Osteoarthritis (OA)
Conditions
Keywords
Knee osteoarthritis, Chondroanabolic drug, Magnetic resonance imaging, Patient Reported Outcomes
Brief summary
This study explored the preliminary efficacy of multiple intra-articular injections of LRX712 by evaluating the ability of the drug to restore structural integrity of articular cartilage. Efficacy was evaluated in the context of the systemic safety and local tolerability of the investigational drug.
Detailed description
This was an exploratory study, with a 7-week screening period, an 8-week treatment period, and a 44-week follow-up period, using a 3-treatment arm, parallel-group, randomized, double-blind, placebo-controlled clinical study design. The study design implemented for the first six participants enrolled was a 2-treatment arm, parallel -group, randomized, double-blind placebo controlled trial (up until the time when the study was temporarily halted in February 2021) included up to 5 weeks of screening, an 8-week treatment period, and a 44-week follow-up period. The original two-arm study design (75 mg LRX712 vs. placebo) was modified to a three-arm design, with two lower doses of LRX712 (15 mg and 25 mg) vs. placebo, following protocol amendment 4 (16-Jul-2021). Data from the three participants who had completed dosing with 75 mg LRX712 were considered exploratory, and data from the three participants who had completed dosing with placebo were pooled with the data from participants enrolled after the study was restarted with the implementation of protocol amendment 4.
Interventions
OTHERPlacebo
Placebo intra-articular injections
DRUGLRX712
LRX712 intra-articular injections
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
35 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
Written informed consent must be obtained before any assessment is performed. To be eligible for inclusion in this study patients must meet all of the following criteria: * Patient must have a BMI between 18 -35 kg/m2 * Patient must have symptomatic knee osteoarthritis predominantly in one knee (index knee) * Patient must have knee osteoarthritis (Kellgren-Lawrence grade 2 or 3) in the index knee, as confirmed by radiography * Patient must have radiographic confirmation of a medial joint space width of 1.5 to 3.5 mm for females, or 2 to 4 mm for males within the medial tibio-femoral compartment of the index knee.
Exclusion criteria
Subjects meeting any of the following criteria are not eligible for inclusion in this study: * Patient has a known autoimmune disease, inflammatory or chronic arthropathy other than OA. * Patient had partial or complete joint replacement in one or both knees. * Patient has symptomatic, isolated patello-femoral pain in the index knee as per the Investigator's examination. * Pregnant or nursing (lactating) women. * Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant. * Previous use of LRX712 or use of other investigational drugs at the time of enrollment, or within 5 half-lives of enrollment, or within 30 days, whichever is longer; or longer if required by local regulations. * Patient has malalignment (valgus- or varus-deformity) ≥ 7.5° in the index knee as per anatomic PA axis measured by weight-bearing short knee radiography. * History of significant cardiac conduction/electrophysiological disorder, e.g. familial long QT syndrome or known family history of Torsades de Pointes or prolonged QT syndrome or QTcF ≥ 450 msec (Fridericia Correction) for males and ≥ 460 msec for females at screening or baseline (by local 12-lead digitized ECG reading). * Signs or symptoms, in the judgment of the investigator, of a clinically significant systemic viral, bacterial or fungal infection within 30 days prior to screening. Other protocol-defined inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Cartilage Volume in the Index Region Measured by 7 Tesla MRI | Baseline, Week 28 | Magnetic resonance images (MRI) were obtained from the target knee to visualize and quantify changes in the volume of cartilage in the index region. The index region was defined as the combination of the femoral medial anterior (FMA), central (FMC) and posterior (FMP) cartilage subregions in the knee. Change from baseline in cartilage volume was analyzed using the mixed effects model for repeated measures (MMRM). The model included baseline, treatment, timepoint and treatment-timepoints as fixed effects, and participant as random effect. Missing data was assumed to be Missing at Random (MAR). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to Reach the Maximum Plasma Concentration (Tmax) of LRX712 | Pre-dose, 0.5, 12, 24 and 168 hours after dose on Day 1; Pre-dose, 24 and 168 hours after dose on Day 29; Pre-dose, 24, 168, 1344 and 3360 hours after dose on Day 57 | Tmax is the time to reach maximum (peak) LRX712 concentration after single-dose administration (time). LRX712 plasma concentrations were determined using the actual recorded sampling times and non-compartmental method with Phoenix WinNonlin (Version 8.3). LRX712 was determined by a validated LC-MS/MS method. Concentrations below the lower limit of quantification (LLOQ) were treated as "zero" . LLOQ was 25 pg/mL. |
