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    Clinical Trial Results:
    A randomized, placebo-controlled, subject and investigator blinded study investigating the safety, tolerability and preliminary efficacy of 8-week treatment with intra-articular LRX712 to regenerate articular cartilage in patients with mild/moderate knee osteoarthritis

    Summary
    EudraCT number
    		 2019-002963-92
    Trial protocol
    		 NL   AT  
    Global end of trial date
    17 Jan 2025

    Results information
    Results version number
    		 v1(current)
    This version publication date
    04 Jan 2026
    First version publication date
    04 Jan 2026
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    CLRX712A12201
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04097379
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Novartis Pharma AG
    Sponsor organisation address
    Lichtstrasse 35, Basel, Switzerland, 4056
    Public contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 613241111, novartis.email@novartis.com
    Scientific contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 613241111, novartis.email@novartis.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    17 Jan 2025
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    17 Jan 2025
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main purpose of this study was to explore the preliminary efficacy of LRX712 when administered as 3 consecutive intra-articularly injections at monthly intervals (i.e., an 8-week treatment period) by evaluating the ability of the drug to regenerate articular cartilage.
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines. All the local regulatory requirements pertinent to safety of trial subjects were also followed during the conduct of the trial.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    20 Jul 2020
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Netherlands: 45
    Worldwide total number of subjects
    45
    EEA total number of subjects
    45
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    25
    From 65 to 84 years
    20
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 Participants took part in 1 investigative site in Netherlands.

    Pre-assignment
    Screening details
    		 This study had a 7-week screening period.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 LRX712 15 mg
    Arm description
    		 LRX712 15 mg was administered intra-articularly (i.a.) every four weeks, for a total of three administrations.
    Arm type
    		 Experimental

    Investigational medicinal product name
    LRX712
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intraarticular use
    Dosage and administration details
    LRX712 15 mg was administered intra-articularly (i.a.) every four weeks, for a total of three administrations.

    Arm title
    		 LRX712 25 mg
    Arm description
    		 LRX712 25 mg was administered i.a. every four weeks, for a total of three administrations.
    Arm type
    		 Experimental

    Investigational medicinal product name
    LRX712
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intraarticular use
    Dosage and administration details
    LRX712 25 mg was administered i.a. every four weeks, for a total of three administrations.

    Arm title
    		 LRX712 75 mg
    Arm description
    		 LRX712 75 mg was administered i.a. every four weeks, for a total of three administrations.
    Arm type
    		 Experimental

    Investigational medicinal product name
    LRX712
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intraarticular use
    Dosage and administration details
    LRX712 75 mg was administered i.a. every four weeks, for a total of three administrations.

    Arm title
    		 Placebo
    Arm description
    		 Placebo was administered i.a. every four weeks, for a total of three administrations.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intraarticular use
    Dosage and administration details
    Placebo was administered i.a. every four weeks, for a total of three administrations.

    Number of subjects in period 1
    		LRX712 15 mg LRX712 25 mg LRX712 75 mg Placebo
    Started
    12
    14
    3
    16
    Completed
    11
    13
    3
    16
    Not completed
    1
    1
    0
    0
         Physician decision
    -
    1
    -
    -
         Adverse event
    1
    -
    -
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    LRX712 15 mg
    Reporting group description
    		 LRX712 15 mg was administered intra-articularly (i.a.) every four weeks, for a total of three administrations.

    Reporting group title
    LRX712 25 mg
    Reporting group description
    		 LRX712 25 mg was administered i.a. every four weeks, for a total of three administrations.

    Reporting group title
    LRX712 75 mg
    Reporting group description
    		 LRX712 75 mg was administered i.a. every four weeks, for a total of three administrations.

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo was administered i.a. every four weeks, for a total of three administrations.

