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    Clinical Trial Results:
    A randomized, Double-Blind Phase 3 Study of Ibrutinib in Combination With Corticosteroids versus Placebo in Combination With Corticosteroids in Subjects with New Onset Chronic Graft Versus Host Disease ( cGVHD)

    Summary
    EudraCT number
    		 2016-003286-26
    Trial protocol
    		 HU   DE   ES   AT   HR   IT   FR  
    Global end of trial date
    12 Jul 2021

    Results information
    Results version number
    		 v2(current)
    This version publication date
    11 Jan 2022
    First version publication date
    31 Mar 2021
    Other versions
    		 v1
    Version creation reason

    Trial information

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    Trial identification
    Sponsor protocol code
    PCYC-1140-IM
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02959944
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Pharmacyclics LLC
    Sponsor organisation address
    995 E Arques Ave, Sunnyvale, United States, CA 94085
    Public contact
    Justin Wahlstrom, MD, Pharmacyclics LLC, +1 (650) 540-6205, jwahlstrom@pcyc.com
    Scientific contact
    Justin Wahlstrom, MD, Pharmacyclics LLC, +1 (650) 540-6205, jwahlstrom@pcyc.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?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    12 Jul 2021
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    12 Jul 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the efficacy of Ibrutinib in combination with Prednisone ( Arm A) versus placebo in combination with Prednisone ( Arm B) based on the response rate at 48 weeks ( the proportion of responders ( CT or PR) as determined by NIH Consensus Development Project criteria in subjects with new onset moderate to severe cGVHD
    Protection of trial subjects
    This study was conducted in accordance with the ethical principles that have their origins in the Declaration of Helsinki and that are consistent with Good Clinical Practices and applicable regulatory requirements
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    11 May 2017
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy
    Long term follow-up duration
    		 5 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Australia: 18
    Country: Number of subjects enrolled
    Austria: 2
    Country: Number of subjects enrolled
    Canada: 5
    Country: Number of subjects enrolled
    China: 5
    Country: Number of subjects enrolled
    Croatia: 2
    Country: Number of subjects enrolled
    France: 22
    Country: Number of subjects enrolled
    Germany: 9
    Country: Number of subjects enrolled
    Hungary: 1
    Country: Number of subjects enrolled
    Italy: 10
    Country: Number of subjects enrolled
    Japan: 11
    Country: Number of subjects enrolled
    Singapore: 2
    Country: Number of subjects enrolled
    Korea, Democratic People's Republic of: 14
    Country: Number of subjects enrolled
    Spain: 4
    Country: Number of subjects enrolled
    Taiwan: 9
    Country: Number of subjects enrolled
    United States: 79
    Worldwide total number of subjects
    193
    EEA total number of subjects
    50
    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)
    2
    Adults (18-64 years)
    156
    From 65 to 84 years
    35
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 This was a Phase 3, multicenter, international, randomized, double-blind study of oral ibrutinib in combination with prednisone vs. placebo in combination with prednisone in subjects with treatment-naive cGVHD. Subjects participated at 66 sites overall; 24 sites in North America, 18 sites in the EU, and 24 sites in the rest of the world.

    Pre-assignment
    Screening details
    		 Eligible patients had to be 12 years or older and had to present with treatment-naive, moderate or severe cGVHD requiring systemic treatment with corticosteroids following allogeneic hematopeietic cell transplant.

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Investigator, Subject, Monitor, Data analyst, Carer, Assessor
    Blinding implementation details
    Treatment was allocated using an interactive web response system (IWRS). Subjects, investigators, and the Sponsor were blinded to the treatment assignment. Sponsor team members did not have access to any data that might reveal treatment assignment. Data that may potentially unblind the treatment assignment (ie, study drug plasma concentrations) were handled with special care to ensure that the integrity of the blind was maintained and the potential for bias was minimized.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Ibrutinib + Prednisone
    Arm description
    		 Ibrutinib (420 mg) was given orally once daily continuously starting on Week 1, Day 1 until cGVHD progression, progression of underlying malignancy, the initiation of another systemic treatment for cGVHD, or unacceptable toxicity. Prednisone 1 mg/kg/day was given orally once daily continuously starting on Week 1, Day 1 until unacceptable toxicity or until the subject was successfully tapered from the prednisone. The starting prednisone dose could be as low as 0.5 mg/kg/day if a subject could not tolerate higher doses.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ibrutinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Ibrutinib (420 mg) was administered using 3 capsule (each containing 140 mg ibrutinib). Ibrutinib (adjusted for cytochrome P450 [CYP] inhibitors or hepatic dysfunction as applicable) was given orally once daily continuously until cGVHD progression, progression of underlying malignancy, the initiation of another systemic treatment for cGVHD, or unacceptable toxicity. Ibrutinib could be withdrawn if cGVHD response was maintained after all immunosuppressants were withdrawn.

