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    Clinical Trial Results:
    A Multicenter, Randomized, Double-blind, Placebo- and Active-Controlled Phase III Study on the Safety and Efficacy of a Single Intra-articular Administration of JTA-004 in Symptomatic Knee Osteoarthritis.

    Summary
    EudraCT number
    		 2019-000796-16
    Trial protocol
    		 DK   BE   GB   PL   CZ  
    Global end of trial date
    09 Dec 2021

    Results information
    Results version number
    		 v1(current)
    This version publication date
    11 Mar 2023
    First version publication date
    11 Mar 2023
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    000014/BT
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Bone Therapeutics S.A.
    Sponsor organisation address
    Rue Granbonpré 11 - Batiment H (bte 24), Mont-St-Guibert, Belgium, 1435
    Public contact
    JTA Clinical Trial Team, BioSenic SA (change in sponsor name on 26-Oct-22), info@biosenic.com
    Scientific contact
    JTA Clinical Trial Team, BioSenic SA (change in sponsor name on 26-Oct-22), info@biosenic.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
    25 Feb 2022
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    16 Apr 2021
    Global end of trial reached?
    Yes
    Global end of trial date
    09 Dec 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To demonstrate that treatment with JTA-004 leads to a reduction in knee pain intensity with respect to placebo in subjects suffering from symptomatic osteoarthritis (OA) of the knee at Month 3.
    Protection of trial subjects
    Study commencement required prior written approval of a properly constituted Institutional Review Board (IRB) or Independent Ethics Committee (IEC). Clinical trial data were monitored at regular intervals by the Sponsor or their representative throughout the study to verify compliance to study protocol, completeness, accuracy and consistency of the data and adherence to local regulations on the conduct of clinical research. Patients were discontinued from investigational product(s) (IP) in case of withdrawal of consent, violation of eligibility criteria, safety concerns (only if the Investigator has clearly determined that the subject’s withdrawal would reduce the safety risks), lost to follow-up, lack of subject compliance to the clinical study protocol and lack of efficacy (early discontinuation for treatment failure).
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    10 Mar 2020
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy
    Long term follow-up duration
    		 6 Months
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Poland: 87
    Country: Number of subjects enrolled
    United Kingdom: 6
    Country: Number of subjects enrolled
    Belgium: 1
    Country: Number of subjects enrolled
    Czechia: 142
    Country: Number of subjects enrolled
    Denmark: 184
    Country: Number of subjects enrolled
    Hong Kong: 213
    Country: Number of subjects enrolled
    Moldova, Republic of: 113
    Worldwide total number of subjects
    746
    EEA total number of subjects
    414
    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)
    420
    From 65 to 84 years
    322
    85 years and over
    4

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Informed consent was obtained before any protocol required assessments were performed. Subjects who signed informed consent, but fail to meet inclusion/exclusion criteria or withdrew consent prior to receiving any study medication were considered screen failures.

    Period 1
    Period 1 title
    Treatment Period (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator
    Blinding implementation details
    Subjects with symptomatic knee OA who meet the eligibility criteria were randomized in a 2:1:1 ratio (JTA-004, placebo or active comparator) using an Interactive Web Response System (IWRS). Considering that the placebo and active comparator could be identified as such by the Investigator, IP injection was performed at Day 0 (Visit 2) by an unblinded Independent Physician/Injector, allowing the Investigator to remain blind.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 JTA-004
    Arm description
    		 Patients receiving one injection of 2 mL JTA-004 at visit 2 (Day 0) after randomization.
    Arm type
    		 Experimental

    Investigational medicinal product name
    JTA-004
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intraarticular use
    Dosage and administration details
    2mL intraarticular injection of JTA-004.

