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    Clinical Trial Results:
    A multicentre, comparative, randomised, double-blind, double-dummy clinical trial on the efficacy and safety of Condrosulf® versus Celebrex® and versus a placebo in the treatment of knee osteoarthritis

    Summary
    EudraCT number
    		 2013-001619-62
    Trial protocol
    		 IT   BE   CZ   PL  
    Global end of trial date
    19 Oct 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    06 May 2022
    First version publication date
    06 May 2022
    Other versions
    Summary report(s)
    		 annrheumdis-2016-210860.full

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    12EU/Ct06
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02079727
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    IBSA, Institut Biochimique S.A.
    Sponsor organisation address
    Via del Piano, Pambio-Noranco, Switzerland, 6915
    Public contact
    Giuseppe Mautone, IBSA, Institut Biochimique S.A., 0041 0583601000, sd@ibsa.ch
    Scientific contact
    Giuseppe Mautone, IBSA, Institut Biochimique S.A., 0041 0583601000, sd@ibsa.ch
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    06 Jun 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    19 Oct 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    19 Oct 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    assess the superiority of Condrosulf 800 mg once daily versus placebo for 182 days. Celebrex will be used as active control. The primary endpoints will be a change in the Lequesne algo-functional index and a change in the VAS from day 1 to day 182
    Protection of trial subjects
    Patients have rescue medication available in case of uncontrolled pain. Patients can stop the study at any time.
    Background therapy
    		 -
    Evidence for comparator
    		 Celebrex® 200 mg (celecoxib) was used as active comparator.
    Actual start date of recruitment
    12 Jun 2014
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Poland: 493
    Country: Number of subjects enrolled
    Belgium: 18
    Country: Number of subjects enrolled
    Czechia: 74
    Country: Number of subjects enrolled
    Italy: 1
    Country: Number of subjects enrolled
    Switzerland: 17
    Worldwide total number of subjects
    603
    EEA total number of subjects
    586
    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)
    276
    From 65 to 84 years
    325
    85 years and over
    2

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study was conducted in 16 centres in 5 European countries (1 in Belgium, 3 in Switzerland, 1 in Italy, 5 in Poland and 6 in Czech Republic). First patient enrolled: 12 June 2014; Last patient completed: 19 October 2015

    Pre-assignment
    Screening details
    		 656 patients have been screened of which 52 Screening failure. 604 patients have been randomized. Of these, 505 patients completed the study and 99 interrupted it prematurely

    Period 1
    Period 1 title
    Trial period (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator
    Blinding implementation details
    The realization of the double-blind, double dummy design was made possible by the production of matched placebo tablets and capsules that were identical to the active product Condrosulf and to the overencapsulated Celebrex, respectively, in terms of size, shape, colour and method of administration.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Condrosulf
    Arm description
    		 Group 1: one tablet of Condrosulf® 800 mg and 1 capsule of Placebo of Celebrex®, once a day by oral route.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Condrosulf® 800 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    One tablet of Condrosulf® 800 mg once a day by oral route. Being a double dummy study the patient also took 1 capsule of Placebo of Celebrex®, once a day by oral route Tablets and capsules had to be swallowed whole with a glass of water without chewing them.

    Arm title
    		 Celebrex® 200 mg
    Arm description
    		 Group 2: One tablet of Placebo of Condrosulf® and 1 capsule of Celebrex® 200 mg, once a day by oral route
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Celebrex®
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    1 capsule of Celebrex® 200 mg, once a day by oral route; Being it a double dummy study, the patient also took one tablet of Placebo of Condrosulf® , once a day by oral route; Tablets and capsules had to be swallowed whole with a glass of water without chewing them.

    Arm title
    		 Placebo
    Arm description
    		 Group 3: one tablet of Placebo of Condrosulf® and 1 capsule of Placebo of Celebrex®, once a day by oral route.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet, Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Patient take one tablet of Placebo of Condrosulf® and 1 capsule of Placebo of Celebrex®, once a day by oral route. Tablets and capsules had to be swallowed whole with a glass of water without chewing them.

    Number of subjects in period 1
    		Condrosulf Celebrex® 200 mg Placebo
    Started
    199
    199
    205
    Completed
    160
    173
    172
    Not completed
    39
    26
    33
         Consent withdrawn by subject
    15
    5
    14
         Adverse event, non-fatal
    9
    12
    6
         Lack of efficacy
    12
    9
    12
         Protocol deviation
    3
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Condrosulf
    Reporting group description
    		 Group 1: one tablet of Condrosulf® 800 mg and 1 capsule of Placebo of Celebrex®, once a day by oral route.

