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    Clinical Trial Results:
    A Randomised, Double Blind Study to Compare the Complete Remission Rate Following a 5-Week Course of Selumetinib or Placebo and Single Dose Adjuvant Radioactive Iodine Therapy in Patients with Differentiated Thyroid Cancer

    Summary
    EudraCT number
    2013-000423-14
    Trial protocol
    SE   DE   IT   FR   DK  
    Global end of trial date
    06 Mar 2019

    Results information
    Results version number
    v1(current)
    This version publication date
    15 Aug 2019
    First version publication date
    15 Aug 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    D1532C00065
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01843062
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    AstraZeneca AB
    Sponsor organisation address
    Research and Development, Södertälje, Sweden, SE-151 85
    Public contact
    Global Clinical Lead, AstraZeneca, ClinicalTrialTransparency@astrazeneca.com
    Scientific contact
    Global Clinical Lead, AstraZeneca, ClinicalTrialTransparency@astrazeneca.com
    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 Mar 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    18 May 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    06 Mar 2019
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    To compare the efficacy of selumetinib (75 milligrams [mg], orally, twice daily [BD]) in combination with adjuvant radioactive iodine (RAI) therapy, versus placebo and adjuvant RAI therapy, by assessment of complete remission rate at 18 months post-RAI treatment.
    Protection of trial subjects
    This study was performed in accordance with the ethical principles that have their origin in the Declaration of Helsinki and that are consistent with International Council for Harmonisation/Good Clinical Practice, applicable regulatory requirements, and the AstraZeneca policy on Bioethics.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    27 Aug 2013
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Brazil: 34
    Country: Number of subjects enrolled
    Denmark: 11
    Country: Number of subjects enrolled
    France: 24
    Country: Number of subjects enrolled
    Germany: 12
    Country: Number of subjects enrolled
    Italy: 30
    Country: Number of subjects enrolled
    Poland: 21
    Country: Number of subjects enrolled
    Sweden: 26
    Country: Number of subjects enrolled
    United States: 75
    Worldwide total number of subjects
    233
    EEA total number of subjects
    124
    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)
    203
    From 65 to 84 years
    30
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Study conducted between 27 Aug 2013 and 06 Mar 2019. 42 centres in 8 countries randomised patients in the study. A primary analysis was performed for the 18 months post-RAI treatment period with a data cut-off of 18 May 2018. All primary and secondary outcome measures were reported at the time of the primary analysis.

    Pre-assignment
    Screening details
    Eligible patients with differentiated thyroid cancer at high risk of primary treatment failure were randomly assigned (ratio 2:1), to receive selumetinib or placebo for approximately 5 weeks. All patients also received adjuvant RAI therapy (100 millicuries [mCi] single oral dose) and recombinant human thyroid stimulating hormone (rhTSH) injections.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Monitor, Carer
    Blinding implementation details
    The active and placebo capsules appeared identical and were presented in the same packaging to ensure blinding of the medication. All patients remained blinded until after the 18 months primary endpoint data analysis had been conducted.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Selumetinib 75 mg BD + RAI
    Arm description
    Patients received selumetinib (75 mg, orally, BD), for a period of approximately 5 weeks. Selumetinib was to be started approximately 4 weeks prior to the planned day of RAI therapy administered as a single oral dose of 100 mCi. To stimulate iodide uptake, patients received a rhTSH injection for each of the 2 days immediately prior to RAI therapy.
    Arm type
    Experimental

    Investigational medicinal product name
    Selumetinib
    Investigational medicinal product code
    AZD6244
    Other name
    Selumetinib hydrogen sulphate, AZD6244 Hyd-Sulfate
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    3 capsules of 25 mg strength, orally BD, for approximately 5 weeks treatment period.

    Arm title
    Placebo + RAI
    Arm description
    Patients received placebo capsules (to match selumetinib, orally BD), for a period of approximately 5 weeks. Placebo was to be started approximately 4 weeks prior to the planned day of RAI therapy administered as a single oral dose of 100 mCi. To stimulate iodide uptake, patients received a rhTSH injection for each of the 2 days immediately prior to RAI therapy.
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    3 capsules of placebo to match selumetinib, orally BD, for approximately 5 weeks treatment period.

