Study of Efficacy, Safety, and Tolerability of LNA043 in Patients With Knee Osteoarthritis (ONWARDS)

A 5-year, Randomized, Double-blind, Placebo-controlled, Multi-center Study Assessing the Efficacy, Safety, and Tolerability of Intra-articular Regimens of LNA043 Versus Placebo in Patients With Symptomatic Knee Osteoarthritis

This was a multicenter, randomized, double-blind, placebo-controlled Phase IIb study evaluating intra-articular LNA043 in patients with knee osteoarthritis.

Study Overview

• Status: Terminated
• Conditions: Osteoarthritis
• Intervention / Treatment: Drug: LNA043; Drug: Placebo

Detailed Description

The study was structured as a two-period design:

• A 2-year Core Period, followed by
• A 3-year Extension Period, consisting of 2 years of continued treatment and 1 year of follow-up, totaling 5 years.

Participants were randomized in a 1:1:1:1:1 ratio into five treatment arms:

• LNA043 20 mg Q4w ×3, repeated every 6 months.
• LNA043 40 mg ×1 and placebo Q4w ×2, repeated every 6 months.
• LNA043 40 mg Q4w ×3 followed six months later by placebo Q4w ×3, repeated every 12 months.
• LNA043 40 mg Q4w ×3, repeated every 6 months.
• Placebo Q4w ×3, repeated every 6 months.

All injections were administered intra-articularly (i.a.) to the target knee. Placebo injections (saline solution) were used throughout the study to maintain blinding and ensure consistency in injection frequency across arms.

During the Extension Period:

• Participants from the 6-month cycle arms continued with a single injection of the same LNA043 dose every 6 months.
• Participants from the 12-month cycle arm received LNA043 40 mg every 12 months and placebo every other 6 months.
• Participants who received placebo during the Core Period continued with a single injection of the same placebo every 6 months.

The final year of the Extension Period was a no-treatment follow-up phase for all participants.

The study was terminated early following the Week 104 primary endpoint analysis due to lack of effect.There was no safety related reasons for early termination or safety concerns for the subjects in the study.

