucocorticoid widely used in the treatment of joint pain such as gout, osteoarthritis and rheumatoid arthritis via IA injection.<br>* Other names: Dexamethasone Sodium Phosphate;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area under the Curve [AUC] | Area under the concentration-time curve | Baseline till 24 weeks post IP administration | 
| Cmax: maximum concentration | Maximum concentration | Baseline till 24 weeks post IP administration | 
| Tmax: time to peak concentration | Time to peak concentration | Baseline till 24 weeks post IP administration | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of AEs, including SAE and treatment-emergent AE | Number of AEs, including SAE and treatment-emergent AE | Screening till 25 weeks post IP administration | 
| Cortisol concentration | Cortisol concentration | baseline till 24 weeks post IP administration |