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    Clinical Trial Results:
    Double blind, randomised, prospective placebo controlled parallel group phase III study to investigate the Effect of EGCG supplementation on disease progression of patients with Multiple System Atrophy (MSA)

    Summary
    EudraCT number
    		 2012-000928-18
    Trial protocol
    		 DE  
    Global end of trial date
    16 Sep 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    27 Aug 2021
    First version publication date
    27 Aug 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    PROMESA
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02008721
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Hospital of the Ludwig-Maximilians-University of Munich
    Sponsor organisation address
    Marchioninistrasse 15, Munich, Germany, 81377
    Public contact
    Sponsor delegated person: Dr. Levin, Hospital of the Ludwig-Maximilians-University of Munich , +49 89440074812, jlevin@med.uni-muenchen.de
    Scientific contact
    Sponsor delegated person: Dr. Levin, Hospital of the Ludwig-Maximilians-University of Munich , +49 89440074812, jlevin@med.uni-muenchen.de
    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
    16 Sep 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    16 Sep 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    16 Sep 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess the efficacy of EGCG vs. Placebo to reduce the progression in the motor examination (ME) of the Unified MSA Rating Scale (UMSARS-ME) from V1 to V7, (80% power, 5% P-level, 50% effect size, i.e. an expected mean yearly UMSARS-ME increase of 3.9 under verum treatment compared to 7.8 ± 6.8 (mean ± standard deviation) under Placebo-treatment.
    Protection of trial subjects
    The reported data suggested a safe pharmacological profile of the compound apart from individual cases of hepatotoxicity which could be controlled for by routine serum liver parameters. The preclinical data suggest a molecular mode of action for EGCG which appears to target core pathological mechanisms active in MSA. In absence of any effective symptomatic, protective or curative intervention in this devastating disorder, the risk benefit evaluation justifies the conduct of the proposed clinical trial. Exclusion criteria included liver disease with aminotransferases and bilirubin concentrations twice the upper limit of normal or higher; regular intake of hepatotoxic drugs; known hypersensitivity to epigallocatechin gallate or to drugs with similar chemical structures.
    Background therapy
    		 Eligible patients had to be on stable anti-Parkinson’s, anti-dysautonomia, anti-dementia, and anti-depressant regimens (if necessary) for at least 1 month without a foreseeable need to change the regimens during the next year.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    23 Apr 2014
    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
    Germany: 92
    Worldwide total number of subjects
    92
    EEA total number of subjects
    92
    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)
    52
    From 65 to 84 years
    40
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Between April 23, 2014, and Sept 3, 2015, 127 participants were screened and 92 were randomly assigned—47 to epigallocatechin gallate and 45 to placebo at 12 specialist centres for diagnosis and treatment of parkinsonism in Germany.

    Pre-assignment
    Screening details
    		 Eligible patients were older than 30 years; met the diagnostic criteria for possible or probable parkinsonism-predominant or cerebellar-ataxia-predominant multiple system atrophy; could ambulate independently (ie, Hoehn and Yahr stages 1–3); and had to be on stable anti-Parkinson’s, anti-dysautonomia, anti-dementia, and anti-depressant regimens.

    Period 1
    Period 1 title
    overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator
    Blinding implementation details
    Participants were randomly assigned (1:1) to epigallocatechin gallate or placebo (mannitol) via a web-generated permuted blockwise randomisation list (block size=2) that was stratified by disease subtype parkinsonism-predominant disease vs cerebellar-ataxia-predominant disease). All participants and study personnel were masked to treatment assignment.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 EGCG (epigallocatechin gallate)
    Arm description
    		 Participants were older than 30 years; met consensus criteria for possible or probable multiple system atrophy and could ambulate independently (ie, were at Hoehn and Yahr stages 1–3); and were on stable anti-Parkinson’s, anti-dysautonomia, anti-dementia, and anti-depressant regimens (if necessary) for at least 1 month. They were given one hard gelatin capsule (containing 400 mg epigallocatechin gallate) orally once daily for 4 weeks, then one capsule twice daily for 4 weeks, and then one capsule three times daily for 40 weeks. After 48 weeks, all patients underwent a 4-week wash-out period.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    epigallocatechin gallate
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Gastroenteral use
    Dosage and administration details
    Participants were given one hard gelatin capsule (containing 400 mg epigallocatechin gallate) orally once daily for 4 weeks, then one capsule twice daily for 4 weeks, and then one capsule three times daily for 40 weeks.