    Number of subjects in period 1
    Selumetinib 75 mg BD + RAI Placebo + RAI
    Started
    155
    78
    Intention to treat (ITT) analysis set
    155
    78
    Safety analysis set
    154
    77
    BRAF/NRAS mutation positive analysis set
    91 [1]
    51 [2]
    Ongoing at primary analysis data cut-off
    134
    71
    Completed
    133
    69
    Not completed
    22
    9
         Protocol deviation
    1
    -
         Incorrect randomisation
    1
    -
         Pregnancy
    1
    -
         Adverse event, serious fatal
    1
    2
         Adverse event, non-fatal
    2
    -
         Consent withdrawn by subject
    12
    3
         New treatment following progression
    2
    -
         Lost to follow-up
    2
    4
    Notes
    [1] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: This represents the number of subjects included in the BRAF/NRAS mutation positive analysis set and should therefore be viewed as a subgroup analysis set, as opposed to an intermediate milestone.
    [2] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: This represents the number of subjects included in the BRAF/NRAS mutation positive analysis set and should therefore be viewed as a subgroup analysis set, as opposed to an intermediate milestone.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Selumetinib 75 mg BD + RAI
    Reporting group description
    Patients received selumetinib (75 mg, orally, BD), for a period of approximately 5 weeks. Selumetinib was to be started approximately 4 weeks prior to the planned day of RAI therapy administered as a single oral dose of 100 mCi. To stimulate iodide uptake, patients received a rhTSH injection for each of the 2 days immediately prior to RAI therapy.

    Reporting group title
    Placebo + RAI
    Reporting group description
    Patients received placebo capsules (to match selumetinib, orally BD), for a period of approximately 5 weeks. Placebo was to be started approximately 4 weeks prior to the planned day of RAI therapy administered as a single oral dose of 100 mCi. To stimulate iodide uptake, patients received a rhTSH injection for each of the 2 days immediately prior to RAI therapy.

    Reporting group values
    Selumetinib 75 mg BD + RAI Placebo + RAI Total
    Number of subjects
    155 78 233
    Age categorical
    Units: Subjects
        In utero
        Preterm newborn infants (gestational age < 37 wks)
        Newborns (0-27 days)
        Infants and toddlers (28 days-23 months)
        Children (2-11 years)
        Adolescents (12-17 years)
        Adults (18-64 years)
        From 65-84 years
        85 years and over
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    46.2 ± 14.20 47.9 ± 14.67 -
    Sex: Female, Male
    Units: Subjects
        Female
    92 40 132
        Male
    63 38 101
    Race
    Units: Subjects
        White
    145 73 218
        Black or African American
    3 1 4
        Asian
    3 3 6
        Other
    4 1 5
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    27 14 41
        Not Hispanic or Latino
    128 64 192

    End points

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    End points reporting groups
    Reporting group title
    Selumetinib 75 mg BD + RAI
    Reporting group description
    Patients received selumetinib (75 mg, orally, BD), for a period of approximately 5 weeks. Selumetinib was to be started approximately 4 weeks prior to the planned day of RAI therapy administered as a single oral dose of 100 mCi. To stimulate iodide uptake, patients received a rhTSH injection for each of the 2 days immediately prior to RAI therapy.

    Reporting group title
    Placebo + RAI
    Reporting group description
    Patients received placebo capsules (to match selumetinib, orally BD), for a period of approximately 5 weeks. Placebo was to be started approximately 4 weeks prior to the planned day of RAI therapy administered as a single oral dose of 100 mCi. To stimulate iodide uptake, patients received a rhTSH injection for each of the 2 days immediately prior to RAI therapy.

