Osteoarthritis
Conditions
Keywords
Articular cartilage, partial thickness cartilage lesion, knee cartilage, regeneration, osteoarthritis, adult
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.
Interventions
BIOLOGICALLNA043
LNA043 intra-articular injection
OTHERPlacebo
Placebo intra-articular injection
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Intervention model description
A total of 142 participants were randomized, but only 141 received treatment. One participant in Part B was discontinued due to poor veins that were not adequate for blood samples.
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
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).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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 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 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 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
| 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 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 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 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 |
| 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 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". |
| 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". |
Countries
Czechia, Denmark, United States
Participant flow
Pre-assignment details
A total of 142 participants were randomized, but only 141 received treatment. One participant in Part B was discontinued due to poor veins that were not adequate for blood samples.
Participants by arm
| Arm | Count |
|---|---|
| LNA043 20 mg Part A Part A: a single intra-articular injection of 20 mg LNA043 was administered weekly for 4 weeks for participants with focal cartilage lesions of the knee. | 43 |
| Placebo Part A Part A: a single intra-articular injection of matching placebo (0 mg) was administered weekly for 4 weeks for participants with focal cartilage lesions of the knee | 15 |
| LNA043 20 mg Part B Part B: a single intra-articular injection of 20 mg LNA043 was administered every 4 weeks from Week 1 to Week 13 (4 injections) for participants with osteoarthritis. | 27 |
| LNA043 40 mg Part B Part B: a single intra-articular injection of 40 mg LNA043 was administered every 4 weeks from Week 1 to Week 13 (4 injections) for participants with osteoarthritis. | 27 |
| Placebo Part B Part B: a single intra-articular injection of matching placebo (0 mg) was administered every 4 weeks from Week 1 to Week 13 (4 injections) for participants with osteoarthritis | 29 |
| Total | 141 |
Baseline characteristics
| Characteristic | Total | LNA043 20 mg Part A | Placebo Part A | LNA043 20 mg Part B | LNA043 40 mg Part B | Placebo Part B |
|---|---|---|---|---|---|---|
| Age, Customized ≥18 and ≤55 years Part A only | 58 participants | 43 participants | 15 participants | — | — | — |
| Age, Customized ≥18 and ≤64 Part B only | 48 participants | — | — | 18 participants | 15 participants | 15 participants |
| Age, Customized ≥65 and ≤76 years - Part B only | 35 participants | — | — | 9 participants | 12 participants | 14 participants |
| Race/Ethnicity, Customized American Indian or Alaska Native | 1 participants | 0 participants | 1 participants | 0 participants | 0 participants | 0 participants |
| Race/Ethnicity, Customized American Unknow | 1 participants | 0 participants | 1 participants | 0 participants | 0 participants | 0 participants |
| Race/Ethnicity, Customized Asian | 3 participants | 1 participants | 1 participants | 0 participants | 0 participants | 1 participants |
| Race/Ethnicity, Customized Black or African | 12 participants | 0 participants | 1 participants | 7 participants | 1 participants | 3 participants |
| Race/Ethnicity, Customized Other | 1 participants | 0 participants | 0 participants | 0 participants | 0 participants | 1 participants |
| Race/Ethnicity, Customized White | 123 participants | 42 participants | 11 participants | 20 participants | 26 participants | 24 participants |
| Sex: Female, Male Female | 86 Participants | 21 Participants | 5 Participants | 19 Participants | 20 Participants | 21 Participants |
| Sex: Female, Male Male | 55 Participants | 22 Participants | 10 Participants | 8 Participants | 7 Participants | 8 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 | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk | EG009 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 43 | 0 / 15 | 0 / 27 | 0 / 27 | 0 / 29 | 0 / 43 | 0 / 15 | 0 / 27 | 0 / 27 | 0 / 29 |
| other Total, other adverse events | 19 / 43 | 7 / 15 | 6 / 27 | 15 / 27 | 10 / 29 | 16 / 43 | 1 / 15 | 3 / 27 | 5 / 27 | 12 / 29 |
| serious Total, serious adverse events | 0 / 43 | 0 / 15 | 1 / 27 | 0 / 27 | 0 / 29 | 2 / 43 | 0 / 15 | 1 / 27 | 0 / 27 | 2 / 29 |
Outcome results
Primary
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.
Time frame: Baseline up to Week 16, Week 28
Population: Pharmacodynamic (PD) analysis set: Subjects with available PD data
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| LNA043 20 mg Part A | Change From Baseline in Articular Cartilage Collagen Organization in the Deep Cartilage Layer (Femoral and Patellar Lesions) - Part A | Week 16 n=41,14 | 5.30 ms | Standard Error 9.17 |
| LNA043 20 mg Part A | Change From Baseline in Articular Cartilage Collagen Organization in the Deep Cartilage Layer (Femoral and Patellar Lesions) - Part A | Week 28 n=39,15 | 7.86 ms | Standard Error 9.36 |
| Placebo Part A | Change From Baseline in Articular Cartilage Collagen Organization in the Deep Cartilage Layer (Femoral and Patellar Lesions) - Part A | Week 16 n=41,14 | 3.61 ms | Standard Error 15.46 |
| Placebo Part A | Change From Baseline in Articular Cartilage Collagen Organization in the Deep Cartilage Layer (Femoral and Patellar Lesions) - Part A | Week 28 n=39,15 | 1.90 ms | Standard Error 15.08 |
Comparison: Week 1690% CI: [-27.7, 31.08]Mixed Models Analysis
Comparison: Week 2890% CI: [-23.03, 34.97]Mixed Models Analysis
Primary
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.
