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    Clinical Trial Results:
    PHASE III RANDOMIZED CHEMOPREVENTION STUDY OF SELENIUM ON THE RECURRENCE OF NON-INVASIVE BLADDER CANCER

    Summary
    EudraCT number
    		 2008-005431-15
    Trial protocol
    		 BE  
    Global end of trial date
    31 Dec 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    07 Feb 2023
    First version publication date
    07 Feb 2023
    Other versions
    Summary report(s)
    		 Publication1
    Publication 2

    Trial information

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    Trial identification
    Sponsor protocol code
    ML 5220
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00729287
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    KU Leuven, Department of General Practice
    Sponsor organisation address
    Kapucijnenvoer 33, blok J bus 7001, Leuven, Belgium, 3000
    Public contact
    Dr Frank Buntinx, KU Leuven, Department of General Practice, 32 0475/ 41 90 53, Maria.Goossens@sciensano.be
    Scientific contact
    Dr Frank Buntinx, KU Leuven, Department of General Practice, 32 089/ 76 13 54 , Maria.Goossens@sciensano.be
    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
    31 Dec 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    08 May 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    31 Dec 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of the study is to determine the effect of selenium, in addition to standard care, on the recurrence of bladder cancer.
    Protection of trial subjects
    Adverse events and adverse reactions will be monitored during each follow-up visit and will be noted on the case report forms. The obligation starts from the moment the informed consent is signed until 30 days after the administration of the last dose. The principal Investigator will decide whether the serious adverse event is related or unrelated to the trial treatment. It is anticipated that the risk and side effects of the additional supplement of 200μg selenium will be minor. Nevertheless, harm-related data will be collected and reported according the recommendation made by the CONSORT statement.
    Background therapy
    		 In Belgium, bladder cancer (BC) is the fifth most common cancer in men. The per-patient lifetime cost is high. Previous epidemiological studies have consistently reported that selenium concentrations were inversely associated with the risk of BC. We therefore hypothesised that selenium may be suitable for chemoprevention of recurrence of BC.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    18 Sep 2009
    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
    Belgium: 292
    Worldwide total number of subjects
    292
    EEA total number of subjects
    292
    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)
    65
    From 65 to 84 years
    195
    85 years and over
    32

    Subject disposition

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    Recruitment
    Recruitment details
    		 Eligible patients were recruited through the urology department of 14 Belgian hospitals. Eligible patients provided their written informed consent. Patients were randomly assigned by a computer program to oral selenium yeast 200 μg once a day or placebo for three years, in addition to standard care.

    Pre-assignment
    Screening details
    		 All randomised patients were included in the intention to treat and safety analyses. Per protocol analyses included all patients in the study three months after start date. Between September 18, 2009 and April 18, 2013, 151 and 141 patients were randomised in the selenium and placebo group. Patients were followed until December 31, 2015.

    Pre-assignment period milestones
    Number of subjects started
    		 694 [1]
    Intermediate milestone: Number of subjects
    Assessed for eligibility: 694
    Intermediate milestone: Number of subjects
    Randomised: 292
    Number of subjects completed
    		 292

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    		 not meeting inclusion criteria: 243
    Reason: Number of subjects
    		 No malignity: 57
    Reason: Number of subjects
    		 Not available: 50
    Reason: Number of subjects
    		 Declined to participate: 39
    Reason: Number of subjects
    		 cystectomy: 8
    Reason: Number of subjects
    		 Adverse event, serious fatal: 5
    Notes
    [1] - The number of subjects reported to have started the pre-assignment period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: 694 pts were assessed for eligibility. Out of this number, 402 pts were exluded, leaving 292 pts that could be randomised. In the Intention to treat analysis (292 pts in total) 151 pts were allocated to the Selenium 200mcg group and 141 pts were allocated to placebo.
    Period 1
    Period 1 title
    Baseline
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Carer

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Selenium
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    selenium (200μg)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    One tablet (selenium/placebo) once daily at breakfast for a period of three years.

    Arm title
    		 Placebo
    Arm description
    		 -
    Arm type
    		 Placebo

    Investigational medicinal product name
    selenium (200μg)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    One tablet (selenium/placebo) once daily at breakfast for a period of three years.

