A Safety and Efficacy Study of Anti-inflammatory (Canakinumab) and Cartilage Stimulating (LNA043) Drugs Injected Into the Knee Joint of Participants With Knee Osteoarthritis (OA)

Phase 2TerminatedNCT04814368

Novartis Pharmaceuticals23 enrolled

Overview

The study was established to show safety and efficacy of canakinumab and LNA043 in patients with knee osteoarthritis (OA).

This was a non-confirmatory, randomized, four arm, placebo-controlled, participant-, investigator and sponsor-blinded study in participants with symptomatic knee OA with synovial inflammation.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

QUADRUPLE

Enrollment

Conditions

Knee Osteoarthritis

Interventions

canakinumabBIOLOGICAL

Canakinumab 600 mg single intra-articular injection (into the knee) on Day 1

LNA043BIOLOGICAL

LNA043 40 mg intra-articular injection (into the knee) every 4 weeks, on Days 15, 43 and 71

Placebo to canakinumabOTHER

Placebo to canakinumab single intra-articular injection (into the knee) on Day 1

Eligibility

Sex: ALLMin age: 40 YearsMax age: 80 Years

Medical Language ↔ Plain English

Inclusion Criteria: * Moderate to severe OA pain (corresponding to NRS Pain ≥5 to ≤9) in the target knee for the majority of days in the last 3 months prior to Screening * KOOS pain subscale \<60 for the target knee during Screening * High sensitivity C-reactive Protein (hsCRP) ≥1.8 mg/L * Radiographic KL grade 2 to 4 knee OA and joint space width (JSW) 2.0-4.0 mm (men) or 1.5-3.5 mm (women) in the medial tibiofemoral compartment (TFC) in the target knee * Contrast-enhanced MRI (CE-MRI) diagnosed moderate or severe knee synovitis based on an established synovititis scoring system (moderate score 9-12 or severe score ≥13) Exclusion Criteria: * History of, or planned; knee replacement (partial or total) in either knee; arthroscopy or lavage in either knee within 6 months prior to screening; any other previous surgical intervention in the target knee, or for the contralateral knee within 12 months prior to Screening, including mosaicplasty, microfracture, meniscectomy \>50% or osteotomy * Moderate to severe pain in the contralateral knee for the majority of days in the last 3 months prior to screening * Malalignment \>7.5° in the target knee (either varus or valgus) * Any diagnosis of systemic inflammatory arthritis or connective tissue disease, including but not limited to rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, gout, Paget's disease, systemic lupus erythematosus) or other systemic condition that might confound assessment of OA (e.g. fibromyalgia) * Ipsilateral hip OA or hip prosthesis recently implanted (within 1 year prior to screening) or hip replacement on either side planned within the study period

Locations (11)

Horizon Clinical Research

La Mesa, California, United States

Clinical Res Of W Florida

Clearwater, Florida, United States

Precision Clinical Research LLC

Sunrise, Florida, United States

Outcomes

Primary Outcomes

Change in Cartilage Volume in the Index Region Measured by MRI at Day 197 (Placebo to ACZ885+LNA043 Versus Placebo to ACZ885)

Magnetic resonance images (MRI) were obtained from the target knee to visualize and quantify changes in volume of cartilage in the index region. The index region was defined as the union of the femoral medial anterior (FMA), central (FMC) and posterior (FMP) cartilage subregions in the knee.

Time frame: Baseline, Day 197

Change in Knee Injury and Osteoarthritis Outcome Score (KOOS) Pain Subscale (ACZ885 Versus Placebo to ACZ885)

The KOOS questionnaire is a commonly used instrument to assess the patient's perception about their knee and associated problems. The original KOOS consists of 5 subscales. One of those is the KOOS pain consisting of 9 questions with a recall of 7days. Each question has 5 standardized answer options with a score from 0 to 4. A normalized score (100 indicating no symptoms and 0 indicating extreme symptoms) is calculated for each subscale.

Time frame: Baseline, Day 85

Secondary Outcomes

Number of Participants With Anti-LNA043 Antibodies (Placebo to ACZ885+LNA043 Versus ACZ885 + LNA043)

To evaluate the immunogenicity of LNA043 via validated ligand-binding assay of potential anti-LNA043 antibodies.

