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    Clinical Trial Results:
    Myeloma X Relapse (Intensive) - A randomised controlled trial to determine the role of a second autologous stem cell transplant as consolidation therapy in patients with relapsed multiple myeloma following prior high-dose chemotherapy and autologous stem cell rescue.

    Summary
    EudraCT number
    2006-005890-24
    Trial protocol
    GB  
    Global end of trial date
    16 Nov 2016

    Results information
    Results version number
    v1(current)
    This version publication date
    30 Nov 2017
    First version publication date
    30 Nov 2017
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    HM05/7287
    Additional study identifiers
    ISRCTN number
    ISRCTN60123120
    US NCT number
    NCT00747877
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Leeds Teaching Hospitals NHS Trust - Research & Innovation Department
    Sponsor organisation address
    Research & Innovation Centre, St James's University Hospital, Beckett Street, Leeds, United Kingdom, LS9 7TF
    Public contact
    Regulatory Affairs and Governance Manager, CTRU QA Department, 0113 3431477, medctruq@leeds.ac.uk
    Scientific contact
    Regulatory Affairs and Governance Manager, CTRU QA Department, 0113 3431477, medctruq@leeds.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
    20 Jan 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    16 Nov 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    16 Nov 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To determine the effect on freedom-from disease progression of a second autologous stem cell transplant (ASCT) compared with low-dose consolidation, following re-induction chemotherapy, in patients with relapsed myeloma previously treated with high-dose chemotherapy and ASCT.
    Protection of trial subjects
    Safety analyses will summarise the adverse event rates and serious adverse events separately for each of the re-induction and consolidation treatments. Safety data will be presented for patients receiving any of the relevant study treatment by treatment group and relationship to study treatment.
    Background therapy
    All trial participants received re-induction therapy of 2-4 cycles of PAD (Bortezomib, doxorubicin, dexamethasone) before proceeding to peripheral blood stem cell (PBSC) mobilisation and harvesting. Cyclophosphamide and granulocyte colony stimulating factor (G-CSF) were suggested for mobilisation. Mobilisation and harvest was optional for patients who already had sufficient stem cells stored from a previous harvest. Patients with an adequate number of PBSC collected were then randomised to the two different treatment arms.
    Evidence for comparator
    The trial will identify whether a second course of high dose melphalan and ASCT performed at relapse in myeloma patients results in an improved duration of response and survival outcome compared to a less intensive, alkylating agent therapy of cyclophosphamide-weekly. No RCTs have been done to assess the outcome of a second autologous transplant at relapse. Some patients will have achieved a good remission following their original ASCT and a second similar procedure undertaken following relapse may be an effective form of therapy. Together with pain and Quality of Life (QoL) assessments, it is proposed that the full effect of the differing treatment strategies on time to disease progression, key symptoms and QoL will assist in the development of an evidence based management plan for treatment of relapse in these patients and allow the best use of available resources.
    Actual start date of recruitment
    16 Apr 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: 297
    Worldwide total number of subjects
    297
    EEA total number of subjects
    297
    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)
    206
    From 65 to 84 years
    91
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    The trial opened at 51 centres across the United Kingdom. Between April 16 2008 and November 19 2012, 297 patients were registered and 174 were randomised. On the grounds of efficacy data reviewed by the DMEC, the trial was closed to recruitment on 21 November 2012.

    Pre-assignment
    Screening details
    Patients with multiple myeloma previously treated with standard chemotherapy and autologous stem cell transplant. Patients requiring therapy for first Progressive Disease & 12 months since 1st transplant. Written informed consent.

    Pre-assignment period milestones
    Number of subjects started
    297
    Number of subjects completed
    293

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    Consent withdrawn by subject: 3
    Reason: Number of subjects
    Received no treatment: 1
    Period 1
    Period 1 title
    Re-Induction PAD and PBSC Harvest
    Is this the baseline period?
    No
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Arm title
    Re-induction PAD and PBSC Harvest
    Arm description
    All patients will be registered at trial entry and will receive re-induction therapy with 2-4 cycles of PAD. Following completion of re-induction therapy, the disease response will be re-assessed and all patients without progressive disease will then proceed to PBSC mobilisation and harvesting. Mobilisation and harvest is encouraged in all patients without progressive disease, but is optional in patients who have sufficient stem cells stored from a previous harvest. Those patients with an adequate number of PBSC (including those who do not mobilise or who were not mobilised but have stored PBSC from prior mobilisations) will be randomised.
    Arm type
    Re-induction

