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    Clinical Trial Results:
    A randomised Phase II trial of Imatinib (IM) versus Hydroxychloroquine (HCQ) and Imatinib (IM) for patients with Chronic Myeloid Leukaemia (CML) in Cytogenetic Response (CyR) with residual disease detectable by quantitative polymerase chain reaction (Q-PCR)

    Summary
    EudraCT number
    		 2009-014373-41
    Trial protocol
    		 GB   DE   FR  
    Global end of trial date
    27 Jun 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    21 Sep 2019
    First version publication date
    21 Sep 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    H135
    Additional study identifiers
    ISRCTN number
    		 ISRCTN61568166
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 Sponsor Ref Number: GN09HM575
    Sponsors
    Sponsor organisation name
    NHS Greater Glasgow and Clyde
    Sponsor organisation address
    Clinical Research and Development Central Office, Dykebar Hospital, Ward 11, Grahamston Road, Paisley, United Kingdom, PA2 7DE
    Public contact
    Dr Margaret Fegen, NHS Greater Glasgow and Clyde, 0141 314 4172, margaret.fegen@ggc.scot.nhs.uk
    Scientific contact
    Dr Margaret Fegen, NHS Greater Glasgow and Clyde, 0141 314 4172, margaret.fegen@ggc.scot.nhs.uk
    Sponsor organisation name
    University of Glasgow
    Sponsor organisation address
    University Avenue, Glasgow, United Kingdom, G12 8QQ
    Public contact
    Dr Debra Stuart, University of Glasgow, 0141 330 4539, debra.stuart@glasgow.ac.uk
    Scientific contact
    Dr Debra Stuart, University of Glasgow, 0141 330 4539, debra.stuart@glasgow.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
    06 Apr 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    14 Dec 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    27 Jun 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    • To provide preliminary evidence that HCQ given in combination with imatinib is more effective than imatinib alone in terms of BCR/ABL levels in CML patients who are in major cytogenetic response with residual BCR/ABL+ cells after at least one year of imatinib treatment. • To determine the safety and tolerability of HCQ given in combination with imatinib in these patients.
    Protection of trial subjects
    The role of the IDMC was to review the accruing trial data and to assess whether there were any safety or efficacy issues that should be brought to participants’ attention or any reasons for the trial not to continue. The IDMC was independent the investigators and was the only body that had access to full accumulating data during the course of the trial. It made recommendations to the UTSC.
    Background therapy
    		 -
    Evidence for comparator
    		 Imatinib treatment induces CCyR in the majority of CML patients, results in significantly improved survival and is currently front-line treatment for CML. However, most patients continue to have evidence of persistent residual disease detectable by quantitative polymerase chain reaction (Q-PCR) and there are several lines of evidence that residual BCR/ABL+ stem cells persist in CML patients despite Imatinib treatment. Therefore patients require to be treated with Imatinib indefinitely and remain at risk of relapse. Measures to enhance elimination of residual disease are needed to further improve outcomes and effect cure. In preclinical studies CML CD34+ cells were cultured for 6 days in the presence of Imatinib (IM), dasatinib (das), chloroquine (CQ) or combinations in serum free medium supplemented with growth factors prior to long term culture. Results show the recovery of CML stem cells, defined as LTCIC, confirming that combinations of IM or das with CQ are more effective in stem cell eradication than IM or das alone. We have therefore conclusively demonstrated that tyrosine kinase inhibitors, Imatinib, and dasatinib, induce the process of autophagy in CML stem and progenitor cells. In these cells autophagy acts as a survival process allowing the cells to generate energy and remain alive. Chloroquine and HCQ are well known inhibitors of autophagy that are used in laboratory studies, but can also be applied clinically. The combination of the autophagy inhibitor chloroquine with Imatinib results in significantly enhanced eradication of CML primitive progenitors compared to Imatinib or chloroquine alone. HCQ has been used extensively in rheumatology and is well tolerated. These results provide a strong rationale for testing whether addition of HCQ to Imatinib can enhance elimination of residual BCR/ABL+ stem/progenitor cells in Imatinib treated CML patients in MCyR.
    Actual start date of recruitment
    01 Apr 2010
    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: 42
    Country: Number of subjects enrolled
    France: 18
    Country: Number of subjects enrolled
    Germany: 2
    Worldwide total number of subjects
    62
    EEA total number of subjects
    62
    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)
    46
    From 65 to 84 years
    16
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Pre-randomisation evaluations: • Inclusions/exclusions • Vital signs • Medical and CML history • Physical examination • ECOG PS • 12 lead ECG • Pregnancy test • Visual acuity testing • Haematology (FBC) • Biochemistry (U+E, LFTs) • Bone marrow aspirate for cytogenetics and PD • Peripheral blood PD • Peripheral blood Q-PCR

