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    Clinical Trial Results:
    A randomized, four-arm, canakinumab placebo-controlled, participant, investigator and sponsor-blinded study investigating the safety, tolerability and efficacy of intra-articular canakinumab followed by intra-articular LNA043 in patients with knee osteoarthritis

    Summary
    EudraCT number
    		 2020-003631-21
    Trial protocol
    		 DE   CZ   HU   EE   LT   LV  
    Global end of trial date
    24 Jun 2024

    Results information
    Results version number
    		 v1(current)
    This version publication date
    26 Jun 2025
    First version publication date
    26 Jun 2025
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    CLNA043A12203
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04814368
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Novartis Pharmaceuticals
    Sponsor organisation address
    Novartis Campus, Basel, Switzerland,
    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
    24 Jun 2024
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    24 Jun 2024
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The primary objective is to assess the ability of LNA043 to regenerate articular cartilage tissue in patients with symptomatic knee osteoarthritis with inflammation, after injection of placebo or canakinumab intra articular and the co-primary objective is the ability of canakinumab to reduce pain and/or inflammation in patients with symptomatic knee osteoarthritis with inflammation.
    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
    27 Aug 2021
    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
    Czechia: 1
    Country: Number of subjects enrolled
    Estonia: 1
    Country: Number of subjects enrolled
    Latvia: 1
    Country: Number of subjects enrolled
    Poland: 1
    Country: Number of subjects enrolled
    Hungary: 5
    Country: Number of subjects enrolled
    United States: 14
    Worldwide total number of subjects
    23
    EEA total number of subjects
    9
    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)
    16
    From 65 to 84 years
    7
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Participants took part in 11 investigative sites in 6 countries.

    Pre-assignment
    Screening details
    		 The study consisted of 4 screening visits (Screening 1-4), of which Screening 2 and 4 could be performed remotely.

    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
    		 Placebo to ACZ885+LNA043 40 mg
    Arm description
    		 Placebo to ACZ885 single dose intra-articular (i.a) followed by LNA043 40 mg administrated i.a every four weeks, three times.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Placebo to ACZ885+LNA043
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection, Powder for solution for injection
    Routes of administration
    Intraarticular use
    Dosage and administration details
    Placebo to ACZ885 single dose i.a followed by LNA043 40 mg administrated i.a every four weeks, three times.

    Arm title
    		 Placebo to ACZ885
    Arm description
    		 Placebo to ACZ885 single dose intra-articular.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo to ACZ885
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intraarticular use
    Dosage and administration details
    Placebo to ACZ885 single dose i.a.

    Arm title
    		 ACZ885 600 mg + LNA043 40 mg
    Arm description
    		 ACZ885 600 mg single dose i.a. followed by LNA043 40 mg administrated i.a every four weeks, three times.
    Arm type
    		 Experimental

    Investigational medicinal product name
    ACZ885+LNA043
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection, Powder for solution for injection
    Routes of administration
    Intraarticular use
    Dosage and administration details
    ACZ885 600 mg single dose i.a. followed by LNA043 40 mg administrated i.a every four weeks, three times.

    Arm title
    		 ACZ885 600 mg
    Arm description
    		 ACZ885 600 mg single dose intra-articular.
    Arm type
    		 Experimental

    Investigational medicinal product name
    ACZ885
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intraarticular use
    Dosage and administration details
    ACZ885 600 mg single dose i.a.

    Number of subjects in period 1
    		Placebo to ACZ885+LNA043 40 mg Placebo to ACZ885 ACZ885 600 mg + LNA043 40 mg ACZ885 600 mg
    Started
    3
    9
    3
    8
    Completed
    2
    4
    3
    6
    Not completed
    1
    5
    0
    2
         Subject Decision
    1
    2
    -
    -
         Study Terminated by Sponsor
    -
    3
    -
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo to ACZ885+LNA043 40 mg
    Reporting group description
    		 Placebo to ACZ885 single dose intra-articular (i.a) followed by LNA043 40 mg administrated i.a every four weeks, three times.

    Reporting group title
    Placebo to ACZ885
    Reporting group description
    		 Placebo to ACZ885 single dose intra-articular.

    Reporting group title
    ACZ885 600 mg + LNA043 40 mg
    Reporting group description
    		 ACZ885 600 mg single dose i.a. followed by LNA043 40 mg administrated i.a every four weeks, three times.

    Reporting group title
    ACZ885 600 mg
    Reporting group description
    		 ACZ885 600 mg single dose intra-articular.