    Arm title
    		 Placebo (mannitol)
    Arm description
    		 Eligible participants were older than 30 years; met consensus criteria for possible or probable multiple system atrophy and could ambulate independently (ie, were at Hoehn and Yahr stages 1–3); and were on stable anti-Parkinson’s, anti-dysautonomia, anti-dementia, and anti-depressant regimens (if necessary) for at least 1 month. Participants in the Placebo arm were given one hard gelatin capsule (containing 400 mg mannitol) orally once daily for 4 weeks, then one capsule twice daily for 4 weeks, and then one capsule three times daily for 40 weeks.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo (mannitol)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Gastroenteral use
    Dosage and administration details
    Participants were given one hard gelatin capsule (containing 400 mg mannitol) orally once daily for 4 weeks, then one capsule twice daily for 4 weeks, and then one capsule three times daily for 40 weeks.

    Investigational medicinal product name
    epigallocatechin gallate
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Gastroenteral use
    Dosage and administration details
    Participants were given one hard gelatin capsule (containing 400 mg epigallocatechin gallate) orally once daily for 4 weeks, then one capsule twice daily for 4 weeks, and then one capsule three times daily for 40 weeks.

    Number of subjects in period 1
    		EGCG (epigallocatechin gallate) Placebo (mannitol)
    Started
    47
    45
    completion of study treatment
    32
    35
    completion of study assessment
    31
    33
    completed without protocol violations
    30
    33
    participation in MRI substudy
    17 [1]
    15 [2]
    completion of MRI substudy
    11 [3]
    8 [4]
    Completed
    30
    33
    Not completed
    17
    12
         Adverse event, serious fatal
    4
    2
         Consent withdrawn by subject
    4
    1
         Adverse event, non-fatal
    4
    7
         did not give reason
    1
    -
         Protocol deviation
    4
    2
    Notes
    [1] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Please consider the MRI substudy (17 of 47 participants) as an additional group arm.
    [2] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Please consider the MRI substudy (15 of 45 participants) as an additional group arm.
    [3] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Only part of the 47 participants in this arm were able to take part in the MRI substudy. In this arm, 17 participants took part and of these, 11 participants completed the substudy, hence the diverging numbers.
    [4] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Of the 45 participants in this arm, only 15 could participate in the MRI substudy. Of those, only 8 completed the substudy, hence the diverging numbers.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    overall trial
    Reporting group description
    		 -

    Reporting group values
    		 overall trial Total
    Number of subjects
    		 92 92
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 52 52
        From 65-84 years
    		 40 40
    Age continuous
    Units: years
        median (inter-quartile range (Q1-Q3))
    		 62 (57 to 70) -
    Gender categorical
    Units: Subjects
        Female
    		 37 37
        Male
    		 55 55
    Subject analysis sets

    Subject analysis set title
    Full analysis set
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All participants who received at least one dose of study medication (ie, the full analysis set)

    Subject analysis sets values
    		 Full analysis set
    Number of subjects
    92
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    52
        From 65-84 years
    40
    Age continuous
    Units: years
        median (inter-quartile range (Q1-Q3))
    Gender categorical
    Units: Subjects
        Female
        Male

    End points

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    End points reporting groups
    Reporting group title
    EGCG (epigallocatechin gallate)
    Reporting group description
    		 Participants were older than 30 years; met consensus criteria for possible or probable multiple system atrophy and could ambulate independently (ie, were at Hoehn and Yahr stages 1–3); and were on stable anti-Parkinson’s, anti-dysautonomia, anti-dementia, and anti-depressant regimens (if necessary) for at least 1 month. They were given one hard gelatin capsule (containing 400 mg epigallocatechin gallate) orally once daily for 4 weeks, then one capsule twice daily for 4 weeks, and then one capsule three times daily for 40 weeks. After 48 weeks, all patients underwent a 4-week wash-out period.

