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    Clinical Trial Results:
    A randomised controlled phase III trial comparing hyperthermia plus mitomycin to a second course of bacillus Calmette-Guerin or standard therapy in patients with recurrence of non-muscle invasive bladder cancer following induction or maintenance bacillus Calmette-Guerin therapy.

    Summary
    EudraCT number
    2008-005428-99
    Trial protocol
    GB  
    Global end of trial date
    07 Oct 2016

    Results information
    Results version number
    v1(current)
    This version publication date
    01 Dec 2018
    First version publication date
    01 Dec 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    08/0365
    Additional study identifiers
    ISRCTN number
    ISRCTN85785327
    US NCT number
    NCT01094964
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    University College London
    Sponsor organisation address
    Joint Research Office, 1st Floor Maple House, 149 Tottenham Court Road, London, United Kingdom, W1T 7DN
    Public contact
    HYMN Trial Office, Cancer Research Clinical Trial Unit University of Birmingham, UK, 44 121 414 6372, HYMN@trials.bham.ac.uk
    Scientific contact
    Professor John Kelly, University College London Medical School , 44 20 7679 6490, j.d.kelly@ucl.ac.uk
    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
    17 Jan 2017
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    07 Oct 2016
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The aim of the trial is to determine whether Hyperthermia plus the chemotherapy drug mitomycin is an effective therapy for patients with non-muscle invasive bladder cancer who have tumour recurrence following bacillus Calmette-Guerin (BCG) therapy. To do this we will be looking at disease-free survival in all patients; and the complete response rate after three months of treatment for those patients who entered the trial with Carcinoma In-Situ (a difference form of non-muscle invasive bladder cancer).
    Protection of trial subjects
    The trial protocol instructed investigators on the treatment of patients, particular to follow the manufacturers' Summaries of Product Characteristics (SmPCs) for all drugs relevant to the trial (ie. mitomycin, BCG and that of the standard therapy specific to the site). The protocol, and training of site staff on induction of the site into the trial, pointed out potential issues, such as patients experiencing intolerance to BCG during induction therapy and expected toxicities, which were listed in the protocol (Section 9.3 and appendix 8). Mitomycin dose reductions were not permitted. Patients on BCG2 were treated on an intention-to-treat basis; any BCG dose reductions were at the discretion of the treating investigator. Treatment delays (potential reasons listed in protocol appendix 10) were permitted.
    Background therapy
    All the drugs used as part of this trial were classed as Investigational Medicinal Products (IMPs) and were prescribed by the investigator and dispensed by the hospital pharmacy from their routine clinical supply, throughout the trial. All doses of Mitomycin and BCG were administered according to the protocol. All doses of the Institutional Standard therapies were administered per local practice.
    Evidence for comparator
    Adjuvant intravesical BCG (bacillus of Calmette and Guérin) is an effective treatment for high risk non-muscle invasive bladder cancer (NMIBC)following transurethral resection (TUR) of papillary disease or as an ablative therapy for carcinoma in situ (CIS). USA and European national guidelines advocate early cystectomy or re-challenge with BCG therapy following BCG failure, though accept its limited efficacy.[1-3] Although early radical cystectomy is the standard of care, there remains a 90-day mortality of between 3·0-6·9%.[4-5] There remains no accepted second line bladder sparing approach following BCG failure. Although radical radiotherapy is not effective for NMIBC, the combination of intravesical mitomycin-C with radiofrequency-induced thermo-chemotherapy effect (RITE) is. Arends et al. compared RITE to intravesical BCG for intermediate and high risk BCG naïve NMIBC, reporting that recurrence free survival at 24 months supported earlier studies that reported RITE benefit for papillary NMIBC.[6] This study represents the first randomised controlled multicentre trial comparing the use of adjuvant RITE with institutional standard of care NMIBC patients who have failed intravesical BCG treatment. The HYMN trial is to our knowledge the only RCT conducted in this setting. Refs: 1. Han RF, et al. Urology 2006; 67(6): 1216-23 2. Sylvester RJ, et al. J Urol 2005; 174(1): 86-91 3. Babjuk M, et al. Eur Urol 2016 (Pub online: 17 Jun 2016) 4. Clark PE, et al. J Natl Compr Canc Netw 2016; 14(10): 1213-24 5.Tan WS, et al. Cancer Treat Rev 2016; 47: 22-31 6. Arends TJ, et al. Eur Urol 2016; 69(6): 1046-52
    Actual start date of recruitment
    06 May 2010
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Efficacy, Scientific research
    Long term follow-up duration
    10 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 104
    Worldwide total number of subjects
    104
    EEA total number of subjects
    104
    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)
    10
    From 65 to 84 years
    85
    85 years and over
    9

