A Study to Evaluate the Safety and Efficacy of 2ccPA in Patients With Symptomatic Knee Osteoarthritis

Study Overview
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Brief Summary
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This phase I/II study aims to evaluate the safety of single doses of 2ccPA 4,800 μg and 7,200 μg (Phase I), as well as the safety and efficacy of multiple doses of 2ccPA (Phase II) in patients with osteoarthritis (OA) of the knee.

Detailed Description
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Osteoarthritis (OA) is a degenerative disease frequently associated with symptoms such as inflammation, stiffness, muscle weakness, joint swollen and joint pain. 2-carba-cyclic phosphatidic acid (2ccPA) is the derivative of natural occurring phospholipid mediator, cyclic phosphatidic acid (cPA). Previous studies suggested that 2ccPA inhibits inflammation and may relieve the pain caused by osteoarthritis. This phase I/II study aims to evaluate the safety of single doses of 2ccPA 4,800 μg and7,200 μg (Phase I), as well as the safety and efficacy of multiple doses of 2ccPA (Phase II) in patients with osteoarthritis (OA) of the knee.

Official Title
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A Phase I-II, Dose-escalation, Double-blinded, Placebo-controlled, and Dose-finding Study to Evaluate the Safety and Efficacy of 2ccPA in Patients With Osteoarthritis of the Knee

Conditions
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Osteoarthritis, Knee

Intervention / Treatment
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* Drug: 2ccPA
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Signed written informed consent from any patient capable of giving consent. Male or female patients, 40 to 80 years of age. Documented clinical diagnosis of symptomatic OA affecting at least one knee of a minimum of 6 months prior to screening. The study knee has OA of Grade 2 to 3 severity based on the Kellgren Lawrence grading scale. A score > 6 and < 16 out of 20 on the WOMAC pain subscale for the study knee. Pain in the study knee for most of the 30 days (i.e., more than half of the days) prior to randomization. Women of childbearing potential must agree to practice a medically acceptable contraceptive regimen from screening visit until at least 1 month after the study treatment and must have a negative pregnancy test no earlier than 72 hours prior to study treatment. Male subjects must agree to practice a medically acceptable contraceptive regimen (i.e., sterilization surgery, barrier method, abstention) from screening visit until at least 1 month after the study treatment. Exclusion Criteria: Patients with known or suspected hypersensitivity to 2ccPA or any of its excipients. Use of intra-articular corticosteroids, hyaluronic acid, or other IA injection in the study knee within 3 months prior to study entry (randomization). Use of chondroitin and/or glucosamine within 4 weeks prior to study entry (randomization). Administered or requiring systemic or topical treatment of the target knee joint including immunosuppressive agents, anti-inflammatory drugs, steroids, analgesics, or opioids for knee OA within 1 week prior to randomization except for acetaminophen (oral daily dose ≤ 3000 mg or topical use at any dose). For long acting steroids (i.e., dexamethasone, betamethasone), subjects who received systemic treatment within 2 weeks before randomization will be excluded. History of post-traumatic knee arthritis, or evidence of intra-articular bleeding of the study knee. Subjects with clinical signs and symptoms of active knee infection (inflammation) or being treated for knee infection at screening. Arthroscopic or open surgery on the study knee within 6 months prior to study entry (randomization). Prior knee replacement on the study knee or planned knee replacement during the study period. Subjects with meniscus tears that required repairment surgery or known anterior cruciate ligament rupture. Subjects with known severe synovitis, synovium necrosis in the target knee joint. Subjects with known malignancy. Use of any chemotherapeutic or systemic immunosuppressant agents for inflammatory diseases within 6 months prior to study entry (randomization). Current use of anticoagulants, including warfarin, heparin, low molecular weight heparin, dabigatran, or factor Xa inhibitors (rivaroxaban, apixaban, edoxaban, and betrixaban). Subject requiring routine use of low-dose aspirin for preventing thrombosis (≤ 100 mg/day) will not be excluded. Abnormalities of laboratory parameters as described below will qualify for exclusion: hemoglobin < 8 g/dL total white blood cell count < 4000/μL serum bilirubin/ alanine aminotransferase (ALT)/ aspartate aminotransferase AST > 2 times upper limit of normal (ULN) serum creatinine > 2 times ULN Pregnancy or lactation. History of drug or alcohol dependence in the past 3 years. Having known infection with HIV-1, active hepatitis B, or active hepatitis C. Patients who are inactive carriers of HBV or HCV can be enrolled if the subjects have stable baseline condition during the screening period. Use of any investigational drug or participation in any drug study within 4 weeks prior to study entry (randomization). Subjects unwilling or unable to comply with study procedures. Any clinical condition, including the presence of laboratory abnormalities, which places the subject at unacceptable risk to participate in the study or confounds the ability to interpret data from the study as judged by the investigator.