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Imatinib alone
    Arm description
    		 Imatinib only.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Imatinib
    Investigational medicinal product code
    IM
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Patients will receive Imatinib at the dose they were taking prior to trial entry. Imatinib will be obtained from the same commercial source as was used prior to enrolment into the study. Patients should be instructed to take their oral dose of Imatinib at the same time each day. Daily treatment will be withheld only in the case of dose limiting toxicities. The prescribed dose should be administered orally, with a meal and a large glass of water. Patients should keep normal eating habits, however a low-fat meal is recommended avoiding xanthine (e.g. caffeine) or grapefruit containing foods or beverages. A minimum of 1h should be allowed between last drug intake and going to bed. If vomiting occurs, no additional Imatinib should be taken that day in an effort to replace the material that has been vomited. If the patient forgets to take his/her Imatinib dose on scheduled treatment days, then he/she should take it on that same day within 12 hours after the missed dose if possible.

    Arm title
    		 Imatinib plus Hydroxychloroquine
    Arm description
    		 Imatinib and Hydroxychloroquine. Note that Hydroxychloroquine is only given for the first 12 months of treatment.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Imatinib
    Investigational medicinal product code
    IM
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Patients will receive Imatinib at the dose they were taking prior to trial entry. Imatinib will be obtained from the same commercial source as was used prior to enrolment into the study. Patients should be instructed to take their oral dose of Imatinib at the same time each day. Daily treatment will be withheld only in the case of dose limiting toxicities. The prescribed dose should be administered orally, with a meal and a large glass of water. Patients should keep normal eating habits, however a low-fat meal is recommended avoiding xanthine (e.g. caffeine) or grapefruit containing foods or beverages. A minimum of 1h should be allowed between last drug intake and going to bed. If vomiting occurs, no additional Imatinib should be taken that day in an effort to replace the material that has been vomited. If the patient forgets to take his/her Imatinib dose on scheduled treatment days, then he/she should take it on that same day within 12 hours after the missed dose if possible.

    Investigational medicinal product name
    Hydroxychloroquine
    Investigational medicinal product code
    HCQ
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Patients will initially receive HCQ at 800mg/day. This will be taken as 400mg twice daily doses approximately 12 hours apart. Patients should be instructed to take their twice-a-day oral doses of HCQ at the same times each day (e.g. 8am and 8pm). Daily treatment will be withheld only in the case of dose limiting toxicities. The prescribed dose should be administered orally, with a meal or a glass of milk. A minimum of 1h should be allowed between last drug intake and going to bed. If the patient forgets to take his/her HCQ dose on scheduled treatment days, then he/she should take it on that same day within 6 hours after the missed dose if possible. After more than 6 hours, that dose should be withheld and the patient should wait to take HCQ at the next scheduled dose either that same day or the following day. Patients should be instructed not to try to make-up the missed dose after 6 hours. The patient should then continue treatment with the original dosing schedule.

    Number of subjects in period 1
    		Imatinib alone Imatinib plus Hydroxychloroquine
    Started
    30
    32
    Completed
    30
    32

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Imatinib alone
    Reporting group description
    		 Imatinib only.

    Reporting group title
    Imatinib plus Hydroxychloroquine
    Reporting group description
    		 Imatinib and Hydroxychloroquine. Note that Hydroxychloroquine is only given for the first 12 months of treatment.

