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    Clinical Trial Results:
    AN INTERNATIONAL, MULTICENTRE, DOUBLE-BLIND, RANDOMISED STUDY OF THE EFFECT OF DIACEREIN VS CELECOXIB ON SYMPTOMS AND STRUCTURAL CHANGES IN SYMPTOMATIC KNEE OSTEOARTHRITIS PATIENTS AS ASSESSED BY MAGNETIC RESONANCE IMAGING

    Summary
    EudraCT number
    		 2015-002933-23
    Trial protocol
    		 CZ   ES   AT   BE  
    Global end of trial date
    26 Jun 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    03 Jul 2019
    First version publication date
    03 Jul 2019
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    DAR-INT-14-01
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02688400
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    TRB Chemedica International SA
    Sponsor organisation address
    Michel-Servet 12, Geneva, Switzerland, CH-1211
    Public contact
    Marie-Claude Gravel, SPharm inc., 1 8198246869, mcgravel@spharm-inc.com
    Scientific contact
    Dr. Jean-Pierre Pelletier, Arthrolab inc., 1 5149924939, dr@jppelletier.ca
    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 Mar 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    26 Jun 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    26 Jun 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study is to show that Diacerein is non-inferior to Celecoxib in terms of pain reduction (WOMAC A pain subscale) after 182 days of treatment in symptomatic knee OA patients.
    Protection of trial subjects
    If the patient is experiencing pain, acetaminophen, dosed at 500 mg, is authorised up to 2 g per day, i.e., 4 tablets per day. Other rescue analgesia with narcotics will be authorised for a maximum of 3 days a month for treatment of pain related to the target knee or any other painful condition for which it is the physician’s judgement that such treatment is indicated.
    Background therapy
    		 Acetaminophen is given as a rescue medication for this study.
    Evidence for comparator
    		 Celecoxib is recognised as the current gold standard in the treatment of knee OA. The clinical effectiveness of Celecoxib in the treatment of OA of the knee and hip was demonstrated in several placebo- and active-controlled clinical studies. Celecoxib demonstrated significant reductions in joint pain and disease activity, and also improvement in patient functional activity and health-related quality of life compared to placebo. In OA patients, treatment with Celecoxib 100 mg twice a day or 200 mg once daily resulted in improvement in functional activity as demonstrated by an improvement in pain, stiffness, function and total Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) scores.
    Actual start date of recruitment
    16 Apr 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
    Spain: 87
    Country: Number of subjects enrolled
    Austria: 9
    Country: Number of subjects enrolled
    Belgium: 3
    Country: Number of subjects enrolled
    Czech Republic: 122
    Country: Number of subjects enrolled
    Canada: 159
    Worldwide total number of subjects
    380
    EEA total number of subjects
    221
    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)
    203
    From 65 to 84 years
    177
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Recruitment between April 2016 to December 2017 in Canada, Spain, Austria, Czech and Belgium

    Pre-assignment
    Screening details
    		 screening period 30 days wash-out 7 days Overall (N=527) Not Randomized patients: 147 Primary reason for non randomization - Lack of efficacy: 0 - Adverse Event(s): 0 - Lost to Follow-Up: 0 - Protocol violation: 0 - Consent withdrawal: 10 - Other : 137

    Period 1
    Period 1 title
    All randomized patients (overall period)
    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
    The test products and placebo capsules will be presented as identical capsules concerning the colour, size and shape and weight. They will be packed in identical blisters and these blisters will be placed in identical plain, carton boxes. Patients in both groups will take the same number of capsules daily.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Diacerein
    Arm description
    		 Diacerein 50 mg capsule and matching placebo (first month)
    Arm type
    		 Experimental

    Investigational medicinal product name
    Diacerein
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Diacerein: one placebo capsule once daily in the morning (breakfast) and one Diacerein 50 mg capsule once daily with meals (dinner) in the evening for the first month; then twice daily with meals in the morning (breakfast) and the evening (dinner)

    Arm title
    		 Celecoxib
    Arm description
    		 Celecoxib 200 mg capsule and matching placebo
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Celecoxib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Celecoxib (Celebrex®): one Celecoxib 200 mg capsule once daily in the morning (breakfast) and one placebo capsule once daily in the evening (dinner)

    Number of subjects in period 1
    		Diacerein Celecoxib
    Started
    187
    193
    Completed
    141
    149
    Not completed
    46
    44
         Consent withdrawn by subject
    15
    13
         Adverse event, non-fatal
    21
    12
         no study medication intake
    1
    4
         Lost to follow-up
    -
    3
         Lack of efficacy
    7
    7
         Protocol deviation
    2
    5