    Investigational medicinal product name
    Prednisone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Prednisone tablets for oral administration supplied by the Sponsor were available in multiple strengths. Prednisone 1 mg/kg/day was given orally once daily continuously starting on Week 1, Day 1 until unacceptable toxicity or until the subject was successfully tapered from the prednisone. The starting prednisone dose could be as low as 0.5 mg/kg/day if a subject could not tolerate higher dose.

    Arm title
    		 Placebo + Prednisone
    Arm description
    		 Placebo (matching ibrutinib) was given orally once daily continuously starting on Week 1, Day 1 until cGVHD progression, progression of underlying malignancy, the initiation of another systemic treatment for cGVHD, or unacceptable toxicity. Prednisone 1 mg/kg/day was given orally once daily continuously starting on Week 1, Day 1 until unacceptable toxicity or until the subject was successfully tapered from the prednisone. The starting prednisone dose could be as low as 0.5 mg/kg/day if a subject could not tolerate higher doses.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo (identical to ibrutinib) was administered using 3 capsule. Placebo (adjusted for cytochrome P450 [CYP] inhibitors or hepatic dysfunction as applicable) was given orally once daily continuously until cGVHD progression, progression of underlying malignancy, the initiation of another systemic treatment for cGVHD, or unacceptable toxicity. Placebo could be withdrawn if cGVHD response was maintained after all immunosuppressants were withdrawn.

    Investigational medicinal product name
    Prednisone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Prednisone tablets for oral administration supplied by the Sponsor were available in multiple strengths. Prednisone 1 mg/kg/day was given orally once daily continuously starting on Week 1, Day 1 until unacceptable toxicity or until the subject was successfully tapered from the prednisone. The starting prednisone dose could be as low as 0.5 mg/kg/day if a subject could not tolerate higher doses.

    Number of subjects in period 1
    		Ibrutinib + Prednisone Placebo + Prednisone
    Started
    95
    98
    Completed
    13
    2
    Not completed
    82
    96
         Physician decision
    22
    26
         Consent withdrawn by subject
    8
    10
         AE not related to progressive disease
    19
    16
         Relapse of underlying disease
    3
    5
         Death
    4
    1
         Progressive disease - cGVHD
    22
    30
         Did not receive study drug
    1
    2
         Subject started another GVHD treatment
    2
    6
         Lost to follow-up
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Ibrutinib + Prednisone
    Reporting group description
    		 Ibrutinib (420 mg) was given orally once daily continuously starting on Week 1, Day 1 until cGVHD progression, progression of underlying malignancy, the initiation of another systemic treatment for cGVHD, or unacceptable toxicity. Prednisone 1 mg/kg/day was given orally once daily continuously starting on Week 1, Day 1 until unacceptable toxicity or until the subject was successfully tapered from the prednisone. The starting prednisone dose could be as low as 0.5 mg/kg/day if a subject could not tolerate higher doses.

    Reporting group title
    Placebo + Prednisone
    Reporting group description
    		 Placebo (matching ibrutinib) was given orally once daily continuously starting on Week 1, Day 1 until cGVHD progression, progression of underlying malignancy, the initiation of another systemic treatment for cGVHD, or unacceptable toxicity. Prednisone 1 mg/kg/day was given orally once daily continuously starting on Week 1, Day 1 until unacceptable toxicity or until the subject was successfully tapered from the prednisone. The starting prednisone dose could be as low as 0.5 mg/kg/day if a subject could not tolerate higher doses.

