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    Clinical Trial Results:
    A two-part randomized, placebo-controlled, patient and investigator blinded, Proof of Concept study investigating the safety, tolerability and preliminary efficacy of multiple intra-articular LNA043 injections in regenerating the articular cartilage of the knee in patients with articular cartilage lesions (Part A) and in patients with knee osteoarthritis (Part B)

    Summary
    EudraCT number
    		 2016-004052-30
    Trial protocol
    		 SE   CZ   DK  
    Global end of trial date
    06 Sep 2022

    Results information
    Results version number
    		 v1(current)
    This version publication date
    20 Sep 2023
    First version publication date
    20 Sep 2023
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    CLNA043X2202
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Novartis Pharma AG
    Sponsor organisation address
    Novartis Campus, Basel, Switzerland,
    Public contact
    Clinical Disclosure Office, Novartis AG, 41 613241111, Novartis.email@Novartis.com
    Scientific contact
    Clinical Disclosure Office, Novartis 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
    06 Sep 2022
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    06 Sep 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The purpose of this two-part study was to assess the efficacy, safety, and tolerability of multiple intra-articular (i.a.) injections of LNA043, in regenerating the articular surface in subjects at an early stage of osteoarthritis with cartilage lesions in the knee (Part A) and subjects at a more advanced stage of knee osteoarthritis K&L grade 2 or 3 (Part B).
    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
    12 Sep 2017
    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: 49
    Country: Number of subjects enrolled
    Denmark: 5
    Country: Number of subjects enrolled
    United States: 87
    Worldwide total number of subjects
    141
    EEA total number of subjects
    54
    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)
    106
    From 65 to 84 years
    35
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 A total of 142 participants were randomized, but only 141 received treatment. One participant in Part B was discontinued due to poor veins that were not adequate for blood samples.

    Period 1
    Period 1 title
    Treatment Period Part A and Part B
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Carer, Data analyst, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 LNA043 20 mg Part A
    Arm description
    		 Part A: a single intra-articular injection of 20 mg LNA043 was administered weekly for 4 weeks for participants with focal cartilage lesions of the knee.
    Arm type
    		 Experimental

    Investigational medicinal product name
    LNA043
    Investigational medicinal product code
    LNA043A
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intraarticular use
    Dosage and administration details
    LNA043 20 mg intra-articular injection

    Arm title
    		 Placebo Part A
    Arm description
    		 Part A: a single intra-articular injection of matching placebo (0 mg) was administered weekly for 4 weeks for participants with focal cartilage lesions of the knee
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intraarticular use
    Dosage and administration details
    Matching placebo 0 mg intra-articular injection

    Arm title
    		 LNA043 20 mg Part B
    Arm description
    		 Part B: a single intra-articular injection of 20 mg LNA043 was administered every 4 weeks from Week 1 to Week 13 (4 injections) for participants with osteoarthritis.
    Arm type
    		 Experimental

    Investigational medicinal product name
    LNA043
    Investigational medicinal product code
    LNA043A
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intraarticular use
    Dosage and administration details
    LNA043 20 mg intra-articular injection

    Arm title
    		 LNA043 40 mg Part B
    Arm description
    		 Part B: a single intra-articular injection of 40 mg LNA043 was administered every 4 weeks from Week 1 to Week 13 (4 injections) for participants with osteoarthritis.
    Arm type
    		 Experimental

    Investigational medicinal product name
    LNA043
    Investigational medicinal product code
    LNA043A
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intraarticular use
    Dosage and administration details
    LNA043 40 mg intra-articular injection

    Arm title
    		 Placebo Part B
    Arm description
    		 Part B: a single intra-articular injection of matching placebo (0 mg) was administered every 4 weeks from Week 1 to Week 13 (4 injections) for participants with osteoarthritis
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intraarticular use
    Dosage and administration details
    Matching placebo 0 mg intra-articular injection

    Number of subjects in period 1
    		LNA043 20 mg Part A Placebo Part A LNA043 20 mg Part B LNA043 40 mg Part B Placebo Part B
    Started
    43
    15
    27
    27
    29
    Completed
    42
    15
    27
    26
    29
    Not completed
    1
    0
    0
    1
    0
         PI decision based on poor veins for blood sampling
    -
    -
    -
    1
    -
         Patient discontinued tx, entered followup
    1
    -
    -
    -
    -
    Period 2
    Period 2 title
    Post-treatment follow-up Parts A and B
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 LNA043 20 mg Part A
    Arm description
    		 Part A: a single intra-articular injection of 20 mg LNA043 was administered weekly for 4 weeks for participants with focal cartilage lesions of the knee.
    Arm type
    		 Experimental

    Investigational medicinal product name
    LNA043
    Investigational medicinal product code
    LNA043A
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intraarticular use
    Dosage and administration details
    LNA043 20 mg intra-articular injection

    Arm title
    		 Placebo Part A
    Arm description
    		 Part A: a single intra-articular injection of matching placebo (0 mg) was administered weekly for 4 weeks for participants with focal cartilage lesions of the knee
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intraarticular use
    Dosage and administration details
    Matching placebo 0 mg intra-articular injection

    Arm title
    		 LNA043 20 mg Part B
    Arm description
    		 Part B: a single intra-articular injection of 20 mg LNA043 was administered every 4 weeks from Week 1 to Week 13 (4 injections) for participants with osteoarthritis.
    Arm type
    		 Experimental

    Investigational medicinal product name
    LNA043
    Investigational medicinal product code
    LNA043A
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intraarticular use
    Dosage and administration details
    LNA043 20 mg intra-articular injection

    Arm title
    		 LNA043 40 mg Part B
    Arm description
    		 Part B: a single intra-articular injection of 40 mg LNA043 was administered every 4 weeks from Week 1 to Week 13 (4 injections) for participants with osteoarthritis.
    Arm type
    		 Experimental

    Investigational medicinal product name
    LNA043
    Investigational medicinal product code
    LNA043A
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intraarticular use
    Dosage and administration details
    LNA043 40 mg intra-articular injection

    Arm title
    		 Placebo Part B
    Arm description
    		 Part B: a single intra-articular injection of matching placebo (0 mg) was administered every 4 weeks from Week 1 to Week 13 (4 injections) for participants with osteoarthritis
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intraarticular use
    Dosage and administration details
    Matching placebo 0 mg intra-articular injection

    Number of subjects in period 2 [1]
    		LNA043 20 mg Part A Placebo Part A LNA043 20 mg Part B LNA043 40 mg Part B Placebo Part B
    Started
    41
    15
    27
    26
    29
    Completed
    39
    15
    24
    25
    28
    Not completed
    2
    0
    3
    1
    1
         No longer required treatment
    -
    -
    -
    1
    -
         Lost to follow-up
    1
    -
    2
    -
    1
         Subject/guardian decision
    1
    -
    1
    -
    -
    Notes
    [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: One participant discontinued the treatment period but entered the follow up period.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    LNA043 20 mg Part A
    Reporting group description
    		 Part A: a single intra-articular injection of 20 mg LNA043 was administered weekly for 4 weeks for participants with focal cartilage lesions of the knee.

    Reporting group title
    Placebo Part A
    Reporting group description
    		 Part A: a single intra-articular injection of matching placebo (0 mg) was administered weekly for 4 weeks for participants with focal cartilage lesions of the knee

    Reporting group title
    LNA043 20 mg Part B
    Reporting group description
    		 Part B: a single intra-articular injection of 20 mg LNA043 was administered every 4 weeks from Week 1 to Week 13 (4 injections) for participants with osteoarthritis.

    Reporting group title
    LNA043 40 mg Part B
    Reporting group description
    		 Part B: a single intra-articular injection of 40 mg LNA043 was administered every 4 weeks from Week 1 to Week 13 (4 injections) for participants with osteoarthritis.