    Arm title
    		 Active comparator (Synvisc-One®)
    Arm description
    		 Patients receiving one injection of 6mL Synvisc-One® (Hylan G-F 20 (8 mg/mL; 48 mg/dose) at visit 2 (Day 0) after randomization.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Synvisc-One® (Hylan G-F 20 (8 mg/mL; 48 mg/dose))
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intraarticular use
    Dosage and administration details
    Synvisc-One® 6mL intraarticular injection (Hylan G-F 20 (8 mg/mL; 48 mg/dose))

    Arm title
    		 Placebo comparator (saline solution)
    Arm description
    		 Patients receiving one injection of 2mL of saline solution at visit 2 (Day 0) after randomization.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Saline solution (Sodium Chloride Injection BP 0.9% w/v)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intraarticular use
    Dosage and administration details
    2mL intraarticular injection of saline solution (Sodium Chloride Injection BP 0.9% w/v)

    Number of subjects in period 1
    		JTA-004 Active comparator (Synvisc-One®) Placebo comparator (saline solution)
    Started
    372
    187
    187
    Completed
    357
    178
    179
    Not completed
    15
    9
    8
         Consent withdrawn by subject
    5
    7
    3
         Adverse event, non-fatal
    1
    -
    -
         Other
    2
    -
    1
         Month 6 Visit not done but study continued
    -
    1
    -
         Lost to follow-up
    4
    1
    2
         Lack of subject compliance
    1
    -
    -
         Violation of eligibility criteria
    1
    -
    1
         Lack of efficacy
    1
    -
    1
    Period 2
    Period 2 title
    Long-term follow-up
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator
    Blinding implementation details
    Subjects with symptomatic knee OA who meet the eligibility criteria were randomized in a 2:1:1 ratio (JTA-004, placebo or active comparator) using an Interactive Web Response System (IWRS). Considering that the placebo and active comparator could be identified as such by the Investigator, IP injection was performed at Day 0 (Visit 2) by an unblinded Independent Physician/Injector, allowing the Investigator to remain blind.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 JTA-004
    Arm description
    		 Long-term follow-up of patients having received one injection of 2 mL JTA-004 at visit 2 (Day 0) after randomization
    Arm type
    		 Experimental

    Investigational medicinal product name
    JTA-004
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intraarticular use
    Dosage and administration details
    2mL intraarticular injection of JTA-004 at visit 2 (Day 0) after randomization.

    Arm title
    		 Active comparator (Synvisc-One®)
    Arm description
    		 Long-term follow-up of patients having received one injection of 6mL Synvisc-One® (Hylan G-F 20 (8 mg/mL; 48 mg/dose) at visit 2 (Day 0) after randomization
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Synvisc-One® (Hylan G-F 20 (8 mg/mL; 48 mg/dose))
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intraarticular use
    Dosage and administration details
    Synvisc-One® 6mL intraarticular injection (Hylan G-F 20 (8 mg/mL; 48 mg/dose)) at Day 0 (Visit 2) after randomization.

    Arm title
    		 Placebo comparator (saline solution)
    Arm description
    		 Long-term follow-up of patients having received one injection of 2mL of saline solution at visit 2 (Day 0) after randomization.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Saline solution (Sodium Chloride Injection BP 0.9% w/v)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intraarticular use
    Dosage and administration details
    2mL intraarticular injection of saline solution (Sodium Chloride Injection BP 0.9% w/v) at Day 0 (Visit 2) after randomization.

    Number of subjects in period 2
    		JTA-004 Active comparator (Synvisc-One®) Placebo comparator (saline solution)
    Started
    357
    178
    179
    Completed
    342
    171
    174
    Not completed
    15
    7
    5
         Consent withdrawn by subject
    4
    5
    -
         Other
    1
    -
    -
         Lost to follow-up
    10
    2
    5

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    JTA-004
    Reporting group description
    		 Patients receiving one injection of 2 mL JTA-004 at visit 2 (Day 0) after randomization.

    Reporting group title
    Active comparator (Synvisc-One®)
    Reporting group description
    		 Patients receiving one injection of 6mL Synvisc-One® (Hylan G-F 20 (8 mg/mL; 48 mg/dose) at visit 2 (Day 0) after randomization.

    Reporting group title
    Placebo comparator (saline solution)
    Reporting group description
    		 Patients receiving one injection of 2mL of saline solution at visit 2 (Day 0) after randomization.

