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    Clinical Trial Results:
    Randomised controlled trial of 6-Mercaptopurine versus placebo to prevent recurrence of Crohn's disease following surgical resection (TOPPIC)

    Summary
    EudraCT number
    2006-005800-15
    Trial protocol
    GB  
    Global end of trial date
    30 Sep 2015

    Results information
    Results version number
    v1(current)
    This version publication date
    08 Sep 2017
    First version publication date
    08 Sep 2017
    Other versions
    Summary report(s)
    TOPPIC Report

    Trial information

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    Trial identification
    Sponsor protocol code
    MRCG060329
    Additional study identifiers
    ISRCTN number
    ISRCTN89489788
    US NCT number
    -
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    University of Edinburgh
    Sponsor organisation address
    Old College, South Bridge, Edinburgh , United Kingdom, EH8 9YL
    Public contact
    Marise Bucukoglu (ACCORD Office), University of Edinburgh, 00 44 01312429262, Marise.Bucukoglu@ed.ac.uk
    Scientific contact
    Marise Bucukoglu (ACCORD Office), University of Edinburgh, 00 44 01312429262, Marise.Bucukoglu@ed.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
    15 Jun 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    30 May 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    30 Sep 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess whether Mercaptopurine can prevent or delay post-operative recurrence of Crohn’s disease
    Protection of trial subjects
    This multicentre clinical trial was carried out with the approval of the national research ethics committee (ref: 07/MRE00/74), in accordance with the Declaration of Helsinki (2000), under a Clinical Trial Authorization (01384/0206/001-0002) from the Medicine and Healthcare Products Regulatory Authority (MHRA, United Kingdom), and the written informed consent of all participants.
    Background therapy
    N/A. All eligible patients were required to be free of medication for Crohn’s disease and to have been off antibiotics for the two weeks prior to randomization.
    Evidence for comparator
    N/A.
    Actual start date of recruitment
    01 May 2008
    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
    United Kingdom: 240
    Worldwide total number of subjects
    240
    EEA total number of subjects
    240
    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)
    3
    Adults (18-64 years)
    232
    From 65 to 84 years
    5
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Patients with a histologically confirmed diagnosis of Crohn's disease undergoing ileocolonic or small bowel resection were recruited from 29 UK hospitals. Patients were ≥ 16 years in Scotland and ≥18 years in England and Wales. Prior to randomisation any post-operative infections were fully treated and existing treatments for Crohn's stopped.

    Pre-assignment
    Screening details
    A total of 329 patients were screened for recruitment of whom 89 were excluded as ineligible or who declined to participate, leaving 240 patients to undergo randomisation.

    Period 1
    Period 1 title
    Treatment Period (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Monitor, Assessor
    Blinding implementation details
    Treatment was blinded to both the research team and the subject, as well as to the central trials team. Study drugs were prepared by pharmacy staff independent of the study investigators or clinical team responsible for patient care. Safety blood test results were sent to the central trials team by independent members of staff and assessed by a blinded, independent panel of clinicians. Data Monitoring Reports were prepared by an unblinded statistician.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Active Arm
    Arm description
    Mercaptopurine tablets containing 50mg of the active substance 6-Mercaptopurine prepared by Glaxo Wellcome GmbH (batch 1) & Co or Aspen Pharma Trading Limited (batch 2) and packaged by Catalent (later Aptuit).
    Arm type
    Active comparator

    Investigational medicinal product name
    Mercaptopurine
    Investigational medicinal product code
    ATC Code: L01BB02
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    50mg tablet taken once a day

    Arm title
    Placebo
    Arm description
    Matching placebo tablets containing Lactose, Microcrystalline cellulose, Povidone, Croscarmellose Sodium, Quinoline yellow, Orange yellow, Magnesium stearate
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Placebo
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    50mg oral tablet

    Number of subjects in period 1
    Active Arm Placebo
    Started
    128
    112
    Completed
    62
    42
    Not completed
    66
    70
         Abnormal safety blood test
    12
    6
         Adverse event, serious fatal
    -
    1
         Adverse event, non-fatal
    39
    41
         Lost to follow-up
    7
    9
         Withdrawn
    8
    13

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Active Arm
    Reporting group description
    Mercaptopurine tablets containing 50mg of the active substance 6-Mercaptopurine prepared by Glaxo Wellcome GmbH (batch 1) & Co or Aspen Pharma Trading Limited (batch 2) and packaged by Catalent (later Aptuit).