    Reporting group title
    Placebo Part B
    Reporting group description
    		 Part B: a single intra-articular injection of matching placebo (0 mg) was administered every 4 weeks from Week 1 to Week 13 (4 injections) for participants with osteoarthritis

    Reporting group values
    		 LNA043 20 mg Part A Placebo Part A LNA043 20 mg Part B LNA043 40 mg Part B Placebo Part B Total
    Number of subjects
    		 43 15 27 27 29 141
    Age Categorical
    Units: participants
        18-64 years
    		 43 15 18 15 15 106
        65 - 76
    		 0 0 9 12 14 35
    Sex: Female, Male
    Units:
        Female
    		 21 5 19 20 21 86
        Male
    		 22 10 8 7 8 55
    Race/Ethnicity, Customized
    Units: Subjects
        Asian
    		 1 1 0 0 1 3
        White
    		 42 11 20 26 24 123
        American Indian or Alaska Native
    		 0 1 0 0 0 1
        Black or African
    		 0 1 7 1 3 12
        American Unknow
    		 0 1 0 0 0 1
        Other
    		 0 0 0 0 1 1

    End points

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    End points reporting groups
    Reporting group title
    LNA043 20 mg Part A
    Reporting group description
    		 Part A: a single intra-articular injection of 20 mg LNA043 was administered weekly for 4 weeks for participants with focal cartilage lesions of the knee.

    Reporting group title
    Placebo Part A
    Reporting group description
    		 Part A: a single intra-articular injection of matching placebo (0 mg) was administered weekly for 4 weeks for participants with focal cartilage lesions of the knee

    Reporting group title
    LNA043 20 mg Part B
    Reporting group description
    		 Part B: a single intra-articular injection of 20 mg LNA043 was administered every 4 weeks from Week 1 to Week 13 (4 injections) for participants with osteoarthritis.

    Reporting group title
    LNA043 40 mg Part B
    Reporting group description
    		 Part B: a single intra-articular injection of 40 mg LNA043 was administered every 4 weeks from Week 1 to Week 13 (4 injections) for participants with osteoarthritis.

    Reporting group title
    Placebo Part B
    Reporting group description
    		 Part B: a single intra-articular injection of matching placebo (0 mg) was administered every 4 weeks from Week 1 to Week 13 (4 injections) for participants with osteoarthritis
    Reporting group title
    LNA043 20 mg Part A
    Reporting group description
    		 Part A: a single intra-articular injection of 20 mg LNA043 was administered weekly for 4 weeks for participants with focal cartilage lesions of the knee.

    Reporting group title
    Placebo Part A
    Reporting group description
    		 Part A: a single intra-articular injection of matching placebo (0 mg) was administered weekly for 4 weeks for participants with focal cartilage lesions of the knee

    Reporting group title
    LNA043 20 mg Part B
    Reporting group description
    		 Part B: a single intra-articular injection of 20 mg LNA043 was administered every 4 weeks from Week 1 to Week 13 (4 injections) for participants with osteoarthritis.

    Reporting group title
    LNA043 40 mg Part B
    Reporting group description
    		 Part B: a single intra-articular injection of 40 mg LNA043 was administered every 4 weeks from Week 1 to Week 13 (4 injections) for participants with osteoarthritis.

    Reporting group title
    Placebo Part B
    Reporting group description
    		 Part B: a single intra-articular injection of matching placebo (0 mg) was administered every 4 weeks from Week 1 to Week 13 (4 injections) for participants with osteoarthritis

    Primary: Change from baseline in articular cartilage collagen organization in the overall cartilage (femoral and patellar lesions) - Part A

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    End point title
    		 Change from baseline in articular cartilage collagen organization in the overall cartilage (femoral and patellar lesions) - Part A [1]
    End point description
    Collagen fibril organization in articular cartilage evaluated by Magnetic Resonance Imaging (MRI) from the cartilage mean T2 relaxation time (with lower values indicative of higher quality). The area of interest is the focal cartilage lesion.
    End point type
    Primary
    End point timeframe
    Baseline up to Week 16, 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: Estimated mean difference was provided.
    End point values
    		 LNA043 20 mg Part A Placebo Part A
    Number of subjects analysed
    43
    15
    Units: ms
    arithmetic mean (standard error)
        Week 16 n=43,14
    3.28 ( 9.78 )
    2.79 ( 16.37 )
        Week 28 n=39,15
    5.66 ( 9.90 )
    1.98 ( 15.97 )
    Statistical analysis title
    		 Week 16
    Comparison groups
    LNA043 20 mg Part A v Placebo Part A
    Number of subjects included in analysis
    58
    Analysis specification
    Pre-specified
    Analysis type
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.48
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -30.73
         upper limit
    		 31.69
    Statistical analysis title
    		 Week 28
    Comparison groups
    LNA043 20 mg Part A v Placebo Part A
    Number of subjects included in analysis
    58
    Analysis specification
    Pre-specified
    Analysis type
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    3.68
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -27.04
         upper limit
    		 34.4

    Primary: Change from baseline in articular cartilage collagen organization in the deep cartilage layer (femoral and patellar lesions) - Part A

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    End point title
    		 Change from baseline in articular cartilage collagen organization in the deep cartilage layer (femoral and patellar lesions) - Part A [2]
    End point description
    Collagen fibril organization in articular cartilage evaluated by MRI from the cartilage mean T2 relaxation time (with lower values indicative of higher quality). The area of interest is the focal cartilage lesion.
    End point type
    Primary
    End point timeframe
    Baseline up to Week 16, Week 28
    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: Estimated mean difference was provided.
    End point values
    		 LNA043 20 mg Part A Placebo Part A
    Number of subjects analysed
    43
    15
    Units: ms
    arithmetic mean (standard error)
        Week 16 n=41,14
    5.30 ( 9.17 )
    3.61 ( 15.46 )
        Week 28 n=39,15
    7.86 ( 9.36 )
    1.90 ( 15.08 )
    Statistical analysis title
    		 Week 28
    Comparison groups
    LNA043 20 mg Part A v Placebo Part A
    Number of subjects included in analysis
    58
    Analysis specification
    Pre-specified
    Analysis type
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    5.97
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -23.03
         upper limit
    		 34.97
    Statistical analysis title
    		 Week 16
    Comparison groups
    LNA043 20 mg Part A v Placebo Part A
    Number of subjects included in analysis
    58
    Analysis specification
    Pre-specified
    Analysis type
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    1.69
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -27.7
         upper limit
    		 31.08

    Primary: Change from baseline in articular cartilage collagen organization in the superficial cartilage layer (femoral and patellar lesions) - Part A

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    End point title
    		 Change from baseline in articular cartilage collagen organization in the superficial cartilage layer (femoral and patellar lesions) - Part A [3]
    End point description
    Collagen fibril organization in articular cartilage evaluated by MRI from the cartilage mean T2 relaxation time (with lower values indicative of higher quality).The area of interest is the focal cartilage lesion.
    End point type
    Primary
    End point timeframe
    Baseline up to Week 16, Week 28
    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: Estimated mean difference was provided.
    End point values
    		 LNA043 20 mg Part A Placebo Part A
    Number of subjects analysed
    43
    15
    Units: ms
    arithmetic mean (standard error)
        Week 16 n=17,7
    -13.05 ( 15.68 )
    -13.93 ( 24.73 )
        Week 28 n=16,9
    -10.45 ( 16.61 )
    -12.73 ( 22.09 )
    Statistical analysis title
    		 Week 28
    Comparison groups
    LNA043 20 mg Part A v Placebo Part A
    Number of subjects included in analysis
    58
    Analysis specification
    Pre-specified
    Analysis type
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    2.27
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -43.11
         upper limit
    		 47.65
    Statistical analysis title
    		 Week 16
    Comparison groups
    LNA043 20 mg Part A v Placebo Part A
    Number of subjects included in analysis
    58
    Analysis specification
    Pre-specified
    Analysis type
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.88
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -47.27
         upper limit
    		 49.04