| Maximum Observed Plasma Concentration (Cmax) of LRX712 | Pre-dose, 0.5, 12, 24 and 168 hours after dose on Day 1; Pre-dose, 24 and 168 hours after dose on Day 29; Pre-dose, 24, 168, 1344 and 3360 hours after dose on Day 57 | Cmax is defined as the maximum (peak) observed concentration following a dose. LRX712 plasma concentrations were determined using the actual recorded sampling times and non-compartmental method with Phoenix WinNonlin (Version 8.3). LRX712 was determined by a validated LC-MS/MS method. Concentrations below the lower limit of quantification (LLOQ) were treated as "zero" . LLOQ was 25 pg/mL. |
| Minimum Observed Plasma Concentration (Cmin) of LRX712 | Pre-dose on Day 29; Pre-dose, 1344 hours after dose on Day 57 (LRX712 15 mg arm) and 3360 hours after dose on Day 57 (LRX712 25 mg and 75 mg arms) | Cmin is defined as the minimum (peak) observed concentration following a dose. LRX712 plasma concentrations were determined using the actual recorded sampling times and non-compartmental method with Phoenix WinNonlin (Version 8.3). LRX712 was determined by a validated LC-MS/MS method. Concentrations below the lower limit of quantification (LLOQ) were treated as "zero" . LLOQ was 25 pg/mL. |
| Synovial Fluid Concentrations of LRX712 | Pre-dose on Day 1, 29 and 57 | The observed synovial concentration following a dose. LRX712 concentrations were determined using the actual recorded sampling times and non-compartmental method with Phoenix WinNonlin (Version 8.3). LRX712 was determined by a validated LC-MS/MS method. Concentrations below the lower limit of quantification (LLOQ) were treated as "zero" . LLOQ was 20 ng/mL. Samples were collected from a limited number of participants. |
| Time to Reach the Maximum Plasma Concentration (Tmax) of MAE344 | Pre-dose, 0.5, 12, 24 and 168 hours after dose on Day 1; Pre-dose, 24 and 168 hours after dose on Day 29; Pre-dose, 24, 168, 1344 and 3360 hours after dose on Day 57 | Tmax is the time to reach maximum (peak) MAE344 concentration after single-dose administration (time). MAE344 is a metabolite of LRX712 and plasma concentrations were determined using the actual recorded sampling times and non-compartmental method with Phoenix WinNonlin (Version 8.3). MAE344 was determined by a validated LC-MS/MS method. Concentrations below the lower limit of quantification (LLOQ) were treated as "zero" . LLOQ was 100 pg/mL. |
| Maximum Observed Plasma Concentration (Cmax) of MAE344 | Pre-dose, 0.5, 12, 24 and 168 hours after dose on Day 1; Pre-dose, 24 and 168 hours after dose on Day 29; Pre-dose, 24, 168, 1344 and 3360 hours after dose on Day 57 | Cmax is defined as the maximum (peak) observed concentration following a dose. MAE344 is a metabolite of LRX712 and plasma concentrations were determined using the actual recorded sampling times and non-compartmental method with Phoenix WinNonlin (Version 8.3). MAE344 was determined by a validated LC-MS/MS method. Concentrations below the lower limit of quantification (LLOQ) were treated as "zero" . LLOQ was 100 pg/mL. |
| Minimum Observed Plasma Concentration (Cmin) of MAE344 | Pre-dose on Day 29; Pre-dose, 1344 hours after dose on Day 57 (LRX712 15 mg arm) and 3360 hours after dose on Day 57 (LRX712 25 mg and 75 mg arms) | Cmin is defined as the minimum (peak) observed concentration following a dose. MAE344 is a metabolite of LRX712 and plasma concentrations were determined using the actual recorded sampling times and non-compartmental method with Phoenix WinNonlin (Version 8.3). MAE344 was determined by a validated LC-MS/MS method. Concentrations below the lower limit of quantification (LLOQ) were treated as "zero" . LLOQ was 100 pg/mL. |
| Synovial Fluid Concentrations of MAE344 | Pre-dose on Day 1, 29 and 57 | The observed synovial concentration following a dose. MAE344 is a metabolite of LRX712 and concentrations were determined using the actual recorded sampling times and non-compartmental method with Phoenix WinNonlin (Version 8.3). MAE344 was determined by a validated LC-MS/MS method. Concentrations below the lower limit of quantification (LLOQ) were treated as "zero" . LLOQ was 80 ng/mL. Samples were collected from a limited number of participants. |
