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    Clinical Trial Results:
    A randomized, placebo-controlled, patient and Investigator blinded, single dose, Proof of Concept study investigating the safety, tolerability and preliminary efficacy of intraarticular LNA043 in regenerating the articular cartilage of the knee at donor sites in patients undergoing autologous chondrocyte implantation

    Summary
    EudraCT number
    		 2016-003418-28
    Trial protocol
    		 AT  
    Global end of trial date
    05 Apr 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    18 Apr 2020
    First version publication date
    18 Apr 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CLNA043X2201
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03334812
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Novartis Pharma AG
    Sponsor organisation address
    CH-4002, 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
    05 Apr 2019
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    05 Apr 2019
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    To assess the efficacy of a single LNA043 i.a. injection in regenerating hyaline cartilage tissue at the donor sites of patients undergoing autologous chondrocyte implantation (ACI) To assess safety and tolerability of a single LNA043 i.a. injection in patients undergoing ACI
    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
    18 Oct 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
    Austria: 14
    Worldwide total number of subjects
    14
    EEA total number of subjects
    14
    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)
    14
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 All patients were recruited from 3 clinical sites in Austria.

    Pre-assignment
    Screening details
    		 The original set up of this trial was for 2 cohorts of LNA043 (20 mg and 40 mg). The trial was terminated before any patient in the LNA043 40 mg cohort was randomized

    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
    		 Investigator, Subject

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 LNA043 20mg
    Arm description
    		 LNA043 20mg/3ml single dose
    Arm type
    		 Experimental

    Investigational medicinal product name
    LNA043
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intraarticular use
    Dosage and administration details
    LNA043 was administered to the subject via i.a injection at the end of the arthroscopy performed for cartilage harvest.

    Arm title
    		 Matching placebo to 20mg
    Arm description
    		 Matching placebo to 20mg/3ml, single dose
    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
    Placebo was administered to the subject via i.a injection at the end of the arthroscopy performed for cartilage harvest.

    Number of subjects in period 1
    		LNA043 20mg Matching placebo to 20mg
    Started
    9
    5
    Completed
    9
    5

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    LNA043 20mg
    Reporting group description
    		 LNA043 20mg/3ml single dose

    Reporting group title
    Matching placebo to 20mg
    Reporting group description
    		 Matching placebo to 20mg/3ml, single dose

    Reporting group values
    		 LNA043 20mg Matching placebo to 20mg Total
    Number of subjects
    		 9 5 14
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 9 5 14
        From 65-84 years
    		 0 0 0
        85 years and over
    		 0 0 0
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 31.0 ( 6.16 ) 39.4 ( 7.40 ) -
    Sex: Female, Male
    Units: Participants
        Female
    		 3 5 8
        Male
    		 6 0 6
    Race/Ethnicity, Customized
    Units: Subjects
        White
    		 9 5 14

    End points

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    End points reporting groups
    Reporting group title
    LNA043 20mg
    Reporting group description
    		 LNA043 20mg/3ml single dose

    Reporting group title
    Matching placebo to 20mg
    Reporting group description
    		 Matching placebo to 20mg/3ml, single dose

    Primary: Change from baseline to Week 4 in GAG content

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    End point title
    		 Change from baseline to Week 4 in GAG content
    End point description
    Sodium MRI-based measurements of change from baseline in glycosaminoglycan (GAG) content were assessed from both defective sites and a nearby healthy cartilage region (as a reference tissue). Specifically, the ratio of normalized sodium signal in the surgically created defect (SCD or donor site) to healthy non-weight bearing region (HNWB), i.e. SCD/HNWB and the defect to be treated (DTBT or main lesion) to healthy weight bearing region (HWB), i.e. DTBT/HWB was of major interest
    End point type
    Primary
    End point timeframe
    Baseline, Week 4
    End point values
    		 LNA043 20mg Matching placebo to 20mg
    Number of subjects analysed
    7
    2
    Units: Ratio
    least squares mean (standard error)
        SCD/HNWB
    0.24 ( 0.06 )
    0.06 ( 0.12 )
        DTBT/HWB
    0.08 ( 0.04 )
    0.09 ( 0.09 )
    Statistical analysis title
    		 LNA043 20mg vs. Placebo
    Statistical analysis description
    SCD/HNWB
    Comparison groups
    Matching placebo to 20mg v LNA043 20mg
    Number of subjects included in analysis
    9
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.1219
    Method
    		 Mixed Effect Model Repeat Measurement
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.18
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.15
         upper limit
    		 0.51
    Statistical analysis title
    		 LNA043 20mg vs. Placebo
    Statistical analysis description
    DTBT/HWB
    Comparison groups
    LNA043 20mg v Matching placebo to 20mg
    Number of subjects included in analysis
    9
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.5438
    Method
    		 Mixed Effect Model Repeat Measurement
    Parameter type
    		 Mean difference (net)
    Point estimate
    -0.01
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.28
         upper limit
    		 0.25