    Reporting group values
    		 Placebo to ACZ885+LNA043 40 mg Placebo to ACZ885 ACZ885 600 mg + LNA043 40 mg ACZ885 600 mg Total
    Number of subjects
    		 3 9 3 8 23
    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)
    		 2 7 2 5 16
        From 65-84 years
    		 1 2 1 3 7
        85 years and over
    		 0 0 0 0 0
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 66.3 ( 10.97 ) 61.1 ( 5.90 ) 59.3 ( 7.02 ) 61.8 ( 8.55 ) -
    Sex: Female, Male
    Units: participants
        Female
    		 1 7 1 7 16
        Male
    		 2 2 2 1 7
    Race/Ethnicity, Customized
    Units: Subjects
        Black or African American
    		 0 0 0 1 1
        Native Hawaiian or other
    		 0 0 0 1 1
        White
    		 3 9 3 6 21

    End points

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    End points reporting groups
    Reporting group title
    Placebo to ACZ885+LNA043 40 mg
    Reporting group description
    		 Placebo to ACZ885 single dose intra-articular (i.a) followed by LNA043 40 mg administrated i.a every four weeks, three times.

    Reporting group title
    Placebo to ACZ885
    Reporting group description
    		 Placebo to ACZ885 single dose intra-articular.

    Reporting group title
    ACZ885 600 mg + LNA043 40 mg
    Reporting group description
    		 ACZ885 600 mg single dose i.a. followed by LNA043 40 mg administrated i.a every four weeks, three times.

    Reporting group title
    ACZ885 600 mg
    Reporting group description
    		 ACZ885 600 mg single dose intra-articular.

    Primary: Change in cartilage volume in the index region measured by MRI at Day 197 (Placebo to ACZ885+LNA043 versus Placebo to ACZ885)

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    End point title
    		 Change in cartilage volume in the index region measured by MRI at Day 197 (Placebo to ACZ885+LNA043 versus Placebo to ACZ885) [1] [2]
    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 union of the femoral medial anterior (FMA), central (FMC) and posterior (FMP) cartilage subregions in the knee.
    End point type
    Primary
    End point timeframe
    Baseline, Day 197
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: only analyzed descriptively.
    [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.
    End point values
    		 Placebo to ACZ885+LNA043 40 mg Placebo to ACZ885
    Number of subjects analysed
    2
    5
    Units: µL
        arithmetic mean (standard deviation)
    108.33 ( 226.451 )
    -26.13 ( 65.204 )
    No statistical analyses for this end point

    Primary: Change in Knee injury and Osteoarthritis Outcome Score (KOOS) Pain subscale (ACZ885 versus Placebo to ACZ885)

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    End point title
    		 Change in Knee injury and Osteoarthritis Outcome Score (KOOS) Pain subscale (ACZ885 versus Placebo to ACZ885) [3] [4]
    End point description
    The KOOS questionnaire is a commonly used instrument to assess the patient's perception about their knee and associated problems. The original KOOS consists of 5 subscales. One of those is the KOOS pain consisting of 9 questions with a recall of 7days. Each question has 5 standardized answer options with a score from 0 to 4. A normalized score (100 indicating no symptoms and 0 indicating extreme symptoms) is calculated for each subscale.
    End point type
    Primary
    End point timeframe
    Baseline, Day 85
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: only analyzed descriptively.
    [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.
    End point values
    		 Placebo to ACZ885 ACZ885 600 mg
    Number of subjects analysed
    7
    8
    Units: score on scale
        arithmetic mean (standard deviation)
    13.9 ( 13.89 )
    22.2 ( 20.09 )
    No statistical analyses for this end point

    Secondary: Number of participants with anti-LNA043 antibodies (Placebo to ACZ885+LNA043 versus ACZ885 + LNA043)

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    End point title
    		 Number of participants with anti-LNA043 antibodies (Placebo to ACZ885+LNA043 versus ACZ885 + LNA043) [5]
    End point description
    To evaluate the immunogenicity of LNA043 via validated ligand-binding assay of potential anti-LNA043 antibodies.
    End point type
    Secondary
    End point timeframe
    From pre-dose up to Day 365
    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: PK Endpoint not analyzed for participants on placebo
    End point values
    		 Placebo to ACZ885+LNA043 40 mg ACZ885 600 mg + LNA043 40 mg
    Number of subjects analysed
    3
    3
    Units: Participants
    0
    0
    No statistical analyses for this end point

    Secondary: Maximum serum concentration (Cmax) of LNA043 (Placebo to ACZ885+LNA043 versus ACZ885+LNA043)

