A Randomized, Placebo-controlled, Subject and Investigator Blinded Study Investigating the Safety, Tolerability and Preliminary Efficacy of 8-week Treatment With Intra-articular LRX712 to Regenerate Articular Cartilage in Patients With Mild/Moderate Knee Osteoarthritis
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 45
- 试验地点
- 2
- 主要终点
- Change From Baseline in Cartilage Volume in the Index Region Measured by 7 Tesla MRI
研究概览
简要总结
This study explored the preliminary efficacy of multiple intra-articular injections of LRX712 by evaluating the ability of the drug to restore structural integrity of articular cartilage. Efficacy was evaluated in the context of the systemic safety and local tolerability of the investigational drug.
详细描述
This was an exploratory study, with a 7-week screening period, an 8-week treatment period, and a 44-week follow-up period, using a 3-treatment arm, parallel-group, randomized, double-blind, placebo-controlled clinical study design. The study design implemented for the first six participants enrolled was a 2-treatment arm, parallel -group, randomized, double-blind placebo controlled trial (up until the time when the study was temporarily halted in February 2021) included up to 5 weeks of screening, an 8-week treatment period, and a 44-week follow-up period. The original two-arm study design (75 mg LRX712 vs. placebo) was modified to a three-arm design, with two lower doses of LRX712 (15 mg and 25 mg) vs. placebo, following protocol amendment 4 (16-Jul-2021). Data from the three participants who had completed dosing with 75 mg LRX712 were considered exploratory, and data from the three participants who had completed dosing with placebo were pooled with the data from participants enrolled after the study was restarted with the implementation of protocol amendment 4.
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
- 35 Years 至 75 Years（Adult, Older 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.
- •To be eligible for inclusion in this study patients must meet all of the following criteria:
- •Patient must have a BMI between 18 -35 kg/m2
- •Patient must have symptomatic knee osteoarthritis predominantly in one knee (index knee)
- •Patient must have knee osteoarthritis (Kellgren-Lawrence grade 2 or 3) in the index knee, as confirmed by radiography
- •Patient must have radiographic confirmation of a medial joint space width of 1.5 to 3.5 mm for females, or 2 to 4 mm for males within the medial tibio-femoral compartment of the index knee.
排除标准
- •Subjects meeting any of the following criteria are not eligible for inclusion in this study:
- •Patient has a known autoimmune disease, inflammatory or chronic arthropathy other than OA.
- •Patient had partial or complete joint replacement in one or both knees.
- •Patient has symptomatic, isolated patello-femoral pain in the index knee as per the Investigator's examination.
- •Pregnant or nursing (lactating) women.
- •Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant.
- •Previous use of LRX712 or use of other investigational drugs at the time of enrollment, or within 5 half-lives of enrollment, or within 30 days, whichever is longer; or longer if required by local regulations.
- •Patient has malalignment (valgus- or varus-deformity) ≥ 7.5° in the index knee as per anatomic PA axis measured by weight-bearing short knee radiography.
- •History of significant cardiac conduction/electrophysiological disorder, e.g. familial long QT syndrome or known family history of Torsades de Pointes or prolonged QT syndrome or QTcF ≥ 450 msec (Fridericia Correction) for males and ≥ 460 msec for females at screening or baseline (by local 12-lead digitized ECG reading).
- •Signs or symptoms, in the judgment of the investigator, of a clinically significant systemic viral, bacterial or fungal infection within 30 days prior to screening.
- •Other protocol-defined inclusion/exclusion criteria may apply.
研究组 & 干预措施
Placebo
Placebo was administered i.a. every four weeks, for a total of three administrations.
干预措施: Placebo (Other)
LRX712 25 mg
LRX712 25 mg was administered i.a. every four weeks, for a total of three administrations.
干预措施: LRX712 (Drug)
LRX712 75 mg
LRX712 75 mg was administered i.a. every four weeks, for a total of three administrations.
干预措施: LRX712 (Drug)
LRX712 15 mg
LRX712 15 mg was administered intra-articularly (i.a.) every four weeks, for a total of three administrations.
干预措施: LRX712 (Drug)
结局指标
主要结局
Change From Baseline in Cartilage Volume in the Index Region Measured by 7 Tesla MRI
时间窗: Baseline, Week 28
Magnetic resonance images (MRI) were obtained from the target knee to visualize and quantify changes in the volume of cartilage in the index region. The index region was defined as the combination of the femoral medial anterior (FMA), central (FMC) and posterior (FMP) cartilage subregions in the knee. Change from baseline in cartilage volume was analyzed using the mixed effects model for repeated measures (MMRM). The model included baseline, treatment, timepoint and treatment-timepoints as fixed effects, and participant as random effect. Missing data was assumed to be Missing at Random (MAR).
次要结局
- Time to Reach the Maximum Plasma Concentration (Tmax) of LRX712(Pre-dose, 0.5, 12, 24 and 168 hours after dose on Day 1; Pre-dose, 24 and 168 hours after dose on Day 29; Pre-dose, 24, 168, 1344 and 3360 hours after dose on Day 57)
- Maximum Observed Plasma Concentration (Cmax) of LRX712(Pre-dose, 0.5, 12, 24 and 168 hours after dose on Day 1; Pre-dose, 24 and 168 hours after dose on Day 29; Pre-dose, 24, 168, 1344 and 3360 hours after dose on Day 57)
- Minimum Observed Plasma Concentration (Cmin) of LRX712(Pre-dose on Day 29; Pre-dose, 1344 hours after dose on Day 57 (LRX712 15 mg arm) and 3360 hours after dose on Day 57 (LRX712 25 mg and 75 mg arms))
- Synovial Fluid Concentrations of LRX712(Pre-dose on Day 1, 29 and 57)
- Time to Reach the Maximum Plasma Concentration (Tmax) of MAE344(Pre-dose, 0.5, 12, 24 and 168 hours after dose on Day 1; Pre-dose, 24 and 168 hours after dose on Day 29; Pre-dose, 24, 168, 1344 and 3360 hours after dose on Day 57)
- Maximum Observed Plasma Concentration (Cmax) of MAE344(Pre-dose, 0.5, 12, 24 and 168 hours after dose on Day 1; Pre-dose, 24 and 168 hours after dose on Day 29; Pre-dose, 24, 168, 1344 and 3360 hours after dose on Day 57)
- Minimum Observed Plasma Concentration (Cmin) of MAE344(Pre-dose on Day 29; Pre-dose, 1344 hours after dose on Day 57 (LRX712 15 mg arm) and 3360 hours after dose on Day 57 (LRX712 25 mg and 75 mg arms))
- Change From Baseline in Articular Cartilage [23Na] Content Measured by 7 Tesla MRI(Baseline, Week 16, 28 and 52)
- Synovial Fluid Concentrations of MAE344(Pre-dose on Day 1, 29 and 57)
- Change From Baseline in Cartilage Volume in the Index Region Measured by 7 Tesla MRI(Baseline, Week 16 and 52)