Safety, Tolerability and Preliminary Efficacy of Multiple Intra-articular Injections of LRX712 in Patients With Knee OA

Study Overview
=================
Brief Summary
-----------------
This study will explore 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 will be evaluated in the context of the systemic safety and local tolerability of the investigational drug.

Detailed Description
-----------------
The purpose of this study is to evaluate the safety, tolerability and preliminary efficacy of multiple intra-articular injections of LRX712 in the knee when treating patients with knee osteoarthritis of mild/moderate severity, in order to support the further clinical development. This study will also allow refinement of the systemic and local pharmacokinetics of LRX712 and the exploration of drug effects on biomarkers of cartilage breakdown and regeneration in OA patients.

Official Title
-----------------
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

Conditions
-----------------
Osteoarthritis (OA)

Intervention / Treatment
-----------------
* Drug: LRX712
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: 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 Exclusion Criteria: 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 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.

Ages Eligible for Study
-----------------
Minimum Age: 35 Years
Maximum Age: 75 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: LRX712 Arm 1<br>Randomized in a 1:1:1 ratio: LRX712 Arm 1:LRX712 Arm 2:placebo | Drug: LRX712<br>* LRX712 intra-articular injections<br>|
| Placebo Comparator: Placebo<br>Randomized in a 1:1:1 ratio: LRX712 Arm 1:LRX712 Arm 2:placebo | Drug: Placebo<br>* Placebo intra-articular injections<br>|
| Experimental: LRX712 Arm 2<br>Randomized in a 1:1:1 ratio: LRX712 Arm 1:LRX712 Arm 2:placebo | Drug: LRX712<br>* LRX712 intra-articular injections<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes from baseline in cartilage volume in the medial femoral condyle at Week 28 | Efficacy of multiple intra-articular injections of LRX712 in regenerating cartilage as measured with 7T MRI | Baseline and Week 28 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in articular cartilage [23Na] content from baseline compared to placebo at Week 16, 28 and 52 | Efficacy of multiple intra-articular injections of LRX712 measured with 7T MRI | Baseline, Week 16, 28 and 52 | 
| Changes from baseline in cartilage volume in the medial femoral condyle at Week 16 and 52 | Efficacy of multiple intra-articular injections of LRX712 measured with 7T MRI | Baseline, Week 16 and 52 | 
| Time to Reach the Maximum Plasma Concentration (Tmax) | The observed time to reach max (Tmax) plasma concentration following drug administration | Pre-dose to 28 weeks | 
| Maximum Observed Plasma Concentration (Cmax) | The observed maximum (Cmax) plasma concentration following drug administration | Pre-dose to 28 weeks | 
| Minimum Observed Plasma Concentration (Cmin) | The observed minimum (Cmin) plasma concentration following drug administration | Pre-dose to 28 weeks | 
| Concentration in synovial fluid | The observed synovial concentration following drug administration | Day 1; week 4; week 8 | 
| Local and systemic adverse events | Safety and tolerability of multiple intra-articular injections of LRX712 | Day 1 to 52 weeks | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Knee osteoarthritis, Chondroanabolic drug, Magnetic resonance imaging, Patient Reported Outcomes