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

Novartis Pharmaceuticals45 enrolled

Overview

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.

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.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

QUADRUPLE

Enrollment

Conditions

Osteoarthritis (OA)

Interventions

LRX712DRUG

LRX712 intra-articular injections

PlaceboOTHER

Placebo intra-articular injections

Eligibility

Sex: ALLMin age: 35 YearsMax age: 75 Years

Medical Language ↔ Plain English

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 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.

Locations (1)

Novartis Investigative Site

Leiden, South Holland, Netherlands

Outcomes

Primary Outcomes

Change From Baseline in Cartilage Volume in the Index Region Measured by 7 Tesla MRI

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).

Time frame: Baseline, Week 28

Secondary Outcomes

Time to Reach the Maximum Plasma Concentration (Tmax) of LRX712

Tmax is the time to reach maximum (peak) LRX712 concentration after single-dose administration (time). LRX712 plasma concentrations were determined using the actual recorded sampling times and non-compartmental method with Phoenix WinNonlin (Version 8.3). LRX712 was determined by a validated LC-MS/MS method. Concentrations below the lower limit of quantification (LLOQ) were treated as "zero" . LLOQ was 25 pg/mL.

Time frame: 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

Cmax is defined as the maximum (peak) observed concentration following a dose. LRX712 plasma concentrations were determined using the actual recorded sampling times and non-compartmental method with Phoenix WinNonlin (Version 8.3). LRX712 was determined by a validated LC-MS/MS method. Concentrations below the lower limit of quantification (LLOQ) were treated as "zero" . LLOQ was 25 pg/mL.

Time frame: 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

Data from ClinicalTrials.gov

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