    Primary: Change from baseline of LNA043 to placebo in cartilage volume in the femoral medial index region (mm3) - Part B

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    End point title
    		 Change from baseline of LNA043 to placebo in cartilage volume in the femoral medial index region (mm3) - Part B [4]
    End point description
    MRI based quantitative assessment using an automated segmentation algorithm
    End point type
    Primary
    End point timeframe
    Baseline, Week 29, Week 53
    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: Estimated mean difference was provided.
    End point values
    		 LNA043 20 mg Part B LNA043 40 mg Part B Placebo Part B
    Number of subjects analysed
    27
    27
    29
    Units: mm3
    arithmetic mean (standard error)
        Week 29 n=12,13,13
    45.52 ( 61.90 )
    -12.79 ( 60.38 )
    -154.7 ( 60.25 )
        Week 53 n=11,13,7
    75.64 ( 54.48 )
    -36.52 ( 51.21 )
    -152.7 ( 67.72 )
    Statistical analysis title
    		 Week 29
    Comparison groups
    LNA043 20 mg Part B v Placebo Part B
    Number of subjects included in analysis
    56
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.0131
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    200.18
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 54.53
         upper limit
    		 345.83
    Statistical analysis title
    		 Week 53
    Comparison groups
    LNA043 20 mg Part B v Placebo Part B
    Number of subjects included in analysis
    56
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.0067
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    228.27
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 80.87
         upper limit
    		 375.67
    Statistical analysis title
    		 Week 53
    Comparison groups
    LNA043 40 mg Part B v Placebo Part B
    Number of subjects included in analysis
    56
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.0931
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    116.21
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -29.52
         upper limit
    		 261.94
    Statistical analysis title
    		 Week 29
    Comparison groups
    LNA043 40 mg Part B v Placebo Part B
    Number of subjects included in analysis
    56
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.0544
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    141.87
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -3.83
         upper limit
    		 287.56

    Primary: Change from baseline of LNA043 to placebo in cartilage thickness in the femoral medial index region (mm) - Part B

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    End point title
    		 Change from baseline of LNA043 to placebo in cartilage thickness in the femoral medial index region (mm) - Part B [5]
    End point description
    MRI based quantitative assessment using an automated segmentation algorithm.
    End point type
    Primary
    End point timeframe
    Baseline, Week 29, Week 53
    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: Estimated mean difference was provided.
    End point values
    		 LNA043 20 mg Part B LNA043 40 mg Part B Placebo Part B
    Number of subjects analysed
    27
    27
    29
    Units: mm
    arithmetic mean (standard error)
        Week 29 n=12,13,13
    0.01 ( 0.02 )
    0.02 ( 0.02 )
    -0.04 ( 0.02 )
        Week 53 n=11,13,7
    -0.01 ( 0.02 )
    -0.00 ( 0.02 )
    -0.02 ( 0.03 )
    Statistical analysis title
    		 Week 29
    Comparison groups
    LNA043 20 mg Part B v Placebo Part B
    Number of subjects included in analysis
    56
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.0574
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.05
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0
         upper limit
    		 0.1
    Statistical analysis title
    		 Week 53
    Comparison groups
    LNA043 20 mg Part B v Placebo Part B
    Number of subjects included in analysis
    56
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.3864
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.01
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -0.05
         upper limit
    		 0.07
    Statistical analysis title
    		 Week 53
    Comparison groups
    LNA043 40 mg Part B v Placebo Part B
    Number of subjects included in analysis
    56
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.329
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.02
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -0.05
         upper limit
    		 0.08
    Statistical analysis title
    		 Week 29
    Comparison groups
    LNA043 40 mg Part B v Placebo Part B
    Number of subjects included in analysis
    56
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.0248
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.06
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.01
         upper limit
    		 0.11

    Secondary: Change from baseline of LNA043 to placebo in cartilage defect volume (mm3) for both groups of patients (femoral and patellar lesions) - Part A

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    End point title
    		 Change from baseline of LNA043 to placebo in cartilage defect volume (mm3) for both groups of patients (femoral and patellar lesions) - Part A [6]
    End point description
    Cartilage volume data were generated from the manual segmentation of the cartilage defect that was identified in MR images.
    End point type
    Secondary
    End point timeframe
    Baseline up to Week 16, Week 28
    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: Estimated mean difference was provided.
    End point values
    		 LNA043 20 mg Part A Placebo Part A
    Number of subjects analysed
    43
    15
    Units: mm
    arithmetic mean (standard error)
        Week 16 n=40,14
    -2.42 ( 8.27 )
    -7.17 ( 13.64 )
        Week 28 n=39,15
    -11.88 ( 8.27 )
    -4.57 ( 13.45 )
    Statistical analysis title
    		 Week 16
    Comparison groups
    LNA043 20 mg Part A v Placebo Part A
    Number of subjects included in analysis
    58
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.6184
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    4.75
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -21.36
         upper limit
    		 30.85
    Statistical analysis title
    		 Week 28
    Comparison groups
    LNA043 20 mg Part A v Placebo Part A
    Number of subjects included in analysis
    58
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.3194
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    -7.32
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -33.16
         upper limit
    		 18.53

    Secondary: Change from baseline in cartilage mean T2 relaxation time as a marker of collagen organization in the medial femoral index region - Overall Part B

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    End point title
    		 Change from baseline in cartilage mean T2 relaxation time as a marker of collagen organization in the medial femoral index region - Overall Part B [7]
    End point description
    Collagen fibril organisation in articular cartilage evaluated by MRI from the cartilage mean T2 relaxation time (with lower values indicative of higher quality). The area of interest is the femoral medial index region comprising the anterior, central and posterior aspects of the femoral condyle.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 29, Week 53
    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: Estimated mean difference was provided.
    End point values
    		 LNA043 20 mg Part B LNA043 40 mg Part B Placebo Part B
    Number of subjects analysed
    27
    27
    29
    Units: ms
    arithmetic mean (standard error)
        Week 29 n=21,21,25
    -1.59 ( 2.25 )
    -5.07 ( 2.26 )
    -4.97 ( 2.07 )
        Week 53 n=20,22,22
    -4.23 ( 2.29 )
    -10.53 ( 2.25 )
    -3.09 ( 2.18 )
    Statistical analysis title
    		 Week 29
    Comparison groups
    LNA043 20 mg Part B v Placebo Part B
    Number of subjects included in analysis
    56
    Analysis specification
    Pre-specified
    Analysis type
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    3.38
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -1.72
         upper limit
    		 8.47
    Statistical analysis title
    		 Week 29
    Comparison groups
    LNA043 40 mg Part B v Placebo Part B
    Number of subjects included in analysis
    56
    Analysis specification
    Pre-specified
    Analysis type
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    -0.1
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -5.22
         upper limit
    		 5.01
    Statistical analysis title
    		 Week 53
    Comparison groups
    LNA043 20 mg Part B v Placebo Part B
    Number of subjects included in analysis
    56
    Analysis specification
    Pre-specified
    Analysis type
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    -1.14
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -6.42
         upper limit
    		 4.15
    Statistical analysis title
    		 Week 53
    Comparison groups
    LNA043 40 mg Part B v Placebo Part B
    Number of subjects included in analysis
    56
    Analysis specification
    Pre-specified
    Analysis type
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    -7.44
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -12.68
         upper limit
    		 -2.2

    Secondary: Change from baseline in cartilage mean T2 relaxation time as a marker of collagen organization in the median femoral index region - Deep Part B