    Primary: Complete remission rate (expressed as percentage of patients in complete remission) at 18 months post-RAI treatment; ITT analysis set

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    End point title
    Complete remission rate (expressed as percentage of patients in complete remission) at 18 months post-RAI treatment; ITT analysis set
    End point description
    Patients were defined to be in complete remission if all of the following criteria were demonstrated: 1. Serum thyroglobulin (Tg) levels <1 nanograms / millilitre (ng/mL) during rhTSH stimulation, in the absence of interfering Tg antibodies, as assessed by standardised central laboratory analysis. 2. No confirmed evidence of thyroid cancer on neck ultrasound, as assessed by investigator site review. 3. No confirmed radiological evidence of thyroid cancer, as assessed by blinded independent central review. 4. No histopathological evidence of thyroid cancer on fine needle aspiration (FNA)/biopsy when performed, as assessed by investigator site review. 5. No further thyroid cancer therapy was administered in the first 18 months following the initial RAI treatment. Analysis performed on the ITT analysis set which included all randomised patients. Patients who were randomised but did not subsequently go on to receive selumetinib/placebo were included in the ITT analysis set.
    End point type
    Primary
    End point timeframe
    At 18 months post-RAI treatment
    End point values
    Selumetinib 75 mg BD + RAI Placebo + RAI
    Number of subjects analysed
    155
    78
    Units: Percentage of participants
        number (not applicable)
    40.0
    38.5
    Statistical analysis title
    Complete remission rate: ITT set
    Statistical analysis description
    Selumetinib in combination with RAI was compared with placebo in combination with RAI. The analysis was performed using a logistic regression model including treatment as the only covariate. An odds ratio >1 favours selumetinib in combination with RAI.
    Comparison groups
    Selumetinib 75 mg BD + RAI v Placebo + RAI
    Number of subjects included in analysis
    233
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.8205 [1]
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.07
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.61
         upper limit
    1.87
    Notes
    [1] - The primary endpoint was to be considered statistically significant if the 2-sided p-value was less than 0.05. P-value and confidence intervals (CIs) were calculated using profile likelihood.

    Secondary: Complete remission rate (expressed as percentage of patients in complete remission) at 18 months post-RAI treatment; subgroup analysis BRAF/NRAS mutation positive

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    End point title
    Complete remission rate (expressed as percentage of patients in complete remission) at 18 months post-RAI treatment; subgroup analysis BRAF/NRAS mutation positive
    End point description
    Patients were defined to be in complete remission if all of the following criteria were demonstrated: 1. Serum Tg levels <1 ng/mL during rhTSH stimulation, in the absence of interfering Tg antibodies, as assessed by standardised central laboratory analysis. 2. No confirmed evidence of thyroid cancer on neck ultrasound, as assessed by investigator site review. 3. No confirmed radiological evidence of thyroid cancer, as assessed by blinded independent central review. 4. No histopathological evidence of thyroid cancer FNA/biopsy when performed, as assessed by investigator site review. 5. No further thyroid cancer therapy was administered in the first 18 months following the initial RAI treatment. Analysis performed on the BRAF/NRAS mutation positive analysis set which included only those patients from the ITT population whose tumour samples were mutation positive for the oncogenes BRAF or NRAS.
    End point type
    Secondary
    End point timeframe
    At 18 months post-RAI treatment
    End point values
    Selumetinib 75 mg BD + RAI Placebo + RAI
    Number of subjects analysed
    91
    51
    Units: Percentage of participants
        number (not applicable)
    37.4
    41.2
    Statistical analysis title
    Complete remission rate: BRAF/NRAS positive set
    Statistical analysis description
    Selumetinib in combination with RAI was compared with placebo in combination with RAI. The analysis was performed using a logistic regression model including treatment as the only covariate. An odds ratio >1 favours selumetinib in combination with RAI.
    Comparison groups
    Selumetinib 75 mg BD + RAI v Placebo + RAI
    Number of subjects included in analysis
    142
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.6549 [2]
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    0.85
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.42
         upper limit
    1.73
    Notes
    [2] - P-value and CIs were calculated using profile likelihood.

    Secondary: Clinical remission rate (expressed as percentage of patients in clinical remission) at 18 months post-RAI treatment; ITT analysis set