    Reporting group title
    Celebrex® 200 mg
    Reporting group description
    		 Group 2: One tablet of Placebo of Condrosulf® and 1 capsule of Celebrex® 200 mg, once a day by oral route

    Reporting group title
    Placebo
    Reporting group description
    		 Group 3: one tablet of Placebo of Condrosulf® and 1 capsule of Placebo of Celebrex®, once a day by oral route.

    Reporting group values
    		 Condrosulf Celebrex® 200 mg Placebo Total
    Number of subjects
    		 199 199 205 603
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 88 89 99 276
        From 65-84 years
    		 110 109 106 325
        85 years and over
    		 1 1 0 2
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 65.5 ± 8 65.5 ± 7.78 64.9 ± 8.04 -
    Gender categorical
    Units: Subjects
        Female
    		 156 160 152 468
        Male
    		 43 39 53 135
    Lequesne'index
    Lequesne’s algo-functional index
    Units: score
        arithmetic mean (standard deviation)
    		 11.78 ± 2.948 11.59 ± 2.886 11.79 ± 3.047 -
    Subject analysis sets

    Subject analysis set title
    Intent-to-treat (ITT) population 1
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Intent-to-treat (ITT) population 1, which consisted of all randomised patients who received the study medication and had at least one post-baseline efficacy evaluation (1 month of treatment)

    Subject analysis set title
    ITT population 2
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    ITT population 2, which consisted of all randomised patients who received the study medication

    Subject analysis set title
    Per-Protocol (PP) population
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Per-Protocol (PP) population, which consisted of all patients in the ITT population who did not have any major protocol violations

    Subject analysis sets values
    		 Intent-to-treat (ITT) population 1 ITT population 2 Per-Protocol (PP) population
    Number of subjects
    591
    603
    534
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    276
        From 65-84 years
    325
        85 years and over
    2
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    65.3 ± 7.86
    65.3 ± 7.93
    65.2 ± 7.83
    Gender categorical
    Units: Subjects
        Female
    130
    135
    120
        Male
    461
    468
    414
    Lequesne'index
    Lequesne’s algo-functional index
    Units: score
        arithmetic mean (standard deviation)
    ±
    ±
    ±

    End points

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    End points reporting groups
    Reporting group title
    Condrosulf
    Reporting group description
    		 Group 1: one tablet of Condrosulf® 800 mg and 1 capsule of Placebo of Celebrex®, once a day by oral route.

    Reporting group title
    Celebrex® 200 mg
    Reporting group description
    		 Group 2: One tablet of Placebo of Condrosulf® and 1 capsule of Celebrex® 200 mg, once a day by oral route

    Reporting group title
    Placebo
    Reporting group description
    		 Group 3: one tablet of Placebo of Condrosulf® and 1 capsule of Placebo of Celebrex®, once a day by oral route.

    Subject analysis set title
    Intent-to-treat (ITT) population 1
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Intent-to-treat (ITT) population 1, which consisted of all randomised patients who received the study medication and had at least one post-baseline efficacy evaluation (1 month of treatment)

    Subject analysis set title
    ITT population 2
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    ITT population 2, which consisted of all randomised patients who received the study medication

    Subject analysis set title
    Per-Protocol (PP) population
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Per-Protocol (PP) population, which consisted of all patients in the ITT population who did not have any major protocol violations