• Study Type: Interventional
• Enrollment (Actual): 576
• Phase: Phase 2

Contacts and Locations

Study Locations

• Argentina
  • Caba, Argentina, C1428AZF
    • Novartis Investigative Site
  • Córdoba, Argentina, X5000EOC
    • Novartis Investigative Site
  • San Miguel de Tucumán, Argentina, 4000
    • Novartis Investigative Site
• Australia
  • Christchurch, Australia, 8011
    • Novartis Investigative Site
  • St Leonards, Australia, 2065
    • Novartis Investigative Site
  • Waikanae Beach, Australia, 5036
    • Novartis Investigative Site
  • New South Wales
    • Broadmeadow, New South Wales, Australia, 2292
      • Novartis Investigative Site
  • Queensland
    • Maroochydore, Queensland, Australia, 4558
      • Novartis Investigative Site
  • South Australia
    • Woodville South, South Australia, Australia, 5011
      • Novartis Investigative Site
  • Tasmania
    • Hobart, Tasmania, Australia, 7000
      • Novartis Investigative Site
  • Victoria
    • Malvern East, Victoria, Australia, 3145
      • Novartis Investigative Site
• Canada
  • Quebec
    • Québec, Quebec, Canada, G1V 3M7
      • Novartis Investigative Site
    • Trois-Rivières, Quebec, Canada, G9A 3Y2
      • Novartis Investigative Site
• China
  • Bengbu, China, 233004
    • Novartis Investigative Site
  • Beijing Municipality
    • Beijing, Beijing Municipality, China, 100044
      • Novartis Investigative Site
• Czechia
  • Brno, Czechia, 638 00
    • Novartis Investigative Site
  • Uherské Hradiště, Czechia, 686 01
    • Novartis Investigative Site
  • CZE
    • Brno-Zidonice, CZE, Czechia, 61500
      • Novartis Investigative Site
  • Czech Republic
    • Brno, Czech Republic, Czechia, 66250
      • Novartis Investigative Site
    • Pardubice, Czech Republic, Czechia, 530 02
      • Novartis Investigative Site
• Denmark
  • Aarhus N, Denmark, 8200
    • Novartis Investigative Site
  • Gandrup, Denmark, 9362
    • Novartis Investigative Site
  • Vejle, Denmark, 7100
    • Novartis Investigative Site
• Estonia
  • Tallinn, Estonia, 10128
    • Novartis Investigative Site
  • Tartu, Estonia, 50708
    • Novartis Investigative Site
• India
  • Pune, India, 411019
    • Novartis Investigative Site
  • Gujarat
    • Vadodara, Gujarat, India, 390022
      • Novartis Investigative Site
  • Karnataka
    • Belagavi, Karnataka, India, 590010
      • Novartis Investigative Site
  • Uttar Pradesh
    • Lucknow, Uttar Pradesh, India, 226003
      • Novartis Investigative Site
• Japan
  • Chuoh-ku, Japan, 104-0031
    • Novartis Investigative Site
  • Osaka, Japan, 543-0027
    • Novartis Investigative Site
  • Tokyo
    • Shinagawa, Tokyo, Japan, 140 0014
      • Novartis Investigative Site
    • Shinjuku Ku, Tokyo, Japan, 160-0008
      • Novartis Investigative Site
    • Suginami, Tokyo, Japan, 166-0002
      • Novartis Investigative Site
• Mexico
  • Ciudad de, Mexico, CP 06700
    • Novartis Investigative Site
  • Jalisco
    • Guadalajara, Jalisco, Mexico, 44650
      • Novartis Investigative Site
  • Sinaloa
    • Culiacán, Sinaloa, Mexico, 80000
      • Novartis Investigative Site
• Poland
  • Kielce, Poland, 25-017
    • Novartis Investigative Site
  • Krakow, Poland, 31-501
    • Novartis Investigative Site
  • Poznan, Poland, 60-446
    • Novartis Investigative Site
  • Warsaw, Poland, 02-677
    • Novartis Investigative Site
• Spain
  • A Coruña, Spain, 15006
    • Novartis Investigative Site
  • Madrid, Spain, 28046
    • Novartis Investigative Site
  • Seville, Spain, 41010
    • Novartis Investigative Site
  • A Coruna
    • Santiago, A Coruna, Spain, 15705
      • Novartis Investigative Site
  • Barcelona
    • Sabadell, Barcelona, Spain, 08208
      • Novartis Investigative Site
  • Catalonia
    • Barcelona, Catalonia, Spain, 08003
      • Novartis Investigative Site
• Taiwan
  • Changhua, Taiwan, 50006
    • Novartis Investigative Site
  • Tainan, Taiwan, 704302
    • Novartis Investigative Site
• United Kingdom
  • Barnet, United Kingdom, EN5 3DJ
    • Novartis Investigative Site
  • Norwich, United Kingdom, NR4 7UY
    • Novartis Investigative Site
  • Scotland
    • Glasgow, Scotland, United Kingdom, G51 4TF
      • Novartis Investigative Site
• United States
  • Arizona
    • Phoenix, Arizona, United States, 85018
      • Elite Clinical Studies
    • Tucson, Arizona, United States, 85712
      • Tucson Orthopedic Institute PC
  • California
    • La Mesa, California, United States, 91942
      • Sharps Hospital Grossmont
    • Lincoln, California, United States, 95648
      • Clinical Trials Research
    • Long Beach, California, United States, 90806
      • Long Beach Clinical Trials
    • Riverside, California, United States, 92503
      • Artemis Institute Clinical Research
    • Sacramento, California, United States, 95821
      • Northern California Research
    • San Diego, California, United States, 92103
      • Arthemis Clinical Research
  • Connecticut
    • Stamford, Connecticut, United States, 06905
      • Stamford Therapeutics Consortium LLC
  • Florida
    • Ocoee, Florida, United States, 34761
      • Sensible Healthcare
    • Tampa, Florida, United States, 33603
      • Clinical Research of West Florida Inc
    • Winter Park, Florida, United States, 32789
      • Conquest Research
  • Illinois
    • Chicago, Illinois, United States, 60607
      • Chicago Clinical Research Inst
  • Louisiana
    • Marrero, Louisiana, United States, 70072
      • Tandem Clinical Research
  • Maryland
    • Wheaton, Maryland, United States, 20902
      • The Center for Rheumatology and Bone Research
  • Missouri
    • Kansas City, Missouri, United States, 64114
      • Center For Pharmaceutical Research
  • New York
    • Hartsdale, New York, United States, 10530
      • Drug Trials America
  • Tennessee
    • Knoxville, Tennessee, United States, 37920
      • AMR Knoxville
  • Texas
    • Dallas, Texas, United States, 75231
      • Metroplex Clinical Research
    • Sugar Land, Texas, United States, 77479
      • Pioneer Research Solutions
  • Virginia
    • Charlottesville, Virginia, United States, 22911
      • Charlottesville Medical Research
    • Fairfax, Virginia, United States, 22033
      • Annapolis Rheumatology LLC
    • Richmond, Virginia, United States, 23238
      • Virginia Ispine Physicians PC

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 40 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Key Inclusion Criteria:

• Males and females between 40 and 75 years of age
• Body mass index (BMI) < 40 kg/m2
• Diagnosis of primary tibiofemoral knee OA by standard American College of Rheumatology clinical and radiographic criteria

Key Exclusion Criteria:

• Participants with radiographic knee OA K-L grade = 4 on the non-target knee
• Arthroscopy of the target knee within the 6 months prior to Screening
• Hemoglobin < 8.5 g/dL (85 g/L) or platelet count < 100,000/μL

Study Plan

How is the study designed?

