Study of Safety, Tolerability, Preliminary Efficacy of Intra-articular LNA043 Injections in Patients With Articular Cartilage Lesions and Knee Osteoarthritis.

Study Overview
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Brief Summary
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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).

Detailed Description
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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). In Part A, this study aims to establish Proof of Concept (PoC), namely regeneration of the articular cartilage, in order to provide information on the potential clinical utility of LNA043, with the ultimate goal of replacing current surgical procedures for cartilage repair with an injectable, less invasive regenerative therapy. In Part B, this study aims at further evaluating the cartilage anabolic activity of LNA043 in a more severe knee OA population, and at testing the potential benefit of a higher dose of LNA043 administered i.a. monthly instead of weekly.

Official Title
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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).

Conditions
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Wounds and Injuries

Intervention / Treatment
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* Biological: LNA043
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion criteria Part A Patient is ≥18 and ≤55 years old at time of screening. Patient has a body mass index (BMI) <30 kg/m2 at screening, for patients with BMI >30 but ≤ 33kg/m2, eligibility will be decided by consultation with the sponsor. Patient has 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 has an onset of pain and impairment of function between two (2) months and two (2) years before screening. Patient reports a KOOS (sports and recreational activities subscale) score of ≤ 60 at both screening and Day 1. Inclusion criteria Part B Patient is ≥18 and ≤75 years old at time of screening. Patient has 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 has a Kellgren & Lawrence (K&L) grade 2 or 3 OA of the knee with Joint Space Width (JSW) 2-4 mm evaluated with X-Ray at screening. Patient must have 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. Exclusion criteria 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 has 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 has 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 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 9 months from screening. Patient has patellofemoral dysplasia Dejour Grade B-D based on X-ray evaluation performed within 9 months from screening Patient has 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 has 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.

Ages Eligible for Study
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Minimum Age: 18 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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: LNA043 40 mg Part B<br>LNA043 40 mg Part B | Biological: LNA043<br>* LNA043 intra-articular injection<br>|
| Experimental: LNA043 20 mg Part B<br>LNA043 20 mg Part B | Biological: LNA043<br>* LNA043 intra-articular injection<br>|
| Experimental: LNA043 20 mg Part A<br>LNA043 20 mg Part A | Biological: LNA043<br>* LNA043 intra-articular injection<br>|
| Placebo Comparator: Placebo Part A<br>Placebo Part A | Other: Placebo<br>* Placebo intra-articular injection<br>|
| Placebo Comparator: Placebo Part B<br>Placebo Part B | Other: Placebo<br>* Placebo intra-articular injection<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Articular cartilage bi-layer collagen organisation evaluated with MRI and measured in milliseconds (ms) (Part A only) | To assess the efficacy of multiple i.a. injections of LNA043 in regenerating the articular cartilage tissue | Up to Week 28 | 
| Number of patients with any adverse events, serious adverse events and death (Part A and Part B) | To assess safety and local tolerability of multiple i.a. injections of LNA043 | Up to 52 weeks | 
| Change in cartilage volume/thickness in the index region (Part B only) | To assess the efficacy of multiple i.a. injections of LNA043 in regenerating the articular cartilage tissue | Up to Week 52 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in volume of cartilage defect filling evaluated with MRI (Part A only) | To assess the extent of the repair cartilage tissue following multiple i.a. injections of LNA043 | Week 16, Week 28 | 
| Maximum Observed Plasma Concentration measured in ng/mL (Part A and Part B) | To evaluate systemic and local PK of LNA043 following multiple i.a. injections of LNA043 | Part A: 0 (pre-dose), 15 min, 60 min and 120 min post-dose Week 1, Week 2, Week 3, Week 4; Part B: Week 1, Week 4, Week 9, Week 13, Week 16, Week 28 and Week 52 | 
| Potential immunogenicity of LNA043 presence and characterisation of anti-LNA043 antibodies in serum (Part A and Part B) | To assess the potential immunogenicity of LNA043 | Week 1, Week 3, Week 6, Week 16, Week 28 | 
| Area Under the Plasma Concentration-time Curve From 0 to the Last Measurable Concentration (Part A and Part B) | To evaluate systemic and local PK of LNA043 following multiple i.a. injections of LNA043 | Part A: 0 (pre-dose), 15 min, 60 min and 120 min post-dose Week 1, Week 2, Week 3, Week 4; Part B: Week 1, Week 4, Week 9, Week 13, Week 16, Week 28 and Week 52 | 
| Articular cartilage bi-layer collagen organization evaluated with T2 relaxation times (in ms) (Part B only) | To assess the extent of the repair cartilage tissue following multiple i.a. injections of LNA043 | Week 28, Week 52 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Articular cartilage, partial thickness cartilage lesion, knee cartilage, regeneration, osteoarthritis, plaque-type psoriasis, metabolic syndrome, Secukinumab, lifestyle intervention, systemic inflammation, metabolism