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    Clinical Trial Results:
    A Randomised, Double-blind Placebo-controlled Phase IIa Study to Evaluate Efficacy, Safety and Tolerability of MIV-711 in Knee Joint Osteoarthritis

    Summary
    EudraCT number
    		 2015-003230-26
    Trial protocol
    		 GB   DE   BG  
    Global end of trial date
    23 May 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    03 Jun 2018
    First version publication date
    03 Jun 2018
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    MIV-711-201
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02705625
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Medivir AB
    Sponsor organisation address
    Box 1086, Huddinge, Sweden, 14122
    Public contact
    MIV-711 Clinical Study Information , Medivir AB, clinicaloperations@medivir.com
    Scientific contact
    MIV-711 Clinical Study Information , Medivir AB, clinicaloperations@medivir.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
    22 Sep 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    23 May 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    23 May 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess the effect of MIV-711 on target knee average pain over 26 weeks as measured by an 11-point numerical rating scale (1 week recall) in patients with symptomatic and radiographic knee osteoarthritis
    Protection of trial subjects
    Patients were observered in the clinics during the study visits. During the whole treatment period, the following safety assessments were performed at each visit; collection of adverse events and concomitant medications, vital signs, physical examination (full or targeted), ECG, standard safety laboratory parameters. The last visit (at week 30) was a safety follow-up where all the above safety assessments were evaluated except physical examination. In addition, a phone call was made after all dosing visits to assess safety and tolerability.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    28 Jan 2016
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Moldova, Republic of: 92
    Country: Number of subjects enrolled
    Georgia: 34
    Country: Number of subjects enrolled
    Romania: 8
    Country: Number of subjects enrolled
    United Kingdom: 2
    Country: Number of subjects enrolled
    Bulgaria: 38
    Country: Number of subjects enrolled
    Germany: 70
    Worldwide total number of subjects
    244
    EEA total number of subjects
    118
    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)
    162
    From 65 to 84 years
    82
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Patients with chronic knee pain and Kellgren and Lawrence (K-L) classification Grade 2 or 3 were included in the study. The study was conducted in 6 study centres in 6 countries, Bulgaria, Georgia, Germany, Moldova, Romania and United Kingdom.

    Pre-assignment
    Screening details
    		 The study population was adults aged between 40 and 80 with symptomatic and radiographic knee Osteoarthritis. The patient's usual analgesic regimen (in case of use) must have remained the same for 4 weeks prior to the signature of the informed consent form. The study had a screening period of approximately 4 weeks.

    Period 1
    Period 1 title
    Baseline
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor
    Blinding implementation details
    All IMPs were supplied in identical packaging and were similar in color, smell, taste and appearance.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Baseline MIV-711 100 mg
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    MIV-711
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    The included excipients were microcrystalline cellulose, Starcap 1500, magnesium stearate and anhydrous colloidal silica.

    Arm title
    		 Baseline MIV-711 200 mg
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    MIV-711
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    The included excipients were microcrystalline cellulose, Starcap 1500, magnesium stearate and anhydrous colloidal silica.

    Arm title
    		 Baseline Placebo
    Arm description
    		 -
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    For the placebo formulation, the excipient composition of the MIV-711 capsule was used, but the active substance was substituted with microcrystalline cellulose and Starcap 1500.

    Number of subjects in period 1
    		Baseline MIV-711 100 mg Baseline MIV-711 200 mg Baseline Placebo
    Started
    82
    82
    80
    Completed
    82
    82
    80
    Period 2
    Period 2 title
    Treatment
    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
    		 MIV-711 100 mg
    Arm description
    		 MIV-711 100 mg once daily for 26 weeks
    Arm type
    		 Experimental

    Investigational medicinal product name
    MIV-711
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    The included excipients were microcrystalline cellulose, Starcap 1500, magnesium stearate and anhydrous colloidal silica.

    Arm title
    		 MIV-711 200 mg
    Arm description
    		 MIV-711 200 mg once daily for 26 weeks
    Arm type
    		 Experimental

    Investigational medicinal product name
    MIV-711
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    The included excipients were microcrystalline cellulose, Starcap 1500, magnesium stearate and anhydrous colloidal silica.