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    End point title
    		 Maximum serum concentration (Cmax) of LNA043 (Placebo to ACZ885+LNA043 versus ACZ885+LNA043) [6]
    End point description
    Cmax is defined as the maximum (peak) observed concentration following a dose. LNA043 serum concentrations were determined using the actual recorded sampling times and non-compartmental method with Phoenix WinNonlin (Version 8 or higher). LNA043 was determined by a validated immuno-capture and LC-MS/MS method; the anticipated LLOQ is 10 ng/mL in serum. Due to EudraCT system limitations, data fields in the table cannot contain letters (eg. NA indicating ‘not applicable’). Therefore, not applicable values are indicated as ‘999’.
    End point type
    Secondary
    End point timeframe
    Day 15: pre-dose, 20, 60, 120 and 240 minutes, and 8 and 24 hours post LNA043 first injection on Day 15
    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: PK Endpoint not analyzed for participants on placebo
    End point values
    		 Placebo to ACZ885+LNA043 40 mg ACZ885 600 mg + LNA043 40 mg
    Number of subjects analysed
    1
    1
    Units: ng/mL
        arithmetic mean (standard deviation)
    120 ( 999 )
    149 ( 999 )
    No statistical analyses for this end point

    Secondary: Synovial fluid concentrations of ANGPTL3 (Placebo to ACZ885+LNA043 versus ACZ885+LNA043)

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    End point title
    		 Synovial fluid concentrations of ANGPTL3 (Placebo to ACZ885+LNA043 versus ACZ885+LNA043) [7]
    End point description
    ANGPTL3 is a protein that is primarily involved in the lipid metabolism but has recently been shown to have chondrogenic and chondroprotective effects. ANGPTL3 was measured in synovial fluid. Due to EudraCT system limitations, data fields in the table cannot contain letters (eg. NA indicating ‘not applicable’). Therefore, not applicable values are indicated as ‘999’.
    End point type
    Secondary
    End point timeframe
    Day 1, 15, 43 and 71
    Notes
    [7] - 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: PK Endpoint not analyzed for participants on placebo
    End point values
    		 Placebo to ACZ885+LNA043 40 mg ACZ885 600 mg + LNA043 40 mg
    Number of subjects analysed
    1
    1
    Units: ng/mL
        arithmetic mean (standard deviation)
    999 ( 999 )
    999 ( 999 )
    No statistical analyses for this end point

    Secondary: Maximum serum concentration (Cmax) of ANGPTL3 (Placebo to ACZ885+LNA043 versus ACZ885+LNA043)

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    End point title
    		 Maximum serum concentration (Cmax) of ANGPTL3 (Placebo to ACZ885+LNA043 versus ACZ885+LNA043) [8]
    End point description
    ANGPTL3 is a protein that is primarily involved in the lipid metabolism but has recently been shown to have chondrogenic and chondroprotective effects. Cmax is defined as the maximum (peak) observed concentration following a dose. ANGPTL3 serum concentrations were determined using the actual recorded sampling times and non-compartmental method with Phoenix WinNonlin (Version 8 or higher). ANGPTL3 was determined by a validated ligand binding assay; the anticipated LLOQ is 39.7 pmol/L in serum.
    End point type
    Secondary
    End point timeframe
    Pre-dose Day 1 and 60 minutes after first injection of LNA043 on Day 15
    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: PK Endpoint not analyzed for participants on placebo
    End point values
    		 Placebo to ACZ885+LNA043 40 mg ACZ885 600 mg + LNA043 40 mg
    Number of subjects analysed
    2
    3
    Units: ng/mL
        arithmetic mean (standard deviation)
    16.2 ( 2.47 )
    24.1 ( 7.32 )
    No statistical analyses for this end point

    Secondary: Time to reach maximum serum concentration (Tmax) of LNA043 (Placebo to ACZ885+LNA043 versus ACZ885+LNA043)

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    End point title
    		 Time to reach maximum serum concentration (Tmax) of LNA043 (Placebo to ACZ885+LNA043 versus ACZ885+LNA043) [9]
    End point description
    Tmax is the time to reach maximum (peak) drug concentration after single-dose administration (time). LNA043 serum concentrations were determined using the actual recorded sampling times and non-compartmental method with Phoenix WinNonlin (Version 8 or higher). LNA043 was determined by a validated immuno-capture and LC-MS/MS method; the anticipated LLOQ is 10 ng/mL in serum. Due to EudraCT system limitations, data fields in the table cannot contain letters (eg. NA indicating ‘not applicable’). Therefore, not applicable values are indicated as ‘999’.
    End point type
    Secondary
    End point timeframe
    Day 15: pre-dose, 20, 60, 120 and 240 minutes, and 8 and 24 hours post LNA043 first injection on Day 15
    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: PK Endpoint not analyzed for participants on placebo
    End point values
    		 Placebo to ACZ885+LNA043 40 mg ACZ885 600 mg + LNA043 40 mg
    Number of subjects analysed
    1
    1
    Units: hour
        arithmetic mean (standard deviation)
    2 ( 999 )
    4.02 ( 999 )
    No statistical analyses for this end point