| Change From Baseline in Articular Cartilage [23Na] Content Measured by 7 Tesla MRI | Baseline, Week 16, 28 and 52 | Magnetic resonance images (MRI) were obtained from the target knee to visualize and quantify changes in articular cartilage quality (assessed by changes in glycosaminoglycans content measured by sodium content) in the index region. The index region was defined as the combination of the femoral medial anterior (FMA), central (FMC) and posterior (FMP) cartilage subregions in the knee quality. Change from baseline in articular cartilage content was analyzed using a mixed effects model for repeated measures (MMRM). The model included baseline, treatment, timepoint and treatment-timepoints as fixed effects, and participant as random effect. Missing data was assumed to be Missing at Random (MAR). The data from the three participants who completed dosing with 75 mg LRX712 were considered exploratory. |
| Change From Baseline in Cartilage Volume in the Index Region Measured by 7 Tesla MRI | Baseline, Week 16 and 52 | 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 combination of the femoral medial anterior (FMA), central (FMC) and posterior (FMP) cartilage subregions in the knee quality. Change from baseline in cartilage volume was analyzed using a mixed effects model for repeated measures (MMRM). The model included baseline, treatment, timepoint and treatment-timepoints as fixed effects, and participant as random effect. Missing data was assumed to be Missing at Random (MAR). The data from the three participants who completed dosing with 75 mg LRX712 were considered exploratory. |
Countries
Netherlands
Contacts
STUDY_DIRECTORNovartis Pharmaceuticals
Novartis Pharmaceuticals
Participant flow
Recruitment details
Participants took part in 1 investigative site in Netherlands.
Pre-assignment details
This study had a 7-week screening period.
Participants by arm
| Arm | Count |
|---|---|
| LRX712 15 mg LRX712 15 mg was administered intra-articularly (i.a.) every four weeks, for a total of three administrations. | 12 |
| LRX712 25 mg LRX712 25 mg was administered i.a. every four weeks, for a total of three administrations. | 14 |
| LRX712 75 mg LRX712 75 mg was administered i.a. every four weeks, for a total of three administrations. | 3 |
| Placebo Placebo was administered i.a. every four weeks, for a total of three administrations. | 16 |
| Total | 45 |
Baseline characteristics
| Characteristic | Total | LRX712 15 mg | LRX712 25 mg | LRX712 75 mg | Placebo |
|---|---|---|---|---|---|
| Age, Continuous | 61.6 years STANDARD_DEVIATION 8.2 | 66.3 years STANDARD_DEVIATION 7.74 | 61.6 years STANDARD_DEVIATION 7.31 | 59.7 years STANDARD_DEVIATION 5.03 | 58.4 years STANDARD_DEVIATION 8.66 |
| Race/Ethnicity, Customized Asian | 2 Participants | 1 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized White | 43 Participants | 11 Participants | 13 Participants | 3 Participants | 16 Participants |
| Sex: Female, Male Female | 20 Participants | 5 Participants | 7 Participants | 1 Participants | 7 Participants |
| Sex: Female, Male Male | 25 Participants | 7 Participants | 7 Participants | 2 Participants | 9 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 | EG010 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 12 | 0 / 14 | 0 / 3 | 0 / 26 | 0 / 16 | 0 / 12 | 0 / 14 | 0 / 3 | 0 / 26 | 0 / 16 | 0 / 45 |
| other Total, other adverse events | 11 / 12 | 14 / 14 | 3 / 3 | 25 / 26 | 16 / 16 | 7 / 12 | 7 / 14 | 0 / 3 | 14 / 26 | 13 / 16 | 44 / 45 |
| serious Total, serious adverse events | 0 / 12 | 0 / 14 | 0 / 3 | 0 / 26 | 0 / 16 | 1 / 12 | 1 / 14 | 0 / 3 | 2 / 26 | 1 / 16 | 3 / 45 |
Outcome results
Primary
Change From Baseline in Cartilage Volume in the Index Region Measured by 7 Tesla MRI
Magnetic resonance images (MRI) were obtained from the target knee to visualize and quantify changes in the volume of cartilage in the index region. The index region was defined as the combination of the femoral medial anterior (FMA), central (FMC) and posterior (FMP) cartilage subregions in the knee. Change from baseline in cartilage volume was analyzed using the mixed effects model for repeated measures (MMRM). The model included baseline, treatment, timepoint and treatment-timepoints as fixed effects, and participant as random effect. Missing data was assumed to be Missing at Random (MAR).