    Reporting group title
    Placebo
    Reporting group description
    Matching placebo tablets containing Lactose, Microcrystalline cellulose, Povidone, Croscarmellose Sodium, Quinoline yellow, Orange yellow, Magnesium stearate

    Reporting group values
    Active Arm Placebo Total
    Number of subjects
    128 112 240
    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)
    1 2 3
        Adults (18-64 years)
    126 106 232
        From 65-84 years
    1 4 5
        85 years and over
    0 0 0
    Gender categorical
    Units: Subjects
        Female
    79 67 146
        Male
    49 45 94
    Previous treatment with Mercaptopurine
    Units: Subjects
        Yes
    14 5 19
        No
    114 107 221
    Previous treatment with Azathioprine
    Units: Subjects
        Yes
    80 48 128
        No
    48 64 112
        Missing
    0 0 0
    Previous treatment with Infliximab
    Units: Subjects
        Yes
    21 15 36
        No
    104 96 200
        Missing
    3 1 4
    Previous treatment with Methotrexate
    Units: Subjects
        Yes
    8 7 15
        No
    120 104 224
        Missing
    0 1 1
    Previous surgery
    Units: Subjects
        Yes
    46 28 74
        No
    82 83 165
        Missing
    0 1 1
    Smoking status
    Units: Subjects
        Yes
    29 26 55
        No
    99 86 185
        Missing
    0 0 0
    Duration of disease
    Units: Subjects
        40 years or less
    37 41 78
        > 40 years
    91 69 160
        Unknown
    0 2 2
    Age at diagnosis
    Units: Subjects
        40 years or less
    103 87 190
        > 40 years
    25 23 48
        Unknown
    0 2 2
    CDAI Score
    Crohn's Disease Activity Index Score
    Units: Points
        arithmetic mean (standard deviation)
    130 ± 86 121 ± 72 -
    Weight
    Units: kg
        arithmetic mean (standard deviation)
    70.7 ± 14.4 70.7 ± 13.7 -

    End points

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    End points reporting groups
    Reporting group title
    Active Arm
    Reporting group description
    Mercaptopurine tablets containing 50mg of the active substance 6-Mercaptopurine prepared by Glaxo Wellcome GmbH (batch 1) & Co or Aspen Pharma Trading Limited (batch 2) and packaged by Catalent (later Aptuit).

    Reporting group title
    Placebo
    Reporting group description
    Matching placebo tablets containing Lactose, Microcrystalline cellulose, Povidone, Croscarmellose Sodium, Quinoline yellow, Orange yellow, Magnesium stearate

    Primary: Primary outcome - postoperative clinical recurrence of Crohn's disease

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    End point title
    Primary outcome - postoperative clinical recurrence of Crohn's disease
    End point description
    Crohn’s Disease Activity Index (CDAI) >150 with an increase from baseline of 100 points, together with the need for anti-inflammatory rescue therapy or primary surgical intervention.
    End point type
    Primary
    End point timeframe
    Up to the end of the trial (3 years).
    End point values
    Active Arm Placebo
    Number of subjects analysed
    128
    112
    Units: Number of patients with recurrence
        Yes
    16
    26
        No
    112
    86
    Statistical analysis title
    Statistical analysis of primary outcome
    Statistical analysis description
    Cox's proportional hazards model
    Comparison groups
    Active Arm v Placebo
    Number of subjects included in analysis
    240
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    = 0.073 [1]
    Method
    Regression, Cox
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.535
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.27
         upper limit
    1.96
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.349
    Notes
    [1] - Adjusted for randomisation stratification variables (centre and smoking status), also adjusted for previous treatment with 6MP or Azathioprine.