    Arm title
    		 Placebo
    Arm description
    		 Placebo once daily for 26 weeks
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    For the placebo formulation, the excipient composition of the MIV-711 capsule was used, but the active substance was substituted with microcrystalline cellulose and Starcap 1500.

    Number of subjects in period 2
    		MIV-711 100 mg MIV-711 200 mg Placebo
    Started
    82
    82
    80
    Completed
    74
    72
    69
    Not completed
    8
    10
    11
         NON COMPLIANCE BY SUBJECT
    -
    1
    -
         Adverse event, serious fatal
    -
    -
    1
         Consent withdrawn by subject
    1
    4
    5
         NON-COMPLIANCE
    -
    -
    1
         Adverse event, non-fatal
    6
    5
    2
         OVERDOSING
    -
    -
    1
         Lost to follow-up
    -
    -
    1
         Protocol deviation
    1
    -
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Baseline MIV-711 100 mg
    Reporting group description
    		 -

    Reporting group title
    Baseline MIV-711 200 mg
    Reporting group description
    		 -

    Reporting group title
    Baseline Placebo
    Reporting group description
    		 -

    Reporting group values
    		 Baseline MIV-711 100 mg Baseline MIV-711 200 mg Baseline Placebo Total
    Number of subjects
    		 82 82 80 244
    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)
    		 53 55 54 162
        From 65-84 years
    		 29 27 26 82
        85 years and over
    		 0 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 61.2 ( 6.58 ) 62 ( 7.30 ) 62.0 ( 6.67 ) -
    Gender categorical
    Units: Subjects
        Female
    		 64 59 65 188
        Male
    		 18 23 15 56

    End points

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    End points reporting groups
    Reporting group title
    Baseline MIV-711 100 mg
    Reporting group description
    		 -

    Reporting group title
    Baseline MIV-711 200 mg
    Reporting group description
    		 -

    Reporting group title
    Baseline Placebo
    Reporting group description
    		 -
    Reporting group title
    MIV-711 100 mg
    Reporting group description
    		 MIV-711 100 mg once daily for 26 weeks

    Reporting group title
    MIV-711 200 mg
    Reporting group description
    		 MIV-711 200 mg once daily for 26 weeks

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo once daily for 26 weeks

    Primary: NRS average target knee pain score at Week 26

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    End point title
    		 NRS average target knee pain score at Week 26
    End point description
    Change from Visit 2 (Baseline) to Visit 8 (Week 26) in NRS average target knee pain score. NRS (Numeric rating scale) ranges from 0 indicating -"no pain", to 10 indicating - "pain as bad as it could be".
    End point type
    Primary
    End point timeframe
    Week 26 compared to baseline
    End point values
    		 MIV-711 100 mg MIV-711 200 mg Placebo
    Number of subjects analysed
    74
    72
    69
    Units: score
        arithmetic mean (standard deviation)
    -1.7 ( 2.01 )
    -1.5 ( 1.95 )
    -1.3 ( 2.15 )
    Statistical analysis title
    		 Change in NRS average target knee pain score.
    Statistical analysis description
    A linear mixed model based on the mITT population was used. The model included fixed factors for treatment, time (measured in weeks), the interaction for treatment-by-time, baseline analgesic user (Yes/No), and random effect for clinical site. Baseline NRS was included as a covariate for adjustment. An unstructured covariance matrix was used to model the covariance pattern in the mixed effects model.
    Comparison groups
    MIV-711 200 mg v Placebo
    Number of subjects included in analysis
    141
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [1]
    P-value
    		 = 0.4055 [2]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.0761
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.703
         upper limit
    		 0.55
    Notes
    [1] - For the primary endpoint, the Type I error for the tests of the two doses was protected by performing a fixed-sequence multiple-testing procedure in the following order: Step 1: 200 mg versus placebo Step 2: 100 mg versus placebo The second step was only considered as confirmatory provided the previous step was significant at a one-sided 5%-level (p<0.05). If the previous step was not significant, the analysis of the following step was considered descriptive.
    [2] - The p-values reported is from Step 1 (comparing 200 mg versus placebo). The corresponding p-value from Step 2 (comparing 100 mg versus placebo) was 0.1458.