    Reporting group values
    		 JTA-004 Active comparator (Synvisc-One®) Placebo comparator (saline solution) Total
    Number of subjects
    		 372 187 187 746
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0
        Adults (18-64 years)
    		 214 103 103 420
        From 65-84 years
    		 157 81 84 322
        85 years and over
    		 1 3 0 4
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 62.2 ( 8.8 ) 63.5 ( 9.4 ) 62.9 ( 9.2 ) -
    Gender categorical
    Units: Subjects
        Female
    		 248 137 137 522
        Male
    		 124 50 50 224

    End points

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    End points reporting groups
    Reporting group title
    JTA-004
    Reporting group description
    		 Patients receiving one injection of 2 mL JTA-004 at visit 2 (Day 0) after randomization.

    Reporting group title
    Active comparator (Synvisc-One®)
    Reporting group description
    		 Patients receiving one injection of 6mL Synvisc-One® (Hylan G-F 20 (8 mg/mL; 48 mg/dose) at visit 2 (Day 0) after randomization.

    Reporting group title
    Placebo comparator (saline solution)
    Reporting group description
    		 Patients receiving one injection of 2mL of saline solution at visit 2 (Day 0) after randomization.
    Reporting group title
    JTA-004
    Reporting group description
    		 Long-term follow-up of patients having received one injection of 2 mL JTA-004 at visit 2 (Day 0) after randomization

    Reporting group title
    Active comparator (Synvisc-One®)
    Reporting group description
    		 Long-term follow-up of patients having received one injection of 6mL Synvisc-One® (Hylan G-F 20 (8 mg/mL; 48 mg/dose) at visit 2 (Day 0) after randomization

    Reporting group title
    Placebo comparator (saline solution)
    Reporting group description
    		 Long-term follow-up of patients having received one injection of 2mL of saline solution at visit 2 (Day 0) after randomization.

    Primary: Mean changes from baseline in WOMAC pain score at month 3

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    End point title
    		 Mean changes from baseline in WOMAC pain score at month 3 [1]
    End point description
    Primary Efficacy Variable: the efficacy of JTA-004 was evaluated as the mean changes from baseline at Month 3 of the WOMAC® VA3.1 Pain Subscale (subscale A) to demonstrate superiority of JTA-004 in comparison to placebo.
    End point type
    Primary
    End point timeframe
    At month 3
    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: This is due to the fact that, in this trial, statistic comparisons were made either for JTA-004 Vs Placebo or for JTA-004 Vs active comparator, depending on the end-point, but never for JTA-004 Vs Placebo Vs active comparator (direct comparisons of the 3 arms for a same endpoint).
    End point values
    		 JTA-004 Placebo comparator (saline solution)
    Number of subjects analysed
    335 [2]
    169 [3]
    Units: Pain score
        arithmetic mean (standard deviation)
    -31.90 ( 20.68 )
    -29.27 ( 19.12 )
    Notes
    [2] - Results from this endpoint are from the Full Analysis Set (FAS).
    [3] - Results from this endpoint are from the Full Analysis Set (FAS).
    Statistical analysis title
    		 Difference (JTA-004 - Placebo)
    Statistical analysis description
    Change from Baseline in WOMAC® Pain Score at Month 3 - JTA-004 Versus Placebo (Main Analysis Based on MMRM) - Full Analysis Set (N=674)
    Comparison groups
    JTA-004 v Placebo comparator (saline solution)
    Number of subjects included in analysis
    504
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.417
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -1.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.12
         upper limit
    		 2.12
    Variability estimate
    Standard error of the mean

    Secondary: Mean changes from baseline in WOMAC pain score at month 6

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    End point title
    		 Mean changes from baseline in WOMAC pain score at month 6 [4]
    End point description
    Mean changes from baseline in knee pain at Month 6 using the WOMAC® VA3.1 pain subscale (subscale A) between JTA-004 and placebo
    End point type
    Secondary
    End point timeframe
    At month 6
    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: This is due to the fact that, in this trial, statistic comparisons were made either for JTA-004 Vs Placebo or for JTA-004 Vs active comparator, depending on the end-point, but never for JTA-004 Vs Placebo Vs active comparator (direct comparisons of the 3 arms for a same endpoint).
    End point values
    		 JTA-004 Placebo comparator (saline solution)
    Number of subjects analysed
    335 [5]
    169 [6]
    Units: Womac pain score
        arithmetic mean (standard deviation)
    -33.31 ( 20.40 )
    -29.19 ( 18.41 )
    Notes
    [5] - Results presented here are from the Full Analysis Set (FAS)
    [6] - Results presented here are from the Full Analysis Set (FAS)
    Statistical analysis title
    		 Difference (JTA-004 - Placebo)
    Comparison groups
    Placebo comparator (saline solution) v JTA-004
    Number of subjects included in analysis
    504
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.154
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -2.64
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.28
         upper limit
    		 0.99
    Variability estimate
    Standard error of the mean