Design Details

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

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm 1: LNA043 40 mg Q4W x3, Q6m; Core Period: Three i.a. injections of LNA043 40 mg, administered once every 4 weeks (Q4W ×3), repeated every 6 months. Extension Period: One i.a. injection of LNA043 40 mg every 6 months for 2 years.	Drug: LNA043; LNA043 was administered intra-articularly in various dosing regimens across four active treatment arms: Arm 1: LNA043 40 mg Q4W ×3, repeated every 6 months; Arm 2: LNA043 40 mg Q4W ×3, followed six months later by placebo Q4W ×3, repeated every 12 months; Arm 3: LNA043 20 mg Q4W ×3, repeated every 6 months; Arm 4: LNA043 40 mg ×1, repeated every 6 months During the Extension Period, participants continued with either single injections every 6 or 12 months, based on their Core Period assignment.
Experimental: Arm 2: LNA043 40 mg Q4W x3, Q12m; Core Period: Three i.a. injections of LNA043 40 mg (Q4W ×3), followed six months later by three placebo injections (Q4W ×3). Extension Period: One i.a. injection of LNA043 40 mg every 12 months for 2 years, with a placebo injection administered six months after each LNA043 dose to maintain blinding.	Drug: LNA043; LNA043 was administered intra-articularly in various dosing regimens across four active treatment arms: Arm 1: LNA043 40 mg Q4W ×3, repeated every 6 months; Arm 2: LNA043 40 mg Q4W ×3, followed six months later by placebo Q4W ×3, repeated every 12 months; Arm 3: LNA043 20 mg Q4W ×3, repeated every 6 months; Arm 4: LNA043 40 mg ×1, repeated every 6 months During the Extension Period, participants continued with either single injections every 6 or 12 months, based on their Core Period assignment.; Drug: Placebo; Placebo (saline solution for injection) was administered intra-articularly in various regimens to maintain blinding and ensure consistency in injection frequency across all arms: Arm 2: Placebo Q4W ×3 administered six months after LNA043 Q4W ×3; Arm 4: Two placebo injections following LNA043 40 mg ×1 to complete the 3-injection cycle every 6 months; Placebo Arm: Placebo Q4W ×3 every 6 months throughout the Core and Extension Periods. In the Extension Period, placebo injections were used to match the frequency of active arms.
Experimental: Arm 3: LNA043 20 mg Q4W x3, Q6m; Core Period: Three i.a. injections of LNA043 20 mg, administered once every 4 weeks (Q4W ×3), repeated every 6 months. Extension Period: One i.a. injection of LNA043 20 mg every 6 months for 2 years.	Drug: LNA043; LNA043 was administered intra-articularly in various dosing regimens across four active treatment arms: Arm 1: LNA043 40 mg Q4W ×3, repeated every 6 months; Arm 2: LNA043 40 mg Q4W ×3, followed six months later by placebo Q4W ×3, repeated every 12 months; Arm 3: LNA043 20 mg Q4W ×3, repeated every 6 months; Arm 4: LNA043 40 mg ×1, repeated every 6 months During the Extension Period, participants continued with either single injections every 6 or 12 months, based on their Core Period assignment.
Experimental: Arm 4: LNA043 40 mg x1, Q6m; Core Period: One i.a. injection of LNA043 40 mg, followed by two placebo injections (Q4W ×3), repeated every 6 months. Extension Period: One i.a. injection of LNA043 40 mg every 6 months for 2 years.	Drug: LNA043; LNA043 was administered intra-articularly in various dosing regimens across four active treatment arms: Arm 1: LNA043 40 mg Q4W ×3, repeated every 6 months; Arm 2: LNA043 40 mg Q4W ×3, followed six months later by placebo Q4W ×3, repeated every 12 months; Arm 3: LNA043 20 mg Q4W ×3, repeated every 6 months; Arm 4: LNA043 40 mg ×1, repeated every 6 months During the Extension Period, participants continued with either single injections every 6 or 12 months, based on their Core Period assignment.; Drug: Placebo; Placebo (saline solution for injection) was administered intra-articularly in various regimens to maintain blinding and ensure consistency in injection frequency across all arms: Arm 2: Placebo Q4W ×3 administered six months after LNA043 Q4W ×3; Arm 4: Two placebo injections following LNA043 40 mg ×1 to complete the 3-injection cycle every 6 months; Placebo Arm: Placebo Q4W ×3 every 6 months throughout the Core and Extension Periods. In the Extension Period, placebo injections were used to match the frequency of active arms.
Placebo Comparator: Placebo; Core Period: Three i.a. injections of placebo, administered once every 4 weeks (Q4W ×3), repeated every 6 months. Extension Period: One i.a. injection of placebo every 6 months for 2 years.	Drug: Placebo; Placebo (saline solution for injection) was administered intra-articularly in various regimens to maintain blinding and ensure consistency in injection frequency across all arms: Arm 2: Placebo Q4W ×3 administered six months after LNA043 Q4W ×3; Arm 4: Two placebo injections following LNA043 40 mg ×1 to complete the 3-injection cycle every 6 months; Placebo Arm: Placebo Q4W ×3 every 6 months throughout the Core and Extension Periods. In the Extension Period, placebo injections were used to match the frequency of active arms.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in Cartilage Thickness in the Central Medial Tibiofemoral Compartment (cMTFC) of the Target Knee at Week 104	The cartilage thickness in the cMTFC of the target knee was assessed by quantitative Magnetic Resonance Imaging (qMRI). The change from baseline at Week 104 was calculated. A negative change from baseline indicated a reduction in the cartilage thickness	Baseline, Week 104