    Primary: Change in Lequesne’s algo-funct. index

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    End point title
    		 Change in Lequesne’s algo-funct. index
    End point description
    The change in the Lequesne’s algo-functional index from Day 1 to Day 182
    End point type
    Primary
    End point timeframe
    From Day 1 to 182
    End point values
    		 Condrosulf Celebrex® 200 mg Placebo
    Number of subjects analysed
    185
    191
    191
    Units: Score
        arithmetic mean (standard deviation)
    -4.51 ± 3.677
    -4.30 ± 3.587
    -3.59 ± 3.651
    Statistical analysis title
    		 LEQUESNE INDEX SCORE REDUCTION AT VISIT 4 ConVsPl
    Statistical analysis description
    Analysis is based on an analysis of covariance model with mean change from baseline in the VAS score at last visit as dependent variable, treatment and centre as fixed effect and baseline as covariate. BOCF = baseline observation carried forward; LOCF = last observation carried forward. Missing values at the each visit have been replaced using the BOCF method.
    Comparison groups
    Condrosulf v Placebo
    Number of subjects included in analysis
    376
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.05
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    -0.914
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.567
         upper limit
    		 -0.261
    Statistical analysis title
    		 LEQUESNE INDEX SCORE REDUCTION AT VISIT 4 ConVsCel
    Statistical analysis description
    Analysis is based on an analysis of covariance model with mean change from baseline in the VAS score at last visit as dependent variable, treatment and centre as fixed effect and baseline as covariate. BOCF = baseline observation carried forward; LOCF = last observation carried forward. Missing values at the each visit have been replaced using the BOCF method.
    Comparison groups
    Condrosulf v Celebrex® 200 mg
    Number of subjects included in analysis
    376
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.05
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.097
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.563
         upper limit
    		 0.757
    Statistical analysis title
    		 LEQUESNE INDEX SCORE REDUCTION AT VISIT 4 CelVsPL
    Statistical analysis description
    Analysis is based on an analysis of covariance model with mean change from baseline in the VAS score at last visit as dependent variable, treatment and centre as fixed effect and baseline as covariate. BOCF = baseline observation carried forward; LOCF = last observation carried forward. Missing values at the each visit have been replaced using the BOCF method.
    Comparison groups
    Placebo v Celebrex® 200 mg
    Number of subjects included in analysis
    382
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.05
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    -1.011
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.662
         upper limit
    		 -0.361

    Primary: Change in the VAS pain (in mm.) from Day 1 to Day 182.

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    End point title
    		 Change in the VAS pain (in mm.) from Day 1 to Day 182.
    End point description
    Changeof pian on the VAS scale (in mm) from Day 1 to Day 182. Pain was measured on a horizontal visual analogical scale (VAS) of 100 mm going from 0 =absent pain, to 100 = maximum pain.
    End point type
    Primary
    End point timeframe
    From Day 1 to Day 182
    End point values
    		 Condrosulf Celebrex® 200 mg Placebo
    Number of subjects analysed
    185
    191
    191
    Units: mm
        arithmetic mean (standard deviation)
    -39.8 ± 24.65
    -38.1 ± 24.26
    -32.4 ± 24.81
    Statistical analysis title
    		 PAIN (VAS) REDUCTION AT VISIT 4 CelVsPL
    Statistical analysis description
    Analysis is based on an analysis of covariance model with mean change from baseline in the VAS score at last visit as dependent variable, treatment and centre as fixed effect and baseline as covariate. BOCF = baseline observation carried forward; LOCF = last observation carried forward. Missing values at the each visit have been replaced using the BOCF method.
    Comparison groups
    Celebrex® 200 mg v Placebo
    Number of subjects included in analysis
    382
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.05
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    -7.017
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -11.696
         upper limit
    		 -2.338
    Statistical analysis title
    		 PAIN (VAS) REDUCTION AT VISIT 4 CondVsPL
    Statistical analysis description
    Analysis is based on an analysis of covariance model with mean change from baseline in the VAS score at last visit as dependent variable, treatment and centre as fixed effect and baseline as covariate. BOCF = baseline observation carried forward; LOCF = last observation carried forward. Missing values at the each visit have been replaced using the BOCF method.
    Comparison groups
    Placebo v Condrosulf
    Number of subjects included in analysis
    376
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.05
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    -7.379
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -12.082
         upper limit
    		 -2.676
    Statistical analysis title
    		 PAIN (VAS) REDUCTION AT VISIT 4 CondVsCel
    Statistical analysis description
    Analysis is based on an analysis of covariance model with mean change from baseline in the VAS score at last visit as dependent variable, treatment and centre as fixed effect and baseline as covariate. BOCF = baseline observation carried forward; LOCF = last observation carried forward. Missing values at the each visit have been replaced using the BOCF method.
    Comparison groups
    Celebrex® 200 mg v Condrosulf
    Number of subjects included in analysis
    376
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.05
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    -0.362
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.113
         upper limit
    		 4.39

    Secondary: Clinically important improvement (MCII)