    Reporting group values
    		 LRX712 15 mg LRX712 25 mg LRX712 75 mg Placebo Total
    Number of subjects
    		 12 14 3 16 45
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0 0
        Adults (18-64 years)
    		 3 8 2 12 25
        From 65-84 years
    		 9 6 1 4 20
        85 years and over
    		 0 0 0 0 0
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 66.3 ( 7.74 ) 61.6 ( 7.31 ) 59.7 ( 5.03 ) 58.4 ( 8.66 ) -
    Sex: Female, Male
    Units: participants
        Female
    		 5 7 1 7 20
        Male
    		 7 7 2 9 25
    Race/Ethnicity, Customized
    Units: Subjects
        Asian
    		 1 1 0 0 2
        White
    		 11 13 3 16 43

    End points

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    End points reporting groups
    Reporting group title
    LRX712 15 mg
    Reporting group description
    		 LRX712 15 mg was administered intra-articularly (i.a.) every four weeks, for a total of three administrations.

    Reporting group title
    LRX712 25 mg
    Reporting group description
    		 LRX712 25 mg was administered i.a. every four weeks, for a total of three administrations.

    Reporting group title
    LRX712 75 mg
    Reporting group description
    		 LRX712 75 mg was administered i.a. every four weeks, for a total of three administrations.

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo was administered i.a. every four weeks, for a total of three administrations.

    Primary: Change from baseline in cartilage volume in the index region measured by 7 Tesla MRI at Week 28

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    End point title
    		 Change from baseline in cartilage volume in the index region measured by 7 Tesla MRI at Week 28 [1]
    End point description
    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).
    End point type
    Primary
    End point timeframe
    Baseline, Week 28
    Notes
    [1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The end point is specific for the arms presented.
    End point values
    		 LRX712 15 mg LRX712 25 mg Placebo
    Number of subjects analysed
    11
    13
    16
    Units: µL
        least squares mean (standard error)
    63.3 ( 54.93 )
    49.8 ( 50.57 )
    11.6 ( 45.54 )
    Statistical analysis title
    		 Cartilage volume
    Comparison groups
    LRX712 25 mg v Placebo
    Number of subjects included in analysis
    29
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.2892
    Method
    		 Mixed effects model for repeated measure
    Parameter type
    		 Least Square Mean
    Point estimate
    38.19
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -76.7
         upper limit
    		 153.1
    Variability estimate
    Standard error of the mean
    Dispersion value
    68.1
    Statistical analysis title
    		 Cartilage volume
    Comparison groups
    LRX712 15 mg v Placebo
    Number of subjects included in analysis
    27
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.2366
    Method
    		 Mixed effects model for repeated measure
    Parameter type
    		 Least Square Mean
    Point estimate
    51.7
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -68.7
         upper limit
    		 172.1
    Variability estimate
    Standard error of the mean
    Dispersion value
    71.327

    Secondary: Maximum Observed Plasma Concentration (Cmax) of LRX712

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    End point title
    		 Maximum Observed Plasma Concentration (Cmax) of LRX712 [2]
    End point description
    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. The Number of Subjects Analyzed differs as stated on the category column, in case of difference from Number of subjects that started the Arm.
    End point type
    Secondary
    End point timeframe
    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
    Notes
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The end point is specific for the arms presented. Placebo is not applicable.
    End point values
    		 LRX712 15 mg LRX712 25 mg LRX712 75 mg
    Number of subjects analysed
    12
    14
    3
    Units: ng/mL
    arithmetic mean (standard deviation)
        Day 1 (n=12,14,3)
    3.52 ( 2.07 )
    6.54 ( 5.33 )
    6.94 ( 4.96 )
        Day 29 (n=10,13,2)
    3.33 ( 2.57 )
    3.50 ( 1.43 )
    27.0 ( 31.6 )
        Day 57 (n=11,13,3)
    2.39 ( 0.951 )
    4.05 ( 2.25 )
    29.5 ( 20.4 )
    No statistical analyses for this end point