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Diacerein
    Reporting group description
    		 Diacerein 50 mg capsule and matching placebo (first month)

    Reporting group title
    Celecoxib
    Reporting group description
    		 Celecoxib 200 mg capsule and matching placebo

    Reporting group values
    		 Diacerein Celecoxib Total
    Number of subjects
    		 187 193 380
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 106 97 203
        From 65-84 years
    		 81 96 177
        85 years and over
    		 0 0 0
    Age continuous
    Male or female aged more than 50 years old
    Units: years
        arithmetic mean (standard deviation)
    		 63.7 ± 6.3 64.4 ± 7.0 -
    Gender categorical
    Units: Subjects
        Female
    		 137 146 283
        Male
    		 50 47 97
    study knee
    Units: Subjects
        right
    		 87 96 183
        left
    		 100 97 197
    Subject analysis sets

    Subject analysis set title
    ITT population
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    The Intention-To-Treat was composed of all randomized patients who received at least one dose of the study medication, had an efficacy measurement at inclusion and at least one corresponding post-inclusion efficacy measurement (for the primary efficacy variable).

    Subject analysis set title
    Per Protocol Set
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The Per Protocol Set (PPS) was a subset of the ITT and included all patients who did not present any major deviation of the protocol over the 6-month follow-up period. These deviations were detected during the blind review meeting.

    Subject analysis sets values
    		 ITT population Per Protocol Set
    Number of subjects
    370
    288
    Age categorical
    Units: Subjects
        In utero
        Preterm newborn infants (gestational age < 37 wks)
        Newborns (0-27 days)
        Infants and toddlers (28 days-23 months)
        Children (2-11 years)
        Adolescents (12-17 years)
        Adults (18-64 years)
    201
    157
        From 65-84 years
    169
    131
        85 years and over
    Age continuous
    Male or female aged more than 50 years old
    Units: years
        arithmetic mean (standard deviation)
    64.1 ± 6.7
    63.9 ± 6.3
    Gender categorical
    Units: Subjects
        Female
    274
    213
        Male
    96
    75
    study knee
    Units: Subjects
        right
    179
    136
        left
    191
    152

    End points

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    End points reporting groups
    Reporting group title
    Diacerein
    Reporting group description
    		 Diacerein 50 mg capsule and matching placebo (first month)

    Reporting group title
    Celecoxib
    Reporting group description
    		 Celecoxib 200 mg capsule and matching placebo

    Subject analysis set title
    ITT population
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    The Intention-To-Treat was composed of all randomized patients who received at least one dose of the study medication, had an efficacy measurement at inclusion and at least one corresponding post-inclusion efficacy measurement (for the primary efficacy variable).

    Subject analysis set title
    Per Protocol Set
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The Per Protocol Set (PPS) was a subset of the ITT and included all patients who did not present any major deviation of the protocol over the 6-month follow-up period. These deviations were detected during the blind review meeting.

    Primary: WOMAC Pain subscale

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    End point title
    		 WOMAC Pain subscale
    End point description
    End point type
    Primary
    End point timeframe
    182 days
    End point values
    		 Diacerein Celecoxib
    Number of subjects analysed
    140
    148
    Units: cm
        least squares mean (standard error)
    -11.14 ± 0.91
    -11.82 ± 0.89
    Statistical analysis title
    		 Absolute change from Baseline
    Comparison groups
    Celecoxib v Diacerein
    Number of subjects included in analysis
    288
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 < 0.05
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.67
    Confidence interval
         level
    		 95%
         sides
    1-sided
         lower limit
    		 -
         upper limit
    		 3.18

    Secondary: WOMAC OA Scores

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    End point title
    		 WOMAC OA Scores
    End point description
    Absolute Changes from Baseline - Intention-To-Treat (N=370)
    End point type
    Secondary
    End point timeframe
    Day 182 or early termination
    End point values
    		 Diacerein Celecoxib
    Number of subjects analysed
    177 [1]
    182
    Units: score
    arithmetic mean (standard deviation)
        Total Score
    -41.0 ± 53.1
    -42.9 ± 55.0
        Pain Score
    -10.03 ± 11.95
    -9.60 ± 12.02
        Stiffness Score
    -3.56 ± 4.99
    -3.99 ± 5.32
        Physical Function Score
    -27.2 ± 39.0
    -29.3 ± 39.8
    Notes
    [1] - For Pain Score and Stiffness Score the number of subjects is 178
    Statistical analysis title
    		 WOMAC OA Statistical Analysis
    Comparison groups
    Diacerein v Celecoxib
    Number of subjects included in analysis
    359
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.05
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Mean difference (final values)
    Confidence interval
         level
    		 95%