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    End point title
    		 Change from baseline in cartilage mean T2 relaxation time as a marker of collagen organization in the median femoral index region - Deep Part B [8]
    End point description
    Collagen fibril organisation in articular cartilage evaluated by MRI from the cartilage mean T2 relaxation time (with lower values indicative of higher quality). The area of interest is the femoral medial index region comprising the anterior, central and posterior aspects of the femoral condyle.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 29, Week 53
    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: Estimated mean difference was provided.
    End point values
    		 LNA043 20 mg Part B LNA043 40 mg Part B Placebo Part B
    Number of subjects analysed
    27
    27
    29
    Units: ms
    arithmetic mean (standard error)
        Week 29 n=21,21,25
    -3.80 ( 2.47 )
    -5.07 ( 2.49 )
    -5.89 ( 2.26 )
        Week 53 n=20,22,22
    -3.93 ( 2.53 )
    -12.17 ( 2.54 )
    -6.21 ( 2.41 )
    Statistical analysis title
    		 Week 29
    Comparison groups
    LNA043 20 mg Part B v Placebo Part B
    Number of subjects included in analysis
    56
    Analysis specification
    Pre-specified
    Analysis type
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    2.09
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -3.49
         upper limit
    		 7.66
    Statistical analysis title
    		 Week 53
    Comparison groups
    LNA043 40 mg Part B v Placebo Part B
    Number of subjects included in analysis
    56
    Analysis specification
    Pre-specified
    Analysis type
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    -5.96
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -11.81
         upper limit
    		 -0.1
    Statistical analysis title
    		 Week 53
    Comparison groups
    LNA043 20 mg Part B v Placebo Part B
    Number of subjects included in analysis
    56
    Analysis specification
    Pre-specified
    Analysis type
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    2.29
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -3.54
         upper limit
    		 8.11
    Statistical analysis title
    		 Week 29
    Comparison groups
    LNA043 40 mg Part B v Placebo Part B
    Number of subjects included in analysis
    56
    Analysis specification
    Pre-specified
    Analysis type
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.82
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -4.82
         upper limit
    		 6.45

    Secondary: Change from baseline in cartilage mean T2 relaxation time as a marker of collagen organization in the medial femoral index region - Superficial Part B

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    End point title
    		 Change from baseline in cartilage mean T2 relaxation time as a marker of collagen organization in the medial femoral index region - Superficial Part B [9]
    End point description
    Collagen fibril organisation in articular cartilage evaluated by MRI from the cartilage mean T2 relaxation time (with lower values indicative of higher quality). The area of interest is the femoral medial index region comprising the anterior, central and posterior aspects of the femoral condyle.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 29, Week 53
    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: Estimated mean difference was provided.
    End point values
    		 LNA043 20 mg Part B LNA043 40 mg Part B Placebo Part B
    Number of subjects analysed
    27
    27
    29
    Units: ms
    arithmetic mean (standard error)
        Week 29 n=21,21,25
    -0.06 ( 2.51 )
    -4.16 ( 2.51 )
    -3.53 ( 2.30 )
        Week 53 n=20,22,22
    -3.54 ( 2.36 )
    -9.07 ( 2.36 )
    -0.91 ( 2.25 )
    Statistical analysis title
    		 Week 29
    Comparison groups
    LNA043 20 mg Part B v Placebo Part B
    Number of subjects included in analysis
    56
    Analysis specification
    Pre-specified
    Analysis type
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    3.47
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -2.21
         upper limit
    		 9.15
    Statistical analysis title
    		 Week 53
    Comparison groups
    LNA043 40 mg Part B v Placebo Part B
    Number of subjects included in analysis
    56
    Analysis specification
    Pre-specified
    Analysis type
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    -8.16
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -13.61
         upper limit
    		 -2.72
    Statistical analysis title
    		 Week 53
    Comparison groups
    LNA043 20 mg Part B v Placebo Part B
    Number of subjects included in analysis
    56
    Analysis specification
    Pre-specified
    Analysis type
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    -2.63
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -8.07
         upper limit
    		 2.82
    Statistical analysis title
    		 Week 29
    Comparison groups
    LNA043 40 mg Part B v Placebo Part B
    Number of subjects included in analysis
    56
    Analysis specification
    Pre-specified
    Analysis type
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    -0.63
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -6.31
         upper limit
    		 5.04

    Secondary: Incidence of immunogenicity (IG) Part A

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    End point title
    		 Incidence of immunogenicity (IG) Part A [10]
    End point description
    A validated ligand binding assay were used for the detection of anti-LNA043 antibodies, and cross-reactivity to ANGPTL3 and ANGPTL4.
    End point type
    Secondary
    End point timeframe
    Week 1,3,8,16,28
    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: No analysis was done
    End point values
    		 LNA043 20 mg Part A Placebo Part A
    Number of subjects analysed
    43
    15
    Units: participants
        Week 1 (Day 1) Predose
    0
    0
        Week 3 (Day 15) Pre-dose
    0
    0
        Week 8 (Day 50)
    0
    0
        Week 16 (Day 106)
    0
    0
        Week 28 (Day 190)
    0
    0
    No statistical analyses for this end point

    Secondary: Incidence of immunogenicity (IG) Part B

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    End point title
    		 Incidence of immunogenicity (IG) Part B [11]
    End point description
    A validated ligand binding assay were used for the detection of anti-LNA043 antibodies, and cross-reactivity to ANGPTL3 and ANGPTL4.
    End point type
    Secondary
    End point timeframe
    Week 1,5,9,13,17,29,53
    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: No analysis was done
    End point values
    		 LNA043 20 mg Part B LNA043 40 mg Part B Placebo Part B
    Number of subjects analysed
    27
    27
    29
    Units: participants
        Week 1 (Day 1) Predose
    0
    0
    0
        Week 5 Pre-dose
    0
    0
    0
        Week 9
    0
    0
    0
        Week 13
    0
    0
    0
        Week 17
    0
    0
    0
        Week 29
    0
    0
    0
        Week 53
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Serum concentrations of LNA043 - Part A

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    End point title
    		 Serum concentrations of LNA043 - Part A [12]
    End point description
    Concentrations for LNA043 were determined by a validated LC-MS/MS method; the anticipated LLOQ was 10ng/mL in serum. Concentrations below the LLOQ were reported as “zero”
    End point type
    Secondary
    End point timeframe
    Week 1: 0 (pre-dose), 0.25 hours, 1, 2 hours post dose; Weeks 2, 3, 4: 0 hour (pre dose), 1 hour post dose
    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: No analysis was done
    End point values
    		 LNA043 20 mg Part A
    Number of subjects analysed
    43
    Units: ng/mL
    arithmetic mean (standard deviation)
        Week 1, 0 hour pre-dose n=43,
    0.00 ( 0.00 )
        Week 1, 0.25 hour post dose n=6
    24.9 ( 16.3 )
        Week 1, 1 hour post dose n=7
    65.1 ( 30.2 )
        Week 1, 2 hours post dose n=41
    64.9 ( 37.5 )
        Week 2,0 hour pre dose n=42
    0.00 ( 0.00 )
        Week 2, 1 hour post dose n=43
    48.1 ( 32.9 )
        Week 3, 0 hour pre dose n=41
    0.00 ( 0.00 )
        Week 3, 1 hour post dose n=39
    51.0 ( 37.6 )
        Week 4, 0 hour pre dose n=42
    3.00 ( 19.4 )
        Week 4, 1 hour post dose n=41
    52.9 ( 38.1 )
    No statistical analyses for this end point