    Secondary: Time to Reach the Maximum Plasma Concentration (Tmax) of LRX712

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    End point title
    		 Time to Reach the Maximum Plasma Concentration (Tmax) of LRX712 [3]
    End point description
    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. The Number of Subjects Analyzed differs as stated on the category column, in case of difference from Number of subjects that started the Arm.
    End point type
    Secondary
    End point timeframe
    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
    Notes
    [3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The end point is specific for the arms presented. Placebo is not applicable.
    End point values
    		 LRX712 15 mg LRX712 25 mg LRX712 75 mg
    Number of subjects analysed
    12
    14
    3
    Units: hours
    median (full range (min-max))
        Day 1 (n=12,14,3)
    17.5 (12.0 to 24.0)
    23.3 (0.50 to 24.1)
    24.0 (12.0 to 24.1)
        Day 29 (n=10,13,2)
    23.8 (22.6 to 24.0)
    24.0 (22.2 to 24.2)
    23.9 (23.8 to 24.0)
        Day 57 (n=11,13,3)
    24.0 (21.9 to 24.0)
    24.0 (22.0 to 24.1)
    24.0 (23.5 to 24.0)
    No statistical analyses for this end point

    Secondary: Minimum Observed Plasma Concentration (Cmin) of LRX712

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    End point title
    		 Minimum Observed Plasma Concentration (Cmin) of LRX712 [4]
    End point description
    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. The Number of Subjects Analyzed differs as stated on the category column, in case of difference from Number of subjects that started the Arm.
    End point type
    Secondary
    End point timeframe
    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)
    Notes
    [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The end point is specific for the arms presented. Placebo is not applicable.
    End point values
    		 LRX712 15 mg LRX712 25 mg LRX712 75 mg
    Number of subjects analysed
    11
    14
    3
    Units: ng/mL
    arithmetic mean (standard deviation)
        Dose 1 (pre-dose Day 29) (n=10,14,3)
    0.0735 ( 0.10 )
    0.0823 ( 0.115 )
    0.231 ( 0.401 )
        Dose 2 (pre-dose Day 57) (n=11,13,3)
    0.111 ( 0.109 )
    0.202 ( 0.204 )
    0.365 ( 0.585 )
        Dose 3 (post-dose Day 57) (n=10,12,3)
    0.0439 ( 0.0740 )
    0.00379 ( 0.0131 )
    0.0120 ( 0.0208 )
    No statistical analyses for this end point

    Secondary: Time to Reach the Maximum Plasma Concentration (Tmax) of MAE344

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    End point title
    		 Time to Reach the Maximum Plasma Concentration (Tmax) of MAE344 [5]
    End point description
    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. The Number of Subjects Analyzed differs as stated on the category column, in case of difference from Number of subjects that started the Arm.
    End point type
    Secondary
    End point timeframe
    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
    Notes
    [5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The end point is specific for the arms presented. Placebo is not applicable.
    End point values
    		 LRX712 15 mg LRX712 25 mg LRX712 75 mg
    Number of subjects analysed
    12
    14
    3
    Units: hours
    median (full range (min-max))
        Day 1 (n=12,14,3)
    23.5 (12.0 to 24.1)
    24.0 (12.0 to 169)
    24.1 (24.0 to 24.1)
        Day 29 (n=10,13,2)
    23.8 (22.6 to 24.0)
    24.0 (22.2 to 193)
    23.9 (23.8 to 24.0)
        Day 57 (n=11,13,3)
    24.0 (21.9 to 169)
    24.0 (22.0 to 24.1)
    24.0 (23.5 to 24.0)
    No statistical analyses for this end point