    Secondary: Pain Visual Analogue Scale

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    End point title
    		 Pain Visual Analogue Scale
    End point description
    Absolute Changes from Baseline - Intention-To-Treat (N=370)
    End point type
    Secondary
    End point timeframe
    Day 182 or early termination
    End point values
    		 Diacerein Celecoxib
    Number of subjects analysed
    178
    182
    Units: score
        arithmetic mean (standard deviation)
    -2.34 ± 2.55
    -2.46 ± 2.61
    Statistical analysis title
    		 Pain Visual Analogue Scale
    Comparison groups
    Celecoxib v Diacerein
    Number of subjects included in analysis
    360
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.05
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Mean difference (final values)
    Confidence interval
         level
    		 95%

    Secondary: OARSI Responders

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    End point title
    		 OARSI Responders
    End point description
    Absolute Changes from Baseline - Intention-To-Treat (N=370)
    End point type
    Secondary
    End point timeframe
    Day 182 or early termination
    End point values
    		 Diacerein Celecoxib
    Number of subjects analysed
    178
    182
    Units: score
        number (not applicable)
    99
    97
    Statistical analysis title
    		 OARSI Responder
    Comparison groups
    Diacerein v Celecoxib
    Number of subjects included in analysis
    360
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.05
    Method
    		 Chi-squared
    Confidence interval

    Secondary: Assessment of Joint Swelling, Effusion or Both

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    End point title
    		 Assessment of Joint Swelling, Effusion or Both
    End point description
    End point type
    Secondary
    End point timeframe
    Day 182 or early termination
    End point values
    		 Diacerein Celecoxib
    Number of subjects analysed
    177
    184
    Units: subject
    number (not applicable)
        Joint Swelling
    47
    48
        Joint Effusion
    37
    37
        Joint Swelling and Effusion
    19
    23
    Statistical analysis title
    		 Joint swelling, effusion or both Analysis
    Comparison groups
    Diacerein v Celecoxib
    Number of subjects included in analysis
    361
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.05
    Method
    		 Chi-squared
    Parameter type
    		 between group comparison
    Confidence interval
         level
    		 95%

    Secondary: Consumption of Acetaminophen

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    End point title
    		 Consumption of Acetaminophen
    End point description
    Overall Daily number of tablets taken during the 6 month study
    End point type
    Secondary
    End point timeframe
    Day 182 or early termination
    End point values
    		 Diacerein Celecoxib
    Number of subjects analysed
    183
    185
    Units: tablets
        arithmetic mean (standard deviation)
    1.06 ± 1.75
    0.91 ± 1.02
    Statistical analysis title
    		 Overall Consumption of Acetaminophen
    Comparison groups
    Diacerein v Celecoxib
    Number of subjects included in analysis
    368
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.05
    Method
    		 Chi-squared
    Parameter type
    		 Mean difference (final values)
    Confidence interval
         level
    		 95%

    Secondary: Global Assessment of Disease Activity

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    End point title
    		 Global Assessment of Disease Activity
    End point description
    End point type
    Secondary
    End point timeframe
    Day 182 or early termination
    End point values
    		 Diacerein Celecoxib
    Number of subjects analysed
    177
    179
    Units: score
    arithmetic mean (standard deviation)
        Patient's Global Assessment
    -1.81 ± 2.79
    -1.97 ± 2.97
        Investigator's Global Assessment
    -2.02 ± 2.55
    -2.65 ± 2.55
    Statistical analysis title
    		 Global Assessment of Disease Activity
    Comparison groups
    Diacerein v Celecoxib
    Number of subjects included in analysis
    356
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.05
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Mean difference (final values)
    Confidence interval
         level
    		 95%