    Secondary: Mean changes from baseline in WOMAC pain score at month 3

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    End point title
    		 Mean changes from baseline in WOMAC pain score at month 3 [7]
    End point description
    Non-inferiority test comparing mean changes from baseline in knee pain at Month 3 using the WOMAC® VA3.1 pain subscale (subscale A) between JTA-004 and active control.
    End point type
    Secondary
    End point timeframe
    At month 3
    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: This is due to the fact that, in this trial, statistic comparisons were made either for JTA-004 Vs Placebo or for JTA-004 Vs active comparator, depending on the end-point, but never for JTA-004 Vs Placebo Vs active comparator (direct comparisons of the 3 arms for a same endpoint).
    End point values
    		 JTA-004 Active comparator (Synvisc-One®)
    Number of subjects analysed
    324 [8]
    163 [9]
    Units: Pain score
        arithmetic mean (standard deviation)
    -31.90 ( 20.68 )
    -34.22 ( 19.51 )
    Notes
    [8] - Results presented here are from Full Analysis Set (FAS). 11 patients were missing.
    [9] - Results presented here were from Full Analysis Set (FAS). 7 patients were missing.
    Statistical analysis title
    		 Difference JTA-004 Versus Active Comparator
    Comparison groups
    JTA-004 v Active comparator (Synvisc-One®)
    Number of subjects included in analysis
    487
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.193
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    2.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.22
         upper limit
    		 6.02
    Variability estimate
    Standard error of the mean

    Secondary: Mean changes from baseline in WOMAC physical function at month 3

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    End point title
    		 Mean changes from baseline in WOMAC physical function at month 3 [10]
    End point description
    Mean changes from baseline in knee physical function at Month 3 using the WOMAC® VA3.1 physical function subscale (subscale C) between JTA-004 and placebo.
    End point type
    Secondary
    End point timeframe
    At month 3.
    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: This is due to the fact that, in this trial, statistic comparisons were made either for JTA-004 Vs Placebo or for JTA-004 Vs active comparator, depending on the end-point, but never for JTA-004 Vs Placebo Vs active comparator (direct comparisons of the 3 arms for a same endpoint).
    End point values
    		 JTA-004 Placebo comparator (saline solution)
    Number of subjects analysed
    323 [11]
    163 [12]
    Units: Physical function score
        arithmetic mean (standard deviation)
    -24.35 ( 22.11 )
    -24.28 ( 20.59 )
    Notes
    [11] - Results presented here are from Full Analysis Set (FAS). 12 patients were missing.
    [12] - Results presented here are from Full Analysis Set (FAS). 6 patients were missing.
    Statistical analysis title
    		 Difference JTA-004 Versus Placebo
    Comparison groups
    JTA-004 v Placebo comparator (saline solution)
    Number of subjects included in analysis
    486
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.682
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.74
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.31
         upper limit
    		 2.82
    Variability estimate
    Standard error of the mean