    Investigational medicinal product name
    Bortezomib
    Investigational medicinal product code
    Other name
    Velcade
    Pharmaceutical forms
    Powder for solution for injection
    Routes of administration
    Intravenous bolus use
    Dosage and administration details
    Bortezomib is supplied as a 3.5 mg powder for solution for injection. It is administered as an intravenous bolous at a maximum dose of 1.3mg/m2 per day of treatment. Treatment days are days 1, 4, 8 and 11 of a 21 day cycle. A minimum of 2 cycles and a maximum of 4 cycles are given.

    Investigational medicinal product name
    Doxorubicin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Doxorubicin is administered as a continuous intravenous infusion at a dose of 9mg/m2/day on days 1 to 4 of a 21 day cycle. A minimum of 2 cycles and a maximum of 4 cycles are given.

    Investigational medicinal product name
    Dexamethasone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Dexamethasone is in the form of tablets containing 2.0mg dexamethasone. It is administered at a dose of 40mg/day on days 1 to 4 of a 21 day cycle, for a minimum of 2 cycles and maximum of 4 cycles. It is also given on days 8-11 and 15-18 in cycle 1.

    Investigational medicinal product name
    Cyclophosphamide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Cyclophosphamide is in the form of powder for solution for injection. Each vial contains cyclophosphamide monohydrate equivalent to 1000mg anhydrous cyclophosphamide. For stem cell mobilisation, it is administered as an intravenous infusion at a dose of 1.5-3g/m2 on day 0.

    Investigational medicinal product name
    G-CSF
    Investigational medicinal product code
    Other name
    Granulocyte cell stimulating factor
    Pharmaceutical forms
    Powder and solvent for solution for injection/infusion
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    G-CSF is administered at a dose of 5-10μg/kg/day, subcutaneously, from day +1 to time of stem cell harvest.

    Number of subjects in period 1
    Re-induction PAD and PBSC Harvest
    Started
    293
    Completed
    174
    Not completed
    119
         Progressive disease
    4
         Protocol deviation
    3
         Physician decision
    34
         Adverse event, serious fatal
    29
         Consent withdrawn by subject
    19
         Did not mobilise sufficient stem cells
    30
    Period 2
    Period 2 title
    Consolidation Randomisation
    Is this the baseline period?
    Yes [1]
    Allocation method
    Randomised - controlled
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    C-weekly
    Arm description
    Oral cyclophosphamide 400 mg/m² per week for 12 weeks.
    Arm type
    Active comparator

    Investigational medicinal product name
    Cyclophosphamide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for injection, Tablet
    Routes of administration
    Intravenous use, Oral use
    Dosage and administration details
    For the C-weekly regimen, cyclophosphamide tablets, containing 50mg anhydrous cyclophosphamide, is administered orally at 400mg/m2 weekly for 12 weeks. Alternatively, cyclophosphamide may be administered at a dose of 300mg/m2 intravenously, weekly for 12 weeks.

    Arm title
    High dose melphalan and ASCT
    Arm description
    Single infusion of intravenous melphalan 200 mg/m² followed by ASCT after 24–48 h.
    Arm type
    Experimental

    Investigational medicinal product name
    Melphalan
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    High-dose melphalan is given as a 200mg/m2 short infusion (as per local protocol) in 100ml NaCL 0.9%.

    Notes
    [1] - Period 1 is not the baseline period. It is expected that period 1 will be the baseline period.
    Justification: Period 1 relates to the trial treatment received prior to randomisation. Period 2 is the period following randomisation. In alliance with the publications this has been defined as our baseline period.
    Number of subjects in period 2 [2]
    C-weekly High dose melphalan and ASCT
    Started
    85
    89
    Completed
    84
    83
    Not completed
    1
    6
         Progressive disease
    -
    3
         Physician decision
    1
    1
         Consent withdrawn by subject
    -
    1
         Lost to follow-up
    -
    1
    Notes
    [2] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: The worldwide number enrolled relates to the total number registered onto the trial. The baseline period relates to the total number randomised. As the trial had registration and randomisation stages these numbers are not identical.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    C-weekly
    Reporting group description
    Oral cyclophosphamide 400 mg/m² per week for 12 weeks.