Time frame: Baseline up to Week 16, Week 28
Population: Pharmacodynamic (PD) analysis set: Subjects with available PD data
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| LNA043 20 mg Part A | Change From Baseline in Articular Cartilage Collagen Organization in the Overall Cartilage (Femoral and Patellar Lesions) - Part A | Week 16 n=43,14 | 3.28 ms | Standard Error 9.78 |
| LNA043 20 mg Part A | Change From Baseline in Articular Cartilage Collagen Organization in the Overall Cartilage (Femoral and Patellar Lesions) - Part A | Week 28 n=39,15 | 5.66 ms | Standard Error 9.9 |
| Placebo Part A | Change From Baseline in Articular Cartilage Collagen Organization in the Overall Cartilage (Femoral and Patellar Lesions) - Part A | Week 16 n=43,14 | 2.79 ms | Standard Error 16.37 |
| Placebo Part A | Change From Baseline in Articular Cartilage Collagen Organization in the Overall Cartilage (Femoral and Patellar Lesions) - Part A | Week 28 n=39,15 | 1.98 ms | Standard Error 15.97 |
Comparison: Week 1690% CI: [-30.73, 31.69]Mixed Models Analysis
Comparison: Week 2890% CI: [-27.04, 34.4]Mixed Models Analysis
Primary
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.
Time frame: Baseline up to Week 16, Week 28
Population: Pharmacodynamic (PD) analysis set: Subjects with available PD data
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| LNA043 20 mg Part A | Change From Baseline in Articular Cartilage Collagen Organization in the Superficial Cartilage Layer (Femoral and Patellar Lesions) - Part A | Week 16 n=17,7 | -13.05 ms | Standard Error 15.68 |
| LNA043 20 mg Part A | Change From Baseline in Articular Cartilage Collagen Organization in the Superficial Cartilage Layer (Femoral and Patellar Lesions) - Part A | Week 28 n=16,9 | -10.45 ms | Standard Error 16.61 |
| Placebo Part A | Change From Baseline in Articular Cartilage Collagen Organization in the Superficial Cartilage Layer (Femoral and Patellar Lesions) - Part A | Week 16 n=17,7 | -13.93 ms | Standard Error 24.73 |
| Placebo Part A | Change From Baseline in Articular Cartilage Collagen Organization in the Superficial Cartilage Layer (Femoral and Patellar Lesions) - Part A | Week 28 n=16,9 | -12.73 ms | Standard Error 22.09 |
Comparison: Week 1690% CI: [-47.27, 49.04]Mixed Models Analysis
Comparison: Week 2890% CI: [-43.11, 47.65]Mixed Models Analysis
Primary
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.
Time frame: Baseline, Week 29, Week 53
Population: Pharmacodynamic (PD) analysis set: participants with baseline and at least one follow-up MRI assessments for thickness of sufficient quality
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| LNA043 20 mg Part A | Change From Baseline of LNA043 to Placebo in Cartilage Thickness in the Femoral Medial Index Region (mm) - Part B | Week 53 n=11,13,7 | -0.01 mm | Standard Error 0.02 |
| LNA043 20 mg Part A | Change From Baseline of LNA043 to Placebo in Cartilage Thickness in the Femoral Medial Index Region (mm) - Part B | Week 29 n=12,13,13 | 0.01 mm | Standard Error 0.02 |
| Placebo Part A | Change From Baseline of LNA043 to Placebo in Cartilage Thickness in the Femoral Medial Index Region (mm) - Part B | Week 53 n=11,13,7 | -0.00 mm | Standard Error 0.02 |
| Placebo Part A | Change From Baseline of LNA043 to Placebo in Cartilage Thickness in the Femoral Medial Index Region (mm) - Part B | Week 29 n=12,13,13 | 0.02 mm | Standard Error 0.02 |
| Placebo Part B | Change From Baseline of LNA043 to Placebo in Cartilage Thickness in the Femoral Medial Index Region (mm) - Part B | Week 53 n=11,13,7 | -0.02 mm | Standard Error 0.03 |
| Placebo Part B | Change From Baseline of LNA043 to Placebo in Cartilage Thickness in the Femoral Medial Index Region (mm) - Part B | Week 29 n=12,13,13 | -0.04 mm | Standard Error 0.02 |
Comparison: Week 29p-value: 0.057490% CI: [0, 0.1]Mixed Models Analysis
Comparison: Week 29p-value: 0.024890% CI: [0.01, 0.11]Mixed Models Analysis
Comparison: Week 53p-value: 0.386490% CI: [-0.05, 0.07]Mixed Models Analysis
Comparison: Week 53p-value: 0.32990% CI: [-0.05, 0.08]Mixed Models Analysis
Primary
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
Time frame: Baseline, Week 29, Week 53
Population: Pharmacodynamic (PD) analysis set: participants with baseline and at least one follow-up MRI assessments for volume of sufficient quality
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| LNA043 20 mg Part A | Change From Baseline of LNA043 to Placebo in Cartilage Volume in the Femoral Medial Index Region (mm3) - Part B | Week 29 n=12,13,13 | 45.52 mm^3 | Standard Error 61.9 |
| LNA043 20 mg Part A | Change From Baseline of LNA043 to Placebo in Cartilage Volume in the Femoral Medial Index Region (mm3) - Part B | Week 53 n=11,13,7 | 75.64 mm^3 | Standard Error 54.48 |