    Reporting group values
    		 Imatinib alone Imatinib plus Hydroxychloroquine Total
    Number of subjects
    		 30 32 62
    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
    Age at randomisation.
    Units: years
        median (inter-quartile range (Q1-Q3))
    		 50 (42 to 66) 50 (39 to 61) -
    Gender categorical
    Units: Subjects
        Female
    		 10 9 19
        Male
    		 20 23 43
    PCR level at study entry
    Units: Subjects
        < 3 logs below baseline
    		 15 18 33
        >= 3 logs below baseline
    		 15 14 29
    Time on Imatinib
    Time on Imatinib, at the time of randomisation.
    Units: Subjects
        < 24 months
    		 4 6 10
        24 to <36 months
    		 5 5 10
        >= 36 months
    		 21 21 42
    Current Imatinib dose
    Imatinib dose, at the time of randomisation.
    Units: Subjects
        < 400mg
    		 2 1 3
        400mg to <600mg
    		 25 26 51
        600 to 800mg
    		 3 5 8
    Centre
    Recruiting hospital.
    Units: Subjects
        BEATSON WEST OF SCOTLAND CANCER CENTRE GLASGOW
    		 10 9 19
        HAMMERSMITH HOSPITAL LONDON
    		 5 6 11
        HOSPICES CIVILS DE LYON LYON
    		 9 9 18
        NOTTINGHAM UNIVERSITY HOSPITAL NHS TRUST
    		 2 3 5
        ROYAL LIVERPOOL UNIVERSITY HOSPITAL LIVERPOOL
    		 3 3 6
        ST JAMES'S UNIVERSITY HOSPITAL LEEDS
    		 1 0 1
        UNIVERSITY HAMBURG HAMBURG
    		 0 1 1
        UNIVERSITY HOSPITAL AACHEN PAUWELSSTRASSE, AACHEN
    		 0 1 1

    End points

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    End points reporting groups
    Reporting group title
    Imatinib alone
    Reporting group description
    		 Imatinib only.

    Reporting group title
    Imatinib plus Hydroxychloroquine
    Reporting group description
    		 Imatinib and Hydroxychloroquine. Note that Hydroxychloroquine is only given for the first 12 months of treatment.

    Subject analysis set title
    Whole blood HCQ population
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Based on the ITT population IM+HCQ arm, excluding the 6 IM + HCQ patients in the safety run-in period where blood samples were not taken. Patients who have not consented to blood sampling or have withdrawn consent have also been excluded.

    Subject analysis set title
    Imatinib plasma population (IM only)
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Based on the ITT population IM only arm, excluding the 6 IM only patients in the safety run-in period where blood samples were not taken. Patients who have not consented to blood sampling or have withdrawn consent have also been excluded.

    Subject analysis set title
    Imatinib plasma population (IM+HCQ)
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Based on the ITT population IM+HCQ arm, excluding the 6 IM+HCQ patients in the safety run-in period where blood samples were not taken. Patients who have not consented to blood sampling or have withdrawn consent have also been excluded.

    Primary: 12 month treatment success proportion

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    End point title
    		 12 month treatment success proportion
    End point description
    The proportion of treatment “successes” defined as patients who have >0.5 log reductions in their 12 month PCR level from baseline. Patients who withdraw before the 12 month assessment or who have an increase in their IM dose prior to the assessment will be classified as treatment “failures”.
    End point type
    Primary
    End point timeframe
    12 months post-randomisation
    End point values
    		 Imatinib alone Imatinib plus Hydroxychloroquine
    Number of subjects analysed
    30
    32
    Units: Percent
        Success
    6
    6
        Failure - did not achieve >0.5 log reduction
    19
    19
        Failure - increase in Imatinib dose
    1
    0
        Failure - withdrew consent prior to assessment
    4
    7
    Statistical analysis title
    		 Primary efficacy analysis
    Statistical analysis description
    The comparisons between the study arms of 12 month treatment “successes” rates will use Fisher’s exact test. A 95% confidence interval for the difference in proportion will be calculated using method 10 in RG Newcombe.
    Comparison groups
    Imatinib alone v Imatinib plus Hydroxychloroquine
    Number of subjects included in analysis
    62
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [1]
    P-value
    		 = 0.58 [2]
    Method
    		 Fisher exact
    Parameter type
    		 Difference in "success" proportions (%)
    Point estimate
    -1.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -21.1
         upper limit
    		 18.4
    Notes
    [1] - 1-sided hypothesis test, set-up to show 12 month treatment “successes” rate is greater in the IM+HCQ arm than the IM alone arm.
    [2] - 1-sided.