    Reporting group title
    Placebo (mannitol)
    Reporting group description
    		 Eligible participants were older than 30 years; met consensus criteria for possible or probable multiple system atrophy and could ambulate independently (ie, were at Hoehn and Yahr stages 1–3); and were on stable anti-Parkinson’s, anti-dysautonomia, anti-dementia, and anti-depressant regimens (if necessary) for at least 1 month. Participants in the Placebo arm were given one hard gelatin capsule (containing 400 mg mannitol) orally once daily for 4 weeks, then one capsule twice daily for 4 weeks, and then one capsule three times daily for 40 weeks.

    Subject analysis set title
    Full analysis set
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All participants who received at least one dose of study medication (ie, the full analysis set)

    Primary: Scores on the motor examination of the UMSARS from baseline to week 52

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    End point title
    		 Scores on the motor examination of the UMSARS from baseline to week 52
    End point description
    The primary endpoint was the change from baseline to week 52 in motor examination scores on the Unified MSA Rating Scale (UMSARS), which assesses 14 operationalised signs of multiple system atrophy.25 Scores for all 14 items range from 0 to 4, thus total scores range from 0 to 56. A higher score means a worse outcome.
    End point type
    Primary
    End point timeframe
    52 weeks
    End point values
    		 EGCG (epigallocatechin gallate) Placebo (mannitol)
    Number of subjects analysed
    47
    45
    Units: 14
        median (standard error)
    5.66 ( 1.01 )
    6.60 ( 0.99 )
    Statistical analysis title
    		 modified intention-to-treat analysis
    Statistical analysis description
    For the primary and secondary outcomes, we did a modified intention-to-treat analysis, which included all participants who received at least one dose of study medication (ie, the full analysis set). We used a linear mixed-effects model to test the primary hypothesis—ie, to compare differences in the change in motor examination scores on UMSARS between baseline and week 52 between the study groups.
    Comparison groups
    EGCG (epigallocatechin gallate) v Placebo (mannitol)
    Number of subjects included in analysis
    92
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority [1]
    P-value
    		 = 0.51
    Method
    		 Mixed models analysis
    Confidence interval
    Notes
    [1] - We did a post-hoc power calculation based on the mean change in motor examination scores on UMSARS and SDs in the placebo group of the per-protocol study completer set to test the assumptions of our initial power calculation.

    Secondary: Change in the UMSARS total score from baseline to week 52

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    End point title
    		 Change in the UMSARS total score from baseline to week 52
    End point description
    Secondary efficacy end point was the change from baseline to week 52 in the UMSARS total score. The UMSARS total score comprises a historical review (12 items) and the motor examination part (14 items). Scores for each item reach from 0 - 4, thus the total score ranges from 0 to 104. A higher score means a worse outcome.
    End point type
    Secondary
    End point timeframe
    52 weeks
    End point values
    		 EGCG (epigallocatechin gallate) Placebo (mannitol)
    Number of subjects analysed
    47
    45
    Units: 26
        median (standard error)
    10.33 ( 1.73 )
    10.35 ( 1.71 )
    Statistical analysis title
    		 modified intention-to-treat analysis
    Statistical analysis description
    We used a linear mixed-effects model to compare differences in the change of scores on the UMSARS total score between baseline and week 52 between the study groups.
    Comparison groups
    EGCG (epigallocatechin gallate) v Placebo (mannitol)
    Number of subjects included in analysis
    92
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 = 0.99
    Method
    		 Mixed models analysis
    Confidence interval