    Secondary: Synovial fluid concentrations of LRX712

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    End point title
    		 Synovial fluid concentrations of LRX712 [6]
    End point description
    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. The Number of Subjects Analyzed differs as stated on the category column, in case of difference from Number of subjects that started the Arm.
    End point type
    Secondary
    End point timeframe
    Pre-dose on Day 1, 29 and 57
    Notes
    [6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The end point is specific for the arms presented. Placebo is not applicable.
    End point values
    		 LRX712 15 mg LRX712 25 mg LRX712 75 mg
    Number of subjects analysed
    2
    3
    0 [7]
    Units: ng/mL
    arithmetic mean (standard deviation)
        Day 1 (n=1,2,0)
    0 ( 0 )
    0 ( 0 )
    ( )
        Day 29 (n=1,1,0)
    0 ( 0 )
    0 ( 0 )
    ( )
        Day 57 (n=0,2,0)
    0 ( 0 )
    0 ( 0 )
    ( )
    Notes
    [7] - The samples collected were outside the stability window.
    No statistical analyses for this end point

    Secondary: Maximum Observed Plasma Concentration (Cmax) of MAE344

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    End point title
    		 Maximum Observed Plasma Concentration (Cmax) of MAE344 [8]
    End point description
    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. The Number of Subjects Analyzed differs as stated on the category column, in case of difference from Number of subjects that started the Arm.
    End point type
    Secondary
    End point timeframe
    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
    Notes
    [8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The end point is specific for the arms presented. Placebo is not applicable.
    End point values
    		 LRX712 15 mg LRX712 25 mg LRX712 75 mg
    Number of subjects analysed
    12
    14
    3
    Units: ng/mL
    arithmetic mean (standard deviation)
        Day 1 (n=12,14,3)
    38.3 ( 23.0 )
    52.1 ( 47.3 )
    75.2 ( 63.1 )
        Day 29 (n=10,13,2)
    42.6 ( 37.4 )
    40.5 ( 24.6 )
    281 ( 329 )
        Day 57 (n=11,13,3)
    26.0 ( 11.8 )
    45.1 ( 33.7 )
    321 ( 170 )
    No statistical analyses for this end point

    Secondary: Minimum Observed Plasma Concentration (Cmin) of MAE344

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    End point title
    		 Minimum Observed Plasma Concentration (Cmin) of MAE344 [9]
    End point description
    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. The Number of Subjects Analyzed differs as stated on the category column, in case of difference from Number of subjects that started the Arm.
    End point type
    Secondary
    End point timeframe
    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)
    Notes
    [9] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The end point is specific for the arms presented. Placebo is not applicable.
    End point values
    		 LRX712 15 mg LRX712 25 mg LRX712 75 mg
    Number of subjects analysed
    11
    14
    3
    Units: ng/mL
    arithmetic mean (standard deviation)
        Dose 1 (pre-dose Day 29) (n=10,14,3)
    1.34 ( 1.76 )
    1.49 ( 1.82 )
    4.11 ( 7.01 )
        Dose 2 (pre-dose Day 57) (n=11,13,3)
    2.12 ( 2.15 )
    3.04 ( 3.06 )
    5.70 ( 9.10 )
        Dose 3 (post-dose Day 57) (n=10,12,3)
    0.916 ( 1.22 )
    0.0557 ( 0.140 )
    0.257 ( 0.445 )
    No statistical analyses for this end point

    Secondary: Synovial fluid concentrations of MAE344

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    End point title
    		 Synovial fluid concentrations of MAE344 [10]
    End point description
    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. The Number of Subjects Analyzed differs as stated on the category column, in case of difference from Number of subjects that started the Arm.
    End point type
    Secondary
    End point timeframe
    Pre-dose on Day 1, 29 and 57
    Notes
    [10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The end point is specific for the arms presented. Placebo is not applicable.
    End point values
    		 LRX712 15 mg LRX712 25 mg LRX712 75 mg
    Number of subjects analysed
    2
    3
    0 [11]
    Units: ng/mL
    arithmetic mean (standard deviation)
        Day 1 (n=1,2,0)
    0 ( 0 )
    0 ( 0 )
    ( )
        Day 29 (n=1,1,0)
    0 ( 0 )
    0 ( 0 )
    ( )
        Day 57 (n=0,2,0)
    0 ( 0 )
    0 ( 0 )
    ( )
    Notes
    [11] - The samples collected were outside the stability window.
    No statistical analyses for this end point