    Primary: Bi-layer collagen organization based on MRI measurements at Week 4

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    End point title
    		 Bi-layer collagen organization based on MRI measurements at Week 4
    End point description
    MRI T2 maps were generated and zonal T2 ratios (superficial layer T2 / deep layer T2) were calculated to assess the collagen fiber organization in the surgically created defect (SCD) and defect to be treated (DTBT) cartilage regions.
    End point type
    Primary
    End point timeframe
    Week 4
    End point values
    		 LNA043 20mg Matching placebo to 20mg
    Number of subjects analysed
    7
    4
    Units: Ratio
        arithmetic mean (standard error)
    1.01 ( 0.07 )
    0.95 ( 0.09 )
    Statistical analysis title
    		 LNA043 20mg vs. Placebo
    Comparison groups
    LNA043 20mg v Matching placebo to 20mg
    Number of subjects included in analysis
    11
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.3067
    Method
    		 Mixed Effect Model Repeat Measurement
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.06
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.19
         upper limit
    		 0.31

    Secondary: Change from baseline in International Cartilage Repair Society (ICRS) scoring

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    End point title
    		 Change from baseline in International Cartilage Repair Society (ICRS) scoring
    End point description
    Extent of the repair tissue at the donor site before surgery. Each criterion was evaluated based on the visual analog scale and graded from 0 (best) to 100 (worst).
    End point type
    Secondary
    End point timeframe
    Week 4
    End point values
    		 LNA043 20mg Matching placebo to 20mg
    Number of subjects analysed
    8
    4
    Units: Unit on a scale
    arithmetic mean (standard error)
        Abnormal Calcification/Ossification
    98.75 ( 1.05 )
    100.00 ( 1.48 )
        Cell Morphology
    61.43 ( 14.14 )
    56.67 ( 21.60 )
        Chondrocyte clustering
    85.71 ( 8.37 )
    85.00 ( 12.78 )
        Inflammation
    92.50 ( 2.15 )
    98.75 ( 3.04 )
        Matrix Staining
    57.14 ( 12.17 )
    25.00 ( 18.59 )
        Overall assessment
    49.29 ( 12.23 )
    55.00 ( 18.68 )
        Tissue Morphology
    71.43 ( 7.78 )
    65.00 ( 11.88 )
        Vascularisation in repaired tissue
    66.25 ( 12.88 )
    77.50 ( 18.21 )
        Basal Integration
    82.86 ( 10.64 )
    90.00 ( 16.26 )
        Formation of a Tidemark
    65.71 ( 18.15 )
    63.33 ( 27.72 )
        Mid/Deep zone assessment
    50.00 ( 14.56 )
    56.67 ( 22.24 )
        Subcondral bone abnormalities/marrow fibrosis
    73.75 ( 13.45 )
    77.50 ( 19.01 )
        Surface Architecture
    57.86 ( 11.33 )
    80.00 ( 17.31 )
        Surface/Superficial assessment
    56.43 ( 11.42 )
    83.33 ( 17.44 )
    No statistical analyses for this end point