    Secondary: MRI bone area of the target knee at Week 26

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    End point title
    		 MRI bone area of the target knee at Week 26
    End point description
    Change from Visit 2 (Baseline) to Visit 8 (Week 26) in MRI (Magnetic Resonance Imaging;) bone area of the target knee in mm^2.
    End point type
    Secondary
    End point timeframe
    Week 26 compared to baseline
    End point values
    		 MIV-711 100 mg MIV-711 200 mg Placebo
    Number of subjects analysed
    69
    69
    66
    Units: mm2
        arithmetic mean (standard deviation)
    8.1290 ( 31.10846 )
    8.2142 ( 29.39941 )
    23.22343 ( 32.68365 )
    Statistical analysis title
    		 Change in knee joint MRI bone area
    Statistical analysis description
    A linear mixed model based on the mITT population was used. The model included fixed factors for treatment, time (measured in weeks), the interaction for treatment-by-time, baseline analgesic user (Yes/No), and random effect for clinical site. Baseline knee joint MRI bone area was included as a covariate for adjustment. An unstructured covariance matrix was used to model the covariance pattern in the mixed effects model.
    Comparison groups
    MIV-711 200 mg v Placebo
    Number of subjects included in analysis
    135
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [3]
    P-value
    		 = 0.0036 [4]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -14.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -25.3
         upper limit
    		 -4.02
    Notes
    [3] - One model is fit for all comparison groups (MIV-711 200 mg, MIV-711 100 mg and placebo). This analysis reports the contrast that compares 200 mg versus placebo with respect to mean change from baseline in knee joint MRI bone area at Week 26.
    [4] - p-values reported are unadjusted p-values for tests of significance for the upper one-tailed alternative hypothesis Ha: bone area increase is lower in the active treatment arm compared to placebo.
    Statistical analysis title
    		 Change in knee joint MRI bone area
    Statistical analysis description
    A linear mixed model based on the mITT population was used. The model included fixed factors for treatment, time (measured in weeks), the interaction for treatment-by-time, baseline analgesic user (Yes/No), and random effect for clinical site. Baseline knee joint MRI bone area was included as a covariate for adjustment. An unstructured covariance matrix was used to model the covariance pattern in the mixed effects model.
    Comparison groups
    MIV-711 100 mg v Placebo
    Number of subjects included in analysis
    135
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [5]
    P-value
    		 = 0.0023 [6]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -15.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -26
         upper limit
    		 -4.83
    Notes
    [5] - One model is fit for all comparison groups (MIV-711 200 mg, MIV-711 100 mg and placebo). This analysis reports the contrast that compares 100 mg versus placebo with respect to mean change from baseline in knee joint MRI bone area at Week 26.
    [6] - p-values reported are unadjusted p-values for tests of significance for the upper one-tailed alternative hypothesis Ha: bone area increase is lower in the active treatment arm compared to placebo.