    Secondary: Change from baseline in articular cartilage [23Na] content measured by 7 Tesla MRI

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    End point title
    		 Change from baseline in articular cartilage [23Na] content measured by 7 Tesla MRI [12]
    End point description
    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. The Number of Subjects Analyzed differs as stated on the category column, in case of difference from Number of subjects that started the Arm.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 16, 28 and 52
    Notes
    [12] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The end point is specific for the arms presented.
    End point values
    		 LRX712 15 mg LRX712 25 mg Placebo
    Number of subjects analysed
    9
    11
    16
    Units: mmol/L
    least squares mean (standard error)
        Week 16 (n=8,8,14)
    -7.4 ( 12.00 )
    12.7 ( 11.99 )
    8.5 ( 9.20 )
        Week 28 (n=9,9,13)
    -15.5 ( 11.21 )
    8.9 ( 11.13 )
    4.0 ( 9.24 )
        Week 52 (n=9,11,16)
    3.1 ( 12.12 )
    26.6 ( 11.19 )
    5.5 ( 9.20 )
    No statistical analyses for this end point

    Secondary: Change from baseline in cartilage volume in the index region measured by 7 Tesla MRI

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    End point title
    		 Change from baseline in cartilage volume in the index region measured by 7 Tesla MRI [13]
    End point description
    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. The Number of Subjects Analyzed differs as stated on the category column, in case of difference from Number of subjects that started the Arm.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 16 and 52
    Notes
    [13] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The end point is specific for the arms presented.
    End point values
    		 LRX712 15 mg LRX712 25 mg Placebo
    Number of subjects analysed
    11
    13
    16
    Units: µL
    least squares mean (standard error)
        Week 16 (n=10,11,15)
    -48.0 ( 52.64 )
    -17.4 ( 50.09 )
    24.4 ( 43.05 )
        Week 52 (n=11,13,16)
    19.5 ( 73.11 )
    49.3 ( 67.29 )
    123.1 ( 60.62 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were reported from first dose until last dose of study treatment plus 30 days.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    27.1
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Placebo

    Reporting group title
    Total
    Reporting group description
    		 Total

    Reporting group title
    LRX712 15mg and 25mg
    Reporting group description
    		 LRX712 15mg and 25mg

    Reporting group title
    LRX712 25 mg
    Reporting group description
    		 LRX712 25 mg

    Reporting group title
    LRX712 75 mg
    Reporting group description
    		 LRX712 75 mg

    Reporting group title
    LRX712 15 mg
    Reporting group description
    		 LRX712 15 mg