    Number of subjects in period 1
    		Selenium Placebo
    Started
    151
    141
    Completed
    151
    141
    Period 2
    Period 2 title
    Follow-up
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Carer

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Selenium
    Arm description
    		 Arm I: Patients receive oral placebo daily additionally to standard care. Arm II: Patients receive oral selenium (200μg) daily additionally to standard care.
    Arm type
    		 Experimental

    Investigational medicinal product name
    selenium (200μg)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    One tablet (selenium/placebo) once daily at breakfast for a period of three years.

    Arm title
    		 Placebo
    Arm description
    		 -
    Arm type
    		 Placebo

    Investigational medicinal product name
    selenium (200μg)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    One tablet (selenium/placebo) once daily at breakfast for a period of three years.

    Number of subjects in period 2
    		Selenium Placebo
    Started
    151
    141
    Follow-up 3 Months
    136
    123
    Follow-up 36 Months
    110
    106
    Completed
    110
    106
    Not completed
    41
    35
         Adverse event, serious fatal
    1
    -
         Consent withdrawn by subject
    32
    19
         cystectomy
    -
    3
         Adverse event, non-fatal
    2
    2
         Recurrence
    -
    1
         not meeting inclusion criteria
    6
    10

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Selenium
    Reporting group description
    		 -

    Reporting group title
    Placebo
    Reporting group description
    		 -

    Reporting group values
    		 Selenium Placebo Total
    Number of subjects
    		 151 141 292
    Age categorical
    Median age was 68 years ranging from 46 to 90 and 91 years for the selenium and the placebo group. Specific numbers per group are not specified in the results.
    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)
    		 57 41 98
        From 65-84 years
    		 82 80 162
        85 years and over
    		 12 20 32
    Age continuous
    Median age was 68 years ranging from 46 to 90 and 91 years for the selenium and the placebo group. No further details regarding age were mentioned in the resulst.
    Units: years
        median (full range (min-max))
    		 68 (46 to 90) 68 (46 to 91) -
    Gender categorical
    Units: Subjects
        Female
    		 20 30 50
        Male
    		 131 111 242
    Number of tumours
    Units: Subjects
        solitary tumour
    		 81 80 161
        2-7
    		 54 44 98
        >=8
    		 2 2 4
        unknown
    		 14 15 29
    Primary tumour
    Units: Subjects
        Primary tumour
    		 102 88 190
        Recurrent
    		 35 41 76
        Unknown
    		 14 12 26
    Subject analysis sets

    Subject analysis set title
    ITT
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    The ITT analysis showed recurrence in 43 (28%; 95% CI, 0.21e0.35) and 45 (32%; 95% CI, 0.24e0.40) patients in the selenium and placebo group. HR (hazard ratio) was 0.85 (95% CI, 0.56e1.29). The log-rank test was not significant (p Z 0.44). Adjustment for age, gender, smoking status, staging, baseline serum selenium level and hospital did not alter the results. There was no interaction between treatment and gender, age or smoking status. Excluding those patients who discontinued the intervention did not alter HR of ITT analysis (p Z 0.39).

    Subject analysis set title
    PPA
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    PPA, performed for all patients still participating at T3, showed an overall recurrence for 42 and 39 (28%; 95% CI, 0.20e0.35) patients in the selenium and placebo group (HR Z 0.96 [95% CI, 0.62e1.48]). The log-rank test was not significant (p Z 0.85) (Fig. 2). Excluding those patients who discontinued the intervention resulted in an HR of 0.94 (95% CI, 0.61e1.45). The log-rank test was not significant (p Z 0.78).

