2ccPA Study in Patients With Symptomatic Knee Osteoarthritis

Study Overview
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Brief Summary
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This clinical trial is designed to determine safety and tolerability as well as the MTD of a single-dose 2ccPA and PK data in symptomatic knee OA.

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 clinical study aims to assess the safety, tolerability, and pharmacokinetics as well as the maximal tolerated dose (MTD) of a single-dose 2ccPA in symptomatic knee OA. Safety and efficacy data for the design and conduction of subsequent studies will also be collected.

Official Title
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Phase I Safety, Tolerability, and Pharmacokinetics Study of 2ccPA in Patients With Symptomatic Knee Osteoarthritis

Conditions
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Osteoarthritis (OA) of the 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: Male or female subjects who are aged between 40 and 75 years old (inclusive) Subjects diagnosed with symptomatic knee OA for at least 6 months prior to study entry (randomization) Subjects whose radiographic evidence of knee OA are classified as grade II or III (according to Kellgren and Lawrence grading system) Subjects with OA knee pain on the majority of days in the past 30 days prior to study entry (randomization). A score of over 8 and below 16 out of 20 for the WOMAC pain subscale in the index knee in screening Male subjects must agree to practice medically acceptable contraceptive regimen (i.e., sterilization surgery, barrier method, abstention) from screening visit until at least 1 month after the study treatment. Subjects who are willing to sign the informed consent form (ICF) Subjects with normal liver and renal function: ALT and AST do not exceed 1.5 ULN (upper limit of normal) Serum Cr levels do not exceed 1.0 ULN Exclusion Criteria: Subjects with known hypersensitivity to study medication Female subjects who are pregnant or lactating. Women of childbearing potential must agree to practice medically acceptable contraceptive regimen from screening visit until at least 1 month after the study treatment and must have a negative urine pregnancy test no earlier than 72 hours prior to study treatment. Intra-articular use of corticosteroid, hyaluronic acid or other intra-articular injection in study knee within 3 months prior to study entry (randomization) Use of chondroitin and/ or glucosamine within 4 weeks prior to study entry (randomization) Subjects with known malignancy History of Reiter's syndrome, rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, lymphoma, arthritis associated with inflammatory bowel disease, sarcoidosis and amyloidosis Prior arthroscopic or open surgery on the study knee within 6 months prior to study entry (randomization) Clinical signs and symptoms of active knee infection or being treated for knee infection at screening Patients with active inflammation: patients with CRP higher than upper limit of normal range at screening visit will be excluded from the study. Subjects with concurrent medical or arthritic condition that could interfere with evaluation of the index knee joint, including fibromyalgia, based on investigator's clinical judgment More significant pain from the back or the hip than the knee Skin breakdown or lesion on the study knee that is not suitable for injection, based on investigator's discretion Prior knee replacement on the study knee or planned knee replacement during the study period Subjects with (1) meniscus tears which requires repairment surgery OR (2) anterior cruciate ligament rupture based on screening MRI results Patients with known severe synovitis, synovium necrosis in the target knee joint judged by investigator at screening Patients with PT/ APTT higher than the upper limit of normal range at screening History of drug