    Serious adverse events
    		 Placebo Total LRX712 15mg and 25mg LRX712 25 mg LRX712 75 mg LRX712 15 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 45 (0.00%)
    0 / 26 (0.00%)
    0 / 14 (0.00%)
    0 / 3 (0.00%)
    0 / 12 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo Total LRX712 15mg and 25mg LRX712 25 mg LRX712 75 mg LRX712 15 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    16 / 16 (100.00%)
    44 / 45 (97.78%)
    25 / 26 (96.15%)
    14 / 14 (100.00%)
    3 / 3 (100.00%)
    11 / 12 (91.67%)
    Investigations
    Electrocardiogram ST segment elevation
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 45 (2.22%)
    1 / 26 (3.85%)
    1 / 14 (7.14%)
    0 / 3 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    1
    1
    0
    0
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    1 / 16 (6.25%)
    1 / 45 (2.22%)
    0 / 26 (0.00%)
    0 / 14 (0.00%)
    0 / 3 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    0
    Bone contusion
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 45 (2.22%)
    1 / 26 (3.85%)
    0 / 14 (0.00%)
    0 / 3 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    1
    0
    0
    1
    Immunisation reaction
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 45 (2.22%)
    1 / 26 (3.85%)
    1 / 14 (7.14%)
    0 / 3 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    1
    1
    0
    0
    Skin abrasion
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 45 (2.22%)
    1 / 26 (3.85%)
    1 / 14 (7.14%)
    0 / 3 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    1
    1
    0
    0
    Cardiac disorders
    Arrhythmia supraventricular
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 45 (2.22%)
    1 / 26 (3.85%)
    1 / 14 (7.14%)
    0 / 3 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    1
    1
    0
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    12 / 16 (75.00%)
    26 / 45 (57.78%)
    13 / 26 (50.00%)
    8 / 14 (57.14%)
    1 / 3 (33.33%)
    5 / 12 (41.67%)
         occurrences all number
    21
    40
    18
    10
    1
    8
    Dizziness
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 45 (2.22%)
    1 / 26 (3.85%)
    0 / 14 (0.00%)
    0 / 3 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    1
    0
    0
    1
    Somnolence
         subjects affected / exposed
    1 / 16 (6.25%)
    2 / 45 (4.44%)
    0 / 26 (0.00%)
    0 / 14 (0.00%)
    1 / 3 (33.33%)
    0 / 12 (0.00%)
         occurrences all number
    1
    3
    0
    0
    2
    0
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    1 / 16 (6.25%)
    3 / 45 (6.67%)
    2 / 26 (7.69%)
    1 / 14 (7.14%)
    0 / 3 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    1
    3
    2
    1
    0
    1
    Asthenia
         subjects affected / exposed
    1 / 16 (6.25%)
    1 / 45 (2.22%)
    0 / 26 (0.00%)
    0 / 14 (0.00%)
    0 / 3 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    0
    Injection site haematoma
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 45 (2.22%)
    1 / 26 (3.85%)
    0 / 14 (0.00%)
    0 / 3 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    1
    0
    0
    1
    Influenza like illness
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 45 (2.22%)
    0 / 26 (0.00%)
    0 / 14 (0.00%)
    1 / 3 (33.33%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    1
    0
    Feeling cold
         subjects affected / exposed
    1 / 16 (6.25%)
    1 / 45 (2.22%)
    0 / 26 (0.00%)
    0 / 14 (0.00%)
    0 / 3 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    0
    Pyrexia
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 45 (2.22%)
    1 / 26 (3.85%)
    0 / 14 (0.00%)
    0 / 3 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    1
    0
    0
    1
    Malaise
         subjects affected / exposed
    1 / 16 (6.25%)
    2 / 45 (4.44%)
    1 / 26 (3.85%)
    1 / 14 (7.14%)
    0 / 3 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    2
    1
    1
    0
    0
    Injection site reaction
         subjects affected / exposed
    4 / 16 (25.00%)
    10 / 45 (22.22%)
    3 / 26 (11.54%)
    1 / 14 (7.14%)
    3 / 3 (100.00%)
    2 / 12 (16.67%)
         occurrences all number
    6
    18
    4
    2
    8
    2
    Ear and labyrinth disorders
    Ear discomfort
         subjects affected / exposed
    1 / 16 (6.25%)
    1 / 45 (2.22%)
    0 / 26 (0.00%)
    0 / 14 (0.00%)
    0 / 3 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    0
    Gastrointestinal disorders