    Secondary: CTX-I at Week 26

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    End point title
    		 CTX-I at Week 26
    End point description
    Biomarkers for bone resorption (serum CTX-I)
    End point type
    Secondary
    End point timeframe
    Week 26 compared to baseline
    End point values
    		 MIV-711 100 mg MIV-711 200 mg Placebo
    Number of subjects analysed
    74
    71
    69
    Units: ug/L
        arithmetic mean (standard deviation)
    -0.1209 ( 0.16733 )
    -0.2575 ( 0.19931 )
    0.0000 ( 0.16165 )
    Statistical analysis title
    		 Change in CTX-I
    Statistical analysis description
    A linear mixed model based on the mITT population was used. The model included fixed factors for treatment, time (measured in weeks), the interaction for treatment-by-time, baseline analgesic user (Yes/No), and random effect for clinical site. Baseline CTX-I score was included as a covariate for adjustment. An unstructured covariance matrix was used to model the covariance pattern in the mixed effects model.
    Comparison groups
    MIV-711 200 mg v Placebo
    Number of subjects included in analysis
    140
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [7]
    P-value
    		 < 0.0001 [8]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.254
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.302
         upper limit
    		 -0.206
    Notes
    [7] - One model is fit for all comparison groups (MIV-711 200 mg, MIV-711 100 mg and placebo). This analysis reports the contrast that compares 200 mg versus placebo with respect to mean change from baseline in CTX-I score at Week 26.
    [8] - p-values reported are unadjusted p-values for tests of significance for the upper one-tailed alternative hypothesis Ha: CTX-I score is lower in the active treatment arm compared to placebo.
    Statistical analysis title
    		 Change in CTX-I
    Statistical analysis description
    A linear mixed model based on the mITT population was used. The model included fixed factors for treatment, time (measured in weeks), the interaction for treatment-by-time, baseline analgesic user (Yes/No), and random effect for clinical site. Baseline CTX-I score was included as a covariate for adjustment. An unstructured covariance matrix was used to model the covariance pattern in the mixed effects model.
    Comparison groups
    Placebo v MIV-711 100 mg
    Number of subjects included in analysis
    143
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [9]
    P-value
    		 < 0.0001 [10]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.145
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.193
         upper limit
    		 -0.0983
    Notes
    [9] - One model is fit for all comparison groups (MIV-711 200 mg, MIV-711 100 mg and placebo). This analysis reports the contrast that compares 100 mg versus placebo with respect to mean change from baseline in CTX-I score at Week 26.
    [10] - p-values reported are unadjusted p-values for tests of significance for the upper one-tailed alternative hypothesis Ha: CTX-I score is lower in the active treatment arm compared to placebo.

    Secondary: CTX-II/Creatinine at Week 26

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    End point title
    		 CTX-II/Creatinine at Week 26
    End point description
    Cartilage degradation (urine CTX-II)
    End point type
    Secondary
    End point timeframe
    Week 26 compared to baseline
    End point values
    		 MIV-711 100 mg MIV-711 200 mg Placebo
    Number of subjects analysed
    73
    72
    68
    Units: ng/mmol
        arithmetic mean (standard deviation)
    -138.0 ( 198.68 )
    -242.5 ( 266.56 )
    28.4 ( 225.69 )
    Statistical analysis title
    		 Change in CTX-II/Creatinine
    Statistical analysis description
    A linear mixed model based on the mITT population was used. The model included fixed factors for treatment, time (measured in weeks), the interaction for treatment-by-time, baseline analgesic user (Yes/No), and random effect for clinical site. Baseline CTX-II score was included as a covariate for adjustment. An unstructured covariance matrix was used to model the covariance pattern in the mixed effects model.
    Comparison groups
    MIV-711 200 mg v Placebo
    Number of subjects included in analysis
    140
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [11]
    P-value
    		 < 0.0001 [12]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -270
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -339
         upper limit
    		 -201
    Notes
    [11] - One model is fit for all comparison groups (MIV-711 200 mg, MIV-711 100 mg and placebo). This analysis reports the contrast that compares 200 mg versus placebo with respect to mean change from baseline in CTX-II score at Week 26.
    [12] - p-values reported are unadjusted p-values for tests of significance for the upper one-tailed alternative hypothesis Ha: CTX-II score is lower in the active treatment arm compared to placebo.
    Statistical analysis title
    		 Change in CTX-II/Creatinine
    Statistical analysis description
    A linear mixed model based on the mITT population was used. The model included fixed factors for treatment, time (measured in weeks), the interaction for treatment-by-time, baseline analgesic user (Yes/No), and random effect for clinical site. Baseline CTX-II score was included as a covariate for adjustment. An unstructured covariance matrix was used to model the covariance pattern in the mixed effects model.
    Comparison groups
    Placebo v MIV-711 100 mg
    Number of subjects included in analysis
    141
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [13]
    P-value
    		 < 0.0001 [14]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -193
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -262
         upper limit
    		 -124
    Notes
    [13] - One model is fit for all comparison groups (MIV-711 200 mg, MIV-711 100 mg and placebo). This analysis reports the contrast that compares 100 mg versus placebo with respect to mean change from baseline in CTX-II score at Week 26.
    [14] - p-values reported are unadjusted p-values for tests of significance for the upper one-tailed alternative hypothesis Ha: CTX-II score is lower in the active treatment arm compared to placebo.