    Secondary: Scores on the motor examination of the UMSARS in the wash-out phase

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    End point title
    		 Scores on the motor examination of the UMSARS in the wash-out phase
    End point description
    Change in the score of the UMSARS-ME during wash-out phase V6-V7 (symptomatic effect) The secondary endpoint was the change from week 48 to week 52 (washout phase)in motor examination scores on UMSARS, which assesses 14 operationalised signs of multiple system atrophy. Scores for all 14 items range from 0 to 4, thus total scores range from 0 to 56. A higher score means a worse outcome.
    End point type
    Secondary
    End point timeframe
    During the wash-out phase V6-V7 (week 48- week 52), i.e. 4 weeks
    End point values
    		 EGCG (epigallocatechin gallate) Placebo (mannitol)
    Number of subjects analysed
    47
    45
    Units: 14
        median (standard error)
    0.68 ( 0.60 )
    0.49 ( 0.58 )
    Statistical analysis title
    		 modified intention-to-treat analysis
    Statistical analysis description
    For the primary and secondary outcomes, we did a modified intention-to-treat analysis, which included all participants who received at least one dose of study medication (ie, the full analysis set). We used a linear mixed-effects model to test the primary hypothesis—ie, to compare differences in the change in motor examination scores on UMSARS between baseline and week 52 between the study groups.
    Comparison groups
    EGCG (epigallocatechin gallate) v Placebo (mannitol)
    Number of subjects included in analysis
    92
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority [2]
    P-value
    		 = 0.82
    Method
    		 Mixed models analysis
    Confidence interval
    Notes
    [2] - We did a post-hoc power calculation based on the mean change in motor examination scores on UMSARS and SDs in the placebo group of the per-protocol study completer set to test the assumptions of our initial power calculation.

    Secondary: Change in the UMSARS total score in the washout phase

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    End point title
    		 Change in the UMSARS total score in the washout phase
    End point description
    Secondary efficacy end point was the change from week 48 to week 52 (washout phase) in the UMSARS total score. The UMSARS total score comprises a historical review (12 items) and the motor examination part (14 items). Scores for each item reach from 0 - 4, thus the total score ranges from 0 to 104. A higher score means a worse outcome.
    End point type
    Secondary
    End point timeframe
    4 weeks (washout phase from week 48 to week 52)
    End point values
    		 EGCG (epigallocatechin gallate) Placebo (mannitol)
    Number of subjects analysed
    47
    45
    Units: 26
        median (standard error)
    0.70 ( 0.21 )
    -0.29 ( 0.88 )
    Statistical analysis title
    		 modified intention-to-treat analysis
    Statistical analysis description
    We used a linear mixed-effects model to compare differences in the change of scores on the UMSARS total score between week 48 and week 52 between the study groups.
    Comparison groups
    EGCG (epigallocatechin gallate) v Placebo (mannitol)
    Number of subjects included in analysis
    92
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 = 0.43
    Method
    		 Mixed models analysis
    Confidence interval

    Secondary: Effect of treatment (EGCG vs. Placebo) on striatal volume loss in MRI

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    End point title
    		 Effect of treatment (EGCG vs. Placebo) on striatal volume loss in MRI
    End point description
    To assess the efficacy of EGCG vs. Placebo to reduce the progression from V1 to V7 in striatal volume loss (3D MPRAGE MRI volumetry, 3D FLAIR)
    End point type
    Secondary
    End point timeframe
    52 weeks
    End point values
    		 EGCG (epigallocatechin gallate) Placebo (mannitol)
    Number of subjects analysed
    11 [3]
    8 [4]
    Units: % of annual striatal volume loss
        number (not applicable)
    3.4
    7.3
    Notes
    [3] - 11 patients completed the MRI sub-study
    [4] - 8 patients completed the MRI substudy
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    April 23, 2014 until September 11, 2016
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17
    Reporting groups
    Reporting group title
    EGCG (= verum) group
    Reporting group description
    		 -