| Placebo Part A | Change From Baseline of LNA043 to Placebo in Cartilage Volume in the Femoral Medial Index Region (mm3) - Part B | Week 29 n=12,13,13 | -12.79 mm^3 | Standard Error 60.38 |
| Placebo Part A | Change From Baseline of LNA043 to Placebo in Cartilage Volume in the Femoral Medial Index Region (mm3) - Part B | Week 53 n=11,13,7 | -36.52 mm^3 | Standard Error 51.21 |
| Placebo Part B | Change From Baseline of LNA043 to Placebo in Cartilage Volume in the Femoral Medial Index Region (mm3) - Part B | Week 29 n=12,13,13 | -154.7 mm^3 | Standard Error 60.25 |
| Placebo Part B | Change From Baseline of LNA043 to Placebo in Cartilage Volume in the Femoral Medial Index Region (mm3) - Part B | Week 53 n=11,13,7 | -152.7 mm^3 | Standard Error 67.72 |
p-value: 0.013190% CI: [54.53, 345.83]Mixed Models Analysis
Comparison: Week 29p-value: 0.054490% CI: [-3.83, 287.56]Mixed Models Analysis
Comparison: Week 53p-value: 0.006790% CI: [80.87, 375.67]Mixed Models Analysis
Comparison: Week 53p-value: 0.093190% CI: [-29.52, 261.94]Mixed Models Analysis
Primary
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
Time frame: Baseline up to end of post treatment follow-up
Population: Safety analysis set
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| LNA043 20 mg Part A | Overview of Number of Participants With Adverse Events and Serious Adverse Events for Part A and Part B | Part A - Follow-up SAE | 2 participants |
| LNA043 20 mg Part A | Overview of Number of Participants With Adverse Events and Serious Adverse Events for Part A and Part B | Part A TEAE | 19 participants |
| LNA043 20 mg Part A | Overview of Number of Participants With Adverse Events and Serious Adverse Events for Part A and Part B | Part A TESAE | 0 participants |
| LNA043 20 mg Part A | Overview of Number of Participants With Adverse Events and Serious Adverse Events for Part A and Part B | Part A - Follow-up AE | 16 participants |
| Placebo Part A | Overview of Number of Participants With Adverse Events and Serious Adverse Events for Part A and Part B | Part A - Follow-up AE | 1 participants |
| Placebo Part A | Overview of Number of Participants With Adverse Events and Serious Adverse Events for Part A and Part B | Part A - Follow-up SAE | 0 participants |
| Placebo Part A | Overview of Number of Participants With Adverse Events and Serious Adverse Events for Part A and Part B | Part A TESAE | 0 participants |
| Placebo Part A | Overview of Number of Participants With Adverse Events and Serious Adverse Events for Part A and Part B | Part A TEAE | 7 participants |
| Placebo Part B | Overview of Number of Participants With Adverse Events and Serious Adverse Events for Part A and Part B | Part B - TESAE | 1 participants |
| Placebo Part B | Overview of Number of Participants With Adverse Events and Serious Adverse Events for Part A and Part B | Part B - Follow-up AE | 1 participants |
| Placebo Part B | Overview of Number of Participants With Adverse Events and Serious Adverse Events for Part A and Part B | Part B - TEAE | 6 participants |
| Placebo Part B | Overview of Number of Participants With Adverse Events and Serious Adverse Events for Part A and Part B | Part B B - Follow-up SAE | 1 participants |
| LNA043 40mg Part B | Overview of Number of Participants With Adverse Events and Serious Adverse Events for Part A and Part B | Part B - TEAE | 15 participants |
| LNA043 40mg Part B | Overview of Number of Participants With Adverse Events and Serious Adverse Events for Part A and Part B | Part B - TESAE | 0 participants |
| LNA043 40mg Part B | Overview of Number of Participants With Adverse Events and Serious Adverse Events for Part A and Part B | Part B - Follow-up AE | 1 participants |
| LNA043 40mg Part B | Overview of Number of Participants With Adverse Events and Serious Adverse Events for Part A and Part B | Part B B - Follow-up SAE | 0 participants |
| Placebo Part B | Overview of Number of Participants With Adverse Events and Serious Adverse Events for Part A and Part B | Part B - Follow-up AE | 7 participants |
| Placebo Part B | Overview of Number of Participants With Adverse Events and Serious Adverse Events for Part A and Part B | Part B - TEAE | 10 participants |
| Placebo Part B | Overview of Number of Participants With Adverse Events and Serious Adverse Events for Part A and Part B | Part B - TESAE | 0 participants |
| Placebo Part B | Overview of Number of Participants With Adverse Events and Serious Adverse Events for Part A and Part B | Part B B - Follow-up SAE | 2 participants |
Secondary
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.