or alcohol dependence in the past 3 years Having known infection with HIV-1, HBV, HCV Use of any investigational drug or participation in any drug study within 4 weeks prior to study entry (randomization) Subjects who are 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: 75 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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 2ccPA<br>Only day 1 Intra-articular injection can be given under direct ultrasound guidance; the only one strength for 2ccPA injection vial is 2,400 μg (1.2 mL per vial). IP name: 2-carba-cyclic phosphatidic acid (2ccPA) | Drug: 2ccPA<br>* Four dose cohorts (50 μg, 200 μg, 800 μg, and 2,400 μg) are planned in this study sequentially. study group: one dose intra-articular on day1<br>* Other names: 2-carba-cyclic phosphatidic acid;|
| Placebo Comparator: Placebo<br>Only day 1 Intra-articular injection can be given under direct ultrasound guidance; placebo | Drug: placebo<br>* A total of 8 subjects will be recruited and randomized in each dose cohort with a 3:1 ratio (6 subjects in the 2ccPA treatment arm and 2 subjects in the placebo arm). control group: one dose intra-articular on day 1<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adverse events will be coded with MedDRA and analyzed by system organ class (SOC) and preferred term. The number of subjects who experience DLT will be calculated at each dose level and the result of MTD will be provided. | To determine safety and tolerability as well as the maximal tolerated dose (MTD) of a single-dose 2ccPA in symptomatic knee OA | 85 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 20% improvement in the The Western Ontario and McMaster Universities Arthritis Index (WOMAC) pain and physical function subscales | Proportion of subjects with a 20% improvement in the WOMAC pain and physical function subscales on Day 2, Day 3, Day 8, Day 15, Day 29 post treatment, compared with placebo group and baseline | 85 days | 
| 50% improvement in the The Western Ontario and McMaster Universities Arthritis Index (WOMAC) pain and physical function subscales | Proportion of subjects with a 50% improvement in the WOMAC pain and physical function subscales on Day 2, Day 3, Day 8, Day 15, Day 29 post treatment, compared with placebo group and baseline | 85 days | 
| 70% improvement in the The Western Ontario and McMaster Universities Arthritis Index (WOMAC) pain and physical function subscales | Proportion of subjects with a 70% improvement in the WOMAC pain and physical function subscales on Day 2, Day 3, Day 8, Day 15, Day 29 post treatment, compared with placebo group and baseline | 85 days | 
| Maximum plasma concentration (Cmax) of 2ccPA | Pharmacokinetic profile of 2ccPA | at baseline (pre-dose), 15 ± 5 minutes, 30 ± 5 minutes, 1 hour ± 10 minutes, 2 hours ± 10 minutes, 4 hours ± 10 minutes, 6 hours ± 10 minutes, 8 hours ± 10 minutes, 12 ± 2 hours, 24 ± 2 hours (Day 2) and 48 ± 2 hours (Day 3) after 2ccPA treatment. | 
| Time to maximum plasma concentration (Tmax) of 2ccPA | Pharmacokinetic profile of 2ccPA | at baseline (pre-dose), 15 ± 5 minutes, 30 ± 5 minutes, 1 hour ± 10 minutes, 2 hours ± 10 minutes, 4 hours ± 10 minutes, 6 hours ± 10 minutes, 8 hours ± 10 minutes, 12 ± 2 hours, 24 ± 2 hours (Day 2) and 48 ± 2 hours (Day 3) after 2ccPA treatment. | 
| Area under plasma concentration-time curve (AUC) of 2ccPA | Pharmacokinetic profile of 2ccPA | at baseline (pre-dose), 15 ± 5 minutes, 30 ± 5 minutes, 1 hour ± 10 minutes, 2 hours ± 10 minutes, 4 hours ± 10 minutes, 6 hours ± 10 minutes, 8 hours ± 10 minutes, 12 ± 2 hours, 24 ± 2 hours (Day 2) and 48 ± 2 hours (Day 3) after 2ccPA treatment. | 
| Apparent total body clearance (CL/F) of 2ccPA | Pharmacokinetic profile of 2ccPA | at baseline (pre-dose), 15 ± 5 minutes, 30 ± 5 minutes, 1 hour ± 10 minutes, 2 hours ± 10 minutes, 4 hours ± 10 minutes, 6 hours ± 10 minutes, 8 hours ± 10 minutes, 12 ± 2 hours, 24 ± 2 hours (Day 2) and 48 ± 2 hours (Day 3) after 2ccPA treatment. | 
