A Two-part, Randomized, Placebo-controlled, Patient and Investigator Blinded, Study Investigating the Safety, Tolerability and Preliminary Efficacy of Intra-articular LNA043 Injections in Regenerating the Articular Cartilage of the Knee in Patients With Articular Cartilage Lesions (Part A) and in Patients With Knee Osteoarthritis (Part B).
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 142
- 试验地点
- 19
- 主要终点
- Change From Baseline in Articular Cartilage Collagen Organization in the Overall Cartilage (Femoral and Patellar Lesions) - Part A
研究概览
简要总结
The purpose of this two-part study is to assess the efficacy, safety and tolerability of multiple intra-articular (i.a.) injections of LNA043, in regenerating the articular surface in patients with cartilage lesions of the knee (Part A) and knee osteoarthritis (Part B).
详细描述
There was a 30 day screening period for both Part A and Part B. In Part A, participants were randomized to 3:1 ratio and received an injection of LNA043 (20 mg in 3 ml) or matching placebo (3 ml) on Days 1, 8,15 and 22 and were monitored in clinic for 3 hours after each injection followed by telephone calls 48 hours after injection. Participants returned to the clinic on Days 50, 106, 190 and 365 for follow up visits. MRIs, safety assessments and pharmacokinetics were assessed at selected clinic visits.
In Part B, this study aimed at further evaluating the cartilage anabolic activity of LNA043 in a more severe knee OA population, and to explore the safety and efficacy of a higher dose.
In Part B, participants were randomized to LNA043 20 mg, LNA043 40 mg or matching placebo according in a 1:1:1 ratio. Injections were given in clinic on Days 1, 29, 57 and 85 and participants were monitored in clinic for 3 hours after each injection followed by telephone calls 48 hours after injection. Participants returned to the clinic on Days 113,197 and 365 (end of study) for follow up visits. MRIs, safety assessments and pharmacokinetics were assessed at selected clinic visits.
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
- Double (Participant, Investigator)
入排标准
- 年龄范围
- 18 Years 至 75 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Patient was ≥18 and ≤55 years old at time of screening.
- •Patient had a body mass index (BMI) <30 kg/m2 at screening,
- •Patient had a symptomatic, single, articular cartilage defect of one knee, grade II or IIIA according to the ICRS classification, localized to either the femoral condyles/femoral trochlea or to the patella, based on MRI or arthroscopy performed within 9 months before screening visit and confirmed by screening 3T MRI.
- •Patient had an onset of pain and impairment of function between two (2) months and two (2) years before screening.
- •Patient had a grade 2 or 3 OA of the knee with Joint Space Width (JSW) 2-4 mm evaluated with X-Ray at screening
- •Inclusion criteria Part B
- •Patient was ≥18 and ≤75 years old at time of screening.
- •Patient had a body mass index (BMI) ≤ 35 kg/m2 at screening
- •Diagnosis of femorotibial osteoarthritis (OA) in the target knee by standard American College of Rheumatology (ACR) criteria at study start (clinical AND radiographic criteria)
- •Patient must have had symptomatic disease predominantly in one (the index) knee, with minimal or no symptoms in the contralateral knee. Symptomatic disease is defined as having pain in the knee more than 50% of the days during the last 3 months from screening.
- •Patient had a K&L grade 2 or 3 OA of the knee with JSW 2.00-4.00 mm (X=0.225) fixed position evaluated with X-Ray by the Central Reader at screening.
排除标准
- •Part A & B
- •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.
- •Patient had surgical treatment of the target knee using mosaicplasty, microfracture, meniscectomy >50% (Note: prior diagnostic arthroscopy with debridement and lavage, <50% meniscectomy, lateral release, patellar realignment, medial patellofemoral ligament reconstruction are acceptable if performed at least 2 months prior to screening; anteriorcruciate ligament reconstrucion is acceptable if performed 12 months prior to screening, or less if restoration of joint function is evident, and agreed by the sponsor).
- •Patient had an unstable target knee joint or insufficiently reconstructed ligaments based on medical history and physical examination by the investigator.
- •Prohibited medication updated with reference to dosing (formerly screening).
- •Exclusion Criteria Part A only
- •Regular smokers (> 5 cigarettes/day). Urine cotinine levels will be measured during screening for all patients. Regular smokers will be defined as any patient who reports tobacco use of > 5 cigarettes/day and/or who has a urine cotinine ≥ 500 ng/mL.
- •Patient had radiologically apparent degenerative joint disease in the target knee as determined by Kellgren and Lawrence grade ≥2 based on X-ray evaluation performed within 9 months from screening.
- •Patient had patellofemoral dysplasia Dejour Grade B-D based on X-ray evaluation performed within 9 months from screening
- •Patient had malalignment (valgus- or varus-deformity) in the target knee ≥ 5° based on X-ray evaluation performed within 9 months from screening. In suspected cases, the mechanical axis must be established radiographically through complete leg imaging during standing and in postero-anterior (PA) projection.
- •Exclusion Criteria Part B only
- •Regular smokers (> 10 cigarettes/day).
- •Clinical signs of inflammation (i.e., redness) in the target knee.
- •History of knee replacement (unilateral or total) in either knee.
- •Presence of severe hip OA conditioning lower limb function according to PI's evaluation.