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    End point title
    		 Clinically important improvement (MCII)
    End point description
    Assessment of minimal clinically important improvement (MCII)
    End point type
    Secondary
    End point timeframe
    From Day 1 to day 182
    End point values
    		 Condrosulf Celebrex® 200 mg Placebo
    Number of subjects analysed
    192
    195
    204
    Units: Subjects
        Responder
    136
    137
    125
        No Responder
    56
    58
    79
    Statistical analysis title
    		 PATIENT REACHING THE MCII AT VISIT 4 ConVsPl
    Statistical analysis description
    SECONDARY EFFICACY ANALYSIS: PROPORTIONS OF PATIENTS REACHING THE MINIMAL CLINICALLY IMPORTANT IMPROVEMENT(MCII) INTENT-TO-TREAT POPULATION 1
    Comparison groups
    Placebo v Condrosulf
    Number of subjects included in analysis
    396
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.05
    Method
    		 Chi-squared
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    1.156
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.003
         upper limit
    		 1.332
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.072
    Statistical analysis title
    		 PATIENT REACHING THE MCII AT VISIT 4 CelVsPl
    Statistical analysis description
    SECONDARY EFFICACY ANALYSIS: PROPORTIONS OF PATIENTS REACHING THE MINIMAL CLINICALLY IMPORTANT IMPROVEMENT(MCII) INTENT-TO-TREAT POPULATION 1
    Comparison groups
    Placebo v Celebrex® 200 mg
    Number of subjects included in analysis
    399
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.05
    Method
    		 Chi-squared
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    1.147
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.995
         upper limit
    		 1.322
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.073
    Statistical analysis title
    		 PATIENT REACHING THE MCII AT VISIT 4 ConVsCel
    Statistical analysis description
    SECONDARY EFFICACY ANALYSIS: PROPORTIONS OF PATIENTS REACHING THE MINIMAL CLINICALLY IMPORTANT IMPROVEMENT(MCII) INTENT-TO-TREAT POPULATION 1
    Comparison groups
    Condrosulf v Celebrex® 200 mg
    Number of subjects included in analysis
    387
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.05
    Method
    		 Chi-squared
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    1.008
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.886
         upper limit
    		 1.147
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.066

    Secondary: Consumption of paracetamol

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    End point title
    		 Consumption of paracetamol
    End point description
    Consumption of paracetamol (noted in a diary);
    End point type
    Secondary
    End point timeframe
    From Day 1 to day 182
    End point values
    		 Condrosulf Celebrex® 200 mg Placebo
    Number of subjects analysed
    192
    195
    204
    Units: Total dose (n. of tablets)
        arithmetic mean (standard deviation)
    86.4 ± 147.37
    73.2 ± 114.87
    90.6 ± 129.67
    Statistical analysis title
    		 TOTAL CONSUMPTION OF RESCUE MED AT VISIT4 CondVsPL
    Statistical analysis description
    TOTAL CONSUMPTION OF RESCUE MEDICATION (TOTAL DOSE - N. of TABLETS)
    Comparison groups
    Placebo v Condrosulf
    Number of subjects included in analysis
    396
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.05
    Method
    		 ANOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -4.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -31.185
         upper limit
    		 23.185
    Statistical analysis title
    		 TOTAL CONSUMPTION OF RESCUE MED AT VISIT4 CelVsPL
    Statistical analysis description
    TOTAL CONSUMPTION OF RESCUE MEDICATION (TOTAL DOSE - N. of TABLETS)
    Comparison groups
    Placebo v Celebrex® 200 mg
    Number of subjects included in analysis
    399
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.05
    Method
    		 ANOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -17.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -41.551
         upper limit
    		 6.751
    Statistical analysis title
    		 TOTAL CONSUMPTION OF RESCUEMED AT VISIT4 CondVsCeL
    Statistical analysis description
    TOTAL CONSUMPTION OF RESCUE MEDICATION (TOTAL DOSE - N. of TABLETS)
    Comparison groups
    Condrosulf v Celebrex® 200 mg
    Number of subjects included in analysis
    387
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.05
    Method
    		 ANOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    13.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -13.186
         upper limit
    		 39.586