    Reporting group values
    		 Ibrutinib + Prednisone Placebo + Prednisone Total
    Number of subjects
    		 95 98 193
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 2 0 2
        Adults (18-64 years)
    		 77 79 156
        From 65-84 years
    		 16 19 35
        85 years and over
    		 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 50.0 ( 14.48 ) 51.1 ( 14.99 ) -
    Gender categorical
    Units: Subjects
        Female
    		 34 33 67
        Male
    		 61 65 126

    End points

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    End points reporting groups
    Reporting group title
    Ibrutinib + Prednisone
    Reporting group description
    		 Ibrutinib (420 mg) was given orally once daily continuously starting on Week 1, Day 1 until cGVHD progression, progression of underlying malignancy, the initiation of another systemic treatment for cGVHD, or unacceptable toxicity. Prednisone 1 mg/kg/day was given orally once daily continuously starting on Week 1, Day 1 until unacceptable toxicity or until the subject was successfully tapered from the prednisone. The starting prednisone dose could be as low as 0.5 mg/kg/day if a subject could not tolerate higher doses.

    Reporting group title
    Placebo + Prednisone
    Reporting group description
    		 Placebo (matching ibrutinib) was given orally once daily continuously starting on Week 1, Day 1 until cGVHD progression, progression of underlying malignancy, the initiation of another systemic treatment for cGVHD, or unacceptable toxicity. Prednisone 1 mg/kg/day was given orally once daily continuously starting on Week 1, Day 1 until unacceptable toxicity or until the subject was successfully tapered from the prednisone. The starting prednisone dose could be as low as 0.5 mg/kg/day if a subject could not tolerate higher doses.

    Primary: Response Rate at 48 Weeks

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    End point title
    		 Response Rate at 48 Weeks
    End point description
    Response rate is estimated using the crude proportion of responders. Responders are subjects who had a response (PR or CR) at 48 weeks (study day 296-379) without starting any subsequent therapy for cGVHD or having evidence of relapse of their underlying disease that was indication for transplant prior to response assessment at 48 week.
    End point type
    Primary
    End point timeframe
    Number of responders with a CR or PR at 48 weeks.
    End point values
    		 Ibrutinib + Prednisone Placebo + Prednisone
    Number of subjects analysed
    95
    98
    Units: percent
        number (not applicable)
    41.1
    36.7
    Statistical analysis title
    		 Response Rate at 48 Weeks
    Statistical analysis description
    Confidence interval is computed using normal approximation and p-value are computed using non-stratified Chi-Square test.
    Comparison groups
    Placebo + Prednisone v Ibrutinib + Prednisone
    Number of subjects included in analysis
    193
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.5384
    Method
    		 Chi-squared
    Parameter type
    		 Normal approximation
    Point estimate
    0.043
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.094
         upper limit
    		 0.181

    Secondary: Time to Withdrawal of all Corticosteroids

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    End point title
    		 Time to Withdrawal of all Corticosteroids
    End point description
    Time to withdrawal of corticosteroids is computed from randomization date to the first date of withdrawal of all corticosteroids for treatment of cGVHD to 0 mg daily for at least 30 days.
    End point type
    Secondary
    End point timeframe
    Assessments were made every 3 months for 2 years.
    End point values
    		 Ibrutinib + Prednisone Placebo + Prednisone
    Number of subjects analysed
    95
    98
    Units: percent
        number (not applicable)
    47.4
    38.8
    Statistical analysis title
    		 Withdrawal of all Corticosteroids
    Statistical analysis description
    Gray’s chi-square test (p-value) and the cumulative incidence function (95% CI) were calculated using SAS lifetest procedure adjusting for competing risks including death, cGVHD progression, relapse of underlying disease, and start of subsequent cGVHD therapy.
    Comparison groups
    Ibrutinib + Prednisone v Placebo + Prednisone
    Number of subjects included in analysis
    193
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.281
    Method
    		 Gray`s chi-square test
    Confidence interval