Time frame: From pre-dose up to Day 365

Maximum Serum Concentration (Cmax) of ANGPTL3 (Placebo to ACZ885+LNA043 Versus ACZ885+LNA043)

ANGPTL3 is a protein that is primarily involved in the lipid metabolism but has recently been shown to have chondrogenic and chondroprotective effects. Cmax is defined as the maximum (peak) observed concentration following a dose. ANGPTL3 serum concentrations were determined using the actual recorded sampling times and non-compartmental method with Phoenix WinNonlin (Version 8 or higher). ANGPTL3 was determined by a validated ligand binding assay; the anticipated LLOQ is 39.7 pmol/L in serum.

Time frame: Pre-dose Day 1, Day 15, Day 43 and 60 minutes after first injection of LNA043 on Day 15

Data from ClinicalTrials.gov

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LV Research

Las Vegas, Nevada, United States

Lucas Research

Morehead City, North Carolina, United States

Novartis Investigative Site

Prague, Czech Republic, Czechia

Novartis Investigative Site

Tartu, Estonia

Novartis Investigative Site

Kecskemét, Bács-Kiskun county, Hungary

Novartis Investigative Site

Budapest, Hungary

Novartis Investigative Site

Riga, Latvia

...and 1 more locations

Synovial Fluid Concentrations of ANGPTL3 (Placebo to ACZ885+LNA043 Versus ACZ885+LNA043)

ANGPTL3 is a protein that is primarily involved in the lipid metabolism but has recently been shown to have chondrogenic and chondroprotective effects. ANGPTL3 was measured in synovial fluid.

Time frame: Pre-dose on Days 1, 15, 43, and 71

Maximum Serum Concentration (Cmax) of LNA043 (Placebo to ACZ885+LNA043 Versus ACZ885+LNA043)

Cmax is defined as the maximum (peak) observed concentration following a dose. LNA043 serum concentrations were determined using the actual recorded sampling times and non-compartmental method with Phoenix WinNonlin (Version 8 or higher). LNA043 was determined by a validated immuno-capture and LC-MS/MS method; the anticipated LLOQ is 10 ng/mL in serum.

Time frame: Day 15: pre-dose, 20, 60, 120 and 240 minutes, and 8 and 24 hours post LNA043 first injection on Day 15

Time to Reach Maximum Serum Concentration (Tmax) of LNA043 (Placebo to ACZ885+LNA043 Versus ACZ885+LNA043)

Tmax is the time to reach maximum (peak) drug concentration after single-dose administration (time). LNA043 serum concentrations were determined using the actual recorded sampling times and non-compartmental method with Phoenix WinNonlin (Version 8 or higher). LNA043 was determined by a validated immuno-capture and LC-MS/MS method; the anticipated LLOQ is 10 ng/mL in serum.

Time frame: Day 15: pre-dose, 20, 60, 120 and 240 minutes, and 8 and 24 hours post LNA043 first injection on Day 15

Area Under Serum Concentration-time Curve From Time Zero to the Last Measurable Concentration Sampling Time (AUClast) of LNA043 (Placebo to ACZ885+LNA043 Versus ACZ885+LNA043)

AUClast is the area under the serum concentration-time curve from time zero to the time of last quantifiable concentration (tlast) of LNA043. LNA043 serum concentrations were determined using the actual recorded sampling times and non-compartmental method with Phoenix WinNonlin (Version 8 or higher). LNA043 was determined by a validated immuno-capture and LC-MS/MS method; the anticipated LLOQ is 10 ng/mL in serum.

Time frame: Day 15: pre-dose, 20, 60, 120 and 240 minutes, and 8 and 24 hours post LNA043 first injection on Day 15

Change in Cartilage Volume of the Index Region Measured by MRI at Day 197 and Day 365 (ACZ885+LNA043 Versus ACZ885, and ACZ885+LNA043 Versus Placebo to ACZ885+LNA043)

Time frame: Baseline, Day 197 and Day 365

Change in Cartilage Volume of the Index Region Measured by MRI at Day 365 (Placebo to ACZ885+LNA043 Versus Placebo to ACZ885)

Time frame: Baseline, Day 365

Change in Cartilage Thickness of the Index Region Measured by MRI at Day 197 and Day 365 (ACZ885+LNA043 Versus ACZ885, and ACZ885+LNA043 Versus Placebo to ACZ885+LNA043)

Magnetic resonance images (MRI) were obtained from the target knee to visualize and quantify changes in thickness of cartilage in the index region. The index region was defined as the union of the femoral medial anterior (FMA), central (FMC) and posterior (FMP) cartilage subregions in the knee.