Time frame: Baseline, Week 28
Population: Participants in the safety analysis set from the arms LRX712 15 mg, LRX712 25 mg and Placebo who had an available value for the outcome measure as aligned with protocol. The Safety Set comprises all enrolled participants who received any investigational treatment.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| LRX712 15 mg | Change From Baseline in Cartilage Volume in the Index Region Measured by 7 Tesla MRI | 63.3 µL | Standard Error 54.93 |
| LRX712 25 mg | Change From Baseline in Cartilage Volume in the Index Region Measured by 7 Tesla MRI | 49.8 µL | Standard Error 50.57 |
| Placebo | Change From Baseline in Cartilage Volume in the Index Region Measured by 7 Tesla MRI | 11.6 µL | Standard Error 45.54 |
p-value: 0.236690% CI: [-68.7, 172.1]Mixed effects model for repeated measure
p-value: 0.289290% CI: [-76.7, 153.1]Mixed effects model for repeated measure
Secondary
Change From Baseline in Articular Cartilage [23Na] Content Measured by 7 Tesla MRI
Magnetic resonance images (MRI) were obtained from the target knee to visualize and quantify changes in articular cartilage quality (assessed by changes in glycosaminoglycans content measured by sodium content) in the index region. The index region was defined as the combination of the femoral medial anterior (FMA), central (FMC) and posterior (FMP) cartilage subregions in the knee quality. Change from baseline in articular cartilage content was analyzed using a mixed effects model for repeated measures (MMRM). The model included baseline, treatment, timepoint and treatment-timepoints as fixed effects, and participant as random effect. Missing data was assumed to be Missing at Random (MAR). The data from the three participants who completed dosing with 75 mg LRX712 were considered exploratory.
Time frame: Baseline, Week 16, 28 and 52
Population: Participants in the safety analysis set from the arms LRX712 15 mg, LRX712 25 mg and Placebo who had an available value for the outcome measure as aligned with protocol. The Safety Set comprises all enrolled participants who received any investigational treatment.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| LRX712 15 mg | Change From Baseline in Articular Cartilage [23Na] Content Measured by 7 Tesla MRI | Week 28 | -15.5 mmol/L | Standard Error 11.21 |
| LRX712 15 mg | Change From Baseline in Articular Cartilage [23Na] Content Measured by 7 Tesla MRI | Week 16 | -7.4 mmol/L | Standard Error 12 |
| LRX712 15 mg | Change From Baseline in Articular Cartilage [23Na] Content Measured by 7 Tesla MRI | Week 52 | 3.1 mmol/L | Standard Error 12.12 |
| LRX712 25 mg | Change From Baseline in Articular Cartilage [23Na] Content Measured by 7 Tesla MRI | Week 28 | 8.9 mmol/L | Standard Error 11.13 |
| LRX712 25 mg | Change From Baseline in Articular Cartilage [23Na] Content Measured by 7 Tesla MRI | Week 16 | 12.7 mmol/L | Standard Error 11.99 |
| LRX712 25 mg | Change From Baseline in Articular Cartilage [23Na] Content Measured by 7 Tesla MRI | Week 52 | 26.6 mmol/L | Standard Error 11.19 |
| Placebo | Change From Baseline in Articular Cartilage [23Na] Content Measured by 7 Tesla MRI | Week 16 | 8.5 mmol/L | Standard Error 9.2 |
| Placebo | Change From Baseline in Articular Cartilage [23Na] Content Measured by 7 Tesla MRI | Week 52 | 5.5 mmol/L | Standard Error 9.2 |
| Placebo | Change From Baseline in Articular Cartilage [23Na] Content Measured by 7 Tesla MRI | Week 28 | 4.0 mmol/L | Standard Error 9.24 |
Secondary
Change From Baseline in Cartilage Volume in the Index Region Measured by 7 Tesla MRI
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 combination of the femoral medial anterior (FMA), central (FMC) and posterior (FMP) cartilage subregions in the knee quality. Change from baseline in cartilage volume was analyzed using a mixed effects model for repeated measures (MMRM). The model included baseline, treatment, timepoint and treatment-timepoints as fixed effects, and participant as random effect. Missing data was assumed to be Missing at Random (MAR). The data from the three participants who completed dosing with 75 mg LRX712 were considered exploratory.