    Secondary: 24 month treatment success proportion

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    End point title
    		 24 month treatment success proportion
    End point description
    The proportion of treatment “successes” defined as patients who have >0.5 log reductions in their 24 month PCR level from baseline. Patients who withdraw before the 24 month assessment or who have an increase in their IM dose prior to the assessment will be classified as treatment “failures”.
    End point type
    Secondary
    End point timeframe
    24 months post-randomisation
    End point values
    		 Imatinib alone Imatinib plus Hydroxychloroquine
    Number of subjects analysed
    30
    32
    Units: Percent
        Success
    5
    12
        Failure - did not achieve >0.5 log reduction
    19
    13
        Failure - no 24 month BCR/ABL data
    1
    0
        Failure - increase in Imatinib dose
    1
    0
        Failure - withdrew consent prior to assessment
    4
    7
    Statistical analysis title
    		 24 month treatment success proportion
    Statistical analysis description
    The comparisons between the study arms of 24 month treatment “successes” rates will use Fisher’s exact test. A 95% confidence interval for the difference in proportion will be calculated using method 10 in RG Newcombe.
    Comparison groups
    Imatinib alone v Imatinib plus Hydroxychloroquine
    Number of subjects included in analysis
    62
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [3]
    P-value
    		 = 0.059 [4]
    Method
    		 Fisher exact
    Parameter type
    		 Difference in "success" proportions (%)
    Point estimate
    20.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.5
         upper limit
    		 40.4
    Notes
    [3] - 1-sided hypothesis test, set-up to show 24 month treatment “successes” rate is greater in the IM+HCQ arm than the IM alone arm.
    [4] - 1-sided

    Secondary: 12 month molecular response

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    End point title
    		 12 month molecular response
    End point description
    The proportion of patients who achieve Complete or Major Molecular Response at 12 months.
    End point type
    Secondary
    End point timeframe
    12 months post-randomisation
    End point values
    		 Imatinib alone Imatinib plus Hydroxychloroquine
    Number of subjects analysed
    30
    32
    Units: Percent
        Complete Molecular Response
    0
    0
        Major Molecular Response
    20
    23
        No Molecular Response
    5
    2
        Missing
    5
    7
    Statistical analysis title
    		 12 month molecular response rates
    Statistical analysis description
    The comparisons between the study arms of 12 month molecular response rates will use a Mann-Whitney test. A 95% confidence interval for the difference in proportion will be calculated using method 10 in RG Newcombe.
    Comparison groups
    Imatinib alone v Imatinib plus Hydroxychloroquine
    Number of subjects included in analysis
    62
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [5]
    P-value
    		 = 0.43 [6]
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Difference in response proportions (%)
    Point estimate
    5.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -17.1
         upper limit
    		 27.1
    Notes
    [5] - 1-sided hypothesis test, set-up to show 12 month molecular response rate is greater in the IM+HCQ arm than the IM alone arm.
    [6] - 1-sided

    Secondary: 24 month molecular response

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    End point title
    		 24 month molecular response
    End point description
    The proportion of patients who achieve Complete or Major Molecular Response at 12 months.
    End point type
    Secondary
    End point timeframe
    24 months post-randomisation
    End point values
    		 Imatinib alone Imatinib plus Hydroxychloroquine
    Number of subjects analysed
    30
    32
    Units: Percent
        Complete Molecular Response
    1
    2
        Major Molecular Response
    19
    22
        No Molecular Response
    4
    1
        Missing
    6
    7
    Statistical analysis title
    		 24 month molecular response rates
    Statistical analysis description
    The comparisons between the study arms of 24 month molecular response rates will use a Mann-Whitney test. A 95% confidence interval for the difference in proportion will be calculated using method 10 in RG Newcombe.
    Comparison groups
    Imatinib alone v Imatinib plus Hydroxychloroquine
    Number of subjects included in analysis
    62
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [7]
    P-value
    		 = 0.33 [8]
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Difference in response proportions (%)
    Point estimate
    8.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -13.8
         upper limit
    		 29.7
    Notes
    [7] - 1-sided hypothesis test, set-up to show 24 month molecular response rate is greater in the IM+HCQ arm than the IM alone arm.
    [8] - 1-sided

    Secondary: 12 month progression rates

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    End point title
    		 12 month progression rates
    End point description
    12 month disease progression proportion. Note that disease progression (suspected or confirmed) was not recorded for any patient, therefore no analyses were performed.
    End point type
    Secondary
    End point timeframe
    12 months post-randomisation
    End point values
    		 Imatinib alone Imatinib plus Hydroxychloroquine
    Number of subjects analysed
    30
    32
    Units: Percent
        No evidence of progression
    29
    30
        Progression suspected
    0
    0
        Confirmed progression
    0
    0
        Missing
    1
    2
    No statistical analyses for this end point