Time frame: Baseline, Week 29, Week 53
Population: Pharmacodynamic (PD) analysis set: Subjects with available PD data
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| LNA043 20 mg Part A | Change From Baseline in Cartilage Mean T2 Relaxation Time as a Marker of Collagen Organization in the Medial Femoral Index Region - Deep Part B | Week 29 n=21,21,25 | -3.80 ms | Standard Error 2.47 |
| LNA043 20 mg Part A | Change From Baseline in Cartilage Mean T2 Relaxation Time as a Marker of Collagen Organization in the Medial Femoral Index Region - Deep Part B | Week 53 n=20,22,22 | -3.93 ms | Standard Error 2.53 |
| Placebo Part A | Change From Baseline in Cartilage Mean T2 Relaxation Time as a Marker of Collagen Organization in the Medial Femoral Index Region - Deep Part B | Week 53 n=20,22,22 | -12.17 ms | Standard Error 2.54 |
| Placebo Part A | Change From Baseline in Cartilage Mean T2 Relaxation Time as a Marker of Collagen Organization in the Medial Femoral Index Region - Deep Part B | Week 29 n=21,21,25 | -5.07 ms | Standard Error 2.49 |
| Placebo Part B | Change From Baseline in Cartilage Mean T2 Relaxation Time as a Marker of Collagen Organization in the Medial Femoral Index Region - Deep Part B | Week 53 n=20,22,22 | -6.21 ms | Standard Error 2.41 |
| Placebo Part B | Change From Baseline in Cartilage Mean T2 Relaxation Time as a Marker of Collagen Organization in the Medial Femoral Index Region - Deep Part B | Week 29 n=21,21,25 | -5.89 ms | Standard Error 2.26 |
Comparison: Week 2990% CI: [-3.49, 7.66]Mixed Models Analysis
Comparison: Week 2990% CI: [-4.82, 6.45]Mixed Models Analysis
Comparison: Week 5390% CI: [-3.54, 8.11]Mixed Models Analysis
Comparison: Week 5390% CI: [-11.81, -0.1]Mixed Models Analysis
Secondary
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.
Time frame: Baseline, Week 29, Week 53
Population: Pharmacodynamic (PD) analysis set: Subjects with available PD data
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| LNA043 20 mg Part A | Change From Baseline in Cartilage Mean T2 Relaxation Time as a Marker of Collagen Organization in the Medial Femoral Index Region - Overall Part B | Week 29 n=21,21,25 | -1.59 ms | Standard Error 2.25 |
| LNA043 20 mg Part A | Change From Baseline in Cartilage Mean T2 Relaxation Time as a Marker of Collagen Organization in the Medial Femoral Index Region - Overall Part B | Week 53 n=20,22,22 | -4.23 ms | Standard Error 2.29 |
| Placebo Part A | Change From Baseline in Cartilage Mean T2 Relaxation Time as a Marker of Collagen Organization in the Medial Femoral Index Region - Overall Part B | Week 53 n=20,22,22 | -10.53 ms | Standard Error 2.25 |
| Placebo Part A | Change From Baseline in Cartilage Mean T2 Relaxation Time as a Marker of Collagen Organization in the Medial Femoral Index Region - Overall Part B | Week 29 n=21,21,25 | -5.07 ms | Standard Error 2.26 |
| Placebo Part B | Change From Baseline in Cartilage Mean T2 Relaxation Time as a Marker of Collagen Organization in the Medial Femoral Index Region - Overall Part B | Week 29 n=21,21,25 | -4.97 ms | Standard Error 2.07 |
| Placebo Part B | Change From Baseline in Cartilage Mean T2 Relaxation Time as a Marker of Collagen Organization in the Medial Femoral Index Region - Overall Part B | Week 53 n=20,22,22 | -3.09 ms | Standard Error 2.18 |
Comparison: Week 2990% CI: [-1.72, 8.47]Mixed Models Analysis
Comparison: Week 2990% CI: [-5.22, 5.01]Mixed Models Analysis
Comparison: Week 5390% CI: [-6.42, 4.15]Mixed Models Analysis
Comparison: Week 5390% CI: [-12.68, -2.2]Mixed Models Analysis
Secondary
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.
Time frame: Baseline, Week 29, Week 53
Population: Pharmacodynamic (PD) analysis set: Subjects with available PD data
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| LNA043 20 mg Part A | Change From Baseline in Cartilage Mean T2 Relaxation Time as a Marker of Collagen Organization in the Medial Femoral Index Region - Superficial Part B | Week 29 n=21,21,25 | -0.06 ms | Standard Error 2.51 |
| LNA043 20 mg Part A | Change From Baseline in Cartilage Mean T2 Relaxation Time as a Marker of Collagen Organization in the Medial Femoral Index Region - Superficial Part B | Week 53 n=20,22,22 | -3.54 ms | Standard Error 2.36 |
| Placebo Part A | Change From Baseline in Cartilage Mean T2 Relaxation Time as a Marker of Collagen Organization in the Medial Femoral Index Region - Superficial Part B | Week 29 n=21,21,25 | -4.16 ms | Standard Error 2.51 |
| Placebo Part A | Change From Baseline in Cartilage Mean T2 Relaxation Time as a Marker of Collagen Organization in the Medial Femoral Index Region - Superficial Part B | Week 53 n=20,22,22 | -9.07 ms | Standard Error 2.36 |
| Placebo Part B | Change From Baseline in Cartilage Mean T2 Relaxation Time as a Marker of Collagen Organization in the Medial Femoral Index Region - Superficial Part B | Week 29 n=21,21,25 | -3.53 ms | Standard Error 2.3 |
| Placebo Part B | Change From Baseline in Cartilage Mean T2 Relaxation Time as a Marker of Collagen Organization in the Medial Femoral Index Region - Superficial Part B | Week 53 n=20,22,22 | -0.91 ms | Standard Error 2.25 |
Comparison: Week 2990% CI: [-2.21, 9.15]Mixed Models Analysis
Comparison: Week 2990% CI: [-6.31, 5.04]Mixed Models Analysis
Comparison: Week 5390% CI: [-8.07, 2.82]Mixed Models Analysis
Comparison: Week 5390% CI: [-13.61, -2.72]Mixed Models Analysis
Secondary
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.