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    End point title
    Clinical remission rate (expressed as percentage of patients in clinical remission) at 18 months post-RAI treatment; ITT analysis set
    End point description
    Patients were defined to be in clinical remission if all of the following criteria were demonstrated: 1. Serum Tg levels <1 ng/mL during rhTSH stimulation, in the absence of interfering Tg antibodies, as assessed by standardised central laboratory analysis. 2. No confirmed evidence of thyroid cancer on neck ultrasound, as assessed by investigator site review. 3. No evidence of thyroid cancer on diagnostic whole body scan (WBS), as assessed by blinded independent central review. 4. No histopathological evidence of thyroid cancer on FNA/biopsy when performed to clarify equivocal ultrasound findings, as assessed by investigator site review. 5. No further thyroid cancer therapy was administered in the first 18 months following the initial RAI treatment. Analysis performed on the ITT analysis set which included all randomised patients. Patients who were randomised but did not subsequently go on to receive selumetinib/placebo were included in the ITT analysis set.
    End point type
    Secondary
    End point timeframe
    At 18 months post-RAI treatment
    End point values
    Selumetinib 75 mg BD + RAI Placebo + RAI
    Number of subjects analysed
    155
    78
    Units: Percentage of participants
        number (not applicable)
    40.0
    38.5
    Statistical analysis title
    Clinical remission rate: ITT set
    Statistical analysis description
    Selumetinib in combination with RAI was compared with placebo in combination with RAI. The analysis was performed using a logistic regression model including treatment as the only covariate. An odds ratio >1 favours selumetinib in combination with RAI.
    Comparison groups
    Selumetinib 75 mg BD + RAI v Placebo + RAI
    Number of subjects included in analysis
    233
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.8205 [3]
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.07
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.61
         upper limit
    1.87
    Notes
    [3] - P-value and CIs were calculated using profile likelihood.

    Secondary: Clinical remission rate (expressed as percentage of patients in clinical remission) at 18 months post-RAI treatment; subgroup analysis BRAF/NRAS mutation positive

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    End point title
    Clinical remission rate (expressed as percentage of patients in clinical remission) at 18 months post-RAI treatment; subgroup analysis BRAF/NRAS mutation positive
    End point description
    Patients were defined to be in clinical remission if all of the following criteria were demonstrated: 1. Serum Tg levels <1 ng/mL during rhTSH stimulation, in the absence of interfering Tg antibodies, as assessed by standardised central laboratory analysis. 2. No confirmed evidence of thyroid cancer on neck ultrasound, as assessed by investigator site review. 3. No evidence of thyroid cancer on diagnostic WBS, as assessed by blinded independent central review. 4. No histopathological evidence of thyroid cancer on FNA/biopsy when performed to clarify equivocal ultrasound findings, as assessed by investigator site review. 5. No further thyroid cancer therapy was administered in the first 18 months following the initial RAI treatment. Analysis performed on the BRAF/NRAS mutation positive analysis set which included only those patients from the ITT population whose tumour samples were mutation positive for the oncogenes BRAF or NRAS.
    End point type
    Secondary
    End point timeframe
    At 18 months post-RAI treatment
    End point values
    Selumetinib 75 mg BD + RAI Placebo + RAI
    Number of subjects analysed
    91
    51
    Units: Percentage of participants
        number (not applicable)
    37.4
    41.2
    Statistical analysis title
    Clinical remission rate: BRAF/NRAS positive set
    Statistical analysis description
    Selumetinib in combination with RAI was compared with placebo in combination with RAI. The analysis was performed using a logistic regression model including treatment as the only covariate. An odds ratio >1 favours selumetinib in combination with RAI.
    Comparison groups
    Selumetinib 75 mg BD + RAI v Placebo + RAI
    Number of subjects included in analysis
    142
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.6549 [4]
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    0.85
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.42
         upper limit
    1.73
    Notes
    [4] - P-value and CIs were calculated using profile likelihood.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Includes adverse events (AEs) with an onset date on or after the date of first dose and up to and including 30 days following the date of last dose of selumetinib/placebo. Overall timeframe for collection of AEs was up to 66 days from the first dose.
    Adverse event reporting additional description
    Deaths (all causes) is reported for the ITT analysis set for the overall study period. Serious and Non-serious) AE data is reported for the safety analysis set (including all patients who received at least 1 dose of randomised treatment) for the 5-week treatment period plus 30-day follow-up phase.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    21.1
    Reporting groups
    Reporting group title
    Selumetinib 75mg BID
    Reporting group description
    Description (Arm-group)

    Reporting group title
    Placebo 75mg BID
    Reporting group description
    Description (Arm-group)