    Secondary: 24 month progression rates

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    End point title
    		 24 month progression rates
    End point description
    24 month disease progression proportion. Note that disease progression (suspected or confirmed) was not recorded for any patient, therefore no analyses were performed.
    End point type
    Secondary
    End point timeframe
    24 months post-randomisation
    End point values
    		 Imatinib alone Imatinib plus Hydroxychloroquine
    Number of subjects analysed
    30
    32
    Units: Percent
        No evidence of progression
    29
    30
        Progression suspected
    0
    0
        Confirmed progression
    0
    0
        Missing
    1
    2
    No statistical analyses for this end point

    Secondary: Imatinib plasma levels (C2D15)

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    End point title
    		 Imatinib plasma levels (C2D15)
    End point description
    Change from baseline in Imatinib plasma levels.
    End point type
    Secondary
    End point timeframe
    Cycle 2, Day 15
    End point values
    		 Imatinib plasma population (IM only) Imatinib plasma population (IM+HCQ)
    Number of subjects analysed
    19
    20
    Units: ng/ml
        median (inter-quartile range (Q1-Q3))
    -14 (-119 to 131)
    -36 (-283 to 329)
    Statistical analysis title
    		 Imatinib plasma levels
    Statistical analysis description
    Comparison of change from baseline to cycle 2 day 15 in Imatinib plasma levels between the study arms. The difference between the arms is tested using a Mann-Whitney test. An adjustment for multiple comparisons (timepoints) has been made using the false discovery rate (FDR) approach. Note - patients who have not consented to blood sampling or have withdrawn consent have also been excluded. Blood samples were not taken for the 12 patients (6 IM alone, 6 IM + HCQ) in the safety run-in period.
    Comparison groups
    Imatinib plasma population (IM only) v Imatinib plasma population (IM+HCQ)
    Number of subjects included in analysis
    39
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.86 [9]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [9] - This is the unadjusted 2-sided p-value. The FDR adjusted 2-sided p-value is 0.93.

    Secondary: Imatinib plasma levels (C4D1)

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    End point title
    		 Imatinib plasma levels (C4D1)
    End point description
    Change from baseline in Imatinib plasma levels.
    End point type
    Secondary
    End point timeframe
    Cycle 4, Day 1
    End point values
    		 Imatinib plasma population (IM only) Imatinib plasma population (IM+HCQ)
    Number of subjects analysed
    19
    17
    Units: ng/ml
        median (inter-quartile range (Q1-Q3))
    118 (-3 to 368)
    69 (-139 to 150)
    Statistical analysis title
    		 Imatinib plasma levels
    Statistical analysis description
    Comparison of change from baseline to cycle 4 day 1 in Imatinib plasma levels between the study arms. The difference between the arms is tested using a Mann-Whitney test. An adjustment for multiple comparisons (timepoints) has been made using the false discovery rate (FDR) approach. Note - patients who have not consented to blood sampling or have withdrawn consent have also been excluded. Blood samples were not taken for the 12 patients (6 IM alone, 6 IM + HCQ) in the safety run-in period.
    Comparison groups
    Imatinib plasma population (IM only) v Imatinib plasma population (IM+HCQ)
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.32 [10]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [10] - This is the unadjusted 2-sided p-value. The FDR adjusted 2-sided p-value is 0.93.

    Secondary: Imatinib plasma levels (C7D1)

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    End point title
    		 Imatinib plasma levels (C7D1)
    End point description
    End point type
    Secondary
    End point timeframe
    Cycle 7, Day 1
    End point values
    		 Imatinib plasma population (IM only) Imatinib plasma population (IM+HCQ)
    Number of subjects analysed
    19
    17
    Units: ng/ml
        median (inter-quartile range (Q1-Q3))
    -41 (-186 to 185)
    29 (-289 to 407)
    Statistical analysis title
    		 Imatinib plasma levels
    Statistical analysis description
    Comparison of change from baseline to cycle 7 day 1 in Imatinib plasma levels between the study arms. The difference between the arms is tested using a Mann-Whitney test. An adjustment for multiple comparisons (timepoints) has been made using the false discovery rate (FDR) approach. Note - patients who have not consented to blood sampling or have withdrawn consent have also been excluded. Blood samples were not taken for the 12 patients (6 IM alone, 6 IM + HCQ) in the safety run-in period.
    Comparison groups
    Imatinib plasma population (IM only) v Imatinib plasma population (IM+HCQ)
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.93 [11]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [11] - This is the unadjusted 2-sided p-value. The FDR adjusted 2-sided p-value is 0.93.