    Subject disposition

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    Recruitment
    Recruitment details
    A total of 104 participants were recruited across 14 UK centres between 6 May 2010 and 15 July 2013, when the trial was terminated early.

    Pre-assignment
    Screening details
    Investigator identified potential patients from surveillance cystoscopy cases, surgery lists or multi-disciplinary team meetings, underwent full screening evaluation after being informed about the trial and giving informed consent. Consenting patients who met the entry criteria were randomised into the trial.

    Period 1
    Period 1 title
    Baseline
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    RITE
    Arm description
    Hyperthermia plus mitomycin
    Arm type
    Experimental

    Investigational medicinal product name
    Mitomycin (with hyperthermia)
    Investigational medicinal product code
    PR1
    Other name
    Pharmaceutical forms
    Powder and solution for solution for injection
    Routes of administration
    Intravesical use
    Dosage and administration details
    Baseline - treatment not given yet.

    Arm title
    Control
    Arm description
    BCG or institutional standard therapy
    Arm type
    Institutional standard

    Investigational medicinal product name
    BCG immunotherapy
    Investigational medicinal product code
    PR2
    Other name
    BCG2
    Pharmaceutical forms
    Powder for bladder irrigation
    Routes of administration
    Intravesical use
    Dosage and administration details
    As per Summary of Product Characteristics (SmPC) or local practice, whichever is applicable and defined at trial entry.

    Investigational medicinal product name
    Epirubicin
    Investigational medicinal product code
    PR3
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravesical use
    Dosage and administration details
    As per Summary of Product Characteristics (SmPC) or local practice, whichever is applicable and defined at trial entry.

    Investigational medicinal product name
    Interferon alfa-2b
    Investigational medicinal product code
    PR4
    Other name
    IFNα, alpha interferon, INTRON-A
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Intravesical use
    Dosage and administration details
    As per Summary of Product Characteristics (SmPC) or local practice, whichever is applicable and defined at trial entry.

    Investigational medicinal product name
    Mitomycin
    Investigational medicinal product code
    PR5
    Other name
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intravitreal use
    Dosage and administration details
    As per Summary of Product Characteristics (SmPC) or local practice, whichever is applicable and defined at trial entry.

    Number of subjects in period 1
    RITE Control
    Started
    48
    56
    Completed
    48
    56
    Period 2
    Period 2 title
    End of Trial
    Is this the baseline period?
    No
    Allocation method
    Randomised - controlled
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    RITE
    Arm description
    Mitomycin C plus hyperthermia (HM) Patients received 6 weekly induction HM instillations using the Synergo® System, followed by a 6 week pause and cystoscopy assessment. If the patient was disease-free at assessment, they proceeded to maintenance HM, consisting of 6-weekly instillations of HM in year 1, then 8-weekly installations in year 2. Further treatment in those remaining disease-free at 24 months was at the clinician's discretion. Each instillation was divided into 2x 30-minute cycles each with 20mg mitomycin dissolved in 50mls of sterile water. Bladder hyperthermia (42 +/-2°C) was delivered in combination with each instillation of mitomycin in accordance with the manufacturer’s operational guidelines. At the end of the treatment, the suspension was held in the bladder for as long as possible (max. 2 hrs).
    Arm type
    Experimental

    Investigational medicinal product name
    Mitomycin plus hyperthermia
    Investigational medicinal product code
    PR1
    Other name
    HM
    Pharmaceutical forms
    Powder for intravesical solution/solution for injection, Powder for solution for infusion
    Routes of administration
    Intravesical use
    Dosage and administration details
    Two 30min instilation cycles of 20mg/50mls. 6 weekly instilations followed by 1 instilation every 6 weeks for thr first year and 1 instilation every 8 weeks for the second year. Further treatment in diease free patients after 2 years is at the discretion of the treating clinician.

