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

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).

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).

Study Overview

• Status: Completed
• Conditions: Osteoarthritis
• Intervention / Treatment: Other: Placebo; Biological: LNA043

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 Type: Interventional
• Enrollment (Actual): 142
• Phase: Phase 2

Contacts and Locations

Study Locations

• Czechia
  • Kladno, Czechia, 272 59
    • Novartis Investigative Site
  • Kolin, Czechia, 280 02
    • Novartis Investigative Site
  • Pardubice, Czechia, 53002
    • Novartis Investigative Site
  • Praha, Czechia, 190 00
    • Novartis Investigative Site
  • Czech Republic
    • Brno, Czech Republic, Czechia, 66250
      • Novartis Investigative Site
    • Mlada Boleslav, Czech Republic, Czechia, 29301
      • Novartis Investigative Site
• Denmark
  • Aarhus C, Denmark, DK 8000
    • Novartis Investigative Site
  • Hvidovre, Denmark, 2650
    • Novartis Investigative Site
• United States
  • Arizona
    • Phoenix, Arizona, United States, 85053
      • Novartis Investigative Site
  • California
    • La Mesa, California, United States, 91942
      • Novartis Investigative Site
    • Sacramento, California, United States, 95821
      • Novartis Investigative Site
  • Florida
    • Miami Lakes, Florida, United States, 33014
      • Novartis Investigative Site
    • Sunrise, Florida, United States, 33351
      • Novartis Investigative Site
    • Tampa, Florida, United States, 33603
      • Novartis Investigative Site
  • Idaho
    • Boise, Idaho, United States, 83702
      • Novartis Investigative Site
  • Illinois
    • Chicago, Illinois, United States, 60612
      • Novartis Investigative Site
  • Missouri
    • Saint Louis, Missouri, United States, 63141
      • Novartis Investigative Site
  • Nevada
    • Las Vegas, Nevada, United States, 89119
      • Novartis Investigative Site
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19140
      • Novartis Investigative Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion criteria Part A

• 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.

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 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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: LNA043 40 mg Part B	Biological: LNA043; LNA043 intra-articular injection
Experimental: LNA043 20 mg Part B	Biological: LNA043; LNA043 intra-articular injection
Experimental: LNA043 20 mg Part A	Biological: LNA043; LNA043 intra-articular injection
Placebo Comparator: Placebo Part A	Other: Placebo; Placebo intra-articular injection
Placebo Comparator: Placebo Part B	Other: Placebo; Placebo intra-articular injection

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in Articular Cartilage Collagen Organization in the Overall Cartilage (Femoral and Patellar Lesions) - Part A	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.	Baseline up to Week 16, Week 28
Change From Baseline in Articular Cartilage Collagen Organization in the Deep Cartilage Layer (Femoral and Patellar Lesions) - Part A	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.	Baseline up to Week 16, Week 28
Change From Baseline in Articular Cartilage Collagen Organization in the Superficial Cartilage Layer (Femoral and Patellar Lesions) - Part A	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.	Baseline up to Week 16, Week 28
Change From Baseline of LNA043 to Placebo in Cartilage Volume in the Femoral Medial Index Region (mm3) - Part B	MRI based quantitative assessment using an automated segmentation algorithm	Baseline, Week 29, Week 53
Change From Baseline of LNA043 to Placebo in Cartilage Thickness in the Femoral Medial Index Region (mm) - Part B	MRI based quantitative assessment using an automated segmentation algorithm.	Baseline, Week 29, Week 53
Overview of Number of Participants With Adverse Events and Serious Adverse Events for Part A and Part B	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	Baseline up to end of post treatment follow-up

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline of LNA043 to Placebo in Cartilage Defect Volume (mm^3) for Both Groups of Patients (Femoral and Patellar Lesions) - Part A	Cartilage volume data were generated from the manual segmentation of the cartilage defect that was identified in MR images.	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	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.	Baseline, Week 29, Week 53
Change From Baseline in Cartilage Mean T2 Relaxation Time as a Marker of Collagen Organization in the Medial Femoral Index Region - Deep Part B	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.	Baseline, Week 29, Week 53
Change From Baseline in Cartilage Mean T2 Relaxation Time as a Marker of Collagen Organization in the Medial Femoral Index Region - Superficial Part B	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.	Baseline, Week 29, Week 53
Incidence of Immunogenicity (IG) Part A	A validated ligand binding assay were used for the detection of anti-LNA043 antibodies, and cross-reactivity to ANGPTL3 and ANGPTL4.	Week 1,3,8,16,28
Incidence of Immunogenicity (IG) Part B	A validated ligand binding assay were used for the detection of anti-LNA043 antibodies, and cross-reactivity to ANGPTL3 and ANGPTL4.	Week 1,5,9,13,17,29,53
Serum Concentrations of LNA043 - Part A	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"	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 A	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"	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 LNA043 - Part A	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".	Weeks 1,2,3,4: 0 hour (pre-dose)
Synovial Fluid Concentrations of ANGPTL3 - Part A	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".	Weeks 1,2,3,4: 0 hour (pre-dose)
Serum Concentrations of LNA043 - Part B	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	Week 1: 0 (pre-dose), 2 hours post dose; Weeks 5 and 13: 1 hour post dose
Serum Concentrations of ANGPTL3 - Part B	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".	Week 1: 0 (pre-dose), 2 hours post dose; Weeks 5 and 13: 1 hour post dose
Synovial Fluid Concentrations of LNA043 Part B	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".	Weeks 1,5.9.13: 0 hour (pre-dose)
Synovial Fluid Concentrations of ANGPTL3 - Part B	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".	Weeks 1,5.9.13: 0 hour (pre-dose)

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals

Study record dates

Study Major Dates

• Study Start (Actual): September 12, 2017
• Primary Completion (Actual): September 6, 2022
• Study Completion (Actual): September 6, 2022

Study Registration Dates

• First Submitted: August 29, 2017
• First Submitted That Met QC Criteria: September 5, 2017
• First Posted (Actual): September 7, 2017

Study Record Updates

• Last Update Posted (Estimated): February 14, 2024
• Last Update Submitted That Met QC Criteria: January 23, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Keywords: osteoarthritis; adult; regeneration; Articular cartilage; partial thickness cartilage lesion; knee cartilage
• Additional Relevant MeSH Terms: Joint Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Arthritis; Osteoarthritis; Osteoarthritis, Knee
• Other Study ID Numbers: CLNA043X2202; 2016-004052-30 (EudraCT Number); CTI-194705 (Other Identifier: Japic CTI)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No