    Serious adverse events
    Selumetinib 75mg BID Placebo 75mg BID
    Total subjects affected by serious adverse events
         subjects affected / exposed
    7 / 154 (4.55%)
    0 / 77 (0.00%)
         number of deaths (all causes)
    1
    2
         number of deaths resulting from adverse events
    Immune system disorders
    Drug hypersensitivity
         subjects affected / exposed
    1 / 154 (0.65%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Syncope
         subjects affected / exposed
    1 / 154 (0.65%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Gastric haemorrhage
         subjects affected / exposed
    1 / 154 (0.65%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Dermatitis acneiform
         subjects affected / exposed
    2 / 154 (1.30%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hypercalcaemia
         subjects affected / exposed
    1 / 154 (0.65%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Cellulitis
         subjects affected / exposed
    1 / 154 (0.65%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Selumetinib 75mg BID Placebo 75mg BID
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    141 / 154 (91.56%)
    43 / 77 (55.84%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    20 / 154 (12.99%)
    3 / 77 (3.90%)
         occurrences all number
    23
    3
    Investigations
    Blood creatine phosphokinase increased
         subjects affected / exposed
    31 / 154 (20.13%)
    1 / 77 (1.30%)
         occurrences all number
    31
    1
    Weight decreased
         subjects affected / exposed
    0 / 154 (0.00%)
    4 / 77 (5.19%)
         occurrences all number
    0
    4
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    3 / 154 (1.95%)
    4 / 77 (5.19%)
         occurrences all number
    3
    4
    Nervous system disorders
    Dysgeusia
         subjects affected / exposed
    6 / 154 (3.90%)
    4 / 77 (5.19%)
         occurrences all number
    6
    4
    Headache
         subjects affected / exposed
    8 / 154 (5.19%)
    10 / 77 (12.99%)
         occurrences all number
    8
    11
    Paraesthesia
         subjects affected / exposed
    4 / 154 (2.60%)
    4 / 77 (5.19%)
         occurrences all number
    4
    4
    Eye disorders
    Periorbital oedema
         subjects affected / exposed
    8 / 154 (5.19%)
    0 / 77 (0.00%)
         occurrences all number
    8
    0
    Vision blurred
         subjects affected / exposed
    16 / 154 (10.39%)
    5 / 77 (6.49%)
         occurrences all number
    16
    5
    General disorders and administration site conditions
    Face oedema
         subjects affected / exposed
    9 / 154 (5.84%)
    0 / 77 (0.00%)
         occurrences all number
    9
    0
    Fatigue
         subjects affected / exposed
    44 / 154 (28.57%)
    13 / 77 (16.88%)
         occurrences all number
    44
    13
    Oedema peripheral
         subjects affected / exposed
    30 / 154 (19.48%)
    4 / 77 (5.19%)
         occurrences all number
    32
    4
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    68 / 154 (44.16%)
    12 / 77 (15.58%)
         occurrences all number
    78
    13
    Constipation
         subjects affected / exposed
    15 / 154 (9.74%)
    3 / 77 (3.90%)
         occurrences all number
    15
    3
    Dry mouth
         subjects affected / exposed
    15 / 154 (9.74%)
    3 / 77 (3.90%)
         occurrences all number
    15
    3
    Dyspepsia
         subjects affected / exposed
    8 / 154 (5.19%)
    1 / 77 (1.30%)
         occurrences all number
    8
    1
    Stomatitis
         subjects affected / exposed
    17 / 154 (11.04%)
    4 / 77 (5.19%)
         occurrences all number
    18
    4
    Nausea
         subjects affected / exposed
    44 / 154 (28.57%)
    8 / 77 (10.39%)
         occurrences all number
    44
    10
    Vomiting
         subjects affected / exposed
    14 / 154 (9.09%)
    0 / 77 (0.00%)
         occurrences all number
    14
    0
    Skin and subcutaneous tissue disorders
    Rash follicular
         subjects affected / exposed
    13 / 154 (8.44%)
    0 / 77 (0.00%)
         occurrences all number
    13
    0
    Rash macular
         subjects affected / exposed
    12 / 154 (7.79%)
    2 / 77 (2.60%)
         occurrences all number
    12
    2
    Dermatitis acneiform
         subjects affected / exposed
    67 / 154 (43.51%)
    4 / 77 (5.19%)
         occurrences all number
    70
    4
    Acne
         subjects affected / exposed
    13 / 154 (8.44%)
    2 / 77 (2.60%)
         occurrences all number
    13
    2
    Pruritus
         subjects affected / exposed
    21 / 154 (13.64%)
    3 / 77 (3.90%)
         occurrences all number
    21
    3
    Dry skin
         subjects affected / exposed
    12 / 154 (7.79%)
    4 / 77 (5.19%)
         occurrences all number
    12
    4
    Rash maculo-papular
         subjects affected / exposed
    19 / 154 (12.34%)
    4 / 77 (5.19%)
         occurrences all number
    19
    4
    Musculoskeletal and connective tissue disorders
    Muscle spasms
         subjects affected / exposed
    1 / 154 (0.65%)
    4 / 77 (5.19%)
         occurrences all number
    1
    4