    Secondary: Secondary outcome - postoperative clinical recurrence of Crohn's disease

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    End point title
    Secondary outcome - postoperative clinical recurrence of Crohn's disease
    End point description
    Crohn’s Disease Activity Index (CDAI) >150 with an increase from baseline of 100 points OR the need for anti-inflammatory rescue therapy OR primary surgical intervention.
    End point type
    Secondary
    End point timeframe
    Up to the end of the trial (3 years)
    End point values
    Active Arm Placebo
    Number of subjects analysed
    128
    112
    Units: Number of patients
        Yes
    34
    40
        No
    94
    72
    Statistical analysis title
    Statistical analysis of secondary outcome
    Statistical analysis description
    Cox’s proportional hazards model
    Comparison groups
    Active Arm v Placebo
    Number of subjects included in analysis
    240
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    = 0.243 [2]
    Method
    Regression, Cox
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.737
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.44
         upper limit
    1.23
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.262
    Notes
    [2] - Adjusted for randomisation stratification variables (centre and smoking status), also adjusted for previous treatment with 6MP or Azathioprine.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All adverse events (AEs) that occurred after signing consent for the trial must be reported within the case report form (CRF) and all reported AEs were followed up before the end of the trial.
    Adverse event reporting additional description
    As above.
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    Coded by trial team
    Dictionary version
    N/A
    Reporting groups
    Reporting group title
    Active Arm
    Reporting group description
    Mercaptopurine tablets containing 50mg of the active substance 6-Mercaptopurine prepared by Glaxo Wellcome GmbH (batch 1) & Co or Aspen Pharma Trading Limited (batch 2) and packaged by Catalent (later Aptuit).

    Reporting group title
    Placebo
    Reporting group description
    Matching placebo tablets containing Lactose, Microcrystalline cellulose, Povidone, Croscarmellose Sodium, Quinoline yellow, Orange yellow, Magnesium stearate

    Serious adverse events
    Active Arm Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    51 / 128 (39.84%)
    49 / 112 (43.75%)
         number of deaths (all causes)
    0
    1
         number of deaths resulting from adverse events
    0
    0
    Vascular disorders
    Vascular disorders
         subjects affected / exposed
    1 / 128 (0.78%)
    0 / 112 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Surgical and medical procedures
         subjects affected / exposed
    9 / 128 (7.03%)
    5 / 112 (4.46%)
         occurrences causally related to treatment / all
    0 / 9
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Neoplasms benign, malignnant and unspecified
         subjects affected / exposed
    1 / 128 (0.78%)
    1 / 112 (0.89%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    General disorders
         subjects affected / exposed
    1 / 128 (0.78%)
    1 / 112 (0.89%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Reproductive system and breast disorders
         subjects affected / exposed
    2 / 128 (1.56%)
    0 / 112 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Injury
         subjects affected / exposed
    1 / 128 (0.78%)
    1 / 112 (0.89%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiac disorders
         subjects affected / exposed
    3 / 128 (2.34%)
    2 / 112 (1.79%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Congenital, familial and genetic disorders
    Congenital, familial and genetic disorders
         subjects affected / exposed
    0 / 128 (0.00%)
    1 / 112 (0.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Nervous system disorders
         subjects affected / exposed
    0 / 128 (0.00%)
    1 / 112 (0.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Ear and labyrinth disorders
         subjects affected / exposed
    0 / 128 (0.00%)
    1 / 112 (0.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Gastrointestinal disorders
         subjects affected / exposed
    23 / 128 (17.97%)
    29 / 112 (25.89%)
         occurrences causally related to treatment / all
    2 / 26
    4 / 33
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hepatobiliary disorders
         subjects affected / exposed
    1 / 128 (0.78%)
    1 / 112 (0.89%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal and urinary disorders
         subjects affected / exposed
    4 / 128 (3.13%)
    2 / 112 (1.79%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Skin and subcutaneous tissue disorders
         subjects affected / exposed
    1 / 128 (0.78%)
    1 / 112 (0.89%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Infections and infestations
         subjects affected / exposed
    4 / 128 (3.13%)
    3 / 112 (2.68%)
         occurrences causally related to treatment / all
    0 / 7
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Active Arm Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    121 / 128 (94.53%)
    105 / 112 (93.75%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Cancers
         subjects affected / exposed
    2 / 128 (1.56%)
    1 / 112 (0.89%)
         occurrences all number
    3
    1
    Nervous system disorders
    Pain
         subjects affected / exposed
    18 / 128 (14.06%)
    17 / 112 (15.18%)
         occurrences all number
    30
    19
    Headache
         subjects affected / exposed
    26 / 128 (20.31%)
    20 / 112 (17.86%)
         occurrences all number
    61
    38
    General disorders and administration site conditions
    Other
         subjects affected / exposed
    85 / 128 (66.41%)
    62 / 112 (55.36%)
         occurrences all number
    212
    153
    Pancreatitis
         subjects affected / exposed
    1 / 128 (0.78%)
    1 / 112 (0.89%)
         occurrences all number
    1
    1
    Gastrointestinal disorders
    GI Symptoms Other
         subjects affected / exposed
    34 / 128 (26.56%)
    28 / 112 (25.00%)
         occurrences all number
    53
    40
    Nausea
         subjects affected / exposed
    45 / 128 (35.16%)
    30 / 112 (26.79%)
         occurrences all number
    78
    41
    Abdominal pain
         subjects affected / exposed
    66 / 128 (51.56%)
    67 / 112 (59.82%)
         occurrences all number
    132
    141
    Constipation
         subjects affected / exposed
    37 / 128 (28.91%)
    37 / 112 (33.04%)
         occurrences all number
    54
    56
    Worsening Crohn's
         subjects affected / exposed
    24 / 128 (18.75%)
    29 / 112 (25.89%)
         occurrences all number
    41
    37
    Hepatobiliary disorders
    Deranged LFTs
         subjects affected / exposed
    4 / 128 (3.13%)
    5 / 112 (4.46%)
         occurrences all number
    4
    5
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    24 / 128 (18.75%)
    14 / 112 (12.50%)
         occurrences all number
    35
    17
    Musculoskeletal and connective tissue disorders
    Joint pain
         subjects affected / exposed
    40 / 128 (31.25%)
    36 / 112 (32.14%)
         occurrences all number
    72
    65
    Infections and infestations
    Infections
         subjects affected / exposed
    81 / 128 (63.28%)
    68 / 112 (60.71%)
         occurrences all number
    171
    184

