NCT04229394已完成1 期
Phase I Safety, Tolerability, and Pharmacokinetics Study of 2ccPA in Patients With Symptomatic Knee Osteoarthritis
适应症
干预措施
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 40
- 试验地点
- 5
- 主要终点
- 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.
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
盲法说明
The subjects and study site personnel (other than the study site pharmacists) are all blinded to the treatment assignment. An un-blind pharmacist is necessary for study drug preparation.
入排标准
- 年龄范围
- 40 Years 至 75 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
排除标准
- •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.
研究组 & 干预措施
2ccPA
Experimental
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)
干预措施: 2ccPA (Drug)
Placebo
Placebo Comparator
Only day 1 Intra-articular injection can be given under direct ultrasound guidance; placebo
干预措施: placebo (Drug)
结局指标
主要结局
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.
时间窗: 85 days
To determine safety and tolerability as well as the maximal tolerated dose (MTD) of a single-dose 2ccPA in symptomatic knee OA
次要结局
- 20% improvement in the The Western Ontario and McMaster Universities Arthritis Index (WOMAC) pain and physical function subscales(85 days)
- Time to maximum plasma concentration (Tmax) 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(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(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 matrix metalloproteinase (MMP)-1 level(before intra-articular injection treatment and 24 hours ± 2 hours after intra-articular injection.)
- Synovial fluid matrix metalloproteinase (MMP)-3 level(before intra-articular injection treatment and 24 hours ± 2 hours after intra-articular injection.)
- Serum matrix metalloproteinase (MMP)-3 levels(at 1 hour, 12 hours, 24 hours, 48 hours, Day 8 and Day 15 (PGE2 only) after 2ccPA treatment)
- Ectopic bone formation(85 days)
- 70% improvement in the The Western Ontario and McMaster Universities Arthritis Index (WOMAC) pain and physical function subscales(85 days)
- Maximum plasma concentration (Cmax) 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.)
- Serum matrix metalloproteinase (MMP)-13 level(at 1 hour, 12 hours, 24 hours, 48 hours, Day 8 and Day 15 (PGE2 only) after 2ccPA treatment)
- Apparent total body clearance (CL/F) 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.)
- 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)
- Joint space narrowing(85 days)
- 50% improvement in the The Western Ontario and McMaster Universities Arthritis Index (WOMAC) pain and physical function subscales(85 days)
- Elimination half-life (t1/2) 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(before intra-articular injection treatment and 24 hours ± 2 hours after intra-articular injection.)
- Serum prostaglandin E2 (PGE2) level(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(at 1 hour, 12 hours, 24 hours, 48 hours, Day 8 and Day 15 (PGE2 only) after 2ccPA treatment)
- Synovial fluid matrix metalloproteinase (MMP)-13 level(before intra-articular injection treatment and 24 hours ± 2 hours after intra-articular injection.)
研究者
研究点 (5)
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