    Secondary: Imatinib plasma levels (C10D1)

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    End point title
    		 Imatinib plasma levels (C10D1)
    End point description
    Change from baseline in Imatinib plasma levels.
    End point type
    Secondary
    End point timeframe
    Cycle 10, Day 1
    End point values
    		 Imatinib plasma population (IM only) Imatinib plasma population (IM+HCQ)
    Number of subjects analysed
    18
    16
    Units: ng/ml
        median (inter-quartile range (Q1-Q3))
    153 (-123 to 330)
    165 (-43 to 392)
    Statistical analysis title
    		 Imatinib plasma levels
    Statistical analysis description
    Comparison of change from baseline to cycle 10 day 1 in Imatinib plasma levels between the study arms. The difference between the arms is tested using a Mann-Whitney test. An adjustment for multiple comparisons (timepoints) has been made using the false discovery rate (FDR) approach. Note - patients who have not consented to blood sampling or have withdrawn consent have also been excluded. Blood samples were not taken for the 12 patients (6 IM alone, 6 IM + HCQ) in the safety run-in period.
    Comparison groups
    Imatinib plasma population (IM only) v Imatinib plasma population (IM+HCQ)
    Number of subjects included in analysis
    34
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.88 [12]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [12] - This is the unadjusted 2-sided p-value. The FDR adjusted 2-sided p-value is 0.93.

    Secondary: Imatinib plasma levels (C13D1)

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    End point title
    		 Imatinib plasma levels (C13D1)
    End point description
    Change from baseline in Imatinib plasma levels.
    End point type
    Secondary
    End point timeframe
    Cycle 13, Day 1
    End point values
    		 Imatinib plasma population (IM only) Imatinib plasma population (IM+HCQ)
    Number of subjects analysed
    19
    15
    Units: ng/ml
        median (inter-quartile range (Q1-Q3))
    163 (-109 to 659)
    268 (-102 to 668)
    Statistical analysis title
    		 Imatinib plasma levels
    Statistical analysis description
    Comparison of change from baseline to cycle 13 day 1 in Imatinib plasma levels between the study arms. The difference between the arms is tested using a Mann-Whitney test. An adjustment for multiple comparisons (timepoints) has been made using the false discovery rate (FDR) approach. Note - patients who have not consented to blood sampling or have withdrawn consent have also been excluded. Blood samples were not taken for the 12 patients (6 IM alone, 6 IM + HCQ) in the safety run-in period.
    Comparison groups
    Imatinib plasma population (IM only) v Imatinib plasma population (IM+HCQ)
    Number of subjects included in analysis
    34
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.81 [13]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [13] - This is the unadjusted 2-sided p-value. The FDR adjusted 2-sided p-value is 0.93.

    Secondary: Whole blood HCQ levels

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    End point title
    		 Whole blood HCQ levels
    End point description
    Proportion of IM+HCQ patients achieving HCQ concentrations of >2000ng/ml at any point up to 12 months post-randomisation. Excludes the 6 IM + HCQ patients in the safety run-in period where blood samples were not taken. Patients who have not consented to blood sampling or have withdrawn consent have also been excluded.
    End point type
    Secondary
    End point timeframe
    Up to 12 months post-randomisation.
    End point values
    		 Whole blood HCQ population
    Number of subjects analysed
    17
    Units: Percent
        Achieved HCQ conc >2000ng/ml
    8
        Did not achieve HCQ conc >2000ng/ml
    9
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    AEs were recorded from the date of randomisation and throughout the study period (24 months post-randomisation) and for at least 30 days after discontinuation of protocol specific medication. All AEs were followed until resolution.
    Adverse event reporting additional description
    Note - it is not possible to determine the number of occurrences of non-serious AEs from our database. Therefore the number of occurrences of non-serious AEs is assumed to be one per patient.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 CTCAE
    Dictionary version
    4
    Reporting groups
    Reporting group title
    IM only safety population
    Reporting group description
    		 -