- •Nephrotic syndrome and/or significant proteinuria
- •History of coagulopathy or medical condition requiring anticoagulation which would preclude knee injection
- •Patient had malalignment (valgus- or varus-deformity) in the target knee ≥ 7.5° based on X-ray evaluation. In suspected cases, the mechanical axis must be established radiographically through complete leg imaging during standing and in postero-anterior (PA) projection.
研究组 & 干预措施
LNA043 20 mg Part A
LNA043 20 mg Part A
干预措施: LNA043 (Biological)
Placebo Part A
Placebo Part A
干预措施: Placebo (Other)
Placebo Part B
Placebo Part B
干预措施: Placebo (Other)
LNA043 40 mg Part B
LNA043 40 mg Part B
干预措施: LNA043 (Biological)
LNA043 20 mg Part B
LNA043 20 mg Part B
干预措施: LNA043 (Biological)
结局指标
主要结局
Change From Baseline in Articular Cartilage Collagen Organization in the Overall Cartilage (Femoral and Patellar Lesions) - Part A
时间窗: Baseline up to Week 16, Week 28
Collagen fibril organization in articular cartilage evaluated by Magnetic Resonance Imaging (MRI) from the cartilage mean T2 relaxation time (with lower values indicative of higher quality). The area of interest is the focal cartilage lesion.
Change From Baseline of LNA043 to Placebo in Cartilage Volume in the Femoral Medial Index Region (mm3) - Part B
时间窗: Baseline, Week 29, Week 53
MRI based quantitative assessment using an automated segmentation algorithm
Change From Baseline in Articular Cartilage Collagen Organization in the Deep Cartilage Layer (Femoral and Patellar Lesions) - Part A
时间窗: Baseline up to Week 16, Week 28
Collagen fibril organization in articular cartilage evaluated by MRI from the cartilage mean T2 relaxation time (with lower values indicative of higher quality). The area of interest is the focal cartilage lesion.
Change From Baseline in Articular Cartilage Collagen Organization in the Superficial Cartilage Layer (Femoral and Patellar Lesions) - Part A
时间窗: Baseline up to Week 16, Week 28
Collagen fibril organization in articular cartilage evaluated by MRI from the cartilage mean T2 relaxation time (with lower values indicative of higher quality).The area of interest is the focal cartilage lesion.
Change From Baseline of LNA043 to Placebo in Cartilage Thickness in the Femoral Medial Index Region (mm) - Part B
时间窗: Baseline, Week 29, Week 53
MRI based quantitative assessment using an automated segmentation algorithm.
Overview of Number of Participants With Adverse Events and Serious Adverse Events for Part A and Part B
时间窗: Baseline up to end of post treatment follow-up
Treatment emergent other and serious adverse events (TEAE and TESAE) period: Part A: Baseline up to Day 50 (included 30 day safety follow-up Part B: Baseline up to Day 113 (included 30 day safety follow-up) Long term Follow-UP period: Part A: Day 51 to Day 365 Part B: Day 114 to Day 365
次要结局
- Change From Baseline in Cartilage Mean T2 Relaxation Time as a Marker of Collagen Organization in the Medial Femoral Index Region - Deep Part B(Baseline, Week 29, Week 53)
- Serum Concentrations of ANGPTL3 - Part A(Week 1: 0 (pre-dose), 0.25 hours, 1, 2 hours post dose; Weeks 2, 3, 4: 0 hour (pre dose), 1 hour post dose)
- Synovial Fluid Concentrations of ANGPTL3 - Part B(Weeks 1,5.9.13: 0 hour (pre-dose))
- Change From Baseline of LNA043 to Placebo in Cartilage Defect Volume (mm^3) for Both Groups of Patients (Femoral and Patellar Lesions) - Part A(Baseline up to Week 16, Week 28)
- Change From Baseline in Cartilage Mean T2 Relaxation Time as a Marker of Collagen Organization in the Medial Femoral Index Region - Overall Part B(Baseline, Week 29, Week 53)
- Synovial Fluid Concentrations of LNA043 - Part A(Weeks 1,2,3,4: 0 hour (pre-dose))
- Synovial Fluid Concentrations of LNA043 Part B(Weeks 1,5.9.13: 0 hour (pre-dose))
- Change From Baseline in Cartilage Mean T2 Relaxation Time as a Marker of Collagen Organization in the Medial Femoral Index Region - Superficial Part B(Baseline, Week 29, Week 53)
- Incidence of Immunogenicity (IG) Part A(Week 1,3,8,16,28)
- Incidence of Immunogenicity (IG) Part B(Week 1,5,9,13,17,29,53)
- Serum Concentrations of LNA043 - Part A(Week 1: 0 (pre-dose), 0.25 hours, 1, 2 hours post dose; Weeks 2, 3, 4: 0 hour (pre dose), 1 hour post dose)
- Serum Concentrations of ANGPTL3 - Part B(Week 1: 0 (pre-dose), 2 hours post dose; Weeks 5 and 13: 1 hour post dose)
- Synovial Fluid Concentrations of ANGPTL3 - Part A(Weeks 1,2,3,4: 0 hour (pre-dose))
- Serum Concentrations of LNA043 - Part B(Week 1: 0 (pre-dose), 2 hours post dose; Weeks 5 and 13: 1 hour post dose)