    Secondary: MRI of Cartilage Thickness (Femur) at Week 26

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    End point title
    		 MRI of Cartilage Thickness (Femur) at Week 26
    End point description
    MRI of cartilage thickness in the Central Medial Femur Region of the target knee
    End point type
    Secondary
    End point timeframe
    Week 26 compared to baseline
    End point values
    		 MIV-711 100 mg MIV-711 200 mg Placebo
    Number of subjects analysed
    69
    69
    66
    Units: mm
        arithmetic mean (standard deviation)
    0.0077 ( 0.19258 )
    -0.0171 ( 0.24113 )
    -0.0658 ( 0.21904 )
    Statistical analysis title
    		 Change in MRI of cartilage thickness (Femur)
    Statistical analysis description
    A linear mixed model based on the mITT population was used. The model included fixed factors for treatment, time (measured in weeks), the interaction for treatment-by-time, baseline analgesic user (Yes/No), and random effect for clinical site. Baseline MRI of cartilage thickness was included as a covariate for adjustment. An unstructured covariance matrix was used to model the covariance pattern in the mixed effects model.
    Comparison groups
    MIV-711 200 mg v Placebo
    Number of subjects included in analysis
    135
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [15]
    P-value
    		 = 0.1253 [16]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.0436
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.031
         upper limit
    		 0.118
    Notes
    [15] - One model is fit for all comparison groups (MIV-711 200 mg, MIV-711 100 mg and placebo). This analysis reports the contrast that compares 200 mg versus placebo with respect to mean change from baseline in MRI of cartilage thickness (Femur Region) at Week 26.
    [16] - p-values reported are unadjusted p-values for tests of significance for the upper one-tailed alternative hypothesis Ha: MRI of cartilage thinning (Femur Region) is lower in the active treatment arm compared to placebo.
    Statistical analysis title
    		 Change in MRI of cartilage thickness (Femur)
    Statistical analysis description
    A linear mixed model based on the mITT population was used. The model included fixed factors for treatment, time (measured in weeks), the interaction for treatment-by-time, baseline analgesic user (Yes/No), and random effect for clinical site. Baseline MRI of cartilage thickness was included as a covariate for adjustment. An unstructured covariance matrix was used to model the covariance pattern in the mixed effects model.
    Comparison groups
    Placebo v MIV-711 100 mg
    Number of subjects included in analysis
    135
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [17]
    P-value
    		 = 0.0225 [18]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.0761
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.00173
         upper limit
    		 0.15
    Notes
    [17] - One model is fit for all comparison groups (MIV-711 200 mg, MIV-711 100 mg and placebo). This analysis reports the contrast that compares 100 mg versus placebo with respect to mean change from baseline in MRI of cartilage thickness (Femur Region) at Week 26.
    [18] - p-values reported are unadjusted p-values for tests of significance for the upper one-tailed alternative hypothesis Ha: MRI of cartilage thinning (Femur Region) is lower in the active treatment arm compared to placebo.