    Secondary: Time to Withdrawal of all Immunosuppressants

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    End point title
    		 Time to Withdrawal of all Immunosuppressants
    End point description
    Time to withdrawal of all immunosuppressants is computed from randomization date to the first date of withdrawal of all immunosuppressants for treatment of cGVHD sustained for at least 30 days. All immunosuppressants include corticosteroid but they do not include ibrutinib.
    End point type
    Secondary
    End point timeframe
    Assessments were made every 3 months for 2 years.
    End point values
    		 Ibrutinib + Prednisone Placebo + Prednisone
    Number of subjects analysed
    95
    98
    Units: percent
        number (not applicable)
    38.9
    30.6
    Statistical analysis title
    		 Withdrawal of all Immunosuppressants
    Statistical analysis description
    Gray’s chi-square test (p-value) and the Cumulative incidence function (95% CI) were calculated using SAS lifetest procedure adjusting for competing risks including death, cGVHD progression, relapse of underlying disease, and start of subsequent cGVHD therapy.
    Comparison groups
    Ibrutinib + Prednisone v Placebo + Prednisone
    Number of subjects included in analysis
    193
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.216
    Method
    		 Gray`s chi-square test
    Confidence interval

    Secondary: Withdrawal of all Immunosuppressants incl. study treatment

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    End point title
    		 Withdrawal of all Immunosuppressants incl. study treatment
    End point description
    Time to withdrawal of all immunosuppressants including corticosteroid is computed from randomization date to the first date of withdrawal of all immunosuppressants for treatment of cGVHD sustained for at least 30 days. In addition, during this 30-day period, subject either should have been on 0 mg for Ibr/Pbo continued for at least 30 days OR discontinued Ibr/Pbo due to Investigator decision related to subject no longer needing treatment for cGVHD.
    End point type
    Secondary
    End point timeframe
    Assessments were made every 3 months for 2 years.
    End point values
    		 Ibrutinib + Prednisone Placebo + Prednisone
    Number of subjects analysed
    95
    98
    Units: percent
        number (not applicable)
    17.9
    8.2
    Statistical analysis title
    		 Withdrawal all Immunosuppressants incl. study drug
    Statistical analysis description
    Gray’s chi-square test (p-value) and the Cumulative incidence function (95% CI) were calculated using SAS lifetest procedure adjusting for competing risks including death, cGVHD progression, relapse of underlying disease, and start of subsequent cGVHD therapy.
    Comparison groups
    Ibrutinib + Prednisone v Placebo + Prednisone
    Number of subjects included in analysis
    193
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.03
    Method
    		 Gray`s chi-square test
    Confidence interval

    Secondary: Response Rate at 24 Weeks

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    End point title
    		 Response Rate at 24 Weeks
    End point description
    Response rate was estimated using the crude proportion of responders. Responders are subjects who had a response (PR or CR) at 24 weeks (Study Day 156-211) without starting any subsequent therapy for cGVHD or having evidence of relapse of their underlying disease that was indication for transplant prior to response assessment at 24 weeks.
    End point type
    Secondary
    End point timeframe
    Percentage of responders with a CR or PR at 24 weeks.
    End point values
    		 Ibrutinib + Prednisone Placebo + Prednisone
    Number of subjects analysed
    95
    98
    Units: percent
        number (not applicable)
    47.4
    54.1
    Statistical analysis title
    		 Response Rate at 24 Weeks
    Statistical analysis description
    Confidence interval is computed using normal approximation and p-value are computed using non-stratified Chi-Square test.
    Comparison groups
    Ibrutinib + Prednisone v Placebo + Prednisone
    Number of subjects included in analysis
    193
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.351
    Method
    		 Chi-squared
    Parameter type
    		 Normal approximation
    Point estimate
    -0.067
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.208
         upper limit
    		 0.074

    Secondary: Improvement in Lee cGVHD Symptom Scale

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    End point title
    		 Improvement in Lee cGVHD Symptom Scale
    End point description
    Clinically meaningful improvement on the Lee cGVHD symptom scale was defined as at least a 7-point decrease in Lee Symptom Scale overall summary score on at least 2 consecutive visits, not preceded by progressive disease, relapse of underlying disease or start of subsequent cGVHD treatment. The Lee cGVD Symptoms Scale score has 7 subscales (Skin, Energy, Lung, Eye, Nutrition, Mouth and Psychological) with ratings as follows: 0 - Not at all, 1- Slightly, 2 - Moderately, 3 - Quite a bit, 4 - Extremely, with lower values representing better outcome. A score is calculated for each subscale by taking the mean of all items completed if more than 50% were answered and normalizing to a 0 to 100 scale. An overall score is calculated as the average of these 7 subscales if at least 4 subscales have valid scores.
    End point type
    Secondary
    End point timeframe
    Lee cGVHD Symptom Scale was assessed at screening, during treatment (Weeks 5, 13, 25, 37, 49 and every 12 weeks thereafter) and if applicable, at the progressive disease visit and the end-of-treatment visit.
    End point values
    		 Ibrutinib + Prednisone Placebo + Prednisone
    Number of subjects analysed
    95
    98
    Units: percent
        number (not applicable)
    43.2
    30.6
    Statistical analysis title
    		 Improvement in Overall Lee Score
    Statistical analysis description
    Confidence interval is computed using normal approximation and p-value are computed using non-stratified Chi-Square test.
    Comparison groups
    Ibrutinib + Prednisone v Placebo + Prednisone
    Number of subjects included in analysis
    193
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0708
    Method
    		 Chi-squared
    Parameter type
    		 Normal approximation
    Point estimate
    0.125
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.01
         upper limit
    		 0.261