    Subject analysis sets values
    		 ITT PPA
    Number of subjects
    292
    259
    Age categorical
    Median age was 68 years ranging from 46 to 90 and 91 years for the selenium and the placebo group. Specific numbers per group are not specified in the results.
    Units: Subjects
        In utero
    0
    0
        Preterm newborn infants (gestational age < 37 wks)
    0
    0
        Newborns (0-27 days)
    0
    0
        Infants and toddlers (28 days-23 months)
    0
    0
        Children (2-11 years)
    0
    0
        Adolescents (12-17 years)
    0
    0
        Adults (18-64 years)
    72
    67
        From 65-84 years
    195
    173
        85 years and over
    25
    19
    Age continuous
    Median age was 68 years ranging from 46 to 90 and 91 years for the selenium and the placebo group. No further details regarding age were mentioned in the resulst.
    Units: years
        median (full range (min-max))
    68 (46 to 90)
    68 (46 to 91)
    Gender categorical
    Units: Subjects
        Female
    39
    55
        Male
    253
    204
    Number of tumours
    Units: Subjects
        solitary tumour
    161
    142
        2-7
    98
    87
        >=8
    4
    3
        unknown
    29
    27
    Primary tumour
    Units: Subjects
        Primary tumour
    190
    162
        Recurrent
    76
    75
        Unknown
    26
    22

    End points

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    End points reporting groups
    Reporting group title
    Selenium
    Reporting group description
    		 -

    Reporting group title
    Placebo
    Reporting group description
    		 -
    Reporting group title
    Selenium
    Reporting group description
    		 Arm I: Patients receive oral placebo daily additionally to standard care. Arm II: Patients receive oral selenium (200μg) daily additionally to standard care.

    Reporting group title
    Placebo
    Reporting group description
    		 -

    Subject analysis set title
    ITT
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    The ITT analysis showed recurrence in 43 (28%; 95% CI, 0.21e0.35) and 45 (32%; 95% CI, 0.24e0.40) patients in the selenium and placebo group. HR (hazard ratio) was 0.85 (95% CI, 0.56e1.29). The log-rank test was not significant (p Z 0.44). Adjustment for age, gender, smoking status, staging, baseline serum selenium level and hospital did not alter the results. There was no interaction between treatment and gender, age or smoking status. Excluding those patients who discontinued the intervention did not alter HR of ITT analysis (p Z 0.39).

    Subject analysis set title
    PPA
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    PPA, performed for all patients still participating at T3, showed an overall recurrence for 42 and 39 (28%; 95% CI, 0.20e0.35) patients in the selenium and placebo group (HR Z 0.96 [95% CI, 0.62e1.48]). The log-rank test was not significant (p Z 0.85) (Fig. 2). Excluding those patients who discontinued the intervention resulted in an HR of 0.94 (95% CI, 0.61e1.45). The log-rank test was not significant (p Z 0.78).

    Primary: Primary outcome: recurrence

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    End point title
    		 Primary outcome: recurrence
    End point description
    Adjustment for age, gender, smoking status, staging, baseline serum selenium level and hospital did not alter the results. There was no interaction between treatment and gender, age or smoking status. Excluding those patients who discontinued the intervention did not alter HR of ITT analysis (p Z 0.39).
    End point type
    Primary
    End point timeframe
    The ITT analysis showed recurrence in 43 (28%; 95% CI, 0.21e0.35) and 45 (32%; 95% CI, 0.24e0.40) patients in the selenium and placebo group. HR was 0.85 (95% CI, 0.56e1.29). The log-rank test was not significant (p Z 0.44).
    End point values
    		 ITT PPA
    Number of subjects analysed
    151
    141
    Units: patients
    number (confidence interval 95%)
        recurrence
    0.28 (0.21 to 0.35)
    0.28 (0.20 to 0.35)
    Attachments
    		 Table 1
    Statistical analysis title
    		 Difference in percent of BC recurrence after 3Y
    Statistical analysis description
    All randomised patients were included in the intention to treat (ITT) and safety analyses. KaplaneMeier estimates of a recurrence-free interval were used to compare treatment groups descriptively, while log-rank tests were used to test the hypothesis of no difference between treatments. Cox proportional hazards regression models were used to estimate the hazard ratio (HR) and 95% confidence intervals (CI) comparing patients randomised to selenium or placebo. T0 was when ICF was signed.
    Comparison groups
    ITT v PPA
    Number of subjects included in analysis
    292
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [1]
    P-value
    		 = 0.05 [2]
    Method
    		 Logrank
    Parameter type
    		 Cox proportional hazard
    Point estimate
    0.85
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.56
         upper limit
    		 1.29
    Variability estimate
    Standard deviation
    Dispersion value
    21.5
    Notes
    [1] - The end date for each pt was the day of recurrence, cystectomy or death, or the day the pt withdrew from the trial, or 3 Y after T0, or the end date of the trial (31Dec15). PPA included all patients in the study 3 months after the starting date (T3). Pts who withdrew as well as pts with cystectomy within the first 3 months were excluded from PPA. Two sensitivity analyses were performed excluding all pts that ended the trial prematurely, the first based on ITT analysis, the second based on PPA.
    [2] - KM estimates of a recurrence-free interval to compare trtmnt groups descriptively, log-rank tests to test the hypothesis of no difference between trtmnts. Cox proportional hazards regression models to estimate HR and 95%CI comparing pts rand to Se/Pl