    Secondary: Serum concentrations of ANGPTL3 - Part A

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    End point title
    		 Serum concentrations of ANGPTL3 - Part A [13]
    End point description
    Validated bioanalytical assays were used to determine ANGPTL3 in serum with an LLOQ of 2.13 ng/mL. Concentrations below the LLOQ were reported as “zero”
    End point type
    Secondary
    End point timeframe
    Week 1: 0 (pre-dose), 0.25 hours, 1, 2 hours post dose; Weeks 2, 3, 4: 0 hour (pre dose), 1 hour post dose
    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: No analysis done
    End point values
    		 LNA043 20 mg Part A Placebo Part A
    Number of subjects analysed
    43
    15
    Units: ng/mL
    arithmetic mean (standard deviation)
        Week 1, 0 hour pre-dose n=41,14
    19.1 ( 9.29 )
    23.3 ( 8.55 )
        Week 1, 0.25 hour post dose n=6,2
    20.8 ( 8.12 )
    20.4 ( 6.36 )
        Week 1, 1 hour post dose n=7,2
    19.7 ( 8.65 )
    18.2 ( 3.32 )
        Week 1, 2 hours post dose n=40,15
    18.9 ( 9.38 )
    24.3 ( 9.52 )
        Week 2,0 hour pre dose n=42,15
    18.9 ( 10.3 )
    21.7 ( 10.2 )
        Week 2, 1 hour post dose n=42,15
    18.3 ( 8.06 )
    19.7 ( 9.58 )
        Week 3, 0 hour pre dose n=42,14
    19.1 ( 7.79 )
    24.2 ( 9.95 )
        Week 3, 1 hour post dose n=39,14
    18.5 ( 7.35 )
    28.9 ( 16.4 )
        Week 4, 0 hour pre dose n=42,15
    19.6 ( 8.71 )
    21.0 ( 7.11 )
        Week 4, 1 hour post dose n=41,15
    19.6 ( 7.87 )
    22.6 ( 9.06 )
    No statistical analyses for this end point

    Secondary: Synovial Fluid concentrations of LNA043 - Part A

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    End point title
    		 Synovial Fluid concentrations of LNA043 - Part A [14]
    End point description
    Concentrations for LNA043 were determined by a validated LC-MS/MS method; the anticipated LLOQ was 10ng/mL in synovial fluid. Concentrations below the LLOQ were reported as “zero”.
    End point type
    Secondary
    End point timeframe
    Weeks 1,2,3,4: 0 hour (pre-dose)
    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: No analysis was done
    End point values
    		 LNA043 20 mg Part A
    Number of subjects analysed
    0 [15]
    Units: ng/mL
        arithmetic mean (standard deviation)
    ( )
    Notes
    [15] - LNA043 Stability in synovial fluid could not be demonstrated.
    No statistical analyses for this end point

    Secondary: Synovial Fluid concentrations of ANGPTL3 - Part A

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    End point title
    		 Synovial Fluid concentrations of ANGPTL3 - Part A [16]
    End point description
    Validated bioanalytical assays were used to determine ANGPTL3 in synovial fluid with an LLOQ of 2.74 ng/mL. Concentrations below the LLOQ were reported as “zero”.
    End point type
    Secondary
    End point timeframe
    Weeks 1,2,3,4: 0 hour (pre-dose)
    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: No analysis was done
    End point values
    		 LNA043 20 mg Part A Placebo Part A
    Number of subjects analysed
    43
    15
    Units: ng/mL
    arithmetic mean (standard deviation)
        Week 1, 0 hour pre-dose n=8,3
    0.00 ( 0.00 )
    00.0 ( 00.0 )
        Week 2,0 hour pre dose n=11,5
    0.00 ( 0.00 )
    00.0 ( 00.0 )
        Week 3, 0 hour pre dose n=13,4
    0.616 ( 2.22 )
    00.0 ( 00.0 )
        Week 4, 0 hour pre dose n=15,3
    1.42 ( 5.50 )
    00.0 ( 00.0 )
    No statistical analyses for this end point

    Secondary: Serum concentrations of LNA043 - Part B

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    End point title
    		 Serum concentrations of LNA043 - Part B [17]
    End point description
    Concentrations for LNA043 were determined by a validated LC-MS/MS method; the anticipated LLOQ was 10ng/mL in serum. Concentrations below the LLOQ were reported as “zero
    End point type
    Secondary
    End point timeframe
    Week 1: 0 (pre-dose), 2 hours post dose; Weeks 5 and 13: 1 hour post dose
    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: No analysis was done
    End point values
    		 LNA043 20 mg Part B LNA043 40 mg Part B
    Number of subjects analysed
    27
    27
    Units: ng/mL
    arithmetic mean (standard deviation)
        Week 1, 0 hours pre-dose n=27,26
    3.48 ( 18.1 )
    7.96 ( 40.6 )
        Week 1, 2 hours post dose n=24,24,
    76.4 ( 51.0 )
    158 ( 94.0 )
        Week 5, 1 hour post dose n=27,26
    55.6 ( 47.0 )
    101 ( 74.2 )
        Week 13, 1 hour post dose n=27,25
    59.5 ( 53.0 )
    118 ( 78.2 )
    No statistical analyses for this end point

    Secondary: Serum concentrations of ANGPTL3 - Part B

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    End point title
    		 Serum concentrations of ANGPTL3 - Part B [18]
    End point description
    Validated bioanalytical assays were used to determine ANGPTL3 in serum with an LLOQ of 2.13 ng/mL. Concentrations below the LLOQ were reported as “zero”.
    End point type
    Secondary
    End point timeframe
    Week 1: 0 (pre-dose), 1, 2 hours post dose; Weeks 2, 3, 4: 0 hour (pre dose), 1 hour post dose
    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: No analysis was done
    End point values
    		 LNA043 20 mg Part B LNA043 40 mg Part B Placebo Part B
    Number of subjects analysed
    27
    26
    29
    Units: ng/mL
    arithmetic mean (standard deviation)
        Week 1, 0 hour pre-dose n=27,26,29
    25.3 ( 11.1 )
    21.9 ( 9.09 )
    26.6 ( 14.0 )
        Week 1, 2 hours post dose n=24,24,26
    26.0 ( 12.8 )
    23.9 ( 10.6 )
    27.6 ( 13.1 )
        Week 5, 1 hour post dose n=26,26,28
    21.8 ( 9.80 )
    23.3 ( 9.97 )
    26.2 ( 10.8 )
        Week 13, 1 hour post dose n=27,25,28
    22.9 ( 8.72 )
    22.5 ( 8.39 )
    24.8 ( 11.8 )
    No statistical analyses for this end point

    Secondary: Synovial Fluid concentrations of LNA043 Part B

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    End point title
    		 Synovial Fluid concentrations of LNA043 Part B [19]
    End point description
    Concentrations for LNA043 were determined by a validated LC-MS/MS method; the anticipated LLOQ was 10ng/mL in synovial fluid. Concentrations below the LLOQ were reported as “zero”.
    End point type
    Secondary
    End point timeframe
    Weeks 1,5.9.13: 0 hour (pre-dose)
    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: No analysis was done
    End point values
    		 LNA043 20 mg Part B LNA043 40 mg Part B
    Number of subjects analysed
    27
    27
    Units: ng/mL
    arithmetic mean (standard deviation)
        Week 1, 0 hours pre dose n=9,5
    28.9 ( 86.7 )
    0.00 ( 0.00 )
        Week 5, 0 hours pre dose n=10,5
    368 ( 1160 )
    18.1 ( 40.6 )
        Week 9, 0 hours pre-dose n=11,6
    0.00 ( 0.00 )
    43600 ( 90900 )
        Week 13, 0 hours pre dose n=8,4
    0.00 ( 0.00 )
    199000 ( 398000 )
    No statistical analyses for this end point

    Secondary: Synovial Fluid concentrations of ANGPTL3 - Part B

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    End point title
    		 Synovial Fluid concentrations of ANGPTL3 - Part B [20]
    End point description
    Validated bioanalytical assays were used to determine ANGPTL3 in synovial fluid with an LLOQ of 2.74 ng/mL. Concentrations below the LLOQ were reported as “zero”.
    End point type
    Secondary
    End point timeframe
    Weeks 1,5.9.13: 0 hour (pre-dose)
    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: No analysis was done
    End point values
    		 LNA043 20 mg Part B LNA043 40 mg Part B Placebo Part B
    Number of subjects analysed
    27
    27
    29
    Units: ng/mL
    arithmetic mean (standard deviation)
        Week 1, 0 hour pre-dose n=8,3,8
    0.00 ( 0.00 )
    0.00 ( 0.00 )
    0.00 ( 0.00 )
        0.00Week 5,,0 hour pre dose n=10,5,12
    1.00 ( 3.16 )
    4.38 ( 9.79 )
    1.57 ( 5.43 )
        Week 9,, 0 hour pre dose n=8,4,9
    0.00 ( 0.00 )
    0.00 ( 0.00 )
    0.00 ( 0.00 )
        Week 13, 0 hour pre dose n=7,4,8
    0.00 ( 0.00 )
    1.87 ( 3.74 )
    0.890 ( 2.52 )
    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 of 99 days plus 30 days post treatment, up to maximum duration of approximately 129 days.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    25.0
    Reporting groups
    Reporting group title
    LNA043 20mg
    Reporting group description
    		 LNA043 20mg