    Secondary: Change in cartilage volume of the index region measured by MRI at Day 197 and Day 365 (ACZ885+LNA043 versus ACZ885, and ACZ885+LNA043 versus Placebo to ACZ885+LNA043)

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    End point title
    		 Change in cartilage volume of the index region measured by MRI at Day 197 and Day 365 (ACZ885+LNA043 versus ACZ885, and ACZ885+LNA043 versus Placebo to ACZ885+LNA043) [10]
    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 union of the femoral medial anterior (FMA), central (FMC) and posterior (FMP) cartilage subregions in the knee.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 197 and Day 365
    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.
    End point values
    		 Placebo to ACZ885+LNA043 40 mg ACZ885 600 mg + LNA043 40 mg ACZ885 600 mg
    Number of subjects analysed
    2
    3
    6
    Units: µL
    arithmetic mean (standard deviation)
        Day 197
    108.33 ( 226.451 )
    307.90 ( 580.213 )
    -82.33 ( 390.645 )
        Day 365
    152.78 ( 135.128 )
    20.54 ( 557.708 )
    -129.93 ( 544.793 )
    No statistical analyses for this end point

    Secondary: Area under serum concentration-time curve from time zero to the last measurable concentration sampling time (AUClast) of LNA043 (Placebo to ACZ885+LNA043 versus ACZ885+LNA043)

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    End point title
    		 Area under serum concentration-time curve from time zero to the last measurable concentration sampling time (AUClast) of LNA043 (Placebo to ACZ885+LNA043 versus ACZ885+LNA043) [11]
    End point description
    AUClast is the area under the serum concentration-time curve from time zero to the time of last quantifiable concentration (tlast) of LNA043. LNA043 serum concentrations were determined using the actual recorded sampling times and non-compartmental method with Phoenix WinNonlin (Version 8 or higher). LNA043 was determined by a validated immuno-capture and LC-MS/MS method; the anticipated LLOQ is 10 ng/mL in serum. Due to EudraCT system limitations, data fields in the table cannot contain letters (eg. NA indicating ‘not applicable’). Therefore, not applicable values are indicated as ‘999’.
    End point type
    Secondary
    End point timeframe
    Day 15: pre-dose, 20, 60, 120 and 240 minutes, and 8 and 24 hours post LNA043 first injection on Day 15
    Notes
    [11] - 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: PK Endpoint not analyzed for participants on placebo
    End point values
    		 Placebo to ACZ885+LNA043 40 mg ACZ885 600 mg + LNA043 40 mg
    Number of subjects analysed
    1
    1
    Units: h*ng/mL
        arithmetic mean (standard deviation)
    800 ( 999 )
    1880 ( 999 )
    No statistical analyses for this end point

    Secondary: Change in cartilage volume of the index region measured by MRI at Day 365 (Placebo to ACZ885+LNA043 versus Placebo to ACZ885)

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    End point title
    		 Change in cartilage volume of the index region measured by MRI at Day 365 (Placebo to ACZ885+LNA043 versus Placebo to ACZ885) [12]
    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 union of the femoral medial anterior (FMA), central (FMC) and posterior (FMP) cartilage subregions in the knee.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 365
    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
    		 Placebo to ACZ885+LNA043 40 mg Placebo to ACZ885
    Number of subjects analysed
    2
    3
    Units: µL
        arithmetic mean (standard deviation)
    152.78 ( 135.128 )
    20.54 ( 557.708 )
    No statistical analyses for this end point

    Secondary: Change in cartilage thickness of the index region measured by MRI at Day 197 and Day 365 (Placebo to ACZ885+LNA043 versus Placebo to ACZ885)

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    End point title
    		 Change in cartilage thickness of the index region measured by MRI at Day 197 and Day 365 (Placebo to ACZ885+LNA043 versus Placebo to ACZ885) [13]
    End point description
    Magnetic resonance images (MRI) were obtained from the target knee to visualize and quantify changes in thickness of cartilage in the index region. The index region was defined as the union of the femoral medial anterior (FMA), central (FMC) and posterior (FMP) cartilage subregions in the knee.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 197 and 365
    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
    		 Placebo to ACZ885+LNA043 40 mg Placebo to ACZ885
    Number of subjects analysed
    2
    3
    Units: mm
    arithmetic mean (standard deviation)
        Day 197
    0.07 ( 0.083 )
    0.06 ( 0.112 )
        Day 365
    -0.03 ( 0.046 )
    0.11 ( 0.072 )
    No statistical analyses for this end point