Time frame: Baseline, Week 16 and 52
Population: Participants in the safety analysis set from the arms LRX712 15 mg, LRX712 25 mg and Placebo who had an available value for the outcome measure as aligned with protocol. The Safety Set comprises all enrolled participants who received any investigational treatment.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| LRX712 15 mg | Change From Baseline in Cartilage Volume in the Index Region Measured by 7 Tesla MRI | Week 16 | -48.0 µL | Standard Error 52.64 |
| LRX712 15 mg | Change From Baseline in Cartilage Volume in the Index Region Measured by 7 Tesla MRI | Week 52 | 19.5 µL | Standard Error 73.11 |
| LRX712 25 mg | Change From Baseline in Cartilage Volume in the Index Region Measured by 7 Tesla MRI | Week 16 | -17.4 µL | Standard Error 50.09 |
| LRX712 25 mg | Change From Baseline in Cartilage Volume in the Index Region Measured by 7 Tesla MRI | Week 52 | 49.3 µL | Standard Error 67.29 |
| Placebo | Change From Baseline in Cartilage Volume in the Index Region Measured by 7 Tesla MRI | Week 16 | 24.4 µL | Standard Error 43.05 |
| Placebo | Change From Baseline in Cartilage Volume in the Index Region Measured by 7 Tesla MRI | Week 52 | 123.1 µL | Standard Error 60.62 |
Secondary
Maximum Observed Plasma Concentration (Cmax) of LRX712
Cmax is defined as the maximum (peak) observed concentration following a dose. LRX712 plasma concentrations were determined using the actual recorded sampling times and non-compartmental method with Phoenix WinNonlin (Version 8.3). LRX712 was determined by a validated LC-MS/MS method. Concentrations below the lower limit of quantification (LLOQ) were treated as zero . LLOQ was 25 pg/mL.
Time frame: Pre-dose, 0.5, 12, 24 and 168 hours after dose on Day 1; Pre-dose, 24 and 168 hours after dose on Day 29; Pre-dose, 24, 168, 1344 and 3360 hours after dose on Day 57
Population: Pharmacokinetic (PK) analysis set: Includes all participants with at least one available valid PK concentration measurement, who received any dose of LRX712 and with no protocol deviations that impact on PK data.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| LRX712 15 mg | Maximum Observed Plasma Concentration (Cmax) of LRX712 | Day 29 | 3.33 ng/mL | Standard Deviation 2.57 |
| LRX712 15 mg | Maximum Observed Plasma Concentration (Cmax) of LRX712 | Day 1 | 3.52 ng/mL | Standard Deviation 2.07 |
| LRX712 15 mg | Maximum Observed Plasma Concentration (Cmax) of LRX712 | Day 57 | 2.39 ng/mL | Standard Deviation 0.951 |
| LRX712 25 mg | Maximum Observed Plasma Concentration (Cmax) of LRX712 | Day 29 | 3.50 ng/mL | Standard Deviation 1.43 |
| LRX712 25 mg | Maximum Observed Plasma Concentration (Cmax) of LRX712 | Day 1 | 6.54 ng/mL | Standard Deviation 5.33 |
| LRX712 25 mg | Maximum Observed Plasma Concentration (Cmax) of LRX712 | Day 57 | 4.05 ng/mL | Standard Deviation 2.25 |
| Placebo | Maximum Observed Plasma Concentration (Cmax) of LRX712 | Day 1 | 6.94 ng/mL | Standard Deviation 4.96 |
| Placebo | Maximum Observed Plasma Concentration (Cmax) of LRX712 | Day 57 | 29.5 ng/mL | Standard Deviation 20.4 |
| Placebo | Maximum Observed Plasma Concentration (Cmax) of LRX712 | Day 29 | 27.0 ng/mL | Standard Deviation 31.6 |
Secondary
Maximum Observed Plasma Concentration (Cmax) of MAE344
Cmax is defined as the maximum (peak) observed concentration following a dose. MAE344 is a metabolite of LRX712 and plasma concentrations were determined using the actual recorded sampling times and non-compartmental method with Phoenix WinNonlin (Version 8.3). MAE344 was determined by a validated LC-MS/MS method. Concentrations below the lower limit of quantification (LLOQ) were treated as zero . LLOQ was 100 pg/mL.