    Secondary: Mean changes in PGA at month 3

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    End point title
    		 Mean changes in PGA at month 3 [13]
    End point description
    Mean changes from baseline in PGA at Month 3) between JTA-004 and placebo.
    End point type
    Secondary
    End point timeframe
    At month 3
    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: This is due to the fact that, in this trial, statistic comparisons were made either for JTA-004 Vs Placebo or for JTA-004 Vs active comparator, depending on the end-point, but never for JTA-004 Vs Placebo Vs active comparator (direct comparisons of the 3 arms for a same endpoint).
    End point values
    		 JTA-004 Placebo comparator (saline solution)
    Number of subjects analysed
    324 [14]
    164 [15]
    Units: Patient Global Assessment
        arithmetic mean (standard deviation)
    -2.16 ( 2.30 )
    -1.88 ( 2.32 )
    Notes
    [14] - Results presented here are from Full Analysis Set (FAS). 11 patients were missing.
    [15] - Results presented here are from Full Analysis Set (FAS). 5 patients were missing.
    Statistical analysis title
    		 Difference JTA-004 versus Placebo
    Comparison groups
    JTA-004 v Placebo comparator (saline solution)
    Number of subjects included in analysis
    488
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.106
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.32
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.72
         upper limit
    		 0.07
    Variability estimate
    Standard error of the mean

    Secondary: Mean changes from baseline in WOMAC physical function at month 6

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    End point title
    		 Mean changes from baseline in WOMAC physical function at month 6 [16]
    End point description
    Mean changes from baseline in knee physical function at Month 6 using the WOMAC® VA3.1 physical function subscale (subscale C) between JTA-004 and placebo.
    End point type
    Secondary
    End point timeframe
    At month 6.
    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: This is due to the fact that, in this trial, statistic comparisons were made either for JTA-004 Vs Placebo or for JTA-004 Vs active comparator, depending on the end-point, but never for JTA-004 Vs Placebo Vs active comparator (direct comparisons of the 3 arms for a same endpoint).
    End point values
    		 JTA-004 Placebo comparator (saline solution)
    Number of subjects analysed
    322 [17]
    163 [18]
    Units: Physical function score
        arithmetic mean (standard deviation)
    -25.28 ( 21.29 )
    -23.27 ( 20.78 )
    Notes
    [17] - Results presented here are from Full Analysis Set (FAS). 13 patients were missing.
    [18] - Results presented here are from Full Analysis Set (FAS). 6 patients were missing.
    Statistical analysis title
    		 Difference JTA-004 versus Placebo
    Comparison groups
    JTA-004 v Placebo comparator (saline solution)
    Number of subjects included in analysis
    485
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.227
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -2.16
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.67
         upper limit
    		 1.35
    Variability estimate
    Standard error of the mean

    Secondary: Mean changes from baseline in subject global health and well-being score at month 3

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    End point title
    		 Mean changes from baseline in subject global health and well-being score at month 3 [19]
    End point description
    Mean changes from baseline in subject global health and well-being score at Month 3 using the EQ-5D-5L questionnaire between JTA-004 and placebo.
    End point type
    Secondary
    End point timeframe
    At month 3.
    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: This is due to the fact that, in this trial, statistic comparisons were made either for JTA-004 Vs Placebo or for JTA-004 Vs active comparator, depending on the end-point, but never for JTA-004 Vs Placebo Vs active comparator (direct comparisons of the 3 arms for a same endpoint).
    End point values
    		 JTA-004 Placebo comparator (saline solution)
    Number of subjects analysed
    325 [20]
    162 [21]
    Units: Utility score
        arithmetic mean (standard deviation)
    0.0829 ( 0.1882 )
    0.0825 ( 0.1843 )
    Notes
    [20] - Results presented here are from Full Analysis Set (FAS). 10 patients were missing.
    [21] - Results presented here are from Full Analysis Set (FAS). 7 patients were missing.
    Statistical analysis title
    		 Difference JTA-004 versus Placebo
    Comparison groups
    JTA-004 v Placebo comparator (saline solution)
    Number of subjects included in analysis
    487
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.732
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.005
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.0236
         upper limit
    		 0.0335
    Variability estimate
    Standard error of the mean