    Arm title
    Control
    Arm description
    One of either: 1) Patients who failed previous induction BCG, ≤ 6 instillations : Second course of bacillus Calmette-Guerin therapy (BCG2) (Note : The small numnber of patients intollerant of BCG during induction therapy were randomised between HM and Intitutional Standard). OR 2) For patients who failed previous maintenance BCG, had > 6 instillations or patients with BCG intolerance. Institutional Standard - best available standard therapy for BCG-failure, chosen at the discretion of the treating clinician on a case-by-case basis. This cohort was followed-up by surveillance visits, as per protocol.
    Arm type
    Active comparator

    Investigational medicinal product name
    BCG immunotherapy
    Investigational medicinal product code
    PR2
    Other name
    BCG2
    Pharmaceutical forms
    Powder for bladder irrigation
    Routes of administration
    Intravesical use
    Dosage and administration details
    As per Summary of Product Characteristics (SmPC) or local practice, whichever is applicable and defined at trial entry.

    Investigational medicinal product name
    Epirubicin
    Investigational medicinal product code
    PR3
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravesical use
    Dosage and administration details
    As per Summary of Product Characteristics (SmPC) or local practice, whichever is applicable and defined at trial entry.

    Investigational medicinal product name
    Interferon alfa-2b
    Investigational medicinal product code
    PR4
    Other name
    IFNα, alpha interferon, INTRON-A
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Intravesical use
    Dosage and administration details
    As per Summary of Product Characteristics (SmPC) or local practice, whichever is applicable and defined at trial entry.

    Investigational medicinal product name
    Mitomycin
    Investigational medicinal product code
    PR5
    Other name
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intravitreal use
    Dosage and administration details
    As per Summary of Product Characteristics (SmPC) or local practice, whichever is applicable and defined at trial entry.

    Number of subjects in period 2
    RITE Control
    Started
    48
    56
    Completed
    48
    56

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    RITE
    Reporting group description
    Hyperthermia plus mitomycin

    Reporting group title
    Control
    Reporting group description
    BCG or institutional standard therapy

    Reporting group values
    RITE Control Total
    Number of subjects
    48 56 104
    Age categorical
    Units: Subjects
        Adults 18 years and over
    0
    Age continuous
    Units: years
        median (inter-quartile range (Q1-Q3))
    76.91 (72.78 to 81.53) 76.24 (70.05 to 81.36) -
    Gender categorical
    Units: Subjects
        Female
    14 12 26
        Male
    34 44 78
    Smoking Status
    Units: Subjects
        Never
    28 33 61
        Previous
    4 2 6
        Current
    16 21 37
        Not known
    0 0 0
    Tumour Stage
    Units: Subjects
        Tis + Ta
    10 4 14
        Tis + T1
    2 6 8
        Tis only
    21 28 49
        Ta only
    11 10 21
        T1 only
    4 8 12
        Not known
    0 0 0
    Tumour Grade
    Units: Subjects
        G1
    0 1 1
        G2
    9 6 15
        G3
    18 21 39
        Not known
    21 28 49
    Number of tumours identified
    Units: Subjects
        1 tumour
    16 24 40
        2 tumours
    7 8 15
        ≥3 tumours
    4 3 7
        Not known
    21 21 42
    Previous BCG
    Units: Subjects
        Induction only (≤6 instillations)
    18 19 37
        Induction + maintenance (>6 instillations)
    30 37 67
    Institutional Standard
    Definitions: BCG - Bacillus Calmette-Guérin; MMC - Mitimycin C; EMDA - electromotive drug administration. Three participants did not receive their institutional standard treatment but were included in the intention to treat analysis.
    Units: Subjects
        BCG alone
    0 14 14
        MMC alone
    0 9 9
        EMDA MMC
    0 13 13
        Not given
    0 20 20
        N/A
    48 0 48
    Resection
    Units: Subjects
        Complete
    28 33 61
        Incomplete
    4 2 6
        Not known
    16 21 37
    Total Tumour Size
    Units: millimeter(s)
        median (full range (min-max))
    5 (2 to 20) 5 (2 to 200) -