    Secondary: Global efficacy assessment

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    End point title
    		 Global efficacy assessment
    End point description
    Global efficacy assessment by the patient and the Investigator
    End point type
    Secondary
    End point timeframe
    Day 30, 91 and 182
    End point values
    		 Condrosulf Celebrex® 200 mg Placebo
    Number of subjects analysed
    192
    195
    204
    Units: Subjects
        None
    21
    22
    37
        Poor
    26
    26
    30
        Fair
    45
    47
    53
        Good
    79
    76
    69
        Excellent
    21
    24
    15
    Statistical analysis title
    		 OVERALL TREATMENT EFFICACY AT VISIT 4 CondVsPL
    Statistical analysis description
    OVERALL TREATMENT EFFICACY JUDGED BY THE PATIENT
    Comparison groups
    Condrosulf v Placebo
    Number of subjects included in analysis
    396
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.05
    Method
    		 Mantel-Haenszel
    Confidence interval
    Statistical analysis title
    		 OVERALL TREATMENT EFFICACY AT VISIT 4 CelVsPL
    Statistical analysis description
    OVERALL TREATMENT EFFICACY JUDGED BY THE PATIENT
    Comparison groups
    Placebo v Celebrex® 200 mg
    Number of subjects included in analysis
    399
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.05
    Method
    		 Mantel-Haenszel
    Confidence interval
    Statistical analysis title
    		 OVERALL TREATMENT EFFICACY AT VISIT 4 CondVsCel
    Statistical analysis description
    OVERALL TREATMENT EFFICACY JUDGED BY THE PATIENT
    Comparison groups
    Condrosulf v Celebrex® 200 mg
    Number of subjects included in analysis
    387
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.05
    Method
    		 Mantel-Haenszel
    Confidence interval

    Secondary: PATIENTS REACHING THE PATIENT ACCEPTABLE SYMPTOM STATE (PASS)

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    End point title
    		 PATIENTS REACHING THE PATIENT ACCEPTABLE SYMPTOM STATE (PASS)
    End point description
    PROPORTIONS OF PATIENTS REACHING THE PATIENT ACCEPTABLE SYMPTOM STATE (PASS)
    End point type
    Secondary
    End point timeframe
    From baseline to Visit 4 (day 182)
    End point values
    		 Condrosulf Celebrex® 200 mg Placebo
    Number of subjects analysed
    192
    195
    204
    Units: Subjects
        Responder
    113
    118
    101
        No Responder
    79
    77
    103
    Statistical analysis title
    		 PATIENTS REACHING PASS AT VISIT 4 CondVsPL
    Statistical analysis description
    PROPORTIONS OF PATIENTS REACHING THE PATIENT ACCEPTABLE SYMPTOM STATE (PASS)
    Comparison groups
    Condrosulf v Placebo
    Number of subjects included in analysis
    396
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.05
    Method
    		 Chi-squared
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    1.217
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.017
         upper limit
    		 1.458
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.092
    Statistical analysis title
    		 PATIENTS REACHING PASS AT VISIT 4 CelVsPL
    Statistical analysis description
    PROPORTIONS OF PATIENTS REACHING THE PATIENT ACCEPTABLE SYMPTOM STATE (PASS)
    Comparison groups
    Placebo v Celebrex® 200 mg
    Number of subjects included in analysis
    399
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.05
    Method
    		 Chi-squared
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    1.205
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.006
         upper limit
    		 1.443
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.092
    Statistical analysis title
    		 PATIENTS REACHING PASS AT VISIT 4 CondVsCel
    Statistical analysis description
    PROPORTIONS OF PATIENTS REACHING THE PATIENT ACCEPTABLE SYMPTOM STATE (PASS)
    Comparison groups
    Condrosulf v Celebrex® 200 mg
    Number of subjects included in analysis
    387
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.05
    Method
    		 Chi-squared
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    1.01
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.861
         upper limit
    		 1.186
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.082