    Secondary: Normalised WOMAC, Pain Score

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    End point title
    		 Normalised WOMAC, Pain Score
    End point description
    End point type
    Secondary
    End point timeframe
    Week 26 compared to baseline
    End point values
    		 MIV-711 100 mg MIV-711 200 mg Placebo
    Number of subjects analysed
    74
    72
    69
    Units: score
        arithmetic mean (standard deviation)
    -16.6 ( 19.35 )
    -13.0 ( 18.6 )
    -9.8 ( 21.89 )
    Statistical analysis title
    		 Change in normalised WOMAC Pain score
    Statistical analysis description
    A linear mixed model based on the mITT population was used. The model included fixed factors for treatment, time (measured in weeks), the interaction for treatment-by- time, baseline analgesic user (Yes/No), and random effect for clinical site. Baseline WOMAC Pain score was included as a covariate for adjustment. An unstructured covariance matrix was used to model the covariance pattern in the mixed effects model.
    Comparison groups
    MIV-711 200 mg v Placebo
    Number of subjects included in analysis
    141
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [19]
    P-value
    		 = 0.2887 [20]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -1.77
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -8.02
         upper limit
    		 4.48
    Notes
    [19] - One model is fit for all comparison groups (MIV-711 200 mg, MIV-711 100 mg and placebo). This analysis reports the contrast that compares 200 mg versus placebo with respect to mean change from baseline in WOMAC Pain score at Week 26.
    [20] - p-values reported are unadjusted p-values for tests of significance for the lower one-tailed alternative hypothesis Ha: Reduction in WOMAC Pain score is higher in the active treatment arm compared to placebo.
    Statistical analysis title
    		 Change in normalised WOMAC Pain score
    Statistical analysis description
    A linear mixed model based on the mITT population was used. The model included fixed factors for treatment, time (measured in weeks), the interaction for treatment-by- time, baseline analgesic (Yes/No) and random effect for clinical site. Baseline WOMAC Pain score was included as a covariate for adjustment. An unstructured covariance matrix was used to model the covariance pattern in the mixed effects model.
    Comparison groups
    MIV-711 100 mg v Placebo
    Number of subjects included in analysis
    143
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [21]
    P-value
    		 = 0.0753 [22]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -4.55
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -10.8
         upper limit
    		 1.67
    Notes
    [21] - One model is fit for all comparison groups (MIV-711 200 mg, MIV-711 100 mg and placebo). This analysis reports the contrast that compares 100 mg versus placebo with respect to mean change from baseline in WOMAC Pain score at Week 26.
    [22] - p-values reported are unadjusted p-values for tests of significance for the lower one-tailed alternative hypothesis Ha: Reduction in WOMAC Pain score is higher in the active treatment arm compared to placebo.

    Secondary: Normalised WOMAC, Difficulty Score

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    End point title
    		 Normalised WOMAC, Difficulty Score
    End point description
    End point type
    Secondary
    End point timeframe
    Week 26 compared to baseline
    End point values
    		 MIV-711 100 mg MIV-711 200 mg Placebo
    Number of subjects analysed
    74
    72
    69
    Units: score
        arithmetic mean (standard deviation)
    -16.39 ( 20.937 )
    -13.95 ( 20.668 )
    -9.9 ( 21.862 )
    Statistical analysis title
    		 Change in normalised WOMAC Difficulty score
    Statistical analysis description
    A linear mixed model based on the mITT population was used. The model included fixed factors for treatment, time (measured in weeks), the interaction for treatment-by-time, baseline analgesic (Yes/No) and random effect for clinical site. Baseline WOMAC Difficulty score was included as a covariate for adjustment. An unstructured covariance matrix was used to model the covariance pattern in the mixed effects model.
    Comparison groups
    MIV-711 200 mg v Placebo
    Number of subjects included in analysis
    141
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [23]
    P-value
    		 = 0.2898 [24]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -1.84
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -8.38
         upper limit
    		 4.7
    Notes
    [23] - One model is fit for all comparison groups (MIV-711 200 mg, MIV-711 100 mg and placebo). This analysis reports the contrast that compares 200 mg versus placebo with respect to mean change from baseline in WOMAC Difficulty score at Week 26.
    [24] - p-values reported are unadjusted p-values for tests of significance for the lower one-tailed alternative hypothesis Ha: Reduction in WOMAC Difficulty score is higher in the active treatment arm compared to placebo.
    Statistical analysis title
    		 Change in normalised WOMAC Difficulty score
    Statistical analysis description
    A linear mixed model based on the mITT population was used. The model included fixed factors for treatment, time (measured in weeks), the interaction for treatment-by-time, baseline analgesic (Yes/No) and random effect for clinical site. Baseline WOMAC Difficulty score was included as a covariate for adjustment. An unstructured covariance matrix was used to model the covariance pattern in the mixed effects model.
    Comparison groups
    Placebo v MIV-711 100 mg
    Number of subjects included in analysis
    143
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [25]
    P-value
    		 = 0.1262 [26]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -3.78
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -10.3
         upper limit
    		 2.72
    Notes
    [25] - One model is fit for all comparison groups (MIV-711 200 mg, MIV-711 100 mg and placebo). This analysis reports the contrast that compares 100 mg versus placebo with respect to mean change from baseline in WOMAC Difficulty score at Week 26.
    [26] - p-values reported are unadjusted p-values for tests of significance for the lower one-tailed alternative hypothesis Ha: Reduction in WOMAC Difficulty score is higher in the active treatment arm compared to placebo.