    End points

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    End points reporting groups
    Reporting group title
    RITE
    Reporting group description
    Hyperthermia plus mitomycin

    Reporting group title
    Control
    Reporting group description
    BCG or institutional standard therapy
    Reporting group title
    RITE
    Reporting group description
    Mitomycin C plus hyperthermia (HM) Patients received 6 weekly induction HM instillations using the Synergo® System, followed by a 6 week pause and cystoscopy assessment. If the patient was disease-free at assessment, they proceeded to maintenance HM, consisting of 6-weekly instillations of HM in year 1, then 8-weekly installations in year 2. Further treatment in those remaining disease-free at 24 months was at the clinician's discretion. Each instillation was divided into 2x 30-minute cycles each with 20mg mitomycin dissolved in 50mls of sterile water. Bladder hyperthermia (42 +/-2°C) was delivered in combination with each instillation of mitomycin in accordance with the manufacturer’s operational guidelines. At the end of the treatment, the suspension was held in the bladder for as long as possible (max. 2 hrs).

    Reporting group title
    Control
    Reporting group description
    One of either: 1) Patients who failed previous induction BCG, ≤ 6 instillations : Second course of bacillus Calmette-Guerin therapy (BCG2) (Note : The small numnber of patients intollerant of BCG during induction therapy were randomised between HM and Intitutional Standard). OR 2) For patients who failed previous maintenance BCG, had > 6 instillations or patients with BCG intolerance. Institutional Standard - best available standard therapy for BCG-failure, chosen at the discretion of the treating clinician on a case-by-case basis. This cohort was followed-up by surveillance visits, as per protocol.

    Primary: Disease-free survival time

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    End point title
    Disease-free survival time
    End point description
    For patients without CIS at baseline and those with CIS at baseline but not at the 3-month surveillance visit - the disease-free survival interval was determined from the date of randomisation into the trial and the earliest of date of detection of recurrent disease, or date of death from any cause. For patients with CIS at baseline and at the 3-month surveillance visit - the interval was measured between the date of randomisation and the date of their 3-month surveillance visit. Disease recurrence was defined as histologically confirmed urothelial cell carcinoma or positive cytology. Disease progression was defined as T2 disease (histologically confirmed) or evidence of extra-vesicular disease. In the absence of recurrent disease or death during the course of the trial, disease-free survival times will be censored at the last follow-up date. Patients who experience a distant upper-tract recurrence will be censored at the last available assessment.
    End point type
    Primary
    End point timeframe
    Outcome was assessed once all patients had completed a minimum of 12 months' follow-up from randomisation.
    End point values
    RITE Control
    Number of subjects analysed
    48
    56
    Units: Months
        median (confidence interval 95%)
    11.56 (7.35 to 18.91)
    14.71 (6.17 to 31.12)
    Statistical analysis title
    Disease free survival Log Rank Test
    Statistical analysis description
    Experimental and control arms will be compared in terms of disease-free survival, recurrence-free survival, progression-free survival, overall survival and disease-specific survival times. Univariate time-to-event analyses will use the Kaplan-Meier method and the log-rank test.
    Comparison groups
    RITE v Control
    Number of subjects included in analysis
    104
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.23
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    1.33
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.84
         upper limit
    2.1

    Primary: Complete response rate at 3 months

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    End point title
    Complete response rate at 3 months
    End point description
    For patients with CIS at randomisation, complete response at 3 months is defined as absence of visible tumour recurrence at cystoscopy, negative cytology and no evidence of CIS on random biopsy of the bladder.
    End point type
    Primary
    End point timeframe
    Outcome was assessed once all patients had completed a minimum of 12 months' follow-up from randomisation.
    End point values
    RITE Control
    Number of subjects analysed
    33
    38
    Units: Patients
    number (not applicable)
        Complete Response
    10
    18
        Not Complete Response
    23
    20
    Statistical analysis title
    Complete Response
    Comparison groups
    RITE v Control
    Number of subjects included in analysis
    71
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.142
    Method
    Chi-squared
    Confidence interval