    Secondary: Global Assessment of Response to Therapy

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    End point title
    		 Global Assessment of Response to Therapy
    End point description
    Absolute Changes from Baseline - Intention-To-Treat (N=370)
    End point type
    Secondary
    End point timeframe
    Day 182 or early termination
    End point values
    		 Diacerein Celecoxib
    Number of subjects analysed
    177 [2]
    182 [3]
    Units: score
    arithmetic mean (standard deviation)
        Patient's Global Assessement
    3.89 ± 2.57
    3.61 ± 2.52
        Investigator's Global Assessment
    3.85 ± 2.51
    3.35 ± 2.42
    Notes
    [2] - 176 subjects evaluated for the Investigator's Global Assessment
    [3] - 180 subjects evaluated for the Investigator's Global Assessment
    Statistical analysis title
    		 Global Assessment Response to Therapy
    Comparison groups
    Diacerein v Celecoxib
    Number of subjects included in analysis
    359
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.05
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Mean difference (final values)
    Confidence interval
         level
    		 95%

    Secondary: Quality of life SF-36

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    End point title
    		 Quality of life SF-36
    End point description
    Absolute Changes from Baseline - Intention-To-Treat (N=370)
    End point type
    Secondary
    End point timeframe
    Day 182 or early termination
    End point values
    		 Diacerein Celecoxib
    Number of subjects analysed
    178
    178
    Units: score
    arithmetic mean (standard deviation)
        Physical Component Summary
    2.46 ± 6.74
    4.57 ± 8.08
        Mental Component Summary
    1.56 ± 8.34
    -0.14 ± 8.87
    Statistical analysis title
    		 Quality of life SF-36
    Statistical analysis description
    Absolute Changes from Baseline by Visit and Comparisons Between Treatment Groups - Intention-To-Treat (N=370)
    Comparison groups
    Diacerein v Celecoxib
    Number of subjects included in analysis
    356
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.05
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Mean difference (final values)
    Confidence interval
         level
    		 95%

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    At each post-screening visit: Day 0, 60, 120 and 182
    Adverse event reporting additional description
    Emergent Adverse Events Related to Study Treatment (non-serious adverse events only) Serious adverse events (SAEs) were experienced in 3 (1.6%) patients in the Diacerein group versus 4 (2.1%) patients in the Celecoxib group (which were considered not related to Celecoxib).
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.0
    Reporting groups
    Reporting group title
    Diacerein
    Reporting group description
    		 Diacerein 50 mg capsule and matching placebo (first month)

    Reporting group title
    Celecoxib
    Reporting group description
    		 Celecoxib 200 mg capsule and matching placebo