    Secondary: Change in the Lequesne’s algo-functional index from Day 1 to Day 30

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    End point title
    		 Change in the Lequesne’s algo-functional index from Day 1 to Day 30
    End point description
    The change in the Lequesne’s algo-functional index from Day 1 to Day 30
    End point type
    Secondary
    End point timeframe
    From Day 1 to Day 30
    End point values
    		 Condrosulf Celebrex® 200 mg Placebo
    Number of subjects analysed
    183
    186
    196
    Units: Score
        arithmetic mean (standard deviation)
    -2.24 ± 2.311
    -2.63 ± 2.631
    -2.09 ± 2.508
    Statistical analysis title
    		 LEQUESNE INDEX SCORE REDUCTION AT VISIT 2 CelVsPL
    Comparison groups
    Celebrex® 200 mg v Placebo
    Number of subjects included in analysis
    382
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [1]
    P-value
    		 < 0.05
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    -0.524
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.998
         upper limit
    		 -0.051
    Notes
    [1] - Analysis is based on an analysis of covariance model with mean change from baseline in the LEQUENE INDEX SCORE at visit 2 as dependent variable, treatment and centre as fixed effect and baseline as covariate. BOCF = baseline observation carried forward; LOCF = last observation carried forward. Missing values at the each visit have been replaced using the BOCF method.
    Statistical analysis title
    		 LEQUESNE INDEX SCORE REDUCTION AT VISIT 2 ConVsPl
    Comparison groups
    Placebo v Condrosulf
    Number of subjects included in analysis
    379
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [2]
    P-value
    		 < 0.05
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    -0.147
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.622
         upper limit
    		 0.329
    Notes
    [2] - Analysis is based on an analysis of covariance model with mean change from baseline in the LEQUENE INDEX SCORE at visit 2 as dependent variable, treatment and centre as fixed effect and baseline as covariate. BOCF = baseline observation carried forward; LOCF = last observation carried forward. Missing values at the each visit have been replaced using the BOCF method.
    Statistical analysis title
    		 LEQUESNE INDEX SCORE REDUCTION AT VISIT 2 ConVsCel
    Comparison groups
    Condrosulf v Celebrex® 200 mg
    Number of subjects included in analysis
    369
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [3]
    P-value
    		 < 0.05
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.377
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.103
         upper limit
    		 0.858
    Notes
    [3] - Analysis is based on an analysis of covariance model with mean change from baseline in the LEQUENE INDEX SCORE at visit 2 as dependent variable, treatment and centre as fixed effect and baseline as covariate. BOCF = baseline observation carried forward; LOCF = last observation carried forward. Missing values at the each visit have been replaced using the BOCF method.

    Secondary: Change in the Lequesne’s algo-functional index from Day 1 to Day 91

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    End point title
    		 Change in the Lequesne’s algo-functional index from Day 1 to Day 91
    End point description
    The change in the Lequesne’s algo-functional index from Day 1 to Day 91
    End point type
    Secondary
    End point timeframe
    From Day 1 to Day 91
    End point values
    		 Condrosulf Celebrex® 200 mg Placebo
    Number of subjects analysed
    165
    175
    179
    Units: Score
        arithmetic mean (standard deviation)
    -3.89 ± 3.215
    -3.77 ± 2.840
    -3.09 ± 2.835
    Statistical analysis title
    		 LEQUESNE INDEX SCORE REDUCTION AT VISIT 3 ConVsPl
    Comparison groups
    Condrosulf v Placebo
    Number of subjects included in analysis
    344
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [4]
    P-value
    		 < 0.05
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    -0.706
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.261
         upper limit
    		 -0.105
    Notes
    [4] - Analysis is based on an analysis of covariance model with mean change from baseline in the LEQUENE INDEX SCORE at visit 2 as dependent variable, treatment and centre as fixed effect and baseline as covariate. BOCF = baseline observation carried forward; LOCF = last observation carried forward. Missing values at the each visit have been replaced using the BOCF method.
    Statistical analysis title
    		 LEQUESNE INDEX SCORE REDUCTION AT VISIT 3 CelVsPL
    Comparison groups
    Placebo v Celebrex® 200 mg
    Number of subjects included in analysis
    354
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [5]
    P-value
    		 < 0.05
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    -0.719
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.272
         upper limit
    		 -0.166
    Notes
    [5] - Analysis is based on an analysis of covariance model with mean change from baseline in the LEQUENE INDEX SCORE at visit 2 as dependent variable, treatment and centre as fixed effect and baseline as covariate. BOCF = baseline observation carried forward; LOCF = last observation carried forward. Missing values at the each visit have been replaced using the BOCF method.
    Statistical analysis title
    		 LEQUESNE INDEX SCORE REDUCTION AT VISIT 3 ConVsCel
    Comparison groups
    Celebrex® 200 mg v Condrosulf
    Number of subjects included in analysis
    340
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [6]
    P-value
    		 < 0.05
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.014
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.547
         upper limit
    		 0.575
    Notes
    [6] - Analysis is based on an analysis of covariance model with mean change from baseline in the LEQUENE INDEX SCORE at visit 2 as dependent variable, treatment and centre as fixed effect and baseline as covariate. BOCF = baseline observation carried forward; LOCF = last observation carried forward. Missing values at the each visit have been replaced using the BOCF method.

    Secondary: Change in the VAS pain (in mm.) from Day 1 to Day 30.