Time frame: Baseline up to Week 16, Week 28
Population: Pharmacodynamic (PD) analysis set: Subjects with available PD data
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| LNA043 20 mg Part A | Change From Baseline of LNA043 to Placebo in Cartilage Defect Volume (mm^3) for Both Groups of Patients (Femoral and Patellar Lesions) - Part A | Week 16 n=40,14 | -2.42 mm^3 | Standard Error 8.27 |
| LNA043 20 mg Part A | Change From Baseline of LNA043 to Placebo in Cartilage Defect Volume (mm^3) for Both Groups of Patients (Femoral and Patellar Lesions) - Part A | Week 28 n=39,15 | -11.88 mm^3 | Standard Error 8.27 |
| Placebo Part A | Change From Baseline of LNA043 to Placebo in Cartilage Defect Volume (mm^3) for Both Groups of Patients (Femoral and Patellar Lesions) - Part A | Week 16 n=40,14 | -7.17 mm^3 | Standard Error 13.64 |
| Placebo Part A | Change From Baseline of LNA043 to Placebo in Cartilage Defect Volume (mm^3) for Both Groups of Patients (Femoral and Patellar Lesions) - Part A | Week 28 n=39,15 | -4.57 mm^3 | Standard Error 13.45 |
Comparison: Week 16p-value: 0.618490% CI: [-21.36, 30.85]Mixed Models Analysis
Comparison: Week 28p-value: 0.319490% CI: [-33.16, 18.53]Mixed Models Analysis
Secondary
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.
Time frame: Week 1,3,8,16,28
Population: Safety analysis set
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| LNA043 20 mg Part A | Incidence of Immunogenicity (IG) Part A | Week 3 (Day 15) Pre-dose | 0 participants |
| LNA043 20 mg Part A | Incidence of Immunogenicity (IG) Part A | Week 16 (Day 106) | 0 participants |
| LNA043 20 mg Part A | Incidence of Immunogenicity (IG) Part A | Week 8 (Day 50) | 0 participants |
| LNA043 20 mg Part A | Incidence of Immunogenicity (IG) Part A | Week 28 (Day 190) | 0 participants |
| LNA043 20 mg Part A | Incidence of Immunogenicity (IG) Part A | Week 1 (Day 1) Predose | 0 participants |
| Placebo Part A | Incidence of Immunogenicity (IG) Part A | Week 28 (Day 190) | 0 participants |
| Placebo Part A | Incidence of Immunogenicity (IG) Part A | Week 1 (Day 1) Predose | 0 participants |
| Placebo Part A | Incidence of Immunogenicity (IG) Part A | Week 3 (Day 15) Pre-dose | 0 participants |
| Placebo Part A | Incidence of Immunogenicity (IG) Part A | Week 8 (Day 50) | 0 participants |
| Placebo Part A | Incidence of Immunogenicity (IG) Part A | Week 16 (Day 106) | 0 participants |
Secondary
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.
Time frame: Week 1,5,9,13,17,29,53
Population: Safety analysis set
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| LNA043 20 mg Part A | Incidence of Immunogenicity (IG) Part B | Week 1 (Day 1) Predose | 0 participants |
| LNA043 20 mg Part A | Incidence of Immunogenicity (IG) Part B | Week 17 | 0 participants |
| LNA043 20 mg Part A | Incidence of Immunogenicity (IG) Part B | Week 13 | 0 participants |
| LNA043 20 mg Part A | Incidence of Immunogenicity (IG) Part B | Week 5 Pre-dose | 0 participants |
| LNA043 20 mg Part A | Incidence of Immunogenicity (IG) Part B | Week 53 | 0 participants |
| LNA043 20 mg Part A | Incidence of Immunogenicity (IG) Part B | Week 29 | 0 participants |
| LNA043 20 mg Part A | Incidence of Immunogenicity (IG) Part B | Week 9 | 0 participants |
| Placebo Part A | Incidence of Immunogenicity (IG) Part B | Week 13 | 0 participants |
| Placebo Part A | Incidence of Immunogenicity (IG) Part B | Week 5 Pre-dose | 0 participants |
| Placebo Part A | Incidence of Immunogenicity (IG) Part B | Week 1 (Day 1) Predose | 0 participants |
| Placebo Part A | Incidence of Immunogenicity (IG) Part B | Week 9 | 0 participants |
| Placebo Part A | Incidence of Immunogenicity (IG) Part B | Week 17 | 0 participants |
| Placebo Part A | Incidence of Immunogenicity (IG) Part B | Week 29 | 0 participants |
| Placebo Part A | Incidence of Immunogenicity (IG) Part B | Week 53 | 0 participants |
| Placebo Part B | Incidence of Immunogenicity (IG) Part B | Week 17 | 0 participants |
| Placebo Part B | Incidence of Immunogenicity (IG) Part B | Week 5 Pre-dose | 0 participants |
| Placebo Part B | Incidence of Immunogenicity (IG) Part B | Week 53 | 0 participants |
| Placebo Part B | Incidence of Immunogenicity (IG) Part B | Week 29 | 0 participants |
| Placebo Part B | Incidence of Immunogenicity (IG) Part B | Week 13 | 0 participants |
| Placebo Part B | Incidence of Immunogenicity (IG) Part B | Week 9 | 0 participants |
| Placebo Part B | Incidence of Immunogenicity (IG) Part B | Week 1 (Day 1) Predose | 0 participants |
Secondary
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