    Reporting group title
    PLACEBO
    Reporting group description
    		 PLACEBO

    Reporting group title
    Total-Part A
    Reporting group description
    		 Total-Part A

    Reporting group title
    Total-Part B
    Reporting group description
    		 Total-Part B

    Reporting group title
    LNA043 40mg@in Part B
    Reporting group description
    		 LNA043 40mg@in Part B

    Reporting group title
    PLACEBO@in Part B
    Reporting group description
    		 PLACEBO@in Part B

    Reporting group title
    LNA043 20mg@in Part B
    Reporting group description
    		 LNA043 20mg@in Part B

    Serious adverse events
    		 LNA043 20mg PLACEBO Total-Part A Total-Part B LNA043 40mg@in Part B PLACEBO@in Part B LNA043 20mg@in Part B
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 43 (0.00%)
    0 / 15 (0.00%)
    0 / 58 (0.00%)
    1 / 83 (1.20%)
    0 / 27 (0.00%)
    0 / 29 (0.00%)
    1 / 27 (3.70%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    0
    0
    Infections and infestations
    COVID-19 pneumonia
         subjects affected / exposed
    0 / 43 (0.00%)
    0 / 15 (0.00%)
    0 / 58 (0.00%)
    1 / 83 (1.20%)
    0 / 27 (0.00%)
    0 / 29 (0.00%)
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 LNA043 20mg PLACEBO Total-Part A Total-Part B LNA043 40mg@in Part B PLACEBO@in Part B LNA043 20mg@in Part B
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    19 / 43 (44.19%)
    7 / 15 (46.67%)
    26 / 58 (44.83%)
    31 / 83 (37.35%)
    15 / 27 (55.56%)
    10 / 29 (34.48%)
    6 / 27 (22.22%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Squamous cell carcinoma of skin
         subjects affected / exposed
    0 / 43 (0.00%)
    0 / 15 (0.00%)
    0 / 58 (0.00%)
    1 / 83 (1.20%)
    0 / 27 (0.00%)
    1 / 29 (3.45%)
    0 / 27 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    1
    0
    Vascular disorders
    Haematoma
         subjects affected / exposed
    0 / 43 (0.00%)
    0 / 15 (0.00%)
    0 / 58 (0.00%)
    1 / 83 (1.20%)
    1 / 27 (3.70%)
    0 / 29 (0.00%)
    0 / 27 (0.00%)
         occurrences all number
    0
    0
    0
    1
    1
    0
    0
    General disorders and administration site conditions
    Injection site haematoma
         subjects affected / exposed
    0 / 43 (0.00%)
    0 / 15 (0.00%)
    0 / 58 (0.00%)
    1 / 83 (1.20%)
    1 / 27 (3.70%)
    0 / 29 (0.00%)
    0 / 27 (0.00%)
         occurrences all number
    0
    0
    0
    1
    1
    0
    0
    Injection site erythema
         subjects affected / exposed
    0 / 43 (0.00%)
    0 / 15 (0.00%)
    0 / 58 (0.00%)
    1 / 83 (1.20%)
    1 / 27 (3.70%)
    0 / 29 (0.00%)
    0 / 27 (0.00%)
         occurrences all number
    0
    0
    0
    1
    1
    0
    0
    Injection site bruising
         subjects affected / exposed
    0 / 43 (0.00%)
    0 / 15 (0.00%)
    0 / 58 (0.00%)
    1 / 83 (1.20%)
    0 / 27 (0.00%)
    1 / 29 (3.45%)
    0 / 27 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    1
    0
    Inflammation
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 15 (0.00%)
    1 / 58 (1.72%)
    0 / 83 (0.00%)
    0 / 27 (0.00%)
    0 / 29 (0.00%)
    0 / 27 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    0
    0
    Injection site joint erythema
         subjects affected / exposed
    0 / 43 (0.00%)
    0 / 15 (0.00%)
    0 / 58 (0.00%)
    1 / 83 (1.20%)
    1 / 27 (3.70%)
    0 / 29 (0.00%)
    0 / 27 (0.00%)
         occurrences all number
    0
    0
    0
    1
    1
    0
    0
    Peripheral swelling
         subjects affected / exposed
    0 / 43 (0.00%)
    0 / 15 (0.00%)
    0 / 58 (0.00%)
    1 / 83 (1.20%)
    1 / 27 (3.70%)
    0 / 29 (0.00%)
    0 / 27 (0.00%)
         occurrences all number
    0
    0
    0
    1
    1
    0
    0
    Injection site joint pain
         subjects affected / exposed
    2 / 43 (4.65%)
    0 / 15 (0.00%)
    2 / 58 (3.45%)
    2 / 83 (2.41%)
    1 / 27 (3.70%)
    1 / 29 (3.45%)
    0 / 27 (0.00%)
         occurrences all number
    2
    0
    2
    2
    1
    1
    0
    Pyrexia
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 15 (0.00%)
    1 / 58 (1.72%)
    0 / 83 (0.00%)
    0 / 27 (0.00%)
    0 / 29 (0.00%)
    0 / 27 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    0
    0
    Vessel puncture site haemorrhage
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 15 (0.00%)
    1 / 58 (1.72%)
    0 / 83 (0.00%)
    0 / 27 (0.00%)
    0 / 29 (0.00%)
    0 / 27 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    0
    0
    Reproductive system and breast disorders
    Atrophic vulvovaginitis
         subjects affected / exposed
    0 / 43 (0.00%)
    0 / 15 (0.00%)
    0 / 58 (0.00%)
    1 / 83 (1.20%)
    1 / 27 (3.70%)
    0 / 29 (0.00%)
    0 / 27 (0.00%)
         occurrences all number
    0
    0
    0
    1
    1
    0
    0
    Ovulation pain
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 15 (0.00%)
    1 / 58 (1.72%)
    0 / 83 (0.00%)
    0 / 27 (0.00%)
    0 / 29 (0.00%)
    0 / 27 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Nasal congestion
         subjects affected / exposed
    0 / 43 (0.00%)
    1 / 15 (6.67%)
    1 / 58 (1.72%)
    0 / 83 (0.00%)
    0 / 27 (0.00%)
    0 / 29 (0.00%)
    0 / 27 (0.00%)
         occurrences all number
    0
    1
    1
    0
    0
    0
    0
    Psychiatric disorders
    Sleep disorder
         subjects affected / exposed
    0 / 43 (0.00%)
    0 / 15 (0.00%)
    0 / 58 (0.00%)
    1 / 83 (1.20%)
    1 / 27 (3.70%)
    0 / 29 (0.00%)
    0 / 27 (0.00%)
         occurrences all number
    0
    0
    0
    1
    1
    0
    0
    Investigations
    Cardiac murmur
         subjects affected / exposed
    0 / 43 (0.00%)
    0 / 15 (0.00%)
    0 / 58 (0.00%)
    1 / 83 (1.20%)
    1 / 27 (3.70%)
    0 / 29 (0.00%)
    0 / 27 (0.00%)
         occurrences all number
    0
    0
    0
    1
    1
    0
    0
    Blood creatine phosphokinase increased
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 15 (0.00%)
    1 / 58 (1.72%)
    2 / 83 (2.41%)
    1 / 27 (3.70%)
    0 / 29 (0.00%)
    1 / 27 (3.70%)
         occurrences all number
    1
    0
    1
    2
    1
    0
    1
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 43 (0.00%)
    0 / 15 (0.00%)
    0 / 58 (0.00%)
    1 / 83 (1.20%)
    1 / 27 (3.70%)
    0 / 29 (0.00%)
    0 / 27 (0.00%)
         occurrences all number
    0
    0
    0
    1
    1
    0
    0
    Haematology test abnormal
         subjects affected / exposed
    0 / 43 (0.00%)
    0 / 15 (0.00%)
    0 / 58 (0.00%)
    1 / 83 (1.20%)
    0 / 27 (0.00%)
    0 / 29 (0.00%)
    1 / 27 (3.70%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    1
    Urine protein/creatinine ratio increased
         subjects affected / exposed
    0 / 43 (0.00%)
    0 / 15 (0.00%)
    0 / 58 (0.00%)
    2 / 83 (2.41%)
    1 / 27 (3.70%)
    1 / 29 (3.45%)
    0 / 27 (0.00%)
         occurrences all number
    0
    0
    0
    2
    1
    1
    0
    SARS-CoV-2 test positive
         subjects affected / exposed
    0 / 43 (0.00%)
    0 / 15 (0.00%)
    0 / 58 (0.00%)
    1 / 83 (1.20%)
    0 / 27 (0.00%)
    0 / 29 (0.00%)
    1 / 27 (3.70%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    1
    Injury, poisoning and procedural complications
    Tooth fracture
         subjects affected / exposed
    0 / 43 (0.00%)
    0 / 15 (0.00%)
    0 / 58 (0.00%)
    1 / 83 (1.20%)
    0 / 27 (0.00%)
    1 / 29 (3.45%)
    0 / 27 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    1
    0
    Tendon injury
         subjects affected / exposed
    0 / 43 (0.00%)
    0 / 15 (0.00%)
    0 / 58 (0.00%)
    1 / 83 (1.20%)
    0 / 27 (0.00%)
    0 / 29 (0.00%)
    1 / 27 (3.70%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    1
    Skin abrasion
         subjects affected / exposed
    0 / 43 (0.00%)
    0 / 15 (0.00%)
    0 / 58 (0.00%)
    1 / 83 (1.20%)
    0 / 27 (0.00%)
    1 / 29 (3.45%)
    0 / 27 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    1
    0
    Limb injury
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 15 (0.00%)
    1 / 58 (1.72%)