    Reporting group title
    High dose melphalan and ASCT
    Reporting group description
    Single infusion of intravenous melphalan 200 mg/m² followed by ASCT after 24–48 h.

    Reporting group values
    C-weekly High dose melphalan and ASCT Total
    Number of subjects
    85 89 174
    Age categorical
    Units: Subjects
        In utero
    0
        Preterm newborn infants (gestational age < 37 wks)
    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)
    0
        From 65-84 years
    0
        85 years and over
    0
    Age continuous
    Units: years
        median (full range (min-max))
    61 (40 to 73) 61 (40 to 73) -
    Gender categorical
    Units: Subjects
        Female
    24 24 48
        Male
    61 65 126
    Haemoglobin at randomisation
    Units: g/dL
        arithmetic mean (standard deviation)
    11.6 ± 1.14 11.5 ± 1.41 -
    Calcium at randomisation
    Units: mmol/L
        arithmetic mean (standard deviation)
    2.3 ± 0.12 2.3 ± 0.12 -
    Time from previous autograft to first progression/relapse
    Units: Years
        arithmetic mean (standard deviation)
    2.8 ± 1.3 3.2 ± 2.11 -
    Beta-2 microglobulin at registriation
    Units: mg/L
        arithmetic mean (standard deviation)
    3.0 ± 1.11 3.1 ± 1.64 -
    Serum creatinine at randomisation
    Units: umol/L
        arithmetic mean (standard deviation)
    82 ± 20.78 79.8 ± 19.45 -

    End points

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    End points reporting groups
    Reporting group title
    Re-induction PAD and PBSC Harvest
    Reporting group description
    All patients will be registered at trial entry and will receive re-induction therapy with 2-4 cycles of PAD. Following completion of re-induction therapy, the disease response will be re-assessed and all patients without progressive disease will then proceed to PBSC mobilisation and harvesting. Mobilisation and harvest is encouraged in all patients without progressive disease, but is optional in patients who have sufficient stem cells stored from a previous harvest. Those patients with an adequate number of PBSC (including those who do not mobilise or who were not mobilised but have stored PBSC from prior mobilisations) will be randomised.
    Reporting group title
    C-weekly
    Reporting group description
    Oral cyclophosphamide 400 mg/m² per week for 12 weeks.

    Reporting group title
    High dose melphalan and ASCT
    Reporting group description
    Single infusion of intravenous melphalan 200 mg/m² followed by ASCT after 24–48 h.

    Primary: Time to disease progression

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    End point title
    Time to disease progression
    End point description
    Time to disease progression is defined as time from randomisation to first documented evidence of disease progression. Documented evidence of progression is defined as: - Progression confirmed by central review (blind to treatment) by the central reviewer. - Progression unconfirmed by central review if central review unable to determine whether or not a patient suffered progression - Death primarily due to progression Patients who die prior to documentation of disease progression will be censored in the analysis. Patients not reaching disease progression at the time of analysis will be censored at the last date known to be progression-free. Patients dying from causes not primarily due to progression will also be censored in the disease progression analysis. The results of this endpoint are based on the final data download on 20/01/2017.
    End point type
    Primary
    End point timeframe
    Time to disease progression is defined as time from randomisation to first documented evidence of disease progression.
    End point values
    C-weekly High dose melphalan and ASCT
    Number of subjects analysed
    85
    89
    Units: Months
        median (confidence interval 95%)
    11 (9 to 12)
    19 (16 to 26)
    Statistical analysis title
    Time to disease progression
    Statistical analysis description
    Cox regression will be used to analyse time to progression accounting for the stratification factors (length of first remission or plateau and response to PAD re-induction therapy), and whether or not mobilisation therapy was received. Patients not reaching disease progression at the time of analysis will be censored at the last date known to be progression-free. Patients dying from causes not primarily due to progression will also be censored.
    Comparison groups
    High dose melphalan and ASCT v C-weekly
    Number of subjects included in analysis
    174
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Regression, Cox
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.4
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.29
         upper limit
    0.56