    Reporting group title
    IM+HCQ safety population
    Reporting group description
    		 -

    Serious adverse events
    		 IM only safety population IM+HCQ safety population
    Total subjects affected by serious adverse events
         subjects affected / exposed
    5 / 29 (17.24%)
    5 / 32 (15.63%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other, specify
         subjects affected / exposed
    1 / 29 (3.45%)
    1 / 32 (3.13%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Intraoperative endocrine injury
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 32 (3.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Heart failure
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 32 (3.13%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinus tachycardia
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 32 (3.13%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Surgical and medical procedures - Other, specify
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 32 (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
    Fever
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspepsia
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hepatobiliary disorders - Other, specify
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 32 (3.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 32 (3.13%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal calculi
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 32 (3.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal colic
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 32 (3.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Bronchial infection
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pharyngitis
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 32 (3.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 IM only safety population IM+HCQ safety population
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    17 / 29 (58.62%)
    25 / 32 (78.13%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    2 / 29 (6.90%)
    0 / 32 (0.00%)
         occurrences all number
    2
    0
    Vascular disorders - Other, specify
         subjects affected / exposed
    0 / 29 (0.00%)
    2 / 32 (6.25%)
         occurrences all number
    0
    2
    General disorders and administration site conditions
    Oedema face
         subjects affected / exposed
    3 / 29 (10.34%)
    0 / 32 (0.00%)
         occurrences all number
    3
    0
    Fatigue
         subjects affected / exposed
    2 / 29 (6.90%)
    6 / 32 (18.75%)
         occurrences all number
    2
    6
    Flu like symptoms
         subjects affected / exposed
    3 / 29 (10.34%)
    3 / 32 (9.38%)
         occurrences all number
    3
    3
    General disorders and administration site conditions - Other, specify
         subjects affected / exposed
    4 / 29 (13.79%)
    5 / 32 (15.63%)
         occurrences all number
    4
    5
    Localized oedema
         subjects affected / exposed
    9 / 29 (31.03%)
    8 / 32 (25.00%)
         occurrences all number
    9
    8
    Pain
         subjects affected / exposed
    7 / 29 (24.14%)
    7 / 32 (21.88%)
         occurrences all number
    7
    7
    Immune system disorders
    Allergic reaction
         subjects affected / exposed
    4 / 29 (13.79%)
    0 / 32 (0.00%)
         occurrences all number
    4
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    3 / 29 (10.34%)
    2 / 32 (6.25%)
         occurrences all number
    3
    2
    Cardiac disorders
    Cardiac disorders - Other, specify
         subjects affected / exposed
    2 / 29 (6.90%)
    2 / 32 (6.25%)
         occurrences all number
    2
    2
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    0 / 29 (0.00%)
    3 / 32 (9.38%)
         occurrences all number
    0
    3
    Headache
         subjects affected / exposed
    3 / 29 (10.34%)
    4 / 32 (12.50%)
         occurrences all number
    3
    4
    Lethargy
         subjects affected / exposed
    2 / 29 (6.90%)
    5 / 32 (15.63%)
         occurrences all number
    2
    5
    Nervous system disorders - Other, specify
         subjects affected / exposed
    2 / 29 (6.90%)
    2 / 32 (6.25%)
         occurrences all number
    2
    2
    Paresthesia
         subjects affected / exposed
    0 / 29 (0.00%)
    2 / 32 (6.25%)
         occurrences all number
    0
    2
    Eye disorders
    Blurred vision
         subjects affected / exposed
    0 / 29 (0.00%)
    2 / 32 (6.25%)
         occurrences all number
    0
    2
    Conjunctivitis
         subjects affected / exposed
    2 / 29 (6.90%)
    0 / 32 (0.00%)
         occurrences all number
    2
    0
    Eye disorders - Other, specify
         subjects affected / exposed
    3 / 29 (10.34%)
    6 / 32 (18.75%)
         occurrences all number
    3
    6