    Secondary: Change in cartilage thickness of the index region measured by MRI at Day 197 and Day 365 (ACZ885+LNA043 versus ACZ885, and ACZ885+LNA043 versus Placebo to ACZ885+LNA043)

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    End point title
    		 Change in cartilage thickness of the index region measured by MRI at Day 197 and Day 365 (ACZ885+LNA043 versus ACZ885, and ACZ885+LNA043 versus Placebo to ACZ885+LNA043) [14]
    End point description
    Magnetic resonance images (MRI) were obtained from the target knee to visualize and quantify changes in thickness of cartilage in the index region. The index region was defined as the union of the femoral medial anterior (FMA), central (FMC) and posterior (FMP) cartilage subregions in the knee. 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, Day 197 and 365
    Notes
    [14] - 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
    		 Placebo to ACZ885+LNA043 40 mg ACZ885 600 mg + LNA043 40 mg ACZ885 600 mg
    Number of subjects analysed
    2
    3
    7
    Units: mm
    arithmetic mean (standard deviation)
        Day 197 (n=2,3,7)
    0.07 ( 0.083 )
    0.13 ( 0.212 )
    -0.02 ( 0.121 )
        Day 365 (n=2,3,6)
    -0.03 ( 0.046 )
    0.04 ( 0.168 )
    -0.05 ( 0.152 )
    No statistical analyses for this end point

    Secondary: Change in numeric rating scale (NRS) over time (ACZ885 versus Placebo to ACZ885)

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    End point title
    		 Change in numeric rating scale (NRS) over time (ACZ885 versus Placebo to ACZ885) [15]
    End point description
    The Numerical Rating Scale (NRS) Pain is a subjective assessment in which individuals rate their pain on an eleven-point numerical scale. The scale ranges from 0 (no pain) to 10 (worst possible pain). The NRS Pain instrument had a recall period of 24 hours and the participants were asked to rate the pain intensity at its worst. 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, Day 15, 29, 43, 57, 71, 85
    Notes
    [15] - 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
    		 Placebo to ACZ885 ACZ885 600 mg
    Number of subjects analysed
    8
    7
    Units: score on scale
    arithmetic mean (standard deviation)
        Day 15 (n=8,7)
    -1.5 ( 2.33 )
    -2.1 ( 2.27 )
        Day 29 (n=8,7)
    -2.5 ( 2.73 )
    -3.1 ( 1.95 )
        Day 43 (n=8,7)
    -1.8 ( 2.25 )
    -2.4 ( 2.15 )
        Day 57 (n=8,6)
    -2.1 ( 2.80 )
    -3.5 ( 2.35 )
        Day 71 (n=7,7)
    -2.1 ( 1.95 )
    -3.1 ( 2.19 )
        Day 85 (n=7,7)
    -1.7 ( 2.29 )
    -2.7 ( 2.06 )
    No statistical analyses for this end point

    Secondary: Change in synovitis level measured from Ktrans by Dynamic Contrast Enhanced MRI (DCE-MRI) (ACZ885 versus Placebo to ACZ885)

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    End point title
    		 Change in synovitis level measured from Ktrans by Dynamic Contrast Enhanced MRI (DCE-MRI) (ACZ885 versus Placebo to ACZ885) [16]
    End point description
    Magnetic resonance images (MRI) were obtained from the target knee with dynamic contrast enhancement (DCE) to visualize and quantify changes in k-trans as a marker of the activity of synovial inflammation. During the DCE-MRI acquisition, while the contrast agent is preferentially taken up at sites with an increased perfusion due to the formation of new vessels with high porosity (such as the inflamed synovial membrane), a temporal variation of the MRI signal intensity occurs. When the contrast distributes through the intravascular and extravascular spaces, the MR signal intensity in the image volume elements (voxels) of the target tissue changes over time, generating so-called signal intensity (SI) curves. These curves can then be analyzed to derive parameters related to tissue perfusion. The parameter of primary interest was the volume transfer rate of the gadolinium-based contrast agent (GBCA) from the blood plasma in synovium, commonly referred to as Ktrans.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 85
    Notes
    [16] - 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
    		 Placebo to ACZ885 ACZ885 600 mg
    Number of subjects analysed
    6
    7
    Units: min^-1
        arithmetic mean (standard deviation)
    -0.0009 ( 0.01185 )
    -0.0051 ( 0.00702 )
    No statistical analyses for this end point