    Secondary: Improvement in modified Lee cGVHD Symptom Scale

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    End point title
    		 Improvement in modified Lee cGVHD Symptom Scale
    End point description
    Clinically meaningful improvement on Modified Lee cGVHD symptom scale is defined as at least a 5- or 6-point decrease in Modified Lee Symptom Scale overall summary score on at least 2 consecutive visits, not preceded by progressive disease, relapse of underlying disease, or start of subsequent cGVHD treatment.
    End point type
    Secondary
    End point timeframe
    Modified Lee cGVHD Symptom Scale was assessed at screening, during treatment (Weeks 5, 13, 25, 37, 49 and every 12 weeks thereafter) and if applicable, at the progressive disease visit and the end-of-treatment visit.
    End point values
    		 Ibrutinib + Prednisone Placebo + Prednisone
    Number of subjects analysed
    95
    98
    Units: percent
        number (not applicable)
    52.6
    38.8
    Statistical analysis title
    		 Improvement in modified Lee Score
    Statistical analysis description
    Confidence interval computed using normal approximation and p-value are computed using non-stratified Chi-Square test.
    Comparison groups
    Placebo + Prednisone v Ibrutinib + Prednisone
    Number of subjects included in analysis
    193
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0533
    Method
    		 Chi-squared
    Parameter type
    		 Normal approximation
    Point estimate
    0.139
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.001
         upper limit
    		 0.278

    Secondary: Reduction in Corticosteroid Dose Level

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    End point title
    		 Reduction in Corticosteroid Dose Level
    End point description
    Reduction in Corticosteroid Dose Level to less than 0.15 mg/kg/day at 24 weeks sustained for at least 30 Days
    End point type
    Secondary
    End point timeframe
    Assessment at 24 weeks.
    End point values
    		 Ibrutinib + Prednisone Placebo + Prednisone
    Number of subjects analysed
    95
    98
    Units: percent
        number (not applicable)
    41.1
    45.9
    Statistical analysis title
    		 Reduction in Corticosteroid Dose Level
    Statistical analysis description
    Confidence interval is computed using normal approximation and p-value is computed using non-stratified Chi-Square test.
    Comparison groups
    Ibrutinib + Prednisone v Placebo + Prednisone
    Number of subjects included in analysis
    193
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4955
    Method
    		 Chi-squared
    Parameter type
    		 Normal approximation
    Point estimate
    -0.049
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.188
         upper limit
    		 0.091

    Secondary: Overall Survival

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    End point title
    		 Overall Survival
    End point description
    End point type
    Secondary
    End point timeframe
    As the median overall survival was not reached in either arm, landmark analysis data at 24 months are provided.
    End point values
    		 Ibrutinib + Prednisone Placebo + Prednisone
    Number of subjects analysed
    95
    98
    Units: percent
        number (not applicable)
    79.6
    79.7
    Statistical analysis title
    		 Overall Survival
    Comparison groups
    Ibrutinib + Prednisone v Placebo + Prednisone
    Number of subjects included in analysis
    193
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.061
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.591
         upper limit
    		 1.904

    Secondary: Duration of Response

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    End point title
    		 Duration of Response
    End point description
    End point type
    Secondary
    End point timeframe
    Response assessments were performed during the treatment phase at Weeks 5, 13, 25, 37, 49 and every 12 weeks thereafter, and if applicable, at the progressive disease visit, and the end-of-treatment visit.
    End point values
    		 Ibrutinib + Prednisone Placebo + Prednisone
    Number of subjects analysed
    95
    98
    Units: month
        number (not applicable)
    19.1
    10.2
    Statistical analysis title
    		 Duration of Response
    Comparison groups
    Ibrutinib + Prednisone v Placebo + Prednisone
    Number of subjects included in analysis
    193
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.717
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.482
         upper limit
    		 1.068