Time frame: Pre-dose, 0.5, 12, 24 and 168 hours after dose on Day 1; Pre-dose, 24 and 168 hours after dose on Day 29; Pre-dose, 24, 168, 1344 and 3360 hours after dose on Day 57
Population: Pharmacokinetic (PK) analysis set: Includes all participants with at least one available valid PK concentration measurement, who received any dose of LRX712 and with no protocol deviations that impact on PK data.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| LRX712 15 mg | Maximum Observed Plasma Concentration (Cmax) of MAE344 | Day 29 | 42.6 ng/mL | Standard Deviation 37.4 |
| LRX712 15 mg | Maximum Observed Plasma Concentration (Cmax) of MAE344 | Day 1 | 38.3 ng/mL | Standard Deviation 23 |
| LRX712 15 mg | Maximum Observed Plasma Concentration (Cmax) of MAE344 | Day 57 | 26.0 ng/mL | Standard Deviation 11.8 |
| LRX712 25 mg | Maximum Observed Plasma Concentration (Cmax) of MAE344 | Day 29 | 40.5 ng/mL | Standard Deviation 24.6 |
| LRX712 25 mg | Maximum Observed Plasma Concentration (Cmax) of MAE344 | Day 1 | 52.1 ng/mL | Standard Deviation 47.3 |
| LRX712 25 mg | Maximum Observed Plasma Concentration (Cmax) of MAE344 | Day 57 | 45.1 ng/mL | Standard Deviation 33.7 |
| Placebo | Maximum Observed Plasma Concentration (Cmax) of MAE344 | Day 1 | 75.2 ng/mL | Standard Deviation 63.1 |
| Placebo | Maximum Observed Plasma Concentration (Cmax) of MAE344 | Day 57 | 321 ng/mL | Standard Deviation 170 |
| Placebo | Maximum Observed Plasma Concentration (Cmax) of MAE344 | Day 29 | 281 ng/mL | Standard Deviation 329 |
Secondary
Minimum Observed Plasma Concentration (Cmin) of LRX712
Cmin is defined as the minimum (peak) observed concentration following a dose. LRX712 plasma concentrations were determined using the actual recorded sampling times and non-compartmental method with Phoenix WinNonlin (Version 8.3). LRX712 was determined by a validated LC-MS/MS method. Concentrations below the lower limit of quantification (LLOQ) were treated as zero . LLOQ was 25 pg/mL.
Time frame: Pre-dose on Day 29; Pre-dose, 1344 hours after dose on Day 57 (LRX712 15 mg arm) and 3360 hours after dose on Day 57 (LRX712 25 mg and 75 mg arms)
Population: Pharmacokinetic (PK) analysis set: Includes all participants with at least one available valid PK concentration measurement, who received any dose of LRX712 and with no protocol deviations that impact on PK data.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| LRX712 15 mg | Minimum Observed Plasma Concentration (Cmin) of LRX712 | Dose 2 (pre-dose Day 57) | 0.111 ng/mL | Standard Deviation 0.109 |
| LRX712 15 mg | Minimum Observed Plasma Concentration (Cmin) of LRX712 | Dose 1 (pre-dose Day 29) | 0.0735 ng/mL | Standard Deviation 0.1 |
| LRX712 15 mg | Minimum Observed Plasma Concentration (Cmin) of LRX712 | Dose 3 (post-dose Day 57) | 0.0439 ng/mL | Standard Deviation 0.074 |
| LRX712 25 mg | Minimum Observed Plasma Concentration (Cmin) of LRX712 | Dose 2 (pre-dose Day 57) | 0.202 ng/mL | Standard Deviation 0.204 |
| LRX712 25 mg | Minimum Observed Plasma Concentration (Cmin) of LRX712 | Dose 1 (pre-dose Day 29) | 0.0823 ng/mL | Standard Deviation 0.115 |
| LRX712 25 mg | Minimum Observed Plasma Concentration (Cmin) of LRX712 | Dose 3 (post-dose Day 57) | 0.00379 ng/mL | Standard Deviation 0.0131 |
| Placebo | Minimum Observed Plasma Concentration (Cmin) of LRX712 | Dose 1 (pre-dose Day 29) | 0.231 ng/mL | Standard Deviation 0.401 |
| Placebo | Minimum Observed Plasma Concentration (Cmin) of LRX712 | Dose 3 (post-dose Day 57) | 0.0120 ng/mL | Standard Deviation 0.0208 |
| Placebo | Minimum Observed Plasma Concentration (Cmin) of LRX712 | Dose 2 (pre-dose Day 57) | 0.365 ng/mL | Standard Deviation 0.585 |
Secondary
Minimum Observed Plasma Concentration (Cmin) of MAE344
Cmin is defined as the minimum (peak) observed concentration following a dose. MAE344 is a metabolite of LRX712 and plasma concentrations were determined using the actual recorded sampling times and non-compartmental method with Phoenix WinNonlin (Version 8.3). MAE344 was determined by a validated LC-MS/MS method. Concentrations below the lower limit of quantification (LLOQ) were treated as zero . LLOQ was 100 pg/mL.