    Vomiting
         subjects affected / exposed
    1 / 16 (6.25%)
    2 / 45 (4.44%)
    1 / 26 (3.85%)
    1 / 14 (7.14%)
    0 / 3 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    2
    1
    1
    0
    0
    Toothache
         subjects affected / exposed
    1 / 16 (6.25%)
    1 / 45 (2.22%)
    0 / 26 (0.00%)
    0 / 14 (0.00%)
    0 / 3 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    0
    Tooth disorder
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 45 (2.22%)
    1 / 26 (3.85%)
    1 / 14 (7.14%)
    0 / 3 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    1
    1
    0
    0
    Diarrhoea
         subjects affected / exposed
    1 / 16 (6.25%)
    3 / 45 (6.67%)
    2 / 26 (7.69%)
    1 / 14 (7.14%)
    0 / 3 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    1
    3
    2
    1
    0
    1
    Abdominal pain upper
         subjects affected / exposed
    1 / 16 (6.25%)
    1 / 45 (2.22%)
    0 / 26 (0.00%)
    0 / 14 (0.00%)
    0 / 3 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    0
    Nausea
         subjects affected / exposed
    3 / 16 (18.75%)
    4 / 45 (8.89%)
    1 / 26 (3.85%)
    1 / 14 (7.14%)
    0 / 3 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    4
    5
    1
    1
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Sinonasal obstruction
         subjects affected / exposed
    1 / 16 (6.25%)
    1 / 45 (2.22%)
    0 / 26 (0.00%)
    0 / 14 (0.00%)
    0 / 3 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    0
    Rhinorrhoea
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 45 (2.22%)
    1 / 26 (3.85%)
    0 / 14 (0.00%)
    0 / 3 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    1
    0
    0
    1
    Oropharyngeal pain
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 45 (2.22%)
    1 / 26 (3.85%)
    1 / 14 (7.14%)
    0 / 3 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    1
    1
    0
    0
    Cough
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 45 (2.22%)
    1 / 26 (3.85%)
    0 / 14 (0.00%)
    0 / 3 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    1
    0
    0
    1
    Sneezing
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 45 (2.22%)
    1 / 26 (3.85%)
    1 / 14 (7.14%)
    0 / 3 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    1
    1
    0
    0
    Skin and subcutaneous tissue disorders
    Dry skin
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 45 (2.22%)
    1 / 26 (3.85%)
    0 / 14 (0.00%)
    0 / 3 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    1
    0
    0
    1
    Psychiatric disorders
    Irritability
         subjects affected / exposed
    1 / 16 (6.25%)
    1 / 45 (2.22%)
    0 / 26 (0.00%)
    0 / 14 (0.00%)
    0 / 3 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    2
    2
    0
    0
    0
    0
    Musculoskeletal and connective tissue disorders
    Osteoarthritis
         subjects affected / exposed
    3 / 16 (18.75%)
    3 / 45 (6.67%)
    0 / 26 (0.00%)
    0 / 14 (0.00%)
    0 / 3 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    4
    4
    0
    0
    0
    0
    Neck pain
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 45 (2.22%)
    1 / 26 (3.85%)
    0 / 14 (0.00%)
    0 / 3 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    1
    0
    0
    1
    Myalgia
         subjects affected / exposed
    1 / 16 (6.25%)
    1 / 45 (2.22%)
    0 / 26 (0.00%)
    0 / 14 (0.00%)
    0 / 3 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    0
    Muscular weakness
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 45 (2.22%)
    1 / 26 (3.85%)
    1 / 14 (7.14%)
    0 / 3 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    1
    1
    0
    0
    Limb discomfort
         subjects affected / exposed
    3 / 16 (18.75%)
    6 / 45 (13.33%)
    3 / 26 (11.54%)
    2 / 14 (14.29%)
    0 / 3 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    3
    6
    3
    2
    0
    1
    Joint warmth
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 45 (2.22%)
    1 / 26 (3.85%)
    0 / 14 (0.00%)
    0 / 3 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    1
    0
    0
    1
    Joint swelling
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 45 (2.22%)
    1 / 26 (3.85%)
    1 / 14 (7.14%)
    0 / 3 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    1
    1
    0
    0
    Joint stiffness
         subjects affected / exposed
    0 / 16 (0.00%)
    10 / 45 (22.22%)
    10 / 26 (38.46%)
    7 / 14 (50.00%)