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in Western Ontario and McMaster Universities Arthritis Index (WOMAC) Pain Scale at Week 104	The WOMAC is a widely used self-administered health status measure used in assessing pain, stiffness, and function in patients with OA of the hip or knee. The WOMAC pain scale included five questions about pain during specific activities such as walking on a flat surface, going up or down stairs, during the night while in bed, sitting or lying down and standing upright. Each item was rated on an 11-point numeric rating scale (NRS) from 0 (no pain) to 10 (worst imaginable pain). The WOMAC pain subscale was calculated as the sum of the 5 pain items, ranging from 0 to 50, with higher scores indicating worse pain. Scores were then re-scaled to normalized 0-100. Change from baseline at Week 104 was assessed, where a negative change indicated improvement.	Baseline, Week 104
Change From Baseline in WOMAC Pain Walking on a Flat Surface Item at Week 104	The WOMAC is a widely used self-administered health status measure used in assessing pain, stiffness, and function in patients with OA of the hip or knee. The WOMAC pain scale included five questions about pain during specific activities such as walking on a flat surface, going up or down stairs, during the night while in bed, sitting or lying down and standing upright. Each item was rated on an 11-point NRS from 0 (no pain) to 10 (worst imaginable pain). Scores were then re-scaled to normalized 0-100. The change from baseline at Week 104 in WOMAC pain walking on a flat surface item score was assessed, where a negative change indicated improvement.	Baseline, Week 104
Change From Baseline in WOMAC Function Scale at Week 104	The WOMAC is a widely used self-administered health status measure used in assessing pain, stiffness, and function in patients with OA of the hip or knee. The WOMAC functional subscale included 17 questions that measured how OA affected their daily activities including going up and down stairs, sitting, standing, squatting to the floor, walking, getting in a car, shopping, putting on and taking off socks, getting out of bed, lying in bed, bathing, sitting, getting on and off the toilet, heavy domestic duties, and light domestic duties. Each item was rated on an 11-point NRS from 0 (no limitation) to 10 (extreme limitation). The WOMAC functional subscale was calculated as the sum of the 17 pain items, ranging from 0 to 170, with higher scores indicating more severe limitations. Scores were then re-scaled to normalized 0-100. Change from baseline at Week 104 was assessed, where a negative change indicated improvement.	Baseline, Week 104
Change From Baseline in Cartilage Thickness in the Total Tibiofemoral Compartments (TFCs) in the Target Knee at Week 104	The cartilage thickness in the total TFC in the target knee was assessed by qMRI. The change from baseline at Week 104 was calculated. A negative change from baseline indicated a reduction in the cartilage thickness.	Baseline, Week 104
Change From Baseline in Cartilage Thickness in the Medial TFCs in the Target Knee at Week 104	The cartilage thickness in the medial TFC in the target knee was assessed by qMRI at Week 104. The change from baseline at Week 104 was calculated. A negative change from baseline indicated a reduction in the cartilage thickness.	Baseline, Week 104
Change From Baseline in Cartilage Thickness in the Lateral TFCs in the Target Knee at Week 104	The cartilage thickness in the lateral TFC in the target knee was assessed by qMRI at Week 104. The change from baseline at Week 104 was calculated. A negative change from baseline indicated a reduction in the cartilage thickness.	Baseline, Week 104
Change From Baseline at Week 104 in the Osteoarthritis Research Society International (OARSI) Physical Performance-based Assessment: 40-meter (4×10m) Fast-paced Walk Test	The OARSI 40-meter (4x10m) fast-paced walk test assessed walking speed and functional mobility over a short distance. Participants were instructed to walk as quickly and safely as possible along a 10-meter walkway, turn around a cone, and repeat the sequence four times for a total of 40 meters. The time taken to complete the 40 meters was recorded. A shorter time indicated better performance. The change from baseline at Week 104 was assessed. A negative change from baseline indicated improvement in physical function.	Baseline, Week 104
Change From Baseline at Week 104 in the OARSI Physical Performance-based Assessments: 30-second Chair Stand Test	The OARSI 30-second chair stand test assessed the number of times a participant stood up from a seated position and sat back down within 30 seconds. A higher number of repetitions reflected better lower limb strength and physical function. The change from baseline was evaluated at Week 104. A positive change from baseline indicated an improvement in physical function.	Baseline, Week 104
Change From Baseline at Week 104 in the OARSI Physical Performance-based Assessments: 6-minute Walking Test	This performance-based endpoint assessed submaximal aerobic capacity and functional walking ability. Participants were instructed to walk as far as possible in six minutes along a standardized, level walkway, following the guidelines of the American Thoracic Society. The total distance walked in meters was recorded. A greater distance walked indicated better physical function. The change from baseline was evaluated at Week 104. A positive change from baseline reflected an improvement in physical function.	Baseline, Week 104
Percentage of Participants With Loss of Medial Minimum Joint Space Width ≥0.70 mm From Baseline at Week 104	Percentage of participants who experienced loss of medial minimum joint space width ≥ 0.70 mm from baseline as measured by X-ray at Week 104	Baseline, Week 104
Number of Participants With Anti-drug Antibodies (ADAs) and Neutralizing Antibodies (NAb) Status	ADA status was categorized based on baseline and post-baseline results as follows: Subjects with ADA-negative sample at baseline: Participants with a negative ADA result at baseline. Subjects with ADA-positive sample at baseline: Participants with a positive ADA result at baseline. Subjects with ADA-positive NAb sample at baseline: Participants with a positive ADA and neutralizing antibody (NAb) result at baseline. Subjects with treatment-emergent ADA-positive: Participants with a positive ADA result post-baseline and a negative result at baseline. Subjects with treatment-emergent ADA-negative: Participants with a negative ADA result at baseline and all post-baseline samples also negative. Subjects with treatment-emergent ADA-inconclusive: Participants who did not meet any of the above definitions	From baseline up to end of study, assessed up to 3.6 years