    Secondary: Progression-free survival time

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    End point title
    Progression-free survival time
    End point description
    The progression-free survival interval was determined as the period between the date of entry into the trial and the earliest of either the date of detection of disease progression or date of death from any cause. Disease progression is defined as histologically confirmed stage T2 disease or greater following TUR (≥ pT2). For those patients who do not experience disease progression or who die during the course of the trial, progression-free survival times were censored at the last follow-up date. Patients who experience a distant upper-tract recurrence will be censored at the last available assessment.
    End point type
    Secondary
    End point timeframe
    Outcome was assessed once all patients had completed a minimum of 12 months' follow-up from randomisation.
    End point values
    RITE Control
    Number of subjects analysed
    48 [1]
    56
    Units: number of patients analysed
        number (not applicable)
    48
    56
    Attachments
    Progression Free survival
    Notes
    [1] - Units have been defined as number of patients analysed as median survival could not be calculated
    Statistical analysis title
    Progression free survival Log Rank Test
    Comparison groups
    RITE v Control
    Number of subjects included in analysis
    104
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.16
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    1.64
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.82
         upper limit
    3.27

    Secondary: Overall survival time

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    End point title
    Overall survival time
    End point description
    Overall survival was determined from the period between the date trial entry and the date of death from any cause. Patients who did not die during the course of the trial were censored at the last available assessment.
    End point type
    Secondary
    End point timeframe
    Outcome was assessed once all patients had completed a minimum of 12 months' follow-up from randomisation.
    End point values
    RITE Control
    Number of subjects analysed
    48 [2]
    56
    Units: number of patients analysed
        number (not applicable)
    48
    56
    Attachments
    Overall Survival
    Notes
    [2] - Units have been defined as number of patients analysed as median survival could not be calculated
    Statistical analysis title
    Overall Survival
    Comparison groups
    RITE v Control
    Number of subjects included in analysis
    104
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.18
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    1.64
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.79
         upper limit
    3.39

    Secondary: Disease-specific survival time

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    End point title
    Disease-specific survival time
    End point description
    The disease-specific surviva interval was determined from the period between the date trial entry and the date of death due to bladder cancer. Patients who survived the course of the trial were censored at the last available assessment. Patients who died of other causes were censored at date of death due to other cause.
    End point type
    Secondary
    End point timeframe
    Outcome was assessed once all patients had completed a minimum of 12 months' follow-up from randomisation.
    End point values
    RITE Control
    Number of subjects analysed
    48
    56
    Units: Months
        number (not applicable)
    48
    56
    Statistical analysis title
    Disease specific survival
    Comparison groups
    RITE v Control
    Number of subjects included in analysis
    104
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.04
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    3.02
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.04
         upper limit
    8.76

    Secondary: Recurrence-free survival time

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    End point title
    Recurrence-free survival time
    End point description
    Recurrence-free survival was measured in patients with papillary disease only. It is defined in the same way as disease-free survival, with the important distinction that CIS at the first 3-month post-treatment visit was not included as an event, but instead a treatment failure which was censored. Patients who entered the trial with CIS and found to be CIS negative at the first surveillance visit, were also followed up for recurrence-free survival.
    End point type
    Secondary
    End point timeframe
    Outcome was assessed once all patients had completed a minimum of 12 months' follow-up from randomisation.
    End point values
    RITE Control
    Number of subjects analysed
    48
    56
    Units: Months
        median (confidence interval 95%)
    12.67 (7.52 to 33.78)
    13.07 (4.92 to 21.44)
    Statistical analysis title
    Recurrence free survival
    Comparison groups
    RITE v Control
    Number of subjects included in analysis
    104
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.98
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    1.01
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.53
         upper limit
    1.91