    Secondary: Responder rates at month 3

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    End point title
    		 Responder rates at month 3 [22]
    End point description
    Responder rates (defined as ≥ 30% pain intensity reduction) at Month 3 between JTA-004 and placebo.
    End point type
    Secondary
    End point timeframe
    At month 3.
    Notes
    [22] - 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: This is due to the fact that, in this trial, statistic comparisons were made either for JTA-004 Vs Placebo or for JTA-004 Vs active comparator, depending on the end-point, but never for JTA-004 Vs Placebo Vs active comparator (direct comparisons of the 3 arms for a same endpoint).
    End point values
    		 JTA-004 Placebo comparator (saline solution)
    Number of subjects analysed
    335 [23]
    169 [24]
    Units: Responder
    250
    122
    Notes
    [23] - Results presented here are from Full Analysis Set (FAS)
    [24] - Results presented here are from Full Analysis Set (FAS)
    Statistical analysis title
    		 Common relative risk JTA-004 versus Placebo
    Comparison groups
    JTA-004 v Placebo comparator (saline solution)
    Number of subjects included in analysis
    504
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.606
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    1.03
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.92
         upper limit
    		 1.15

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From injection at day 0 until month 6 (period 1): reporting of serious adverse events and non-serious adverse events. From month 6 until month 12 (period 2, long-term follow-up): reporting of serious adverse events only.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    24.0
    Reporting groups
    Reporting group title
    JTA-004 (Period 1)
    Reporting group description
    		 One injection of 2 mL JTA-004 at visit 2 (Day 0) after randomization. Safety Analysis Set (SAS).

    Reporting group title
    Active comparator (Synvisc-One®) (Period 1)
    Reporting group description
    		 One injection of 6mL Synvisc-One® (Hylan G-F 20 (8 mg/mL; 48 mg/dose) at visit 2 (Day 0) after randomization. Safety Analysis Set (SAS).

    Reporting group title
    Placebo comparator (saline solution) (Period 1)
    Reporting group description
    		 One injection of 2mL of saline solution at visit 2 (Day 0) after randomization. Safety Analysis Set (SAS).

    Reporting group title
    JTA-004 (Period 2)
    Reporting group description
    		 Long-term safety follow-up. Only SAEs were reported. Safety Analysis Set (SAS).

    Reporting group title
    Active comparator (Synvisc-One®) (Period 2)
    Reporting group description
    		 Long-term safety follow-up. Only SAEs were reported. Safety Analysis Set (SAS).

    Reporting group title
    Placebo comparator (saline solution) (Period 2)
    Reporting group description
    		 Long-term safety follow-up. Only SAEs were reported. Safety Analysis Set (SAS).