    Secondary: Change in numeric rating scale (NRS) over time (ACZ885+LNA043 versus ACZ885, and ACZ885+LNA043 versus Placebo to ACZ885+LNA043)

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    End point title
    		 Change in numeric rating scale (NRS) over time (ACZ885+LNA043 versus ACZ885, and ACZ885+LNA043 versus Placebo to ACZ885+LNA043) [17]
    End point description
    The Numerical Rating Scale (NRS) Pain is a subjective assessment in which individuals rate their pain on an eleven-point numerical scale. The scale ranges from 0 (no pain) to 10 (worst possible pain). The NRS Pain instrument had a recall period of 24 hours and the participants were asked to rate the pain intensity at its worst. Due to EudraCT system limitations, data fields in the table cannot contain letters (eg. NA indicating ‘not applicable’). Therefore, not applicable values are indicated as ‘999’. 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, Day 15, 29, 43, 57, 71, 85, 197 and 365
    Notes
    [17] - 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
    		 Placebo to ACZ885+LNA043 40 mg ACZ885 600 mg + LNA043 40 mg ACZ885 600 mg
    Number of subjects analysed
    2
    3
    7
    Units: score on scale
    arithmetic mean (standard deviation)
        Day 15 (n=1,3,7)
    -3.0 ( 999 )
    -0.7 ( 1.15 )
    -2.1 ( 2.27 )
        Day 29 (n=1,3,7)
    -3.0 ( 999 )
    -1.0 ( 1.00 )
    -3.1 ( 1.95 )
        Day 43 (n=2,3,7)
    -4.5 ( 2.12 )
    -0.7 ( 0.58 )
    -2.4 ( 2.15 )
        Day 57 (n=1,3,6)
    -4.0 ( 999 )
    -2.0 ( 0.00 )
    -3.5 ( 2.35 )
        Day 71 (n=1,3,7)
    -4.0 ( 999 )
    -2.0 ( 1.00 )
    -3.1 ( 2.19 )
        Day 85 (n=2,3,7)
    -5.5 ( 0.71 )
    -3.3 ( 0.58 )
    -2.7 ( 2.06 )
        Day 197 (n=1,3,6)
    -6.0 ( 999 )
    -3.3 ( 2.08 )
    -2.8 ( 2.64 )
        Day 365 (n=1,3,4)
    -3.0 ( 999 )
    -4.3 ( 2.31 )
    -3.0 ( 3.83 )
    No statistical analyses for this end point

    Secondary: Change in Knee Injury and Osteoarthritis Outcome Score (KOOS) Pain subscale over time (ACZ885 versus Placebo to ACZ885)

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    End point title
    		 Change in Knee Injury and Osteoarthritis Outcome Score (KOOS) Pain subscale over time (ACZ885 versus Placebo to ACZ885) [18]
    End point description
    The KOOS questionnaire is a commonly used instrument to assess the patient's perception about their knee and associated problems. The original KOOS consists of 5 subscales. One of those is the KOOS pain consisting of 9 questions with a recall of 7days. Each question has 5 standardized answer options with a score from 0 to 4. A normalized score (100 indicating no symptoms and 0 indicating extreme symptoms) is calculated for each subscale. 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, Day 15, 29, 43, 57, 71, 85
    Notes
    [18] - 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
    		 Placebo to ACZ885 ACZ885 600 mg
    Number of subjects analysed
    8
    8
    Units: score on scale
    arithmetic mean (standard deviation)
        Day 15 (n=8,8)
    12.8 ( 21.72 )
    20.1 ( 20.40 )
        Day 29 (n=8,8)
    16.3 ( 17.60 )
    24.0 ( 20.52 )
        Day 43 (n=8,8)
    11.8 ( 12.31 )
    21.9 ( 21.28 )
        Day 57 (n=8,8)
    13.9 ( 18.96 )
    28.1 ( 19.38 )
        Day 71 (n=7,8)
    14.3 ( 15.75 )
    26.4 ( 20.03 )
        Day 85 (n=7,8)
    25.0 ( 3.93 )
    22.2 ( 20.09 )
    No statistical analyses for this end point

    Secondary: Change in Knee Injury and Osteoarthritis Outcome Score (KOOS) Pain subscale over time (ACZ885+LNA043 versus ACZ885, and ACZ885+LNA043 versus Placebo to ACZ885+LNA043)