Ages Eligible for Study
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Minimum Age: 40 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 2ccPA<br>IP name: 2-carba-cyclic phosphatidic acid (2ccPA) | Drug: 2ccPA<br>* 2-carba-cyclic phosphatidic acid (2ccPA) is a first-in-class phospholipase autotaxin (ATX) inhibitor that may act as a disease-modifying drug and may relieve OA associated symptoms. Phase I: 2 dose cohorts (4800μg, 7200μg) single dose at Day 1 Phase II: 3 dose cohorts (2400μg, 4800μg, 7200μg) multiple dose at Day 1, 15, 29<br>* Other names: 2-carba-cyclic phosphatidic acid;|
| Placebo Comparator: placebo<br>Placebo | Drug: Placebo<br>* Phase I: 2 dose cohorts (4800μg, 7200μg) single dose at Day 1 Phase II: 3 dose cohorts (2400μg, 4800μg, 7200μg) multiple dose at Day 1, 15, 29<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To define maximum tolerated dose (MTD) following the intra-articular (IA) administration of a single ascending dose (SAD) 2ccPA in patients with osteoarthritis of the knee. |  | 85 Days | 
| To evaluate the safety of 2ccPA including incidence of adverse events (AEs) and serious adverse events (SAEs). |  | 85 Days | 
| To evaluate the efficacy of multiple doses of 2ccPA vs placebo in terms of changes in the Western Ontario and McMaster Universities Arthritis Index (WOMAC) on Day 85 | The Western Ontario and McMaster Universities Osteoarthritis (WOMAC) is a widely-used, proprietary outcome measurement tool used to evaluate the condition of subjects with Osteoarthritis (OA) of the knee and hip, including pain (5 questions), stiffness (2 questions) and physical functioning (17 questions) of the joints. Each question is scored on a scale of 0-4, which corresponds to: None (0), Mild (1), Moderate (2), Severe (3), and Extreme (4). | 85 Days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To evaluate the efficacy of 2ccPA vs placebo in terms of changes in Western Ontario and McMaster Universities Osteoarthritis (WOMAC) on Day 15, 29, 57 and 168 | WOMAC questionnaire consists of 24 items divided into 3 subscales: Pain (5 items), Stiffness (2 items), Physical Function (17 items). The scores for each subscale are summed up, with a possible score range of 0-20 for Pain, 0-8 for Stiffness, and 0-68 for Physical Function. Higher scores on the WOMAC indicate worse pain, stiffness, and functional limitations. | 85 Days | 
| To evaluate the efficacy of 2ccPA vs placebo in terms of proportion of subjects with a 20% (WOMAC20), 50% (WOMAC50), and 70% (WOMAC70) improvement in the Western Ontario and McMaster Universities Osteoarthritis (WOMAC) on Days 15, 29, 57, 85 and 168 |  | 168 Days | 
| To evaluate the efficacy of 2ccPA vs placebo in terms of pain assessed by Numeric Rating Scale (NRS) on Days 15, 29, 57, 85 and 168. | NRS is an 11-point numeric scale ranges from '0' indicating no pain to '10' indicating extreme pain. | 168 Days | 
| To evaluate the efficacy of 2ccPA vs placebo in terms of changes in Joint Space Narrowing (JSN) measured by x-ray on Day 168 |  | 168 Days | 
| Maximum plasma concentration (Cmax) of 2ccPA | Pharmacokinetic profile of 2ccPA | 168 Days | 
| Time to maximum plasma concentration (Tmax) of 2ccPA | Pharmacokinetic profile of 2ccPA | 168 Days | 
| Area under plasma concentration-time curve (AUC0-infinity and AUC0-t) of 2ccPA | Pharmacokinetic profile of 2ccPA | 168 Days | 
| Apparent total body clearance (CL/F) of 2ccPA | Pharmacokinetic profile of 2ccPA | 168 Days | 
| Apparent volume of distribution (Vz/F) of 2ccPA | Pharmacokinetic profile of 2ccPA | 168 Days | 
| Elimination half-life (t1/2) of 2ccPA | Pharmacokinetic profile of 2ccPA | 168 Days |