    Secondary: Response rate to PAD

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    End point title
    Response rate to PAD
    End point description
    Response to treatment will be assessed according to the international uniform response criteria for multiple myeloma. For all analyses, responses will be categorised into the following five groups: Complete Response (sCR and CR), Partial Response (VGPR and PR), Stable Disease (SD), Progressive Disease (PD) and early death. For response rate to PAD, early death is defined as death between registration and up to and including 21 days post date last PAD cycle started. Results for this endpoint are based on the first data cut off of 9/7/2013.
    End point type
    Secondary
    End point timeframe
    This is measured following re-induction treatment with PAD.
    End point values
    Re-induction PAD and PBSC Harvest
    Number of subjects analysed
    293
    Units: Participants
        Complete Response
    49
        Partial Response
    186
        Stable Disease
    44
        Progressive Disease
    2
        Early Death
    2
        Response not available
    10
    No statistical analyses for this end point

    Secondary: Overall response rate following randomised treatments

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    End point title
    Overall response rate following randomised treatments
    End point description
    Response to treatment will be assessed according to the international uniform response criteria for multiple myeloma. For all analyses, responses will be categorised into the following five groups: Complete Response (sCR and CR), Partial Response (VGPR and PR), Stable Disease (SD), Progressive Disease (PD) and early death. At 100 days post transplant or 30 days post end of C-weekly treatment, early death is defined as death between randomisation and up to and including 100 days post randomisation. Results for this endpoint are based on the first data cut off of 9/7/2013.
    End point type
    Secondary
    End point timeframe
    Response rate is measured following the completion of the randomised treatments (100 days post transplant or 30 days post end of C-weekly treatment).
    End point values
    C-weekly High dose melphalan and ASCT
    Number of subjects analysed
    85
    89
    Units: Participants
        Complete Response
    19
    35
        Partial Response
    45
    39
        Stable Disease
    2
    4
        Progressive Disease
    15
    2
        Early Death
    0
    1
        Response not available
    3
    2
        No treatment received
    1
    6
    Statistical analysis title
    Overall response rate
    Statistical analysis description
    Treatment groups will be compared using ordinal logistic regression to adjust for the stratification factors (length of first remission or plateau and response to PAD re-induction therapy) and whether or not mobilisation therapy was received.
    Comparison groups
    High dose melphalan and ASCT v C-weekly
    Number of subjects included in analysis
    174
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0069
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    0.42
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.22
         upper limit
    0.79

    Secondary: Overall Survival

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    End point title
    Overall Survival
    End point description
    Overall survival is defined as the time from randomisation to death from any cause. If a patient is still alive at the time of analysis or lost to follow-up, they will be treated as censored at the date last known to be alive. The analysis of this end point is based off data from the final download 20/1/2017. The upper 95% confidence interval limit was not reached for the median survival time in the high dose melphalan and ASCT arm, this has been indicated by 999.
    End point type
    Secondary
    End point timeframe
    Overall survival is defined as the time from randomisation to death from any cause.
    End point values
    C-weekly High dose melphalan and ASCT
    Number of subjects analysed
    85
    89
    Units: Months
        median (confidence interval 95%)
    55 (44 to 67)
    67 (59 to 999)
    Statistical analysis title
    Overall Survival
    Statistical analysis description
    Cox regression analysis will be used to analyse overall survival accounting for the stratification factors (length of first remission or plateau and response to PAD re-induction therapy) and whether or not mobilisation therapy was received.
    Comparison groups
    High dose melphalan and ASCT v C-weekly
    Number of subjects included in analysis
    174
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0435
    Method
    Regression, Cox
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.64
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.42
         upper limit
    0.99

    Secondary: Progression-Free Survival

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    End point title
    Progression-Free Survival
    End point description
    Disease progression will be determined according to the international uniform response criteria for multiple myeloma. Progression-free survival is defined as the time from randomisation to first documented evidence of disease progression or death from any cause. Patients who do not progress will be censored at the last date they were known to be alive and progression free. The analysis of this end point is based off data from the final download on 20/1/2017.
    End point type
    Secondary
    End point timeframe
    Progression-free survival is defined as the time from randomisation to first documented evidence of disease progression or death from any cause.
    End point values
    C-weekly High dose melphalan and ASCT
    Number of subjects analysed
    85
    89
    Units: Months
        median (confidence interval 95%)
    11 (9 to 12)
    19 (16 to 25)
    Statistical analysis title
    Progression-Free Survival
    Statistical analysis description
    Cox regression analysis will be used to analyse progression-free survival accounting for the stratification factors (length of first remission or plateau and response to PAD re-induction therapy) and whether or not mobilisation therapy was received.
    Comparison groups
    High dose melphalan and ASCT v C-weekly
    Number of subjects included in analysis
    174
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Regression, Cox
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.41
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.3
         upper limit
    0.58