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals
• Investigators: Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Publications and helpful links

General Publications

• Gerwin N, Scotti C, Halleux C, Fornaro M, Elliott J, Zhang Y, Johnson K, Shi J, Walter S, Li Y, Jacobi C, Laplanche N, Belaud M, Paul J, Glowacki G, Peters T, Wharton KA Jr, Vostiar I, Polus F, Kramer I, Guth S, Seroutou A, Choudhury S, Laurent D, Gimbel J, Goldhahn J, Schieker M, Brachat S, Roubenoff R, Kneissel M. Angiopoietin-like 3-derivative LNA043 for cartilage regeneration in osteoarthritis: a randomized phase 1 trial. Nat Med. 2022 Dec;28(12):2633-2645. doi: 10.1038/s41591-022-02059-9. Epub 2022 Dec 1.

Helpful Links

• A Plain Language Trial Summary is available on www.novctrd.com

Study record dates

Study Major Dates

• Study Start (Actual): May 31, 2021
• Primary Completion (Actual): September 29, 2024
• Study Completion (Actual): May 29, 2025

Study Registration Dates

• First Submitted: February 26, 2021
• First Submitted That Met QC Criteria: April 27, 2021
• First Posted (Actual): April 28, 2021

Study Record Updates

• Last Update Posted (Actual): April 2, 2026
• Last Update Submitted That Met QC Criteria: March 31, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Keywords: knee; arthritis; OA; LNA043; knees
• Additional Relevant MeSH Terms: Musculoskeletal Diseases; Joint Diseases; Rheumatic Diseases; Arthritis; Osteoarthritis
• Other Study ID Numbers: CLNA043A12202; 2020-004897-22 (EudraCT Number); 2023-509937-37-00 (Registry Identifier: EU CT NUMBER)

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