    Serious adverse events
    		 JTA-004 (Period 1) Active comparator (Synvisc-One®) (Period 1) Placebo comparator (saline solution) (Period 1) JTA-004 (Period 2) Active comparator (Synvisc-One®) (Period 2) Placebo comparator (saline solution) (Period 2)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    7 / 371 (1.89%)
    6 / 187 (3.21%)
    4 / 185 (2.16%)
    4 / 371 (1.08%)
    1 / 187 (0.53%)
    0 / 185 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Parathyroid tumour benign
         subjects affected / exposed
    0 / 371 (0.00%)
    0 / 187 (0.00%)
    1 / 185 (0.54%)
    0 / 371 (0.00%)
    0 / 187 (0.00%)
    0 / 185 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Facial bones fracture
         subjects affected / exposed
    0 / 371 (0.00%)
    1 / 187 (0.53%)
    0 / 185 (0.00%)
    0 / 371 (0.00%)
    0 / 187 (0.00%)
    0 / 185 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Femoral neck fracture
         subjects affected / exposed
    0 / 371 (0.00%)
    1 / 187 (0.53%)
    0 / 185 (0.00%)
    0 / 371 (0.00%)
    0 / 187 (0.00%)
    0 / 185 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Patella fracture
         subjects affected / exposed
    0 / 371 (0.00%)
    0 / 187 (0.00%)
    0 / 185 (0.00%)
    1 / 371 (0.27%)
    0 / 187 (0.00%)
    0 / 185 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tibia fracture
         subjects affected / exposed
    0 / 371 (0.00%)
    0 / 187 (0.00%)
    0 / 185 (0.00%)
    1 / 371 (0.27%)
    0 / 187 (0.00%)
    0 / 185 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    1 / 371 (0.27%)
    0 / 187 (0.00%)
    0 / 185 (0.00%)
    0 / 371 (0.00%)
    0 / 187 (0.00%)
    0 / 185 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Sinus node dysfunction
         subjects affected / exposed
    0 / 371 (0.00%)
    1 / 187 (0.53%)
    0 / 185 (0.00%)
    0 / 371 (0.00%)
    0 / 187 (0.00%)
    0 / 185 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    0 / 371 (0.00%)
    0 / 187 (0.00%)
    0 / 185 (0.00%)
    1 / 371 (0.27%)
    0 / 187 (0.00%)
    0 / 185 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Surgical and medical procedures
    Knee arthroplasty
         subjects affected / exposed
    0 / 371 (0.00%)
    0 / 187 (0.00%)
    0 / 185 (0.00%)
    1 / 371 (0.27%)
    0 / 187 (0.00%)
    0 / 185 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    0 / 371 (0.00%)
    1 / 187 (0.53%)
    0 / 185 (0.00%)
    0 / 371 (0.00%)
    0 / 187 (0.00%)
    0 / 185 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    0 / 371 (0.00%)
    0 / 187 (0.00%)
    1 / 185 (0.54%)
    0 / 371 (0.00%)
    0 / 187 (0.00%)
    0 / 185 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Incarcerated inguinal hernia
         subjects affected / exposed
    0 / 371 (0.00%)
    0 / 187 (0.00%)
    1 / 185 (0.54%)
    0 / 371 (0.00%)
    0 / 187 (0.00%)
    0 / 185 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pulmonary embolism
         subjects affected / exposed
    1 / 371 (0.27%)
    0 / 187 (0.00%)
    0 / 185 (0.00%)
    0 / 371 (0.00%)
    0 / 187 (0.00%)
    0 / 185 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Excessive skin
         subjects affected / exposed
    1 / 371 (0.27%)
    0 / 187 (0.00%)
    0 / 185 (0.00%)
    0 / 371 (0.00%)
    0 / 187 (0.00%)
    0 / 185 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal artery stenosis
         subjects affected / exposed
    1 / 371 (0.27%)
    0 / 187 (0.00%)
    0 / 185 (0.00%)
    0 / 371 (0.00%)
    0 / 187 (0.00%)
    0 / 185 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Stress urinary incontinence
         subjects affected / exposed
    1 / 371 (0.27%)
    0 / 187 (0.00%)
    0 / 185 (0.00%)
    0 / 371 (0.00%)
    0 / 187 (0.00%)
    0 / 185 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Intervertebral disc protrusion
         subjects affected / exposed
    0 / 371 (0.00%)
    1 / 187 (0.53%)
    0 / 185 (0.00%)
    0 / 371 (0.00%)
    0 / 187 (0.00%)
    0 / 185 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neck pain
         subjects affected / exposed
    0 / 371 (0.00%)
    0 / 187 (0.00%)
    0 / 185 (0.00%)
    0 / 371 (0.00%)
    1 / 187 (0.53%)
    0 / 185 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    0 / 371 (0.00%)
    0 / 187 (0.00%)
    0 / 185 (0.00%)
    1 / 371 (0.27%)
    0 / 187 (0.00%)
    0 / 185 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    COVID-19 pneumonia
         subjects affected / exposed
    3 / 371 (0.81%)
    1 / 187 (0.53%)
    1 / 185 (0.54%)
    0 / 371 (0.00%)
    0 / 187 (0.00%)
    0 / 185 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abscess limb
         subjects affected / exposed
    0 / 371 (0.00%)
    0 / 187 (0.00%)
    1 / 185 (0.54%)