    Secondary: Percentage of donor site refilling based on MRI measurements

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    End point title
    		 Percentage of donor site refilling based on MRI measurements
    End point description
    Extent of filling of the donor site over a longer term. Percentage change from baseline in refilling of cartilage defect based on 7T MRI for donor Region.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 4, Week 12 and Week 28
    End point values
    		 LNA043 20mg Matching placebo to 20mg
    Number of subjects analysed
    8
    4
    Units: Percent
    least squares mean (standard error)
        Week 4
    64.38 ( 7.80 )
    38.15 ( 11.03 )
        Week 12
    60.25 ( 14.55 )
    32.44 ( 19.09 )
        Week 28 (EOS)
    86.53 ( 11.09 )
    62.73 ( 14.52 )
    Statistical analysis title
    		 LNA043 20mg vs. Placebo
    Statistical analysis description
    Week 4
    Comparison groups
    LNA043 20mg v Matching placebo to 20mg
    Number of subjects included in analysis
    12
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.0404
    Method
    		 Mixed Effect Model Repeat Measurement
    Parameter type
    		 Mean difference (net)
    Point estimate
    26.23
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.86
         upper limit
    		 56.32
    Statistical analysis title
    		 LNA043 20mg vs. Placebo
    Statistical analysis description
    Week 12
    Comparison groups
    LNA043 20mg v Matching placebo to 20mg
    Number of subjects included in analysis
    12
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.1381
    Method
    		 Mixed Effect Model Repeat Measurement
    Parameter type
    		 Mean difference (net)
    Point estimate
    27.82
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -26.5
         upper limit
    		 82.1
    Statistical analysis title
    		 LNA043 20mg vs. Placebo
    Statistical analysis description
    Week 28 (EOS)
    Comparison groups
    LNA043 20mg v Matching placebo to 20mg
    Number of subjects included in analysis
    12
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.1168
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    23.8
    Confidence interval
         level
    		 96%
         sides
    2-sided
         lower limit
    		 -19.3
         upper limit
    		 66.89

    Secondary: Change from baseline in GAG content

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    End point title
    		 Change from baseline in GAG content
    End point description
    Sodium MRI-based measurements of change from baseline in glycosaminoglycan (GAG) content was assessed from both defective sites and a nearby healthy cartilage region (as a reference tissue). Specifically, the ratio of normalized sodium signal in the surgically created defect (SCD or donor site) to healthy non-weight bearing region (HNWB), i.e. SCD/HNWB was of major interest
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12 and Week 28
    End point values
    		 LNA043 20mg Matching placebo to 20mg
    Number of subjects analysed
    7
    4
    Units: Ratio
    least squares mean (standard error)
        SCD/HNWB - Week 12
    0.14 ( 0.07 )
    0.15 ( 0.09 )
        SCD/HNWB - Week 28
    0.33 ( 0.10 )
    0.14 ( 0.14 )
    Statistical analysis title
    		 LNA043 20mg vs. Placebo
    Statistical analysis description
    SCD/HNWB - Week 12
    Comparison groups
    LNA043 20mg v Matching placebo to 20mg
    Number of subjects included in analysis
    11
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.5175
    Method
    		 Mixed Effect Model Repeat Measurement
    Parameter type
    		 Mean difference (net)
    Point estimate
    -0.01
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.26
         upper limit
    		 0.25
    Statistical analysis title
    		 LNA043 20mg vs. Placebo
    Statistical analysis description
    SCD/HNWB - Week 28
    Comparison groups
    LNA043 20mg v Matching placebo to 20mg
    Number of subjects included in analysis
    11
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.1476
    Method
    		 Mixed Effect Model Repeat Measurement
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.19
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.22
         upper limit
    		 0.6

    Secondary: Bi-layer collagen organization based on MRI measurements

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    End point title
    		 Bi-layer collagen organization based on MRI measurements
    End point description
    MRI T2 maps were generated and zonal T2 ratios (superficial layer T2 / deep layer T2) were calculated to assess the collagen fiber organization in the SCD cartilage region.
    End point type
    Secondary
    End point timeframe
    Week 12 and Week 28
    End point values
    		 LNA043 20mg Matching placebo to 20mg
    Number of subjects analysed
    6
    4
    Units: Ratio
    arithmetic mean (standard error)
        Week 12
    1.44 ( 0.15 )
    1.57 ( 0.18 )
        Week 28
    1.33 ( 0.11 )
    1.45 ( 0.14 )
    No statistical analyses for this end point

    Secondary: PK profile of LNA043 and of AngPTL3 in serum Cmax

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    End point title
    		 PK profile of LNA043 and of AngPTL3 in serum Cmax
    End point description
    Local and systemic pharmacokinetics (PK) of LNA043 following a single i.a. administration
    End point type
    Secondary
    End point timeframe
    4 weeks
    End point values
    		 LNA043 20mg Matching placebo to 20mg
    Number of subjects analysed
    8
    5 [1]
    Units: ng/mL
    arithmetic mean (standard deviation)
        LNA043
    57.4 ( 22.1 )
    999 ( 999 )
        AngPTL3
    22.9 ( 9.03 )
    26.6 ( 7.62 )
    Notes
    [1] - PK profile not assessed for LNA043 in Placebo Group (999)
    No statistical analyses for this end point