    Secondary: Quality of Life

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    End point title
    Quality of Life
    End point description
    Quality of life was assessed at trial entry and every 3 months for the first year of treatment using the questionnaires EORTC QLQ-C30, BLS24 (a 24-item questionnaire for patients with superficial bladder cancer) and EQ5D.
    End point type
    Secondary
    End point timeframe
    Outcome was assessed once all patients had completed a minimum of 12 months' follow-up from randomisation.
    End point values
    RITE Control
    Number of subjects analysed
    9
    15
    Units: EQ5D
        arithmetic mean (standard deviation)
    0.877 ± 0.139
    0.876 ± 0.154
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All AEs and SAEs between trial entry until 30 days post final trial treatment and SAEs occurring after 30 days post last trial treatment considered treatment-related by the Investigator.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    NCI CTCAE
    Dictionary version
    4.0
    Reporting groups
    Reporting group title
    RITE
    Reporting group description
    -

    Reporting group title
    Control
    Reporting group description
    -

    Serious adverse events
    RITE Control
    Total subjects affected by serious adverse events
         subjects affected / exposed
    8 / 48 (16.67%)
    3 / 56 (5.36%)
         number of deaths (all causes)
    16
    14
         number of deaths resulting from adverse events
    0
    0
    Injury, poisoning and procedural complications
    Fractured hip (neck of humerus)
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 56 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Peripheral ischaemia
         subjects affected / exposed
    2 / 48 (4.17%)
    0 / 56 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiac arrest
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 56 (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
    0 / 48 (0.00%)
    1 / 56 (1.79%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Renal and urinary disorders
    Urinary retention
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 56 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Increased urinary frequency
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 56 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute kidney Injury
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 56 (1.79%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Haematuria
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 56 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthritis
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 56 (1.79%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 56 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    RITE Control
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    42 / 48 (87.50%)
    42 / 56 (75.00%)
    Blood and lymphatic system disorders
    Myelosuppression
         subjects affected / exposed
    2 / 48 (4.17%)
    0 / 56 (0.00%)
         occurrences all number
    2
    0
    Ear and labyrinth disorders
    Nausea
         subjects affected / exposed
    4 / 48 (8.33%)
    5 / 56 (8.93%)
         occurrences all number
    8
    4
    General disorders and administration site conditions
    Pain
    Additional description: Pain/spasm
         subjects affected / exposed
    28 / 48 (58.33%)
    23 / 56 (41.07%)
         occurrences all number
    101
    82
    Fever
         subjects affected / exposed
    5 / 48 (10.42%)
    13 / 56 (23.21%)
         occurrences all number
    6
    30
    Fatigue
         subjects affected / exposed
    15 / 48 (31.25%)
    19 / 56 (33.93%)
         occurrences all number
    62
    79
    Gastrointestinal disorders
    Vomiting
         subjects affected / exposed
    2 / 48 (4.17%)
    2 / 56 (3.57%)
         occurrences all number
    4
    2
    Renal and urinary disorders
    Dysuria
         subjects affected / exposed
    26 / 48 (54.17%)
    30 / 56 (53.57%)
         occurrences all number
    90
    106
    Increased urinary frequency
         subjects affected / exposed
    26 / 48 (54.17%)
    30 / 56 (53.57%)
         occurrences all number
    98
    153
    Increased urinary urgency
         subjects affected / exposed
    19 / 48 (39.58%)
    27 / 56 (48.21%)
         occurrences all number
    85
    101
    Incontinence
         subjects affected / exposed
    10 / 48 (20.83%)
    9 / 56 (16.07%)
         occurrences all number
    28
    32
    Nocturia
         subjects affected / exposed
    29 / 48 (60.42%)
    30 / 56 (53.57%)
         occurrences all number
    90
    106
    Haematuria
         subjects affected / exposed
    23 / 48 (47.92%)
    22 / 56 (39.29%)
         occurrences all number
    57
    33
    Stricture
         subjects affected / exposed
    3 / 48 (6.25%)
    7 / 56 (12.50%)
         occurrences all number
    6
    8
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    7 / 48 (14.58%)
    12 / 56 (21.43%)
         occurrences all number
    9
    23
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    13 / 48 (27.08%)
    13 / 56 (23.21%)
         occurrences all number
    21
    15