    Secondary: Secondary outcome: progression

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    End point title
    		 Secondary outcome: progression
    End point description
    Twenty-nine patients showed progression of whom 15 occurred in the selenium group and 14 in the placebo group. Performing the ITT analysis resulted in an HR of 0.97 (95% CI, 0.47e2.00; p Z 0.93). Patients taking selenium had 48% more chance of progression than those in the placebo group, although not statistically significant (HR Z 1.48 [95% CI, 0.65e3.38]; p Z 0.35). Excluding those patients from the analysis who discontinued their treatment resulted in a similar HR.
    End point type
    Secondary
    End point timeframe
    After three months (T3), progression was seen in 24 patients. The mean progression time was 22 months for both groups.
    End point values
    		 ITT
    Number of subjects analysed
    292
    Units: patients
    number (confidence interval 95%)
        Progression
    0.97 (0.47 to 2.00)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events and adverse reactions were monitored during each follow-up visit and were noted on the case report forms. The obligation started from the moment the informed consent was signed until 30 days after the administration of the last dose.
    Adverse event reporting additional description
    The principal Investigator will decide whether the serious adverse event is related or unrelated to the trial treatment. The decision will be recorded on the serious adverse event form. The principal Investigator will sign the form.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 CTCAE
    Dictionary version
    3
    Reporting groups
    Reporting group title
    Selenium
    Reporting group description
    		 -

    Reporting group title
    Placebo
    Reporting group description
    		 -

    Serious adverse events
    		 Selenium Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 151 (0.00%)
    0 / 141 (0.00%)
         number of deaths (all causes)
    1
    0
         number of deaths resulting from adverse events
    0
    0
    Frequency threshold for reporting non-serious adverse events: 1.3%
    Non-serious adverse events
    		 Selenium Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    8 / 151 (5.30%)
    9 / 141 (6.38%)
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    1 / 151 (0.66%)
    2 / 141 (1.42%)
         occurrences all number
    1
    2
    Pain
         subjects affected / exposed
    1 / 151 (0.66%)
    0 / 141 (0.00%)
         occurrences all number
    1
    0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    1 / 151 (0.66%)
    0 / 141 (0.00%)
         occurrences all number
    1
    0
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    1 / 151 (0.66%)
    0 / 141 (0.00%)
         occurrences all number
    1
    0
    Diarrhoea
         subjects affected / exposed
    1 / 151 (0.66%)
    1 / 141 (0.71%)
         occurrences all number
    1
    1
    stomach/intestinal
         subjects affected / exposed
    1 / 151 (0.66%)
    4 / 141 (2.84%)
         occurrences all number
    1
    4
    Constipation
         subjects affected / exposed
    1 / 151 (0.66%)
    1 / 141 (0.71%)
         occurrences all number
    1
    1
    Musculoskeletal and connective tissue disorders
    Nail injury
         subjects affected / exposed
    0 / 151 (0.00%)
    1 / 141 (0.71%)
         occurrences all number
    0
    1
    Back pain
         subjects affected / exposed
    1 / 151 (0.66%)
    0 / 141 (0.00%)
         occurrences all number
    1
    0

    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

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/27814472
    http://www.ncbi.nlm.nih.gov/pubmed/22436453
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