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    03 Apr 2013
    • Additional safety assessments were added and blood volumes for clinical chemistry and haematology assessments were increased accordingly (Food and Drug Administration [FDA] request). • Inclusion criterion 13 was updated (clarification). • Text added to specify that all adverse events were to be graded according to National Cancer Institute Common Terminology Criteria for Adverse Events Version 4 (clarification at FDA request). • BRAF/NRAS mutation status definitions were added (clarification). • Haematoxylin and eosin stained sections were to be prepared by the central laboratory (to ensure sample processing consistency).
    15 Jul 2013
    • Primary and secondary objectives were updated (FDA comments): efficacy in the genetic subgroup population of BRAF or NRAS mutation positive patients was considered a secondary objective (previously a co primary objective). It was also clarified that complete remission rate and clinical remission rate at 18 months were to be assessed in the ITT study population. Text describing the analysis of the primary endpoint was updated accordingly and further details of sensitivity analyses were added. Description of the Dunnett and Tamhane step-up procedure was removed as this was no longer applicable. • Exclusion criterion 7 was added (FDA request). • Text was added to clarify that archival tumour analyses may have included, but were not limited to, BRAF V600E and NRAS Q61R, Q61K and Q61L (FDA comments). • It was clarified that randomisation of 228 patients in a 2:1 ratio was expected to provide at least 80% power to show statistical significance for the primary endpoint (FDA comments).
    01 Jul 2014
    • The treatment plan was updated to clarify that if a patient suspended study drug (selumetinib or placebo) treatment for more than 14 days, they were no longer eligible to re-start treatment (to provide clear instruction on allowed study drug interruption). • It was clarified that the visit window for Visit 4, RAI treatment dose administration (Visit 5) and Visit 6 was +1 week (clarification). • Inclusion criterion 14 was updated (to specify the time frame for adequate organ function assessment). • Exclusion criteria 4, 10 and 22 were updated (to allow patient rescreening, enrolment of patients without external beam radiation therapy in the 6 months before randomisation and to specify the time frame for assessment of blood pressure and adequate organ function). • The maximum daily dose of vitamin E received from selumetinib/placebo was increased to 261.6 mg/day (new calculation). • Text added to allow re-screening. • Instructions on handling patients who had discontinued selumetinib/placebo were updated. • It was clarified that assessment of the percentage uptake in the thyroid bed was to be assessed by the local investigator site according to local clinical practice (to reflect the current situation in clinical practice). • Plasma clinical chemistry assessments and leucocyte differential count as a percentage were added (to allow local laboratories to perform clinical chemistry assessments in plasma). • Guidance for the management of visual symptoms was updated (retinal pigment epithelial detachment added). • Guidance for the management of patients with dyspnoea was updated (dyspnoea is an expected event of selumetinib; however, dyspnoea could also be the symptom of underlying serious lung conditions).
    25 Oct 2018
    • Study was to be terminated early and all randomised patients who had not yet completed their 3-year follow up were to instead have an end of study phone call. The wording of the 3-years post-RAI follow-up was changed to final study follow-up, in-line with the change. Reason: In the primary analysis (DCO date: 18 May 2018), the primary endpoint was not met and, consequently, collection of further data on efficacy endpoints was no longer considered relevant.

    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.
    The study was terminated early (based on the findings of the primary analysis at 18 months post-RAI treatment) and all randomised patients who had not yet completed their 3-year follow-up visit were instead to have an end of study phone call.
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