    Reporting group title
    Placebo group
    Reporting group description
    		 -

    Serious adverse events
    		 EGCG (= verum) group Placebo group
    Total subjects affected by serious adverse events
         subjects affected / exposed
    18 / 47 (38.30%)
    8 / 45 (17.78%)
         number of deaths (all causes)
    4
    2
         number of deaths resulting from adverse events
    4
    2
    Injury, poisoning and procedural complications
    fracture of femural bone
         subjects affected / exposed
    1 / 47 (2.13%)
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    synkope
         subjects affected / exposed
    1 / 47 (2.13%)
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    surgery
         subjects affected / exposed
    1 / 47 (2.13%)
    3 / 45 (6.67%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Headache
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Death
         subjects affected / exposed
    4 / 47 (8.51%)
    2 / 45 (4.44%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 4
    0 / 2
    General worsening of overall health
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    heat stroke and exsikkosis
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    gastrointestinal adverse event
         subjects affected / exposed
    5 / 47 (10.64%)
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 9
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    hepatotoxicity
         subjects affected / exposed
    2 / 47 (4.26%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    pneumonia due to aspiration
         subjects affected / exposed
    3 / 47 (6.38%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Skin and subcutaneous tissue disorders
    Phlegmone hand
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    UTI
         subjects affected / exposed
    0 / 47 (0.00%)
    2 / 45 (4.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthritis
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 45 (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
    		 EGCG (= verum) group Placebo group
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    25 / 47 (53.19%)
    33 / 45 (73.33%)
    Vascular disorders
    edema
         subjects affected / exposed
    3 / 47 (6.38%)
    3 / 45 (6.67%)
         occurrences all number
    3
    3
    Nervous system disorders
    Dysphagia
         subjects affected / exposed
    4 / 47 (8.51%)
    0 / 45 (0.00%)
         occurrences all number
    5
    0
    Dysarthria
         subjects affected / exposed
    0 / 47 (0.00%)
    4 / 45 (8.89%)
         occurrences all number
    0
    4
    falls
         subjects affected / exposed
    17 / 47 (36.17%)
    17 / 45 (37.78%)
         occurrences all number
    26
    31
    orthostatic hypotension
         subjects affected / exposed
    3 / 47 (6.38%)
    5 / 45 (11.11%)
         occurrences all number
    6
    5
    swallowing problems
         subjects affected / exposed
    3 / 47 (6.38%)
    0 / 45 (0.00%)
         occurrences all number
    5
    0
    worsening of parkinsonism, ataxia, autonomic dysfunction
         subjects affected / exposed
    10 / 47 (21.28%)
    9 / 45 (20.00%)
         occurrences all number
    24
    17
    Gastrointestinal disorders
    gastrointestinal adverse event
         subjects affected / exposed
    17 / 47 (36.17%)
    13 / 45 (28.89%)
         occurrences all number
    28
    21
    Hepatobiliary disorders
    hepatotoxicity
         subjects affected / exposed
    6 / 47 (12.77%)
    0 / 45 (0.00%)
         occurrences all number
    6
    0
    Psychiatric disorders
    Depression
         subjects affected / exposed
    5 / 47 (10.64%)
    2 / 45 (4.44%)
         occurrences all number
    5
    2
    Renal and urinary disorders
    UTI
         subjects affected / exposed
    9 / 47 (19.15%)
    12 / 45 (26.67%)
         occurrences all number
    14
    18
    urinary dysfunction
         subjects affected / exposed
    3 / 47 (6.38%)
    6 / 45 (13.33%)
         occurrences all number
    3
    6

    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.
    The trial was powered to detect a 50% reduction in disease progression, not to detect smaller changes. The assummed dropout rate was 20% while the observed drop out rate was approximately 27%. Only 4 of the 12 centres recruited 10 or more patients.

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/31278067
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