    Secondary: PK profile of LNA043 and of AngPTL3 in serum AUC

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    End point title
    		 PK profile of LNA043 and of AngPTL3 in serum AUC
    End point description
    Local and systemic pharmacokinetics (PK) of LNA043 following a single i.a. administration
    End point type
    Secondary
    End point timeframe
    4 weeks
    End point values
    		 LNA043 20mg Matching placebo to 20mg
    Number of subjects analysed
    8
    5 [2]
    Units: hr*ng/mL
    arithmetic mean (standard deviation)
        LNA043
    821 ( 349 )
    999 ( 999 )
        AngPTL3
    3130 ( 1440 )
    3030 ( 1060 )
    Notes
    [2] - PK profile not assessed for LNA043 in Placebo Group (999)
    No statistical analyses for this end point

    Secondary: Number of participants with anti-LNA043 antibodies in serum

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    End point title
    		 Number of participants with anti-LNA043 antibodies in serum
    End point description
    Potential immunogenicity of LNA043
    End point type
    Secondary
    End point timeframe
    Baseline, Week 1, Week 4, Week 12 and Week 28
    End point values
    		 LNA043 20mg Matching placebo to 20mg
    Number of subjects analysed
    9
    5
    Units: Participants
        Day 1: anti-LNA043 antibodies present|YES
    0
    0
        Day 8: anti-LNA043 antibodies present|YES
    0
    0
        Day 29: anti-LNA043 antibodies present|YES
    0
    0
        Day 85: anti-LNA043 antibodies present|YES
    0
    0
        Day 197: anti-LNA043 antibodies present|YES
    0
    0
        Day 1: anti-LNA043 antibodies present|NO
    9
    5
        Day 8: anti-LNA043 antibodies present|NO
    9
    5
        Day 29: anti-LNA043 antibodies present|NO
    9
    5
        Day 85: anti-LNA043 antibodies present|NO
    9
    5
        Day 197: anti-LNA043 antibodies present|NO
    9
    5
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were collected from the dose of study treatment until up to 28 weeks post treatment
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    22.0
    Reporting groups
    Reporting group title
    LNA043 20mg
    Reporting group description
    		 LNA043 20mg

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo

    Serious adverse events
    		 LNA043 20mg Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 5 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 LNA043 20mg Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    4 / 9 (44.44%)
    4 / 5 (80.00%)
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    Fall
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    Traumatic haematoma
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    2 / 9 (22.22%)
    0 / 5 (0.00%)
         occurrences all number
    2
    0
    General disorders and administration site conditions
    Influenza like illness
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    0 / 9 (0.00%)
    2 / 5 (40.00%)
         occurrences all number
    0
    2
    Endocrine disorders
    Thyroid mass
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    Joint range of motion decreased
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    1
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    1
    Urinary tract infection
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    05 May 2017
    The original protocol was amended to shift the baseline MRI from the screening epoch between days -14 and -1 to day 3, in the post-treatment follow-up epoch.
    11 Dec 2017
    To update specific protocol sections according the updated Investigator Brochure. To clarify the use of the 7 Tesla (7T) MRI as an exploratory medical device. To clarify about the site where the 7 Tesla MRI was performed, now defined specifically as the investigational site for medical device, and to describe how to report possible adverse device effects or serious adverse device effects associated with the 7 T MRI, if any; To increase the number of days between randomization and treatment to give more time to the sites to organize the activities for subject treatment: from 1 day to 7 days before treatment; To delete the PK sample collection 15 min after drug administration to simplify study procedures; To enlarge the interval within which performing the second surgery, from 3 to 5 days to simplify study procedures; To enlarge the interval within which performing the MRI before the surgery at Week 4, from 2 to 3 days to simplify study procedures.
    24 May 2018
    To add a second cohort to treat subjects with a single dose of 40 mg LNA043 or matching placebo, without increasing the number of total subjects to be enrolled and without stopping enrolment.

    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.
    None reported
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