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    4 / 29 (13.79%)
    9 / 32 (28.13%)
         occurrences all number
    4
    9
    Diarrhoea
         subjects affected / exposed
    13 / 29 (44.83%)
    22 / 32 (68.75%)
         occurrences all number
    13
    22
    Dyspepsia
         subjects affected / exposed
    2 / 29 (6.90%)
    0 / 32 (0.00%)
         occurrences all number
    2
    0
    Gastrointestinal disorders - Other, specify
         subjects affected / exposed
    4 / 29 (13.79%)
    2 / 32 (6.25%)
         occurrences all number
    4
    2
    Nausea
         subjects affected / exposed
    7 / 29 (24.14%)
    15 / 32 (46.88%)
         occurrences all number
    7
    15
    Vomiting
         subjects affected / exposed
    5 / 29 (17.24%)
    7 / 32 (21.88%)
         occurrences all number
    5
    7
    Skin and subcutaneous tissue disorders
    Dry skin
         subjects affected / exposed
    4 / 29 (13.79%)
    4 / 32 (12.50%)
         occurrences all number
    4
    4
    Pruritus
         subjects affected / exposed
    2 / 29 (6.90%)
    0 / 32 (0.00%)
         occurrences all number
    2
    0
    Rash maculo-papular
         subjects affected / exposed
    6 / 29 (20.69%)
    3 / 32 (9.38%)
         occurrences all number
    6
    3
    Skin and subcutaneous tissue disorders - Other, specify
         subjects affected / exposed
    4 / 29 (13.79%)
    3 / 32 (9.38%)
         occurrences all number
    4
    3
    Renal and urinary disorders
    Renal and urinary disorders - Other, specify
         subjects affected / exposed
    0 / 29 (0.00%)
    2 / 32 (6.25%)
         occurrences all number
    0
    2
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    3 / 29 (10.34%)
    0 / 32 (0.00%)
         occurrences all number
    3
    0
    Musculoskeletal and connective tissue disorder - Other, specify
         subjects affected / exposed
    11 / 29 (37.93%)
    10 / 32 (31.25%)
         occurrences all number
    11
    10
    Musculoskeletal deformity
         subjects affected / exposed
    2 / 29 (6.90%)
    2 / 32 (6.25%)
         occurrences all number
    2
    2
    Infections and infestations
    Infections and infestations - Other, specify
         subjects affected / exposed
    6 / 29 (20.69%)
    10 / 32 (31.25%)
         occurrences all number
    6
    10
    Otitis externa
         subjects affected / exposed
    0 / 29 (0.00%)
    2 / 32 (6.25%)
         occurrences all number
    0
    2
    Pharyngitis
         subjects affected / exposed
    0 / 29 (0.00%)
    2 / 32 (6.25%)
         occurrences all number
    0
    2
    Rhinitis infective
         subjects affected / exposed
    3 / 29 (10.34%)
    2 / 32 (6.25%)
         occurrences all number
    3
    2
    Skin infection
         subjects affected / exposed
    2 / 29 (6.90%)
    0 / 32 (0.00%)
         occurrences all number
    2
    0
    Upper respiratory infection
         subjects affected / exposed
    2 / 29 (6.90%)
    0 / 32 (0.00%)
         occurrences all number
    2
    0
    Metabolism and nutrition disorders
    Anorexia
         subjects affected / exposed
    0 / 29 (0.00%)
    2 / 32 (6.25%)
         occurrences all number
    0
    2

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    26 May 2010
    Amendment Number 1: Amendment to patient information sheet and protocol. Update to the visit schedule for patients on the Imatinib arm of the trial - these patients were not required to come for weekly visits as they had been on a stable dose of Imatinib for >6 months therefore the protocol and patient information sheet were changed to this effect. Change to the timeline of supportive care for patients with grade 3 nausea, vomiting or diarrhoea from 24 hours to 72 hours made to protocol.
    20 Oct 2010
    Amendment Number 2: For information only, change in the product license number of the IMP (Hydroxychloroquine) and clarification provided regarding the repackaging, labelling and distribution of the IMP.
    14 Mar 2011
    Amendment Number 5: Changes to protocol to incorporate - change of eligibility criteria to include patients that have been on Imatinib treatment for more than 3 years, increase the number of recruiting sites (addition of 2 new sites), reduction in the number of eye exams based on review of the eye toxicity data, and other minor administrative changes to the protocol.
    20 Sep 2011
    Amendment Number 6: Protocol amendment to remove a number of the screening tests which were considered unnecessary and hindering recruitment to the trial and other minor administrative changes.
    08 Dec 2011
    Amendment Number 7: Changes to protocol and provision of further patient information documentation around the visual acuity tests included within the trial.

    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
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