    0 / 83 (0.00%)
    0 / 27 (0.00%)
    0 / 29 (0.00%)
    0 / 27 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    0
    0
    Ligament sprain
         subjects affected / exposed
    0 / 43 (0.00%)
    0 / 15 (0.00%)
    0 / 58 (0.00%)
    1 / 83 (1.20%)
    1 / 27 (3.70%)
    0 / 29 (0.00%)
    0 / 27 (0.00%)
         occurrences all number
    0
    0
    0
    1
    1
    0
    0
    Fall
         subjects affected / exposed
    1 / 43 (2.33%)
    1 / 15 (6.67%)
    2 / 58 (3.45%)
    0 / 83 (0.00%)
    0 / 27 (0.00%)
    0 / 29 (0.00%)
    0 / 27 (0.00%)
         occurrences all number
    1
    1
    2
    0
    0
    0
    0
    Traumatic haematoma
         subjects affected / exposed
    0 / 43 (0.00%)
    0 / 15 (0.00%)
    0 / 58 (0.00%)
    1 / 83 (1.20%)
    1 / 27 (3.70%)
    0 / 29 (0.00%)
    0 / 27 (0.00%)
         occurrences all number
    0
    0
    0
    1
    1
    0
    0
    Nervous system disorders
    Syncope
         subjects affected / exposed
    0 / 43 (0.00%)
    0 / 15 (0.00%)
    0 / 58 (0.00%)
    1 / 83 (1.20%)
    1 / 27 (3.70%)
    0 / 29 (0.00%)
    0 / 27 (0.00%)
         occurrences all number
    0
    0
    0
    1
    1
    0
    0
    Paraesthesia
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 15 (0.00%)
    1 / 58 (1.72%)
    0 / 83 (0.00%)
    0 / 27 (0.00%)
    0 / 29 (0.00%)
    0 / 27 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    0
    0
    Headache
         subjects affected / exposed
    6 / 43 (13.95%)
    1 / 15 (6.67%)
    7 / 58 (12.07%)
    0 / 83 (0.00%)
    0 / 27 (0.00%)
    0 / 29 (0.00%)
    0 / 27 (0.00%)
         occurrences all number
    9
    1
    10
    0
    0
    0
    0
    Dizziness
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 15 (0.00%)
    1 / 58 (1.72%)
    0 / 83 (0.00%)
    0 / 27 (0.00%)
    0 / 29 (0.00%)
    0 / 27 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    0
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 43 (0.00%)
    0 / 15 (0.00%)
    0 / 58 (0.00%)
    1 / 83 (1.20%)
    0 / 27 (0.00%)
    1 / 29 (3.45%)
    0 / 27 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    1
    0
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 15 (0.00%)
    1 / 58 (1.72%)
    0 / 83 (0.00%)
    0 / 27 (0.00%)
    0 / 29 (0.00%)
    0 / 27 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    0
    0
    Dental caries
         subjects affected / exposed
    0 / 43 (0.00%)
    1 / 15 (6.67%)
    1 / 58 (1.72%)
    0 / 83 (0.00%)
    0 / 27 (0.00%)
    0 / 29 (0.00%)
    0 / 27 (0.00%)
         occurrences all number
    0
    1
    1
    0
    0
    0
    0
    Skin and subcutaneous tissue disorders
    Lichenoid keratosis
         subjects affected / exposed
    0 / 43 (0.00%)
    0 / 15 (0.00%)
    0 / 58 (0.00%)
    1 / 83 (1.20%)
    0 / 27 (0.00%)
    1 / 29 (3.45%)
    0 / 27 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    1
    0
    Eczema
         subjects affected / exposed
    0 / 43 (0.00%)
    0 / 15 (0.00%)
    0 / 58 (0.00%)
    1 / 83 (1.20%)
    1 / 27 (3.70%)
    0 / 29 (0.00%)
    0 / 27 (0.00%)
         occurrences all number
    0
    0
    0
    1
    1
    0
    0
    Dermatitis contact
         subjects affected / exposed
    0 / 43 (0.00%)
    0 / 15 (0.00%)
    0 / 58 (0.00%)
    1 / 83 (1.20%)
    1 / 27 (3.70%)
    0 / 29 (0.00%)
    0 / 27 (0.00%)
         occurrences all number
    0
    0
    0
    1
    1
    0
    0
    Rash
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 15 (0.00%)
    1 / 58 (1.72%)
    1 / 83 (1.20%)
    0 / 27 (0.00%)
    1 / 29 (3.45%)
    0 / 27 (0.00%)
         occurrences all number
    1
    0
    1
    1
    0
    1
    0
    Renal and urinary disorders
    Microalbuminuria
         subjects affected / exposed
    0 / 43 (0.00%)
    0 / 15 (0.00%)
    0 / 58 (0.00%)
    1 / 83 (1.20%)
    1 / 27 (3.70%)
    0 / 29 (0.00%)
    0 / 27 (0.00%)
         occurrences all number
    0
    0
    0
    1
    1
    0
    0
    Musculoskeletal and connective tissue disorders
    Muscle spasms
         subjects affected / exposed
    0 / 43 (0.00%)
    0 / 15 (0.00%)
    0 / 58 (0.00%)
    1 / 83 (1.20%)
    0 / 27 (0.00%)
    1 / 29 (3.45%)
    0 / 27 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    1
    0
    Arthralgia
         subjects affected / exposed
    3 / 43 (6.98%)
    1 / 15 (6.67%)
    4 / 58 (6.90%)
    6 / 83 (7.23%)
    4 / 27 (14.81%)
    1 / 29 (3.45%)
    1 / 27 (3.70%)
         occurrences all number
    3
    1
    4
    9
    7
    1
    1
    Back pain
         subjects affected / exposed
    1 / 43 (2.33%)
    1 / 15 (6.67%)
    2 / 58 (3.45%)
    1 / 83 (1.20%)
    0 / 27 (0.00%)
    1 / 29 (3.45%)
    0 / 27 (0.00%)
         occurrences all number
    1
    1
    2
    1
    0
    1
    0
    Joint swelling
         subjects affected / exposed
    4 / 43 (9.30%)
    0 / 15 (0.00%)
    4 / 58 (6.90%)
    5 / 83 (6.02%)
    1 / 27 (3.70%)
    3 / 29 (10.34%)
    1 / 27 (3.70%)
         occurrences all number
    7
    0
    7
    5
    1
    3
    1
    Pain in extremity
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 15 (0.00%)
    1 / 58 (1.72%)
    1 / 83 (1.20%)
    1 / 27 (3.70%)
    0 / 29 (0.00%)
    0 / 27 (0.00%)
         occurrences all number
    1
    0
    1
    1
    1
    0
    0
    Neck pain
         subjects affected / exposed
    0 / 43 (0.00%)
    0 / 15 (0.00%)
    0 / 58 (0.00%)
    1 / 83 (1.20%)
    0 / 27 (0.00%)
    0 / 29 (0.00%)
    1 / 27 (3.70%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    1
    Myalgia
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 15 (0.00%)
    1 / 58 (1.72%)
    1 / 83 (1.20%)
    1 / 27 (3.70%)
    0 / 29 (0.00%)
    0 / 27 (0.00%)
         occurrences all number
    1
    0
    1
    1
    1
    0
    0
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    0 / 43 (0.00%)
    0 / 15 (0.00%)
    0 / 58 (0.00%)
    1 / 83 (1.20%)
    1 / 27 (3.70%)
    0 / 29 (0.00%)
    0 / 27 (0.00%)
         occurrences all number
    0
    0
    0
    1
    1
    0
    0
    COVID-19 pneumonia
         subjects affected / exposed
    0 / 43 (0.00%)
    0 / 15 (0.00%)
    0 / 58 (0.00%)
    1 / 83 (1.20%)
    0 / 27 (0.00%)
    0 / 29 (0.00%)
    1 / 27 (3.70%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    1
    Gastroenteritis
         subjects affected / exposed
    0 / 43 (0.00%)
    1 / 15 (6.67%)
    1 / 58 (1.72%)
    0 / 83 (0.00%)
    0 / 27 (0.00%)
    0 / 29 (0.00%)
    0 / 27 (0.00%)
         occurrences all number
    0
    1
    1
    0
    0
    0
    0
    Herpes zoster
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 15 (0.00%)
    1 / 58 (1.72%)
    0 / 83 (0.00%)
    0 / 27 (0.00%)
    0 / 29 (0.00%)
    0 / 27 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    0
    0
    Infected dermal cyst
         subjects affected / exposed
    0 / 43 (0.00%)
    0 / 15 (0.00%)
    0 / 58 (0.00%)
    1 / 83 (1.20%)
    1 / 27 (3.70%)
    0 / 29 (0.00%)
    0 / 27 (0.00%)
         occurrences all number
    0
    0
    0
    1
    1
    0
    0
    Urinary tract infection
         subjects affected / exposed
    0 / 43 (0.00%)
    0 / 15 (0.00%)
    0 / 58 (0.00%)
    1 / 83 (1.20%)
    1 / 27 (3.70%)
    0 / 29 (0.00%)
    0 / 27 (0.00%)
         occurrences all number
    0
    0
    0
    1
    1
    0
    0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 43 (2.33%)
    1 / 15 (6.67%)
    2 / 58 (3.45%)
    0 / 83 (0.00%)
    0 / 27 (0.00%)
    0 / 29 (0.00%)
    0 / 27 (0.00%)
         occurrences all number
    1
    1
    2
    0
    0
    0
    0
    Tonsillitis
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 15 (0.00%)
    1 / 58 (1.72%)
    0 / 83 (0.00%)
    0 / 27 (0.00%)
    0 / 29 (0.00%)
    0 / 27 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    0
    0
    Respiratory tract infection viral
         subjects affected / exposed
    1 / 43 (2.33%)
    1 / 15 (6.67%)
    2 / 58 (3.45%)
    0 / 83 (0.00%)
    0 / 27 (0.00%)
    0 / 29 (0.00%)
    0 / 27 (0.00%)
         occurrences all number
    1
    1
    2
    0
    0
    0
    0