    Secondary: Normalised WOMAC, Stiffness Score

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    End point title
    		 Normalised WOMAC, Stiffness Score
    End point description
    End point type
    Secondary
    End point timeframe
    Week 26 compared to baseline
    End point values
    		 MIV-711 100 mg MIV-711 200 mg Placebo
    Number of subjects analysed
    74
    72
    69
    Units: score
        arithmetic mean (standard deviation)
    -17 ( 24.69 )
    -14.5 ( 22.71 )
    -9.8 ( 24.71 )
    Statistical analysis title
    		 Change in normalised WOMAC Stiffness score
    Statistical analysis description
    A linear mixed model based on the mITT population was used. The model included fixed factors for treatment, time (measured in weeks), the interaction for treatment-by-time, baseline analgesic (Yes/No) and random effect for clinical site. Baseline WOMAC Stiffness score was included as a covariate for adjustment. An unstructured covariance matrix was used to model the covariance pattern in the mixed effects model.
    Comparison groups
    MIV-711 200 mg v Placebo
    Number of subjects included in analysis
    141
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [27]
    P-value
    		 = 0.2 [28]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -3.07
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -10.2
         upper limit
    		 4.1
    Notes
    [27] - One model is fit for all comparison groups (MIV-711 200 mg, MIV-711 100 mg and placebo). This analysis reports the contrast that compares 200 mg versus placebo with respect to mean change from baseline in WOMAC Stiffness score at Week 26.
    [28] - p-values reported are unadjusted p-values for tests of significance for the lower one-tailed alternative hypothesis Ha: Reduction in WOMAC Stiffness score is higher in the active treatment arm compared to placebo.
    Statistical analysis title
    		 Change in normalised WOMAC Stiffness score
    Statistical analysis description
    A linear mixed model based on the mITT population was used. The model included fixed factors for treatment, time (measured in weeks), the interaction for treatment-by- time, baseline analgesic user (Yes/No), and random effect for clinical site. Baseline WOMAC Stiffness score was included as a covariate for adjustment. An unstructured covariance matrix was used to model the covariance pattern in the mixed effects model.
    Comparison groups
    Placebo v MIV-711 100 mg
    Number of subjects included in analysis
    143
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [29]
    P-value
    		 = 0.0861 [30]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -4.95
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -12.1
         upper limit
    		 2.17
    Notes
    [29] - One model is fit for all comparison groups (MIV-711 200 mg, MIV-711 100 mg and placebo). This analysis reports the contrast that compares 100 mg versus placebo with respect to mean change from baseline in WOMAC Stiffness score at Week 26.
    [30] - p-values reported are unadjusted p-values for tests of significance for the lower one-tailed alternative hypothesis Ha: Reduction in WOMAC Stiffness score is higher in the active treatment arm compared to placebo.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were collected from baseline to safety follow-up visit
    Adverse event reporting additional description
    This study reports treatment-emergent AEs (TEAEs). A TEAE was defined as an AE that begins or that worsens in severity after at least one dose of IMP has been administered.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.1
    Reporting groups
    Reporting group title
    MIV-711 100 mg
    Reporting group description
    		 -

    Reporting group title
    MIV-711 200 mg
    Reporting group description
    		 -