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    End point title
    		 Change in Knee Injury and Osteoarthritis Outcome Score (KOOS) Pain subscale over time (ACZ885+LNA043 versus ACZ885, and ACZ885+LNA043 versus Placebo to ACZ885+LNA043) [19]
    End point description
    The KOOS questionnaire is a commonly used instrument to assess the patient's perception about their knee and associated problems. The original KOOS consists of 5 subscales. One of those is the KOOS pain consisting of 9 questions with a recall of 7days. Each question has 5 standardized answer options with a score from 0 to 4. A normalized score (100 indicating no symptoms and 0 indicating extreme symptoms) is calculated for each subscale. 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, Day 15, 29, 43, 57, 71, 85, 197 and 365
    Notes
    [19] - 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
    		 Placebo to ACZ885+LNA043 40 mg ACZ885 600 mg + LNA043 40 mg ACZ885 600 mg
    Number of subjects analysed
    2
    3
    8
    Units: score on scale
    arithmetic mean (standard deviation)
        Day 15 (n=2,3,8)
    25.0 ( 27.50 )
    3.7 ( 18.91 )
    20.1 ( 20.40 )
        Day 29 (n=2,3,8)
    36.1 ( 19.64 )
    15.7 ( 9.76 )
    24.0 ( 20.52 )
        Day 43 (n=2,3,8)
    25.0 ( 15.71 )
    15.7 ( 16.74 )
    21.9 ( 21.28 )
        Day 57 (n=2,3,8)
    25.0 ( 7.86 )
    17.6 ( 5.78 )
    28.1 ( 19.38 )
        Day 71 (n=2,3,8)
    29.2 ( 5.89 )
    16.7 ( 2.78 )
    26.4 ( 20.03 )
        Day 85 (n=2,3,8)
    25.0 ( 3.93 )
    22.2 ( 14.70 )
    22.2 ( 20.09 )
        Day 197 (n=2,3,8)
    37.5 ( 9.82 )
    38.0 ( 12.83 )
    25.0 ( 21.87 )
        Day 365 (n=2,3,6)
    31.9 ( 17.68 )
    45.4 ( 10.52 )
    31.5 ( 26.33 )
    No statistical analyses for this end point

    Secondary: Change in Knee Injury and Osteoarthritis Outcome Score (KOOS) Function in daily living (ADL) subscale over time (ACZ885 versus Placebo to ACZ885)

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    End point title
    		 Change in Knee Injury and Osteoarthritis Outcome Score (KOOS) Function in daily living (ADL) subscale over time (ACZ885 versus Placebo to ACZ885) [20]
    End point description
    The KOOS questionnaire is a commonly used instrument to assess the patient's perception about their knee and associated problems. The original KOOS consists of 5 subscales. One of those is the KOOS Function in Daily Living (ADL) subscale consisting of 17 questions with a recall of 7days. Each question has 5 standardized answer options with a score from 0 to 4. A normalized score (100 indicating no symptoms and 0 indicating extreme symptoms) is calculated for each subscale. 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, Day 15, 29, 43, 57, 71, 85
    Notes
    [20] - 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
    		 Placebo to ACZ885 ACZ885 600 mg
    Number of subjects analysed
    8
    8
    Units: score on scale
    arithmetic mean (standard deviation)
        Day 15 (n=8,8)
    11.9 ( 23.87 )
    18.4 ( 18.35 )
        Day 29 (n=8,8)
    14.3 ( 24.74 )
    25.7 ( 20.72 )
        Day 43 (n=8,8)
    9.7 ( 17.04 )
    26.1 ( 19.79 )
        Day 57 (n=8,8)
    16.7 ( 28.06 )
    31.8 ( 21.99 )
        Day 71 (n=7,8)
    16.8 ( 22.30 )
    28.7 ( 19.40 )
        Day 85 (n=7,8)
    14.7 ( 23.05 )
    23.7 ( 19.26 )
    No statistical analyses for this end point

    Secondary: Change in Knee Injury and Osteoarthritis Outcome Score (KOOS) Function in daily living (ADL) subscale over time (ACZ885+LNA043 versus ACZ885, and ACZ885+LNA043 versus Placebo to ACZ885+LNA043)