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    01 May 2017
    Amendment 01 was generated in response to request from the State Institute for Drug Control (SUKL) in Czech Republic during the CTA review, in order to add more specific definition of the primary efficacy endpoint and details on the blinding levels of the MRI assessments, as well as an update of the wording for the exclusion criterion 9 for more clarity.
    01 Jun 2017
    Amendment 02 is to introduce clarifications requested by health authorities at CTA review regarding the End of Trial definition and the corresponding activities. In adjustment to local practices, inclusion criterion n°5 is updated to allow arthroscopic confirmation of the symptomatic, single, partial thickness articular cartilage defect of one knee, grade II or IIIA according to the ICRS classification, localized to either the femoral condyles/femoral trochlea or to the patella, performed within 9 months before screening visit In order to improve clarity, exclusion criterion n°13 is updated to allow enrolment of bipolar lesions if the tibial lesion does not exceed ICRS grade 1, and for exclusion criterion n°16, definition is specified. Exclusion criteria n°17 and n°18 are updated regarding the requirement for imaging diagnostics no longer limited to 9 month. The restraints regarding prohibited medication are updated to dajust the time frame towards the dosing start, to reduce patient’s burden.
    01 Dec 2017
    Amendment 03 is to adjust the screening period and the eligibility criteria following input from investigators. Furthermore, the number of PK samples to be collected is lowered, as additional PK and safety information from the First-in-Human study has become available, Section 1.3 is updated accordingly. Also, clarification is added regarding the restriction of rescue medications during follow-up visits to prevent any bias for patient-related outcomes.
    01 Jul 2019
    Amendment 04 is to add a 52-week visit schedule for clinical and MRI evaluations
    01 Mar 2020
    Amendment 05 is to add a Part B to the study protocol with the aim of: (i) evaluating monthly dosing efficacy, safety and tolerability; (ii) exploring dose-dependence by testing multiple doses of 40 mg and 20 mg dose levels; (iii) broadening the population by including Kellgren & Lawrence (K&L) 2-3 patients, based on the positive results of the X2201 study and the positive IA of the current study; (iv) adding additional safety measures (e.g., post-dosing monitoring extended to 3 hours; more stringent stopping rules, with patients who experience any grade hypersensitivity reaction not to be re-dosed), following the Urgent Safety Measure (USM) implemented in August 2019.
    01 Jul 2020
    Amendment 06 is generated in response to the request from the Danish Medicines Agency (DKMA) to include monthly pregnancy testing, to match it with the duration of LNA043 pharmacodynamic effect. Additionally, a modification of the stopping rule related to acute allergic reactions is included, with the aim of extending safety monitoring, by adding criteria to pause the study should one (1) fatal or life-threatening event occur. Lastly, the assessment of the Benefit/Risk concluded the absence of additional risks related to COVID-19.
    01 Dec 2020
    Amendment 07 is generated to address the request from the U.S. Food and Drug Administration (FDA) to collect safety ECG monitoring (around Tmax) to provide information on whether a QT study would be required for the LNA043 program. Additionally, a modification of the radiologic selection criteria is introduced to better match the population expected to benefit from LNA043.

    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.
    For several outcomes there was a loss in samples size, which may limit the interpretability of results. Due to some errors in calculations that require re- analysis, some p values will be updated and provided at a later time.
    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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