    Reporting group title
    Placebo
    Reporting group description
    		 -

    Serious adverse events
    		 MIV-711 100 mg MIV-711 200 mg Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 82 (3.66%)
    2 / 82 (2.44%)
    1 / 80 (1.25%)
         number of deaths (all causes)
    0
    0
    1
         number of deaths resulting from adverse events
    0
    0
    0
    Injury, poisoning and procedural complications
    Compression fracture
         subjects affected / exposed
    1 / 82 (1.22%)
    0 / 82 (0.00%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Contusion
         subjects affected / exposed
    1 / 82 (1.22%)
    0 / 82 (0.00%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Haematoma
         subjects affected / exposed
    1 / 82 (1.22%)
    0 / 82 (0.00%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    1 / 82 (1.22%)
    0 / 82 (0.00%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    0 / 82 (0.00%)
    0 / 82 (0.00%)
    1 / 80 (1.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Prinzmetal angina
         subjects affected / exposed
    1 / 82 (1.22%)
    0 / 82 (0.00%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebral infarction
         subjects affected / exposed
    0 / 82 (0.00%)
    1 / 82 (1.22%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis acute
         subjects affected / exposed
    0 / 82 (0.00%)
    1 / 82 (1.22%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Pyelonephritis chronic
         subjects affected / exposed
    1 / 82 (1.22%)
    0 / 82 (0.00%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 MIV-711 100 mg MIV-711 200 mg Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    45 / 82 (54.88%)
    43 / 82 (52.44%)
    43 / 80 (53.75%)
    Investigations
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    1 / 82 (1.22%)
    0 / 82 (0.00%)
    4 / 80 (5.00%)
         occurrences all number
    1
    0
    4
    Vascular disorders
    Hypertension
         subjects affected / exposed
    0 / 82 (0.00%)
    1 / 82 (1.22%)
    4 / 80 (5.00%)
         occurrences all number
    0
    1
    4
    Nervous system disorders
    Headache
         subjects affected / exposed
    5 / 82 (6.10%)
    5 / 82 (6.10%)
    6 / 80 (7.50%)
         occurrences all number
    6
    5
    8
    Musculoskeletal and connective tissue disorders
    Osteoarthritis
         subjects affected / exposed
    7 / 82 (8.54%)
    6 / 82 (7.32%)
    7 / 80 (8.75%)
         occurrences all number
    7
    6
    8
    Back pain
         subjects affected / exposed
    1 / 82 (1.22%)
    6 / 82 (7.32%)
    3 / 80 (3.75%)
         occurrences all number
    1
    6
    3
    Arthralgia
         subjects affected / exposed
    5 / 82 (6.10%)
    2 / 82 (2.44%)
    2 / 80 (2.50%)
         occurrences all number
    5
    2
    4
    Muscle spasms
         subjects affected / exposed
    6 / 82 (7.32%)
    0 / 82 (0.00%)
    1 / 80 (1.25%)
         occurrences all number
    7
    0
    1
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    8 / 82 (9.76%)
    7 / 82 (8.54%)
    6 / 80 (7.50%)
         occurrences all number
    8
    9
    6

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    13 Jan 2016
    The purposes of this amendment were: • to update the protocol with all revisions to date including amendments made at the request of country health authorities and to update patient and study-related spects such as assessments, objectives, and inclusion/exclusion criteria that were found necessary upon further internal review. Minor typographic and grammar errors were corrected but are not detailed in this amendment summary, as they do not affect the conduct of the study.
    20 Jul 2016
    The purposes of this amendment were: • to include details about the option for all patients enrolled in the current study at the participating sites included in Extension Study MIV-711-202 to have the opportunity to participate in the extension protocol provided that they meet the eligibility criteria • to confirm that females must be non-pregnant at study screening • to delete the following: "At a patient's request, their data collected up to the point of withdrawal can also be withdrawn from the study and will not be used in the final analysis" • to clarify which concomitant steroids can be used during the study • to add a new subsection on Kellgren and Lawrence grade scoring • to provide further detail on magnetic resonance imaging (MRI) procedures • to provide clarity on visit numbers for Study MIV-711-201 and MIV-711-202 • to amend details of some of the footnotes in study schedule • to provide further detail on the safety follow-up visit • to provide an update on the planned analysis methods employed for the voluntarily consented pharmacogenomics samples • to update the wording pertaining to the potential phototoxicity that could not be excluded at the start of study MIV-711-201 but that meanwhile has been discarded following cell based assays as outlined in the updated Investigator Brochure. Even though no signs of phototoxicity potential could be seen in the in vitro cell assay, it is desirable to maintain assay conditions all through the study, hence the suggested wording change Minor typographic, formatting and grammar errors were corrected but are not detailed in this amendment summary, as they do not affect the conduct of the study or the safety of subjects.

    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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