A Randomized, Placebo-controlled, Patient and Investigator Blinded, Single Dose, Proof of Concept Study Investigating the Safety, Tolerability and Preliminary Efficacy of Intra-articular LNA043 in Regenerating the Articular Cartilage of the Knee at Donor Sites in Patients Undergoing Autologous Chondrocyte Implantation
试验速览
- 阶段
- 2 期
- 状态
- 终止
- 入组人数
- 14
- 试验地点
- 3
- 主要终点
- Change From Baseline in GAG Content
研究概览
简要总结
The purpose of this study was to assess safety, tolerability, pharmacokinetics and preliminary efficacy of a single intra-articular (i.a.) administration of LNA043 in regenerating the articular cartilage of the knee, in a standardized clinical scenario of acute cartilage defect. The study aimed at characterizing the mechanism of action of LNA043
详细描述
This was a non-confirmatory, patient and investigator blinded, randomized, placebo-controlled, parallel group, single dose study in patients with cartilage lesions undergoing autologous cartilage implantation (ACI). Participants were treated only on one occasion (Day 1) with a single i.a. injection that was performed under arthroscopic visualization and followed up for 28 weeks.
Originally approximately 22 patients were planned to be enrolled in two cohorts (LNA043 20 mg and LNA043 40 mg). The study was terminated before any patient was randomized into the LNA043 40 mg cohort
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)
入排标准
- 年龄范围
- 18 Years 至 50 Years（Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Written informed consent must be obtained before any assessment is performed
- •Patient is ≥18 and≤ 50 years old at time of screening
- •Patient has a body mass index (BMI) <30 kg/m2 at screening
- •Patient has a localized articular cartilage defect of the knee and is scheduled for an ACI procedure
- •Able to communicate well with the investigator, to understand and comply with the requirements of the study.
排除标准
- •Patient has radiologically apparent degenerative joint disease in the target knee as determined by Kellgren and Lawrence grade ≥2 based on X-ray evaluation performed within 6 months from screening
- •Patient has unstable knee joint or insufficiently reconstructed ligaments, based on medical history and physical examination by the investigator.
- •Patient scheduled for a concomitant articular surgical procedure (e.g., anterior cruciate ligament reconstruction) other than debridement or partial meniscectomy
- •Patient has malalignment (valgus- or varus-deformity) in the target knee ≥ 5° based on based on X-ray evaluation performed within 6 months from screening.at screeningmedical history. In suspected cases, the mechanical axis must be established radiographically through complete leg imaging during standing and in postero-anterior projection.
- •Patient has a known autoimmune disease, inflammatory arthropathy (including but not limited to rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, CPPD, gout), active acute or chronic infection of the joint, recent Lyme disease to the knee, systemic cartilage disorder, or a known systemic connective tissue disease.
- •Patient has had surgical treatment of the target knee using autologous osteochondral transplantation/mosaicplasty within 12 months prior to screening (Note: prior diagnostic arthroscopy with debridement and lavage, meniscal surgery, microfracture, anterior cruciate ligament reconstruction, and extra-articular surgery e.g., high-tibial osteotomy are acceptable).
- •Patient is unable to undergo magnetic resonance imaging (MRI) or presents absolute contraindications to MRI (e.g., metallic implants, metallic foreign bodies, pacemaker, defibrillator).
- •Patient taking medications prohibited by the protocol: corticosteroids by any route (except topical) from 4 weeks prior to screening; nonsteroidal anti-inflammatories or aspirin (greater than 100 mg per day) within 2 weeks prior to screening; paracetamol greater than 3000 mg per day within 2 weeks prior to screening; glucosamine or chondroitin sulfate within 2 weeks prior to screening; any local treatment i.a. into the knee within 3 months from screening.
- •Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception during dosing and for 15 days after stopping of investigational drug.
- •Regular smokers (use of tobacco/nicotine products in the previous 3 months > 5 cigarettes/day). Urine cotinine levels will be measured during screening for all subjects. Regular smokers will be defined as any subject who reports tobacco use of > 5 cigarettes/day and/or who has a urine cotinine ≥ 500 ng/mL.
结局指标
主要结局
Change From Baseline in GAG Content
时间窗: Baseline, Week 4
Sodium MRI-based measurements of change from baseline in glycosaminoglycan (GAG) content were assessed from both defective sites and a nearby healthy cartilage region (as a reference tissue). Specifically, the ratio of normalized sodium signal in the surgically created defect (SCD or donor site) to healthy non-weight bearing region (HNWB), i.e. SCD/HNWB and the defect to be treated (DTBT or main lesion) to healthy weight bearing region (HWB), i.e. DTBT/HWB was of major interest
Bi-layer Collagen Organization Based on MRI Measurements
时间窗: Week 4
MRI T2 maps were generated and zonal T2 ratios (superficial layer T2 / deep layer T2) were calculated to assess the collagen fiber organization in the surgically created defect (SCD) and defect to be treated (DTBT) cartilage regions.
次要结局
- Percentage of Donor Site Refilling Based on MRI Measurements.(Baseline, Week 4, Week 12 and Week 28)
- Change From Baseline in International Cartilage Repair Society (ICRS) Scoring(Week 4)
- Bi-layer Collagen Organization Based on MRI Measurements(Week 12 and Week 28)
- Number of Participants With Anti-LNA043 Antibodies in Serum(Baseline, Week 1, Week 4, Week 12 and Week 28)
- PK Profile of LNA043 and of AngPTL3 in Serum Cmax(4 weeks)
- Change From Baseline in GAG Content(Baseline, Week 12 and Week 28)
- PK Profile of LNA043 and of AngPTL3 in Serum AUC(4 weeks)