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    End point title
    		 Change in the VAS pain (in mm.) from Day 1 to Day 30.
    End point description
    Change of pian on the VAS scale (in mm) from Day 1 to Day 30. Pain was measured on a horizontal visual analogical scale (VAS) of 100 mm going from 0 = absent pain, to 100 = maximum pain.
    End point type
    Secondary
    End point timeframe
    From Day 1 to Day 30.
    End point values
    		 Condrosulf Celebrex® 200 mg Placebo
    Number of subjects analysed
    183
    186
    196
    Units: VAS (mm.)
        arithmetic mean (standard deviation)
    -22.6 ± 18.11
    -24 ± 19.2
    -21.1 ± 20.61
    Statistical analysis title
    		 PAIN (VAS) REDUCTION AT VISIT 2 CondVsPL
    Comparison groups
    Condrosulf v Placebo
    Number of subjects included in analysis
    379
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [7]
    P-value
    		 < 0.05
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    -1.177
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.819
         upper limit
    		 2.465
    Notes
    [7] - Analysis is based on an analysis of covariance model with mean change from baseline in the VAS score at visit 2 as dependent variable, treatment and centre as fixed effect and baseline as covariate. BOCF = baseline observation carried forward; LOCF = last observation carried forward. Missing values at the each visit have been replaced using the BOCF method.
    Statistical analysis title
    		 PAIN (VAS) REDUCTION AT VISIT 2 CelVsPL
    Comparison groups
    Placebo v Celebrex® 200 mg
    Number of subjects included in analysis
    382
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [8]
    P-value
    		 < 0.05
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    -2.508
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.131
         upper limit
    		 1.116
    Notes
    [8] - Analysis is based on an analysis of covariance model with mean change from baseline in the VAS score at visit 2 as dependent variable, treatment and centre as fixed effect and baseline as covariate. BOCF = baseline observation carried forward; LOCF = last observation carried forward. Missing values at the each visit have been replaced using the BOCF method.
    Statistical analysis title
    		 PAIN (VAS) REDUCTION AT VISIT 2 CondVsCel
    Comparison groups
    Celebrex® 200 mg v Condrosulf
    Number of subjects included in analysis
    369
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [9]
    P-value
    		 < 0.05
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    1.331
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.349
         upper limit
    		 5.01
    Notes
    [9] - Analysis is based on an analysis of covariance model with mean change from baseline in the VAS score at visit 2 as dependent variable, treatment and centre as fixed effect and baseline as covariate. BOCF = baseline observation carried forward; LOCF = last observation carried forward. Missing values at the each visit have been replaced using the BOCF method.

    Secondary: Change in the VAS pain (in mm.) from Day 1 to Day 91

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    End point title
    		 Change in the VAS pain (in mm.) from Day 1 to Day 91
    End point description
    Change of pain on the VAS scale (in mm) from Day 1 to Day 91. Pain was measured on a horizontal visual analogical scale (VAS) of 100 mm going from 0 =absent pain, to 100 = maximum pain.
    End point type
    Secondary
    End point timeframe
    From Day 1 to Day 91
    End point values
    		 Condrosulf Celebrex® 200 mg Placebo
    Number of subjects analysed
    165
    175
    179
    Units: VAS (mm.)
        arithmetic mean (standard deviation)
    -34.1 ± 21.26
    -32.7 ± 22.04
    -30.2 ± 20.46
    Statistical analysis title
    		 PAIN (VAS) REDUCTION AT VISIT 3 CondVsPL
    Comparison groups
    Placebo v Condrosulf
    Number of subjects included in analysis
    344
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [10]
    P-value
    		 < 0.05
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    -2.778
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.999
         upper limit
    		 1.443
    Notes
    [10] - Analysis is based on an analysis of covariance model with mean change from baseline in the VAS score at visit 3 as dependent variable, treatment and centre as fixed effect and baseline as covariate. BOCF = baseline observation carried forward; LOCF = last observation carried forward. Missing values at the each visit have been replaced using the BOCF method.
    Statistical analysis title
    		 PAIN (VAS) REDUCTION AT VISIT 3 CondVsCel
    Comparison groups
    Condrosulf v Celebrex® 200 mg
    Number of subjects included in analysis
    340
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [11]
    P-value
    		 < 0.05
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.316
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.949
         upper limit
    		 4.581
    Notes
    [11] - Analysis is based on an analysis of covariance model with mean change from baseline in the VAS score at visit 3 as dependent variable, treatment and centre as fixed effect and baseline as covariate. BOCF = baseline observation carried forward; LOCF = last observation carried forward. Missing values at the each visit have been replaced using the BOCF method.
    Statistical analysis title
    		 PAIN (VAS) REDUCTION AT VISIT 3 CelVsPla
    Comparison groups
    Celebrex® 200 mg v Placebo
    Number of subjects included in analysis
    354
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [12]
    P-value
    		 < 0.05
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    -3.094
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -7.294
         upper limit
    		 1.106
    Notes
    [12] - Analysis is based on an analysis of covariance model with mean change from baseline in the VAS score at visit 3 as dependent variable, treatment and centre as fixed effect and baseline as covariate. BOCF = baseline observation carried forward; LOCF = last observation carried forward. Missing values at the each visit have been replaced using the BOCF method.