| Apparent volume of distribution (Vz/F) of 2ccPA | Pharmacokinetic profile of 2ccPA | at baseline (pre-dose), 15 ± 5 minutes, 30 ± 5 minutes, 1 hour ± 10 minutes, 2 hours ± 10 minutes, 4 hours ± 10 minutes, 6 hours ± 10 minutes, 8 hours ± 10 minutes, 12 ± 2 hours, 24 ± 2 hours (Day 2) and 48 ± 2 hours (Day 3) after 2ccPA treatment. | 
| Elimination half-life (t1/2) of 2ccPA | Pharmacokinetic profile of 2ccPA | at baseline (pre-dose), 15 ± 5 minutes, 30 ± 5 minutes, 1 hour ± 10 minutes, 2 hours ± 10 minutes, 4 hours ± 10 minutes, 6 hours ± 10 minutes, 8 hours ± 10 minutes, 12 ± 2 hours, 24 ± 2 hours (Day 2) and 48 ± 2 hours (Day 3) after 2ccPA treatment. | 
| Synovial fluid 2ccPA level | Changes from baseline (pre-dose) in synovial fluid 2ccPA and synovial fluid matrix metalloproteinase (MMP)-1, -3 and -13 levels at 24 hours after 2ccPA treatment | before intra-articular injection treatment and 24 hours ± 2 hours after intra-articular injection. | 
| Synovial fluid matrix metalloproteinase (MMP)-1 level | Changes from baseline (pre-dose) in synovial fluid 2ccPA and synovial fluid matrix metalloproteinase (MMP)-1, -3 and -13 levels at 24 hours after 2ccPA treatment | before intra-articular injection treatment and 24 hours ± 2 hours after intra-articular injection. | 
| Synovial fluid matrix metalloproteinase (MMP)-3 level | Changes from baseline (pre-dose) in synovial fluid 2ccPA and synovial fluid matrix metalloproteinase (MMP)-1, -3 and -13 levels at 24 hours after 2ccPA treatment | before intra-articular injection treatment and 24 hours ± 2 hours after intra-articular injection. | 
| Synovial fluid matrix metalloproteinase (MMP)-13 level | Changes from baseline (pre-dose) in synovial fluid 2ccPA and synovial fluid matrix metalloproteinase (MMP)-1, -3 and -13 levels at 24 hours after 2ccPA treatment | before intra-articular injection treatment and 24 hours ± 2 hours after intra-articular injection. | 
| Serum prostaglandin E2 (PGE2) level | Changes from baseline (pre-dose) in serum prostaglandin E2 (PGE2) levels at 30 minutes, 1 hour, 2 hours, 4 hours, 12 hours and 24 hours after 2ccPA treatment | at 1 hour, 12 hours, 24 hours, 48 hours, Day 8 and Day 15 (PGE2 only) after 2ccPA treatment | 
| Serum matrix metalloproteinase (MMP)-1 level | Changes from baseline (pre-dose) in serum matrix metalloproteinase (MMP)-1,at 30 minutes, 1 hour, 2 hours, 4 hours, 12 hours and 24 hours after 2ccPA treatment | at 1 hour, 12 hours, 24 hours, 48 hours, Day 8 and Day 15 (PGE2 only) after 2ccPA treatment | 
| Serum matrix metalloproteinase (MMP)-3 levels | Changes from baseline (pre-dose) in serum matrix metalloproteinase (MMP)-3,at 30 minutes, 1 hour, 2 hours, 4 hours, 12 hours and 24 hours after 2ccPA treatment | at 1 hour, 12 hours, 24 hours, 48 hours, Day 8 and Day 15 (PGE2 only) after 2ccPA treatment | 
| Serum matrix metalloproteinase (MMP)-13 level | Changes from baseline (pre-dose) in serum matrix metalloproteinase (MMP)-13,at 30 minutes, 1 hour, 2 hours, 4 hours, 12 hours and 24 hours after 2ccPA treatment | at 1 hour, 12 hours, 24 hours, 48 hours, Day 8 and Day 15 (PGE2 only) after 2ccPA treatment | 
| Plasma concentration of 2ccPA | Plasma concentration of 2ccPA at pre-dose and at 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 12 hours, 24 hours and 48 hours after 2ccPA treatment | at pre-dose and at 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 12 hours, 24 hours and 48 hours after 2ccPA treatment | 
| Joint space narrowing | To investigate joint space narrowing by MRI at Day 85, compared with baseline and the placebo group | 85 days | 
| Ectopic bone formation | To investigate ectopic bone formation by MRI at Day 85, compared with baseline and the placebo group | 85 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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2ccPA