    0 / 371 (0.00%)
    0 / 187 (0.00%)
    0 / 185 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Arthritis bacterial
         subjects affected / exposed
    0 / 371 (0.00%)
    1 / 187 (0.53%)
    0 / 185 (0.00%)
    0 / 371 (0.00%)
    0 / 187 (0.00%)
    0 / 185 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    COVID-19
         subjects affected / exposed
    1 / 371 (0.27%)
    0 / 187 (0.00%)
    0 / 185 (0.00%)
    0 / 371 (0.00%)
    0 / 187 (0.00%)
    0 / 185 (0.00%)
         occurrences causally related to treatment / all
    0 / 15
    0 / 4
    0 / 7
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Incision site abscess
         subjects affected / exposed
    0 / 371 (0.00%)
    0 / 187 (0.00%)
    1 / 185 (0.54%)
    0 / 371 (0.00%)
    0 / 187 (0.00%)
    0 / 185 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 371 (0.00%)
    0 / 187 (0.00%)
    1 / 185 (0.54%)
    0 / 371 (0.00%)
    0 / 187 (0.00%)
    0 / 185 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 JTA-004 (Period 1) Active comparator (Synvisc-One®) (Period 1) Placebo comparator (saline solution) (Period 1) JTA-004 (Period 2) Active comparator (Synvisc-One®) (Period 2) Placebo comparator (saline solution) (Period 2)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    162 / 371 (43.67%)
    96 / 187 (51.34%)
    65 / 185 (35.14%)
    0 / 371 (0.00%)
    0 / 187 (0.00%)
    0 / 185 (0.00%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    53 / 371 (14.29%)
    32 / 187 (17.11%)
    21 / 185 (11.35%)
    0 / 371 (0.00%)
    0 / 187 (0.00%)
    0 / 185 (0.00%)
         occurrences all number
    53
    32
    21
    0
    0
    0
    General disorders and administration site conditions
    Injection site joint pain
         subjects affected / exposed
    14 / 371 (3.77%)
    10 / 187 (5.35%)
    4 / 185 (2.16%)
    0 / 371 (0.00%)
    0 / 187 (0.00%)
    0 / 185 (0.00%)
         occurrences all number
    14
    10
    4
    0
    0
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    51 / 371 (13.75%)
    30 / 187 (16.04%)
    19 / 185 (10.27%)
    0 / 371 (0.00%)
    0 / 187 (0.00%)
    0 / 185 (0.00%)
         occurrences all number
    51
    30
    19
    0
    0
    0
    Back pain
         subjects affected / exposed
    30 / 371 (8.09%)
    12 / 187 (6.42%)
    15 / 185 (8.11%)
    0 / 371 (0.00%)
    0 / 187 (0.00%)
    0 / 185 (0.00%)
         occurrences all number
    30
    12
    15
    0
    0
    0
    Pain in extremity
         subjects affected / exposed
    14 / 371 (3.77%)
    12 / 187 (6.42%)
    6 / 185 (3.24%)
    0 / 371 (0.00%)
    0 / 187 (0.00%)
    0 / 185 (0.00%)
         occurrences all number
    14
    12
    6
    0
    0
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    25 Jun 2020
    This amendment includes the following major changes: - Inclusion criterion #4 and exclusion criterion #7 were modified in order to align eligibility criteria (previously based on a VAS assessment of knee pain) and the primary endpoint based on WOMAC® V3.1 pain subscale. - Other sections were revised as a consequence of these changes.
    14 Oct 2020
    This amendment includes the following major changes: - Additional clarifications were added to the visit schedule and procedures. - The description of the criteria for assessment of relationship of AEs to IMP were aligned to what was specified in the eCRF (unrelated/unlikely related/ possibly related/related/unknown). - The statistical section was revised to align endpoint analysis with changes from Version 2.0 of the protocol, including: The stratification classes associated with the target knee pain at baseline (VAS) were reworded from "≥40 - <59 mm / ≥59- <70 mm / ≥70 mm” to “ <59 mm / ≥59- <70 mm / ≥70 mm". The number of subjects to be treated was increased from 676 to 742, considering that some subjects enrolled under protocol Version 1.1 would be excluded from the main analysis (as they had a baseline WOMAC® V3.1 pain subscale score out of the range defined in Version 2.0 (i.e. target knee pain ≥ 200 mm and ≤ 400 mm). Text clarifications regarding the hypotheses used for sample size calculation and the timing of analysis.
    06 Apr 2021
    The amendment includes the following major changes: - The last protocol amendment allowed monitoring activities on some data points (specifically on-site data cleaning for the primary endpoint analysis at Month 6 and for the final analysis at Month 12) to be performed remotely using electronic equipment. This amendment was related to the context of the COVID-19 pandemic. All eligible data points were prospectively defined in the Clinical Monitoring Plan.

    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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