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    12 Aug 2010
    Version 2 Changes included • Eligibility exclusions changed to allow patients with stable hormonally controlled prostate cancer to enter the trial • Other Exclusion criteria clarified • Update the CTCAE from version 3 to version 4 thought out the protocol including appendix 9 and the supporting trial documents • Details of Photo dynamic detection (PDD) surveillance methods added • Device reporting responsibilities • Addition of contraception requirements • Update of contact details for trial coordinator due to a change in departmental name • Minor typographical and grammatical errors amended
    26 Nov 2012
    Version 3 Changes included • The Institutional Standard Therapy (control arm for patients who failed BCG maintenance) was changed from a pre-defined within site institutional standard, to the best standard of care chosen at the discretion of the treating clinician on a case-by-case basis. The protocol provides some examples of possible treatment options but the list is not all-inclusive. For these reasons, ATC codes have been used to cover the treatments that can be used (PR9). If the Standard Therapy chosen is not covered by the PIS appendices prepared, sites will use their own patient leaflet used in their routine local clinical practice. • In addition, active monitoring was added as an option for institutional standard therapy. • In response to the national BCG shortage we have added in the CTA the BCG-Medac brand with marketing authorisation outside the UK but within Europe Union (PR10). Because the BCG-Medac is available from several European countries, we cannot predict from which European country it will be ordered from. Therefore it is neither possible nor practical to include details of all the country specific Marketing Authorisation that may be used. For this reason we have completed section D2-1 of PR10 by leaving blank the Trade name, EV product code, which country granted the MA; under the MA number section we entered that “all intravesical BCG products have a marketing authorisation in a member state”; and finally, the question “Is this the Member State concerned with this application” could not be answered and “Not Answered” was ticked.
    30 Sep 2013
    Version 4 Amended to: • Include a central pathology review to collect tissue samples from pathology departments • Specify how CIS recurrences are confirmed locally: the presence of CIS will be determined locally by histology and by cytokeratin 20 (CK20) immunohistochemical staining following TUR • Add fluorescence in situ hybridisation (FISH) test for subsequent confirmation of CIS recurrences. FISH analysis will be performed by an independent laboratory on all CIS recurrences detected locally.

    Interruptions (globally)

    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    19 Jul 2013
    Early termination of recruitment. At a planned DMC meeting (2 Jul 2013) for the trial, the Chief Investigator and Trial Coordinator were advised that the DMC would be recommending to the TSC that recruitment of patients with CIS to the trial should be stopped. Because of the unusual nature of the recommendation, arrangements were made for the DMC to discuss their decision directly with the TSC. After their initial discussion, the trial management team received a communication from the TSC on the 17th July indicating closure of recruitment, and the necessity of re-examination of the data collected to date. On that basis recruitment was halted as a cautionary measure on the 19 Jul 2013. The TSC subsequently reviewed the interim analyses and, following discussion with the Chief Investigator, believed that further investigations and analyses were needed before any conclusions could be drawn or recommendations made to investigators. Part of the difficulty related to a concern that hyperthermia treatment may have lead to misinterpretation of the pathology. Following further discussions and a joint TSC/DMC meeting (6 Sep 2013), it was agreed that central pathology review for patients who failed to respond, or recurred on treatment, was crucially required. Central pathology review of the results plus an updated statistical analysis of the trial data were requested and reviewed after 3 months at a further joint TSC/DMC meeting when the decision was made to close the trial. In the intervening period, the TSC recommended that all trial patients remained on trial treatment. The TSC in consultation with the Chief Investigator wrote to the Principal Investigators, the Sponsor, the funding body (CTAAC) and Bladder Cancer CSG Chair on 25-Sep-2013.
    -

    Limitations and caveats

    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    Only 104 of the 242 subject target were recruited with 71 having CIS at baseline. Disease-free survival time analysis was underpowered but the CIS at baseline target was exceeded. There were insufficient data for cost effectiveness analysis.

    Online references

    http://www.ncbi.nlm.nih.gov/pubmed/30274699
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