    Serious adverse events
    		 Diacerein Celecoxib
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 186 (1.61%)
    4 / 190 (2.11%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Neoplasm prostate
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 190 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 190 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transaminases increased
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 190 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Accidental overdose
         subjects affected / exposed
    0 / 186 (0.00%)
    1 / 190 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower limb fracture
         subjects affected / exposed
    0 / 186 (0.00%)
    1 / 190 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Temporal arteritis
         subjects affected / exposed
    0 / 186 (0.00%)
    1 / 190 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebrovascular accident
         subjects affected / exposed
    0 / 186 (0.00%)
    1 / 190 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 190 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Depression
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 190 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Diacerein Celecoxib
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    111 / 186 (59.68%)
    103 / 190 (54.21%)
    Vascular disorders
    Hot flush
         subjects affected / exposed
    0 / 186 (0.00%)
    1 / 190 (0.53%)
         occurrences all number
    0
    1
    Hypertensive crisis
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 190 (0.00%)
         occurrences all number
    1
    0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 186 (0.00%)
    1 / 190 (0.53%)
         occurrences all number
    0
    1
    Chest pain
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 190 (0.00%)
         occurrences all number
    1
    0
    Fatigue
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 190 (0.00%)
         occurrences all number
    1
    0
    Immune system disorders
    Seasonal allergy
         subjects affected / exposed
    0 / 186 (0.00%)
    1 / 190 (0.53%)
         occurrences all number
    0
    1
    Reproductive system and breast disorders
    Benign prostatic hyperplasia
         subjects affected / exposed
    0 / 186 (0.00%)
    1 / 190 (0.53%)
         occurrences all number
    0
    1
    Psychiatric disorders
    Libido decreased
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 190 (0.00%)
         occurrences all number
    1
    0
    Investigations
    Blood pressure increased
         subjects affected / exposed
    1 / 186 (0.54%)
    1 / 190 (0.53%)
         occurrences all number
    1
    1
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 190 (0.00%)
         occurrences all number
    1
    0
    Platelet count decreased
         subjects affected / exposed
    0 / 186 (0.00%)
    1 / 190 (0.53%)
         occurrences all number
    0
    1
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 190 (0.00%)
         occurrences all number
    1
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    1 / 186 (0.54%)
    3 / 190 (1.58%)
         occurrences all number
    1
    4
    Dizziness
         subjects affected / exposed
    0 / 186 (0.00%)
    1 / 190 (0.53%)
         occurrences all number
    0
    1
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    19 / 186 (10.22%)
    7 / 190 (3.68%)
         occurrences all number
    21
    7
    Dyspepsia
         subjects affected / exposed
    5 / 186 (2.69%)
    5 / 190 (2.63%)
         occurrences all number
    5
    5
    Faeces soft
         subjects affected / exposed
    3 / 186 (1.61%)
    6 / 190 (3.16%)
         occurrences all number
    3
    6
    Abdominal pain
         subjects affected / exposed
    6 / 186 (3.23%)
    2 / 190 (1.05%)
         occurrences all number
    7
    2
    Abdominal pain upper
         subjects affected / exposed
    4 / 186 (2.15%)
    1 / 190 (0.53%)
         occurrences all number
    4
    1
    Nausea
         subjects affected / exposed
    2 / 186 (1.08%)
    2 / 190 (1.05%)
         occurrences all number
    2
    2
    Constipation
         subjects affected / exposed
    2 / 186 (1.08%)
    0 / 190 (0.00%)
         occurrences all number
    2
    0
    Frequent bowel movements
         subjects affected / exposed
    1 / 186 (0.54%)
    1 / 190 (0.53%)
         occurrences all number
    1
    1
    Gastrooesophageal reflux disease
         subjects affected / exposed
    2 / 186 (1.08%)
    0 / 190 (0.00%)
         occurrences all number
    2
    0
    Vomiting
         subjects affected / exposed
    1 / 186 (0.54%)
    1 / 190 (0.53%)
         occurrences all number
    1
    1
    Abdominal tenderness
         subjects affected / exposed
    0 / 186 (0.00%)
    1 / 190 (0.53%)
         occurrences all number
    0
    1
    Epigastric discomfort
         subjects affected / exposed
    0 / 186 (0.00%)
    1 / 190 (0.53%)
         occurrences all number
    0
    1
    Flatulence
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 190 (0.00%)
         occurrences all number
    1
    0
    Gastritis
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 190 (0.00%)
         occurrences all number
    1
    0
    Hypoaesthesia oral
         subjects affected / exposed
    0 / 186 (0.00%)
    1 / 190 (0.53%)
         occurrences all number
    0
    1
    Paraesthesia oral
         subjects affected / exposed
    0 / 186 (0.00%)
    1 / 190 (0.53%)
         occurrences all number
    0
    1
    Tongue geographic
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 190 (0.00%)
         occurrences all number
    1
    0
    Toothache
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 190 (0.00%)
         occurrences all number
    1
    0
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    0 / 186 (0.00%)
    2 / 190 (1.05%)
         occurrences all number
    0
    2
    Angioedema
         subjects affected / exposed
    0 / 186 (0.00%)
    1 / 190 (0.53%)
         occurrences all number
    0
    1
    Hyperhidrosis
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 190 (0.00%)
         occurrences all number
    1
    0
    Rash pruritic
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 190 (0.00%)
         occurrences all number
    1
    0
    Renal and urinary disorders
    Chromaturia
         subjects affected / exposed
    5 / 186 (2.69%)
    0 / 190 (0.00%)
         occurrences all number
    5
    0
    Haematuria
         subjects affected / exposed
    2 / 186 (1.08%)
    0 / 190 (0.00%)
         occurrences all number
    2
    0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    2 / 186 (1.08%)
    1 / 190 (0.53%)
         occurrences all number
    2
    1
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    1 / 186 (0.54%)
    1 / 190 (0.53%)
         occurrences all number
    1
    1
    Labyrinthitis
         subjects affected / exposed
    0 / 186 (0.00%)
    1 / 190 (0.53%)
         occurrences all number
    0
    1
    Tooth infection
         subjects affected / exposed
    0 / 186 (0.00%)
    1 / 190 (0.53%)
         occurrences all number
    0
    1
    Cardiac disorder
         subjects affected / exposed
    2 / 186 (1.08%)
    1 / 190 (0.53%)
         occurrences all number
    2
    1
    Palpitations
         subjects affected / exposed
    2 / 186 (1.08%)
    1 / 190 (0.53%)
         occurrences all number
    2
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    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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    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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