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    16 Dec 2007
    Substantial Amendment 1: Amendment to protocol concerning use of 6MP in pregnancy/subjects of childbearing age, switch to matching placebo (rather than over-encapsulation) supplied by GSK and amendment to safety blood procedures.
    07 Jul 2008
    Substantial Amendment 6: Decision to stop study drug if subjects prescribed Allopurinol.
    18 Nov 2008
    Substantial Amendment 3: Use of all Scottish district hospitals for referrals, repeat safety bloods not required at V2, clarifications to protocol: V2 ≤7 days of V1; point 3 of inclusion criteria added.
    15 Jun 2009
    Substantial Amendment 5: Reduce number of colonoscopies and clarification in PIL/Consent the types of sample and how they are handled and stored.
    15 Dec 2009
    Substantial Amendment 7: Amendment to safety assessments in protocol, prohibited medications added as appendix.
    03 Mar 2010
    Substantial Amendment 8: Isolated elevation of GGT do not represent exclusion to recruitment or withdrawal.
    28 Sep 2010
    Substantial Amendment 12: Extension to study, clarifications to protocol including amendment to exclusion criteria, retention of original signed consent forms in site files, updated policy on pharmacovigilance and protocol deviations.
    10 Feb 2011
    Substantial Amendment 13: Clarifications to the protocol
    15 Mar 2012
    Substantial Amendment 17: Protocol modified to add a secondary outcome, amend exclusion criteria error, MA holder and SmPC change, amendments to appendices 3,4,6,7.
    03 Oct 2013
    Substantial Amendment 20: Protocol modified: change of MA holder name and address, SmPc update of drug brand name, trial manager and trial statistician change, clarification of Appendix 8 on prohibited medications.
    07 May 2015
    Substantial Amendment 21: Protocol modified: health economics analysis plan revised, revisions to planned analysis section to bring in line with Statistical Analysis Plan, minor change to MA Holder and SmPC, removal of blank Annexes.

    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/28404197
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