Time frame: Baseline, Day 197 and 365

Change in Cartilage Thickness of the Index Region Measured by MRI at Day 197 and Day 365 (Placebo to ACZ885+LNA043 Versus Placebo to ACZ885)

Time frame: Baseline, Day 197 and 365

Change in Synovitis Level Measured From Ktrans by Dynamic Contrast Enhanced MRI (DCE-MRI) (ACZ885 Versus Placebo to ACZ885)

Magnetic resonance images (MRI) were obtained from the target knee with dynamic contrast enhancement (DCE) to visualize and quantify changes in k-trans as a marker of the activity of synovial inflammation. During the DCE-MRI acquisition, while the contrast agent is preferentially taken up at sites with an increased perfusion due to the formation of new vessels with high porosity (such as the inflamed synovial membrane), a temporal variation of the MRI signal intensity occurs. When the contrast distributes through the intravascular and extravascular spaces, the MR signal intensity in the image volume elements (voxels) of the target tissue changes over time, generating so-called signal intensity (SI) curves. These curves can then be analyzed to derive parameters related to tissue perfusion. The parameter of primary interest was the volume transfer rate of the gadolinium-based contrast agent (GBCA) from the blood plasma in synovium, commonly referred to as Ktrans.

Time frame: Baseline, Day 85

Change in Numeric Rating Scale (NRS) Over Time (ACZ885 Versus Placebo to ACZ885)

The Numerical Rating Scale (NRS) Pain is a subjective assessment in which individuals rate their pain on an eleven-point numerical scale. The scale ranges from 0 (no pain) to 10 (worst possible pain). The NRS Pain instrument had a recall period of 24 hours and the participants were asked to rate the pain intensity at its worst.

Time frame: Baseline, Day 15, 29, 43, 57, 71, 85

Change in Numeric Rating Scale (NRS) Over Time (ACZ885+LNA043 Versus ACZ885, and ACZ885+LNA043 Versus Placebo to ACZ885+LNA043)

Time frame: Baseline, Day 15, 29, 43, 57, 71, 85, 197 and 365

Change in Knee Injury and Osteoarthritis Outcome Score (KOOS) Pain Subscale Over Time (ACZ885 Versus Placebo to ACZ885)

Time frame: Baseline, Day 15, 29, 43, 57, 71, 85

Change in Knee Injury and Osteoarthritis Outcome Score (KOOS) Pain Subscale Over Time (ACZ885+LNA043 Versus ACZ885, and ACZ885+LNA043 Versus Placebo to ACZ885+LNA043)

Time frame: Baseline, Day 15, 29, 43, 57, 71, 85, 197 and 365

Change in Knee Injury and Osteoarthritis Outcome Score (KOOS) Function in Daily Living (ADL) Subscale Over Time (ACZ885 Versus Placebo to ACZ885)

The KOOS questionnaire is a commonly used instrument to assess the patient's perception about their knee and associated problems. The original KOOS consists of 5 subscales. One of those is the KOOS Function in Daily Living (ADL) subscale consisting of 17 questions with a recall of 7days. Each question has 5 standardized answer options with a score from 0 to 4. A normalized score (100 indicating no symptoms and 0 indicating extreme symptoms) is calculated for each subscale.

Time frame: Baseline, Day 15, 29, 43, 57, 71, 85

Change in Knee Injury and Osteoarthritis Outcome Score (KOOS) Function in Daily Living (ADL) Subscale Over Time (ACZ885+LNA043 Versus ACZ885, and ACZ885+LNA043 Versus Placebo to ACZ885+LNA043)

The KOOS questionnaire is a commonly used instrument to assess the patient's perception about their knee and associated problems. The original KOOS consists of 5 subscales. One of those is the KOOS Function in Daily Living (ADL) subscale consisting of 17 questions with a recall of 7days. Each question has 5 standardized answer options with a score from 0 to 4. A normalized score (100 indicating no symptoms and 0 indicating extreme symptoms) is calculated for each subscale.

Time frame: Baseline, Day 15, 29, 43, 57, 71, 85, 197 and 365