    Secondary: Feasibility of stem cell collection

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    End point title
    Feasibility of stem cell collection
    End point description
    The feasibility of stem cell collection will be determined by the satisfactory mobilisation of an adequate number of peripheral blood stem cells (≥10 CD34+ cells/µl blood) and the subsequent harvest of sufficient numbers of stem cells to support high-dose chemotherapy (≥2.0x106 CD34+ cells/kg or ≥2.0x108 PBMC/kg). Note that any results relating to this endpoint are based on data downloaded following the original data lock on 9/7/2013.
    End point type
    Secondary
    End point timeframe
    This is measured following PAD re-induction therapy only in patients who had PBSC mobilisation and harvest as part of the trial.
    End point values
    Re-induction PAD and PBSC Harvest
    Number of subjects analysed
    100 [1]
    Units: Participants
        Not adequate
    30
        Adequate
    70
    Notes
    [1] - Only 100 participants completed PBSC mobilisation and harvest on the trial.
    No statistical analyses for this end point

    Secondary: Effect of type of PBSC mobilisation and harvest on time to disease progression

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    End point title
    Effect of type of PBSC mobilisation and harvest on time to disease progression [2]
    End point description
    Type of PBSC mobilisation and harvest is categorised as: pre-relapse harvest with no mobilisation therapy received post-relapse; pre-relapse harvest with mobilisation therapy received post-relapse; post-relapse harvest; or mixed harvest. Mobilisation therapy includes re-mobilisation therapy. The results relating to this endpoint are based off data from the first follow-up analysis download, dated 14/7/15. The upper 95% confidence interval limit was not reached for the median survival time in the mixed harvest group, this has been indicated by 999.
    End point type
    Secondary
    End point timeframe
    Time to disease progression is measured from randomisation to the first documented evidence of disease progression.
    Notes
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint is only applicable to those who underwent an ASCT following randomisation and therefore values are only given for one arm.
    End point values
    High dose melphalan and ASCT
    Number of subjects analysed
    82 [3]
    Units: Months
    median (confidence interval 95%)
        All stem cells harvested prior to first ASCT
    16 (13 to 20)
        All stem cells harvested post PAD
    25 (19 to 32)
        Mixed harvest
    43 (12 to 999)
    Notes
    [3] - Information on this endpoint was not available for 7 participants.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information [1]
    Timeframe for reporting adverse events
    Adverse reactions were collected from the time of registration until 100 days post-ASCT or 30 days post cyclophosphamide.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    CTCAE
    Dictionary version
    3
    Frequency threshold for reporting non-serious adverse events: 0%
    Notes
    [1] - There are no non-serious adverse events recorded for these results. It is expected that there will be at least one non-serious adverse event reported.
    Justification: Leeds Institute of Clinical Trials Research is an academic trials unit where full MedDRA coding is not the standard. It has therefore not been possible for adverse event data to be accurately entered into the full data view within EudraCT as all mandatory categories cannot be completed.

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    07 Aug 2007
    Protocol version 2 and PIS version 2, with updates to clarify exclusion criteria and correct mistakes. Addition of sites.
    02 Nov 2007
    Protocol version 3 and PIS version 3
    01 Apr 2008
    Protocol version 4
    07 Nov 2008
    Protocol version 5
    20 Oct 2010
    Protocol version 6
    10 Oct 2011
    Protocol version 7

    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.
    On the grounds of efficacy data reviewed by the DMEC, the trial was closed to recruitment on 21 November 2012.

    Online references

    http://www.ncbi.nlm.nih.gov/pubmed/24033132
    http://www.ncbi.nlm.nih.gov/pubmed/24948586
    http://www.ncbi.nlm.nih.gov/pubmed/27374467
    http://www.ncbi.nlm.nih.gov/pubmed/26827659
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