    0 / 3 (0.00%)
    3 / 12 (25.00%)
         occurrences all number
    0
    15
    15
    11
    0
    4
    Back pain
         subjects affected / exposed
    1 / 16 (6.25%)
    2 / 45 (4.44%)
    1 / 26 (3.85%)
    0 / 14 (0.00%)
    0 / 3 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    1
    2
    1
    0
    0
    1
    Arthritis
         subjects affected / exposed
    1 / 16 (6.25%)
    1 / 45 (2.22%)
    0 / 26 (0.00%)
    0 / 14 (0.00%)
    0 / 3 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    0
    Arthralgia
         subjects affected / exposed
    4 / 16 (25.00%)
    11 / 45 (24.44%)
    7 / 26 (26.92%)
    2 / 14 (14.29%)
    0 / 3 (0.00%)
    5 / 12 (41.67%)
         occurrences all number
    7
    16
    9
    4
    0
    5
    Pain in extremity
         subjects affected / exposed
    1 / 16 (6.25%)
    1 / 45 (2.22%)
    0 / 26 (0.00%)
    0 / 14 (0.00%)
    0 / 3 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    0
    Infections and infestations
    Rhinitis
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 45 (2.22%)
    1 / 26 (3.85%)
    1 / 14 (7.14%)
    0 / 3 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    1
    1
    0
    0
    Oral herpes
         subjects affected / exposed
    1 / 16 (6.25%)
    1 / 45 (2.22%)
    0 / 26 (0.00%)
    0 / 14 (0.00%)
    0 / 3 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    0
    Nasopharyngitis
         subjects affected / exposed
    3 / 16 (18.75%)
    5 / 45 (11.11%)
    2 / 26 (7.69%)
    1 / 14 (7.14%)
    0 / 3 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    3
    6
    3
    2
    0
    1
    Gastrointestinal infection
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 45 (2.22%)
    1 / 26 (3.85%)
    0 / 14 (0.00%)
    0 / 3 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    1
    0
    0
    1
    Gastroenteritis viral
         subjects affected / exposed
    1 / 16 (6.25%)
    2 / 45 (4.44%)
    1 / 26 (3.85%)
    1 / 14 (7.14%)
    0 / 3 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    2
    1
    1
    0
    0
    COVID-19
         subjects affected / exposed
    1 / 16 (6.25%)
    2 / 45 (4.44%)
    1 / 26 (3.85%)
    0 / 14 (0.00%)
    0 / 3 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    1
    2
    1
    0
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    08 Jan 2020
    The main purpose of this amendment was to update the study duration and the sample size calculation.
    29 Jun 2020
    The main purpose of this amendment was to update the language of essential protocol sections, such as Eligibility criteria and Prohibited medication among others, in order to better align them, correct inconsistencies that may have contributed to errors, and improve overall clarity.
    26 Nov 2020
    The main purpose of this amendment was to include flexible language for participating countries to follow their national regulatory requirements or guidelines related to the COVID-19 pandemic and SARS-CoV-2 testing.
    16 Jul 2021
    The main purpose of this amendment was to restart the study following an investigation to ensure subject safety, after a temporary hold had been placed on the study by Novartis in February 2021 due to tolerability concerns.

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    24 Feb 2021
    Preliminary data from the first six subjects enrolled in LRX712A12201 identified injection site adverse events, including but not limited to joint warmth and/or swelling, along with transient elevations in inflammatory biomarkers, following dose administration in subjects (n=3) receiving active drug. As a result, Novartis put the study on temporary hold in February 2021 while further investigations were initiated. Analysis of stored biomarker samples from the FIH study also identified a pattern of transient elevations in high sensitivity C-Reactive Protein (hsCRP) post-administration, primarily at LRX712 dose levels > 15 mg. In addition, the estimated probability of local tolerability AEs rose with LRX712 dose from 15 mg (5% higher than placebo) to 25 mg (10% higher than placebo) to 75 mg (45% higher than placebo). Therefore, based on available preclinical efficacy data, and on the available safety and tolerability data from human studies, two dose levels of LRX712 were implemented in the revised study design. 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.
    05 Nov 2021

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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