    Other pre-specified: Treatment compliance

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    End point title
    		 Treatment compliance
    End point description
    Treatment compliance
    End point type
    Other pre-specified
    End point timeframe
    Day 30, 91, 182
    End point values
    		 Condrosulf Celebrex® 200 mg Placebo
    Number of subjects analysed
    192
    195
    204
    Units: Compliance mean %
        arithmetic mean (standard deviation)
    95.3 ± 12.24
    96.9 ± 8.54
    96.8 ± 8.55
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All over the study, from the signature of the Informed consent until the end of the study
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17.0
    Reporting groups
    Reporting group title
    Condrosulf
    Reporting group description
    		 Group 1: one tablet of Condrosulf® 800 mg and 1 capsule of Placebo of Celebrex®, once a day by oral route.

    Reporting group title
    Celebrex® 200 mg
    Reporting group description
    		 Group 2: One tablet of Placebo of Condrosulf® and 1 capsule of Celebrex® 200 mg, once a day by oral route

    Reporting group title
    Placebo
    Reporting group description
    		 Group 3: one tablet of Placebo of Condrosulf® and 1 capsule of Placebo of Celebrex®, once a day by oral route.

    Serious adverse events
    		 Condrosulf Celebrex® 200 mg Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 199 (1.01%)
    1 / 199 (0.50%)
    2 / 205 (0.98%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Surgical and medical procedures
    Cataract operation
         subjects affected / exposed
    0 / 199 (0.00%)
    0 / 199 (0.00%)
    1 / 205 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ligament operation
         subjects affected / exposed
    1 / 199 (0.50%)
    0 / 199 (0.00%)
    0 / 205 (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
    Skin and subcutaneous tissue disorders
    Urticaria
         subjects affected / exposed
    0 / 199 (0.00%)
    0 / 199 (0.00%)
    1 / 205 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    1 / 199 (0.50%)
    1 / 199 (0.50%)
    0 / 205 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Mobility decreased
         subjects affected / exposed
    1 / 199 (0.50%)
    0 / 199 (0.00%)
    0 / 205 (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
    spinal column stenosis
         subjects affected / exposed
    1 / 199 (0.50%)
    0 / 199 (0.00%)
    0 / 205 (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
    		 Condrosulf Celebrex® 200 mg Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    73 / 199 (36.68%)
    70 / 199 (35.18%)
    80 / 205 (39.02%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    25 / 199 (12.56%)
    27 / 199 (13.57%)
    22 / 205 (10.73%)
         occurrences all number
    50
    49
    40
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    14 / 199 (7.04%)
    12 / 199 (6.03%)
    13 / 205 (6.34%)
         occurrences all number
    17
    13
    13
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    9 / 199 (4.52%)
    6 / 199 (3.02%)
    14 / 205 (6.83%)
         occurrences all number
    11
    20
    26
    Back pain
         subjects affected / exposed
    7 / 199 (3.52%)
    4 / 199 (2.01%)
    12 / 205 (5.85%)
         occurrences all number
    19
    4
    17
    Spinal pain
         subjects affected / exposed
    17 / 199 (8.54%)
    8 / 199 (4.02%)
    12 / 205 (5.85%)
         occurrences all number
    28
    13
    21
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    18 / 199 (9.05%)
    27 / 199 (13.57%)
    30 / 205 (14.63%)
         occurrences all number
    19
    30
    36

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    26 Mar 2014
    One substantial protocol amendment was issued on 26 March 2014. The original protocol already excluded patients with cardiovascular risks. Following the Belgian IEC request, the protocol amendment was submitted to better reflect the cardiovascular and non-cardiovascular contraindications listed in the package leaflet for Celebrex, and to better ensure that patients with any risk of adverse events potentially related with the treatment with celecoxib would have been excluded from trial participation, including those with a history of heart attack, ischemic heart disease or cerebrovascular disease (including transient ischemic attacks) or those having or having had peripheral arterial disease or past surgery of peripheral arteries.

    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

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/28533290
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