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    End point title
    		 Change in Knee Injury and Osteoarthritis Outcome Score (KOOS) Function in daily living (ADL) subscale over time (ACZ885+LNA043 versus ACZ885, and ACZ885+LNA043 versus Placebo to ACZ885+LNA043) [21]
    End point description
    The KOOS questionnaire is a commonly used instrument to assess the patient's perception about their knee and associated problems. The original KOOS consists of 5 subscales. One of those is the KOOS Function in Daily Living (ADL) subscale consisting of 17 questions with a recall of 7days. Each question has 5 standardized answer options with a score from 0 to 4. A normalized score (100 indicating no symptoms and 0 indicating extreme symptoms) is calculated for each subscale. 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, Day 15, 29, 43, 57, 71, 85, 197 and 365
    Notes
    [21] - 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
    		 Placebo to ACZ885+LNA043 40 mg ACZ885 600 mg + LNA043 40 mg ACZ885 600 mg
    Number of subjects analysed
    2
    3
    8
    Units: score on scale
    arithmetic mean (standard deviation)
        Day 15 (n=2,3,8)
    37.5 ( 34.32 )
    2.9 ( 8.82 )
    18.4 ( 18.35 )
        Day 29 (n=2,3,8)
    42.6 ( 20.80 )
    17.2 ( 4.49 )
    25.7 ( 20.72 )
        Day 43 (n=2,3,8)
    41.9 ( 28.08 )
    16.2 ( 11.76 )
    26.1 ( 19.79 )
        Day 57 (n=2,3,8)
    40.4 ( 19.76 )
    19.1 ( 8.95 )
    31.8 ( 21.99 )
        Day 71 (n=2,3,8)
    43.4 ( 23.92 )
    20.6 ( 10.29 )
    28.7 ( 19.40 )
        Day 85 (n=2,3,8)
    41.9 ( 19.76 )
    28.4 ( 15.09 )
    23.7 ( 19.26 )
        Day 197 (n=2,3,8)
    50.7 ( 19.76 )
    36.8 ( 1.47 )
    27.4 ( 23.92 )
        Day 365 (n=2,3,6)
    44.9 ( 26.00 )
    42.2 ( 13.34 )
    33.6 ( 23.79 )
    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 of study treatment until end of study treatment plus follow up period, up to a maximum duration of approximately 52 weeks.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    27.1
    Reporting groups
    Reporting group title
    Placebo to ACZ885+LNA043 40 mg
    Reporting group description
    		 Placebo to ACZ885 single dose intra-articular (i.a) followed by LNA043 40 mg administrated i.a every four weeks, three times.

    Reporting group title
    Placebo to ACZ885
    Reporting group description
    		 Placebo to ACZ885 single dose intra-articular.

    Reporting group title
    Total
    Reporting group description
    		 Total

    Reporting group title
    ACZ885 600 mg
    Reporting group description
    		 ACZ885 600 mg single dose intra-articular.

    Reporting group title
    ACZ885 600 mg + LNA043 40 mg
    Reporting group description
    		 ACZ885 600 mg single dose i.a. followed by LNA043 40 mg administrated i.a every four weeks, three times.

    Serious adverse events
    		 Placebo to ACZ885+LNA043 40 mg Placebo to ACZ885 Total ACZ885 600 mg ACZ885 600 mg + LNA043 40 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 23 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo to ACZ885+LNA043 40 mg Placebo to ACZ885 Total ACZ885 600 mg ACZ885 600 mg + LNA043 40 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    1 / 3 (33.33%)
    2 / 9 (22.22%)
    8 / 23 (34.78%)
    4 / 8 (50.00%)
    1 / 3 (33.33%)
    Investigations
    Blood creatine phosphokinase increased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    1 / 23 (4.35%)
    1 / 8 (12.50%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    Cardiac disorders
    Bundle branch block right
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    1 / 23 (4.35%)
    0 / 8 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    0
    1
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    1 / 23 (4.35%)
    1 / 8 (12.50%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    Infections and infestations
    Abscess limb
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    1 / 23 (4.35%)
    1 / 8 (12.50%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    Nasopharyngitis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    1 / 23 (4.35%)
    1 / 8 (12.50%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    COVID-19
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    1 / 23 (4.35%)
    0 / 8 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    0
    1
    0
    1
    Body tinea
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 9 (11.11%)
    1 / 23 (4.35%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    1
    0
    0
    Oral herpes
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    1 / 23 (4.35%)
    1 / 8 (12.50%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    Rhinitis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    1 / 23 (4.35%)
    1 / 8 (12.50%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 9 (11.11%)
    1 / 23 (4.35%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    1
    0
    0
    Urinary tract infection
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    1 / 23 (4.35%)
    1 / 8 (12.50%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    Metabolism and nutrition disorders
    Hypophosphataemia
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 9 (0.00%)
    1 / 23 (4.35%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    15 Dec 2021
    This amendment was generated to investigate differences in pain endpoints between all the four treatment arms (also comparing TA3 vs TA1 and TA3 vs TA4).
    08 Dec 2022
    This amendment was generated to clarify permissible re-screening scenarios and to specify the required period of contraception use for women of child-bearing potential after the last investigational drug administration. The amendment also describes an Informed Consent Form used for healthy volunteers during the MRI qualification process, if required by local regulations.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    The small sample size overall and the difference in group sizes do not allow a valid interpretation of the data regarding efficacy, pharmacokinetics and immunogenicity.
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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