Time frame: Pre-dose on Day 29; Pre-dose, 1344 hours after dose on Day 57 (LRX712 15 mg arm) and 3360 hours after dose on Day 57 (LRX712 25 mg and 75 mg arms)
Population: Pharmacokinetic (PK) analysis set: Includes all participants with at least one available valid PK concentration measurement, who received any dose of LRX712 and with no protocol deviations that impact on PK data.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| LRX712 15 mg | Minimum Observed Plasma Concentration (Cmin) of MAE344 | Dose 2 (pre-dose Day 57) | 2.12 ng/mL | Standard Deviation 2.15 |
| LRX712 15 mg | Minimum Observed Plasma Concentration (Cmin) of MAE344 | Dose 1 (pre-dose Day 29) | 1.34 ng/mL | Standard Deviation 1.76 |
| LRX712 15 mg | Minimum Observed Plasma Concentration (Cmin) of MAE344 | Dose 3 (post-dose Day 57) | 0.916 ng/mL | Standard Deviation 1.22 |
| LRX712 25 mg | Minimum Observed Plasma Concentration (Cmin) of MAE344 | Dose 2 (pre-dose Day 57) | 3.04 ng/mL | Standard Deviation 3.06 |
| LRX712 25 mg | Minimum Observed Plasma Concentration (Cmin) of MAE344 | Dose 1 (pre-dose Day 29) | 1.49 ng/mL | Standard Deviation 1.82 |
| LRX712 25 mg | Minimum Observed Plasma Concentration (Cmin) of MAE344 | Dose 3 (post-dose Day 57) | 0.0557 ng/mL | Standard Deviation 0.14 |
| Placebo | Minimum Observed Plasma Concentration (Cmin) of MAE344 | Dose 1 (pre-dose Day 29) | 4.11 ng/mL | Standard Deviation 7.01 |
| Placebo | Minimum Observed Plasma Concentration (Cmin) of MAE344 | Dose 3 (post-dose Day 57) | 0.257 ng/mL | Standard Deviation 0.445 |
| Placebo | Minimum Observed Plasma Concentration (Cmin) of MAE344 | Dose 2 (pre-dose Day 57) | 5.70 ng/mL | Standard Deviation 9.1 |
Secondary
Synovial Fluid Concentrations of LRX712
The observed synovial concentration following a dose. LRX712 concentrations were determined using the actual recorded sampling times and non-compartmental method with Phoenix WinNonlin (Version 8.3). LRX712 was determined by a validated LC-MS/MS method. Concentrations below the lower limit of quantification (LLOQ) were treated as zero . LLOQ was 20 ng/mL. Samples were collected from a limited number of participants.
Time frame: Pre-dose on Day 1, 29 and 57
Population: Participants in the PK analysis set with a synovial sample collected and a valid value for the outcome measure.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| LRX712 15 mg | Synovial Fluid Concentrations of LRX712 | Day 1 | 0 ng/mL | — |
| LRX712 15 mg | Synovial Fluid Concentrations of LRX712 | Day 29 | 0 ng/mL | — |
| LRX712 25 mg | Synovial Fluid Concentrations of LRX712 | Day 1 | 0 ng/mL | Standard Deviation 0 |
| LRX712 25 mg | Synovial Fluid Concentrations of LRX712 | Day 29 | 0 ng/mL | — |
| LRX712 25 mg | Synovial Fluid Concentrations of LRX712 | Day 57 | 0 ng/mL | Standard Deviation 0 |
Secondary
Synovial Fluid Concentrations of MAE344
The observed synovial concentration following a dose. MAE344 is a metabolite of LRX712 and concentrations were determined using the actual recorded sampling times and non-compartmental method with Phoenix WinNonlin (Version 8.3). MAE344 was determined by a validated LC-MS/MS method. Concentrations below the lower limit of quantification (LLOQ) were treated as zero . LLOQ was 80 ng/mL. Samples were collected from a limited number of participants.
Time frame: Pre-dose on Day 1, 29 and 57
Population: Participants in the PK analysis set with a synovial sample collected and a valid value for the outcome measure.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| LRX712 15 mg | Synovial Fluid Concentrations of MAE344 | Day 1 | 0 ng/mL | — |
| LRX712 15 mg | Synovial Fluid Concentrations of MAE344 | Day 29 | 0 ng/mL | — |
| LRX712 25 mg | Synovial Fluid Concentrations of MAE344 | Day 1 | 0 ng/mL | Standard Deviation 0 |
| LRX712 25 mg | Synovial Fluid Concentrations of MAE344 | Day 29 | 0 ng/mL | — |
| LRX712 25 mg | Synovial Fluid Concentrations of MAE344 | Day 57 | 0 ng/mL | Standard Deviation 0 |
Secondary
Time to Reach the Maximum Plasma Concentration (Tmax) of LRX712
Tmax is the time to reach maximum (peak) LRX712 concentration after single-dose administration (time). LRX712 plasma concentrations were determined using the actual recorded sampling times and non-compartmental method with Phoenix WinNonlin (Version 8.3). LRX712 was determined by a validated LC-MS/MS method. Concentrations below the lower limit of quantification (LLOQ) were treated as zero . LLOQ was 25 pg/mL.
