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

Phase 2

Completed

• Conditions: Osteoarthritis
• Interventions: Biological: LNA043; Other: Placebo

• Registration Number: NCT03275064
• Lead Sponsor: Novartis Pharmaceuticals

Brief Summary

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

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.

Study Timeline

• Study First Submitted: 2017-08-29
• Study First Submitted QC: 2017-09-05
• Study First Posted: 2017-09-07
• Study Start: 2017-09-12
• Primary Completion: 2022-09-06
• Study Completion: 2022-09-06
• Results First Submitted: 2023-09-04
• Results First Submitted QC: 2024-01-23
• Results First Posted: 2024-02-14
• Status Verified: 2024-10
• Last Update Submitted: 2024-10-07
• Last Update Posted: 2024-10-09

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 142

Inclusion Criteria

Not provided

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Exclusion Criteria

Not provided

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
LNA043 20 mg Part A	LNA043	LNA043 20 mg Part A
Placebo Part A	Placebo	Placebo Part A
LNA043 40 mg Part B	LNA043	LNA043 40 mg Part B
LNA043 20 mg Part B	LNA043	LNA043 20 mg Part B
Placebo Part B	Placebo	Placebo Part B

Primary Outcome Measures

Name	Time	Method
Change From Baseline in Articular Cartilage Collagen Organization in the Overall Cartilage (Femoral and Patellar Lesions) - Part A	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	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	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	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	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	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

Secondary Outcome Measures

Name	Time	Method
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	Collagen fibril organisation 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 femoral medial index region comprising the anterior, central and posterior aspects of the femoral condyle.
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	Validated bioanalytical assays were used to determine ANGPTL3 in serum with an LLOQ of 2.13 ng/mL. Concentrations below the LLOQ were reported as "zero"
Synovial Fluid Concentrations of ANGPTL3 - Part B	Weeks 1,5.9.13: 0 hour (pre-dose)	Validated bioanalytical assays were used to determine ANGPTL3 in synovial fluid with an LLOQ of 2.74 ng/mL. Concentrations below the LLOQ were reported as "zero".
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	Cartilage volume data were generated from the manual segmentation of the cartilage defect that was identified in MR images.
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	Collagen fibril organisation 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 femoral medial index region comprising the anterior, central and posterior aspects of the femoral condyle.
Synovial Fluid Concentrations of LNA043 - Part A	Weeks 1,2,3,4: 0 hour (pre-dose)	Concentrations for LNA043 were determined by a validated LC-MS/MS method; the anticipated LLOQ was 10ng/mL in synovial fluid. Concentrations below the LLOQ were reported as "zero".
Synovial Fluid Concentrations of LNA043 Part B	Weeks 1,5.9.13: 0 hour (pre-dose)	Concentrations for LNA043 were determined by a validated LC-MS/MS method; the anticipated LLOQ was 10ng/mL in synovial fluid. Concentrations below the LLOQ were reported as "zero".
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	Collagen fibril organisation 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 femoral medial index region comprising the anterior, central and posterior aspects of the femoral condyle.
Incidence of Immunogenicity (IG) Part A	Week 1,3,8,16,28	A validated ligand binding assay were used for the detection of anti-LNA043 antibodies, and cross-reactivity to ANGPTL3 and ANGPTL4.
Incidence of Immunogenicity (IG) Part B	Week 1,5,9,13,17,29,53	A validated ligand binding assay were used for the detection of anti-LNA043 antibodies, and cross-reactivity to ANGPTL3 and ANGPTL4.
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	Concentrations for LNA043 were determined by a validated LC-MS/MS method; the anticipated LLOQ was 10ng/mL in serum. Concentrations below the LLOQ were reported as "zero"
Serum Concentrations of ANGPTL3 - Part B	Week 1: 0 (pre-dose), 2 hours post dose; Weeks 5 and 13: 1 hour post dose	Validated bioanalytical assays were used to determine ANGPTL3 in serum with an LLOQ of 2.13 ng/mL. Concentrations below the LLOQ were reported as "zero".
Synovial Fluid Concentrations of ANGPTL3 - Part A	Weeks 1,2,3,4: 0 hour (pre-dose)	Validated bioanalytical assays were used to determine ANGPTL3 in synovial fluid with an LLOQ of 2.74 ng/mL. Concentrations below the LLOQ were reported as "zero".
Serum Concentrations of LNA043 - Part B	Week 1: 0 (pre-dose), 2 hours post dose; Weeks 5 and 13: 1 hour post dose	Concentrations for LNA043 were determined by a validated LC-MS/MS method; the anticipated LLOQ was 10ng/mL in serum. Concentrations below the LLOQ were reported as "zero

Trial Locations

Locations (1)

Novartis Investigative Site; 🇩🇰 Hvidovre, Denmark