Time frame: 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
Population: Pharmacokinetic analysis set
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| LNA043 20 mg Part A | Serum Concentrations of ANGPTL3 - Part A | Week 3, 1 hour post dose n=39,14 | 18.5 ng/mL | Standard Deviation 7.35 |
| LNA043 20 mg Part A | Serum Concentrations of ANGPTL3 - Part A | Week 1, 2 hours post dose n=40,15 | 18.9 ng/mL | Standard Deviation 9.38 |
| LNA043 20 mg Part A | Serum Concentrations of ANGPTL3 - Part A | Week 2,0 hour pre dose n=42,15 | 18.9 ng/mL | Standard Deviation 10.3 |
| LNA043 20 mg Part A | Serum Concentrations of ANGPTL3 - Part A | Week 4, 0 hour pre dose n=42,15 | 19.6 ng/mL | Standard Deviation 8.71 |
| LNA043 20 mg Part A | Serum Concentrations of ANGPTL3 - Part A | Week 4, 1 hour post dose n=41,15 | 19.6 ng/mL | Standard Deviation 7.87 |
| LNA043 20 mg Part A | Serum Concentrations of ANGPTL3 - Part A | Week 1, 0 hour pre-dose n=41,14 | 19.1 ng/mL | Standard Deviation 9.29 |
| LNA043 20 mg Part A | Serum Concentrations of ANGPTL3 - Part A | Week 1, 0.25 hour post dose n=6,2 | 20.8 ng/mL | Standard Deviation 8.12 |
| LNA043 20 mg Part A | Serum Concentrations of ANGPTL3 - Part A | Week 1, 1 hour post dose n=7,2 | 19.7 ng/mL | Standard Deviation 8.65 |
| LNA043 20 mg Part A | Serum Concentrations of ANGPTL3 - Part A | Week 2, 1 hour post dose n=42,15 | 18.3 ng/mL | Standard Deviation 8.06 |
| LNA043 20 mg Part A | Serum Concentrations of ANGPTL3 - Part A | Week 3, 0 hour pre dose n=42,14 | 19.1 ng/mL | Standard Deviation 7.79 |
| Placebo Part A | Serum Concentrations of ANGPTL3 - Part A | Week 3, 0 hour pre dose n=42,14 | 24.2 ng/mL | Standard Deviation 9.95 |
| Placebo Part A | Serum Concentrations of ANGPTL3 - Part A | Week 1, 0 hour pre-dose n=41,14 | 23.3 ng/mL | Standard Deviation 8.55 |
| Placebo Part A | Serum Concentrations of ANGPTL3 - Part A | Week 1, 2 hours post dose n=40,15 | 24.3 ng/mL | Standard Deviation 9.52 |
| Placebo Part A | Serum Concentrations of ANGPTL3 - Part A | Week 2, 1 hour post dose n=42,15 | 19.7 ng/mL | Standard Deviation 9.58 |
| Placebo Part A | Serum Concentrations of ANGPTL3 - Part A | Week 2,0 hour pre dose n=42,15 | 21.7 ng/mL | Standard Deviation 10.2 |
| Placebo Part A | Serum Concentrations of ANGPTL3 - Part A | Week 3, 1 hour post dose n=39,14 | 28.9 ng/mL | Standard Deviation 16.4 |
| Placebo Part A | Serum Concentrations of ANGPTL3 - Part A | Week 1, 0.25 hour post dose n=6,2 | 20.4 ng/mL | Standard Deviation 6.36 |
| Placebo Part A | Serum Concentrations of ANGPTL3 - Part A | Week 4, 0 hour pre dose n=42,15 | 21.0 ng/mL | Standard Deviation 7.11 |
| Placebo Part A | Serum Concentrations of ANGPTL3 - Part A | Week 1, 1 hour post dose n=7,2 | 18.2 ng/mL | Standard Deviation 3.32 |
| Placebo Part A | Serum Concentrations of ANGPTL3 - Part A | Week 4, 1 hour post dose n=41,15 | 22.6 ng/mL | Standard Deviation 9.06 |
Secondary
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.
Time frame: Week 1: 0 (pre-dose), 2 hours post dose; Weeks 5 and 13: 1 hour post dose
Population: Pharmacokinetic analysis set
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| LNA043 20 mg Part A | Serum Concentrations of ANGPTL3 - Part B | Week 13, 1 hour post dose n=27,25,28 | 22.9 ng/mL | Standard Deviation 8.72 |
| LNA043 20 mg Part A | Serum Concentrations of ANGPTL3 - Part B | Week 1, 0 hour pre-dose n=27,26,29 | 25.3 ng/mL | Standard Deviation 11.1 |
| LNA043 20 mg Part A | Serum Concentrations of ANGPTL3 - Part B | Week 1, 2 hours post dose n=24,24,26 | 26.0 ng/mL | Standard Deviation 12.8 |
| LNA043 20 mg Part A | Serum Concentrations of ANGPTL3 - Part B | Week 5, 1 hour post dose n=26,26,28 | 21.8 ng/mL | Standard Deviation 9.8 |
| Placebo Part A | Serum Concentrations of ANGPTL3 - Part B | Week 1, 0 hour pre-dose n=27,26,29 | 21.9 ng/mL | Standard Deviation 9.09 |
| Placebo Part A | Serum Concentrations of ANGPTL3 - Part B | Week 13, 1 hour post dose n=27,25,28 | 22.5 ng/mL | Standard Deviation 8.39 |
| Placebo Part A | Serum Concentrations of ANGPTL3 - Part B | Week 5, 1 hour post dose n=26,26,28 | 23.3 ng/mL | Standard Deviation 9.97 |
| Placebo Part A | Serum Concentrations of ANGPTL3 - Part B | Week 1, 2 hours post dose n=24,24,26 | 23.9 ng/mL | Standard Deviation 10.6 |
| Placebo Part B | Serum Concentrations of ANGPTL3 - Part B | Week 13, 1 hour post dose n=27,25,28 | 24.8 ng/mL | Standard Deviation 11.8 |
| Placebo Part B | Serum Concentrations of ANGPTL3 - Part B | Week 1, 0 hour pre-dose n=27,26,29 | 26.6 ng/mL | Standard Deviation 14 |
