Osteoarthritis
Conditions
Keywords
LNA043, knee, arthritis, OA, knees
Brief summary
This was a multicenter, randomized, double-blind, placebo-controlled Phase IIb study evaluating intra-articular LNA043 in patients with knee osteoarthritis.
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.
Interventions
DRUGLNA043
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.
DRUGPlacebo
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.
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
40 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Cartilage Thickness in the Central Medial Tibiofemoral Compartment (cMTFC) of the Target Knee at Week 104 | Baseline, 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 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Western Ontario and McMaster Universities Arthritis Index (WOMAC) Pain Scale at Week 104 | Baseline, 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. |
| Change From Baseline in WOMAC Pain Walking on a Flat Surface Item at Week 104 | Baseline, 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. |
| Change From Baseline in WOMAC Function Scale at Week 104 | Baseline, 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. |
| Change From Baseline in Cartilage Thickness in the Total Tibiofemoral Compartments (TFCs) in the Target Knee at Week 104 | Baseline, 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. |
| Change From Baseline in Cartilage Thickness in the Medial TFCs in the Target Knee at Week 104 | Baseline, 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. |
| Change From Baseline in Cartilage Thickness in the Lateral TFCs in the Target Knee at Week 104 | Baseline, 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. |
| 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 | Baseline, Week 104 | 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. |
| Change From Baseline at Week 104 in the OARSI Physical Performance-based Assessments: 30-second Chair Stand Test | Baseline, Week 104 | 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. |
| Change From Baseline at Week 104 in the OARSI Physical Performance-based Assessments: 6-minute Walking Test | Baseline, Week 104 | 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. |
| Percentage of Participants With Loss of Medial Minimum Joint Space Width ≥0.70 mm From Baseline at Week 104 | Baseline, 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 |
| Number of Participants With Anti-drug Antibodies (ADAs) and Neutralizing Antibodies (NAb) Status | From baseline up to end of study, assessed up to 3.6 years | 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 |
Countries
Argentina, Australia, Canada, China, Czechia, Denmark, Estonia, India, Japan, Mexico, Poland, Spain, Taiwan, United Kingdom, United States
Contacts
STUDY_DIRECTORNovartis Pharmaceuticals
Novartis Pharmaceuticals
Participant flow
Recruitment details
Participants were recruited from 76 centers across 16 countries. Only participants who completed the Core Period were eligible to enter the Extension Period. One participant from Arm 4 who completed the Core Period did not enter the Extension Period and is therefore not included in the Extension Period counts.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 60.0 Years STANDARD_DEVIATION 8.07 |
| Race/Ethnicity, Customized American Indian or Alaska Native | 4 Participants |
| Race/Ethnicity, Customized Asian | 24 Participants |
| Race/Ethnicity, Customized Black or African American | 4 Participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race/Ethnicity, Customized Unknown | 0 Participants |
| Race/Ethnicity, Customized White | 80 Participants |
| Sex: Female, Male Female | 64 Participants |
| Sex: Female, Male Male | 50 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 114 | 0 / 117 | 1 / 116 | 1 / 114 | 2 / 461 | 1 / 115 |
| other Total, other adverse events | 69 / 114 | 69 / 117 | 77 / 116 | 78 / 114 | 293 / 461 | 68 / 115 |
| serious Total, serious adverse events | 17 / 114 | 13 / 117 | 13 / 116 | 11 / 114 | 54 / 461 | 13 / 115 |
Outcome results
None listed