Time frame: Pre-dose, 0.5, 12, 24 and 168 hours after dose on Day 1; Pre-dose, 24 and 168 hours after dose on Day 29; Pre-dose, 24, 168, 1344 and 3360 hours after dose on Day 57
Population: Pharmacokinetic (PK) analysis set: Includes all participants with at least one available valid PK concentration measurement, who received any dose of LRX712 and with no protocol deviations that impact on PK data.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| LRX712 15 mg | Time to Reach the Maximum Plasma Concentration (Tmax) of LRX712 | Day 29 | 23.8 hours |
| LRX712 15 mg | Time to Reach the Maximum Plasma Concentration (Tmax) of LRX712 | Day 1 | 17.5 hours |
| LRX712 15 mg | Time to Reach the Maximum Plasma Concentration (Tmax) of LRX712 | Day 57 | 24.0 hours |
| LRX712 25 mg | Time to Reach the Maximum Plasma Concentration (Tmax) of LRX712 | Day 29 | 24.0 hours |
| LRX712 25 mg | Time to Reach the Maximum Plasma Concentration (Tmax) of LRX712 | Day 1 | 23.3 hours |
| LRX712 25 mg | Time to Reach the Maximum Plasma Concentration (Tmax) of LRX712 | Day 57 | 24.0 hours |
| Placebo | Time to Reach the Maximum Plasma Concentration (Tmax) of LRX712 | Day 1 | 24.0 hours |
| Placebo | Time to Reach the Maximum Plasma Concentration (Tmax) of LRX712 | Day 57 | 24.0 hours |
| Placebo | Time to Reach the Maximum Plasma Concentration (Tmax) of LRX712 | Day 29 | 23.9 hours |
Secondary
Time to Reach the Maximum Plasma Concentration (Tmax) of MAE344
Tmax is the time to reach maximum (peak) MAE344 concentration after single-dose administration (time). MAE344 is a metabolite of LRX712 and plasma concentrations were determined using the actual recorded sampling times and non-compartmental method with Phoenix WinNonlin (Version 8.3). MAE344 was determined by a validated LC-MS/MS method. Concentrations below the lower limit of quantification (LLOQ) were treated as zero . LLOQ was 100 pg/mL.
Time frame: Pre-dose, 0.5, 12, 24 and 168 hours after dose on Day 1; Pre-dose, 24 and 168 hours after dose on Day 29; Pre-dose, 24, 168, 1344 and 3360 hours after dose on Day 57
Population: Pharmacokinetic (PK) analysis set: Includes all participants with at least one available valid PK concentration measurement, who received any dose of LRX712 and with no protocol deviations that impact on PK data.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| LRX712 15 mg | Time to Reach the Maximum Plasma Concentration (Tmax) of MAE344 | Day 29 | 23.8 hours |
| LRX712 15 mg | Time to Reach the Maximum Plasma Concentration (Tmax) of MAE344 | Day 1 | 23.5 hours |
| LRX712 15 mg | Time to Reach the Maximum Plasma Concentration (Tmax) of MAE344 | Day 57 | 24.0 hours |
| LRX712 25 mg | Time to Reach the Maximum Plasma Concentration (Tmax) of MAE344 | Day 29 | 24.0 hours |
| LRX712 25 mg | Time to Reach the Maximum Plasma Concentration (Tmax) of MAE344 | Day 1 | 24.0 hours |
| LRX712 25 mg | Time to Reach the Maximum Plasma Concentration (Tmax) of MAE344 | Day 57 | 24.0 hours |
| Placebo | Time to Reach the Maximum Plasma Concentration (Tmax) of MAE344 | Day 1 | 24.1 hours |
| Placebo | Time to Reach the Maximum Plasma Concentration (Tmax) of MAE344 | Day 57 | 24.0 hours |
| Placebo | Time to Reach the Maximum Plasma Concentration (Tmax) of MAE344 | Day 29 | 23.9 hours |