| Placebo Part B | Serum Concentrations of ANGPTL3 - Part B | Week 5, 1 hour post dose n=26,26,28 | 26.2 ng/mL | Standard Deviation 10.8 |
| Placebo Part B | Serum Concentrations of ANGPTL3 - Part B | Week 1, 2 hours post dose n=24,24,26 | 27.6 ng/mL | Standard Deviation 13.1 |
Secondary
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
Time frame: 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
Population: Pharmacokinetic analysis set
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| LNA043 20 mg Part A | Serum Concentrations of LNA043 - Part A | Week 1, 0 hour pre-dose | 0 ng/mL | Standard Deviation 0 |
| LNA043 20 mg Part A | Serum Concentrations of LNA043 - Part A | Week 1, 0.25 hour post dose n=6 | 24.9 ng/mL | Standard Deviation 16.3 |
| LNA043 20 mg Part A | Serum Concentrations of LNA043 - Part A | Week 1, 1 hour post dose n=7 | 65.1 ng/mL | Standard Deviation 30.2 |
| LNA043 20 mg Part A | Serum Concentrations of LNA043 - Part A | Week 1, 2 hours post dose n=41 | 64.9 ng/mL | Standard Deviation 37.5 |
| LNA043 20 mg Part A | Serum Concentrations of LNA043 - Part A | Week 2,0 hour pre dose n=42 | 0.00 ng/mL | Standard Deviation 0 |
| LNA043 20 mg Part A | Serum Concentrations of LNA043 - Part A | Week 2, 1 hour post dose n=43 | 48.1 ng/mL | Standard Deviation 32.9 |
| LNA043 20 mg Part A | Serum Concentrations of LNA043 - Part A | Week 3, 0 hour pre dose n=41 | 0.00 ng/mL | Standard Deviation 0 |
| LNA043 20 mg Part A | Serum Concentrations of LNA043 - Part A | Week 3, 1 hour post dose n=39 | 51.0 ng/mL | Standard Deviation 37.6 |
| LNA043 20 mg Part A | Serum Concentrations of LNA043 - Part A | Week 4, 0 hour pre dose n=42 | 3.00 ng/mL | Standard Deviation 19.4 |
| LNA043 20 mg Part A | Serum Concentrations of LNA043 - Part A | Week 4, 1 hour post dose n=41 | 52.9 ng/mL | Standard Deviation 38.1 |
Secondary
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
Time frame: Week 1: 0 (pre-dose), 2 hours post dose; Weeks 5 and 13: 1 hour post dose
Population: Pharmacokinetic analysis set
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| LNA043 20 mg Part A | Serum Concentrations of LNA043 - Part B | Week 1, 0 hours pre-dose n=27,26 | 3.48 ng/mL | Standard Deviation 18.1 |
| LNA043 20 mg Part A | Serum Concentrations of LNA043 - Part B | Week 5, 1 hour post dose n=27,26 | 55.6 ng/mL | Standard Deviation 47 |
| LNA043 20 mg Part A | Serum Concentrations of LNA043 - Part B | Week 1, 2 hours post dose n=24,24, | 76.4 ng/mL | Standard Deviation 51 |
| LNA043 20 mg Part A | Serum Concentrations of LNA043 - Part B | Week 13, 1 hour post dose n=27,25 | 59.5 ng/mL | Standard Deviation 53 |
| Placebo Part A | Serum Concentrations of LNA043 - Part B | Week 1, 2 hours post dose n=24,24, | 158 ng/mL | Standard Deviation 94 |
| Placebo Part A | Serum Concentrations of LNA043 - Part B | Week 1, 0 hours pre-dose n=27,26 | 7.96 ng/mL | Standard Deviation 40.6 |
| Placebo Part A | Serum Concentrations of LNA043 - Part B | Week 13, 1 hour post dose n=27,25 | 118 ng/mL | Standard Deviation 78.2 |
| Placebo Part A | Serum Concentrations of LNA043 - Part B | Week 5, 1 hour post dose n=27,26 | 101 ng/mL | Standard Deviation 74.2 |
Secondary
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.
Time frame: Weeks 1,2,3,4: 0 hour (pre-dose)
Population: Pharmacokinetic analysis set
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| LNA043 20 mg Part A | Synovial Fluid Concentrations of ANGPTL3 - Part A | Week 1, 0 hour pre-dose n=8,3 | 0.00 ng/mL | Standard Deviation 0 |
| LNA043 20 mg Part A | Synovial Fluid Concentrations of ANGPTL3 - Part A | Week 2,0 hour pre dose n=11,5 | 0.00 ng/mL | Standard Deviation 0 |
| LNA043 20 mg Part A | Synovial Fluid Concentrations of ANGPTL3 - Part A | Week 3, 0 hour pre dose n=13,4 | 0.616 ng/mL | Standard Deviation 2.22 |
| LNA043 20 mg Part A | Synovial Fluid Concentrations of ANGPTL3 - Part A | Week 4, 0 hour pre dose n=15,3 | 1.42 ng/mL | Standard Deviation 5.5 |
| Placebo Part A | Synovial Fluid Concentrations of ANGPTL3 - Part A | Week 4, 0 hour pre dose n=15,3 | 00.0 ng/mL | Standard Deviation 0 |
| Placebo Part A | Synovial Fluid Concentrations of ANGPTL3 - Part A | Week 1, 0 hour pre-dose n=8,3 | 00.0 ng/mL | Standard Deviation 0 |
| Placebo Part A | Synovial Fluid Concentrations of ANGPTL3 - Part A | Week 3, 0 hour pre dose n=13,4 | 00.0 ng/mL | Standard Deviation 0 |
| Placebo Part A | Synovial Fluid Concentrations of ANGPTL3 - Part A | Week 2,0 hour pre dose n=11,5 | 00.0 ng/mL | Standard Deviation 0 |
Secondary
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.
Time frame: Weeks 1,5.9.13: 0 hour (pre-dose)
Population: Pharmacokinetic analysis set
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| LNA043 20 mg Part A | Synovial Fluid Concentrations of ANGPTL3 - Part B | Week 1, 0 hour pre-dose n=8,3,8 | 0.00 ng/mL | Standard Deviation 0 |
| LNA043 20 mg Part A | Synovial Fluid Concentrations of ANGPTL3 - Part B | 0.00Week 5,,0 hour pre dose n=10,5,12 | 1.00 ng/mL | Standard Deviation 3.16 |
| LNA043 20 mg Part A | Synovial Fluid Concentrations of ANGPTL3 - Part B | Week 9,, 0 hour pre dose n=8,4,9 | 0.00 ng/mL | Standard Deviation 0 |
| LNA043 20 mg Part A | Synovial Fluid Concentrations of ANGPTL3 - Part B | Week 13, 0 hour pre dose n=7,4,8 | 0.00 ng/mL | Standard Deviation 0 |
| Placebo Part A | Synovial Fluid Concentrations of ANGPTL3 - Part B | Week 13, 0 hour pre dose n=7,4,8 | 1.87 ng/mL | Standard Deviation 3.74 |
| Placebo Part A | Synovial Fluid Concentrations of ANGPTL3 - Part B | Week 1, 0 hour pre-dose n=8,3,8 | 0.00 ng/mL | Standard Deviation 0 |
| Placebo Part A | Synovial Fluid Concentrations of ANGPTL3 - Part B | Week 9,, 0 hour pre dose n=8,4,9 | 0.00 ng/mL | Standard Deviation 0 |
| Placebo Part A | Synovial Fluid Concentrations of ANGPTL3 - Part B | 0.00Week 5,,0 hour pre dose n=10,5,12 | 4.38 ng/mL | Standard Deviation 9.79 |
| Placebo Part B | Synovial Fluid Concentrations of ANGPTL3 - Part B | Week 13, 0 hour pre dose n=7,4,8 | 0.890 ng/mL | Standard Deviation 2.52 |
| Placebo Part B | Synovial Fluid Concentrations of ANGPTL3 - Part B | 0.00Week 5,,0 hour pre dose n=10,5,12 | 1.57 ng/mL | Standard Deviation 5.43 |
| Placebo Part B | Synovial Fluid Concentrations of ANGPTL3 - Part B | Week 9,, 0 hour pre dose n=8,4,9 | 0.00 ng/mL | Standard Deviation 0 |
| Placebo Part B | Synovial Fluid Concentrations of ANGPTL3 - Part B | Week 1, 0 hour pre-dose n=8,3,8 | 0.00 ng/mL | Standard Deviation 0 |
Secondary
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.
Time frame: Weeks 1,2,3,4: 0 hour (pre-dose)
Population: LNA043 Stability in synovial fluid could not be demonstrated. Consequently, the assay was not considered suitable for the determination of LNA043 in synovial fluid collected in Part A and no reportable concentrations of LNA043 in synovial fluid are available in Part A, samples were never assayed and so data are not available for LNA043 concentrations in synovial fluid for Part A.
Secondary
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.
Time frame: Weeks 1,5.9.13: 0 hour (pre-dose)
Population: Pharmacokinetic analysis set
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| LNA043 20 mg Part A | Synovial Fluid Concentrations of LNA043 Part B | Week 13, 0 hours pre dose n=8,4 | 0.00 ng/mL | Standard Deviation 0 |
| LNA043 20 mg Part A | Synovial Fluid Concentrations of LNA043 Part B | Week 5, 0 hours pre dose n=10,5 | 368 ng/mL | Standard Deviation 1160 |
| LNA043 20 mg Part A | Synovial Fluid Concentrations of LNA043 Part B | Week 1, 0 hours pre dose n=9,5 | 28.9 ng/mL | Standard Deviation 86.7 |
| LNA043 20 mg Part A | Synovial Fluid Concentrations of LNA043 Part B | Week 9, 0 hours pre-dose n=11,6 | 0.00 ng/mL | Standard Deviation 0 |
| Placebo Part A | Synovial Fluid Concentrations of LNA043 Part B | Week 13, 0 hours pre dose n=8,4 | 199000 ng/mL | Standard Deviation 398000 |
| Placebo Part A | Synovial Fluid Concentrations of LNA043 Part B | Week 9, 0 hours pre-dose n=11,6 | 43600 ng/mL | Standard Deviation 90900 |
| Placebo Part A | Synovial Fluid Concentrations of LNA043 Part B | Week 1, 0 hours pre dose n=9,5 | 0.00 ng/mL | Standard Deviation 0 |
| Placebo Part A | Synovial Fluid Concentrations of LNA043 Part B | Week 5, 0 hours pre dose n=10,5 | 18.1 ng/mL | Standard Deviation 40.6 |