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From first dose of study drug up to 30 days after the last dose of study drug or the day before initiation of subsequent cGVHD treatment, whichever comes first
    Adverse event reporting additional description
    As of the date of the data cutoff (20 March 2020), the median time on treatment in the ibrutinib plus prednisone arm was 5.4 months and in the placebo plus prednisone arm was 6.4 months
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    22.1
    Reporting groups
    Reporting group title
    Ibrutinib
    Reporting group description
    		 -

    Reporting group title
    Placebo
    Reporting group description
    		 -

    Serious adverse events
    		 Ibrutinib Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    51 / 94 (54.26%)
    49 / 96 (51.04%)
         number of deaths (all causes)
    23
    21
         number of deaths resulting from adverse events
    13
    7
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    ACUTE MYELOID LEUKAEMIA
         subjects affected / exposed
    0 / 94 (0.00%)
    1 / 96 (1.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ACUTE MYELOID LEUKAEMIA RECURRENT
         subjects affected / exposed
    2 / 94 (2.13%)
    4 / 96 (4.17%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 2
    0 / 2
    ACUTE PROMYELOCYTIC LEUKAEMIA
         subjects affected / exposed
    1 / 94 (1.06%)
    0 / 96 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    BENIGN NEOPLASM OF TESTIS
         subjects affected / exposed
    1 / 94 (1.06%)
    0 / 96 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    BLADDER CANCER
         subjects affected / exposed
    0 / 94 (0.00%)
    1 / 96 (1.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    COLON CANCER
         subjects affected / exposed
    0 / 94 (0.00%)
    1 / 96 (1.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    LEUKAEMIA RECURRENT
         subjects affected / exposed
    1 / 94 (1.06%)
    2 / 96 (2.08%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 2
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    POST TRANSPLANT LYMPHOPROLIFERATIVE DISORDER
         subjects affected / exposed
    1 / 94 (1.06%)
    0 / 96 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    PRIMARY MYELOFIBROSIS
         subjects affected / exposed
    0 / 94 (0.00%)
    1 / 96 (1.04%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Vascular disorders
    DEEP VEIN THROMBOSIS
         subjects affected / exposed
    0 / 94 (0.00%)
    2 / 96 (2.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PHLEBITIS
         subjects affected / exposed
    0 / 94 (0.00%)
    1 / 96 (1.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    DEATH
         subjects affected / exposed
    2 / 94 (2.13%)
    0 / 96 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    1 / 2
    0 / 0
    MALAISE
         subjects affected / exposed
    1 / 94 (1.06%)
    0 / 96 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    OEDEMA PERIPHERAL
         subjects affected / exposed
    0 / 94 (0.00%)
    1 / 96 (1.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PYREXIA
         subjects affected / exposed
    1 / 94 (1.06%)
    3 / 96 (3.13%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    CHRONIC GRAFT VERSUS HOST DISEASE
         subjects affected / exposed
    3 / 94 (3.19%)
    3 / 96 (3.13%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    GRAFT VERSUS HOST DISEASE
         subjects affected / exposed
    0 / 94 (0.00%)
    3 / 96 (3.13%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    HYPOGAMMAGLOBULINAEMIA
         subjects affected / exposed
    1 / 94 (1.06%)
    0 / 96 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    INTERMENSTRUAL BLEEDING
         subjects affected / exposed
    0 / 94 (0.00%)
    1 / 96 (1.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SCROTAL OEDEMA
         subjects affected / exposed
    0 / 94 (0.00%)
    1 / 96 (1.04%)
         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
    ACUTE RESPIRATORY FAILURE
         subjects affected / exposed
    0 / 94 (0.00%)
    1 / 96 (1.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    BRONCHITIS CHRONIC
         subjects affected / exposed
    1 / 94 (1.06%)
    0 / 96 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DYSPNOEA
         subjects affected / exposed
    0 / 94 (0.00%)
    1 / 96 (1.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HYPOXIA
         subjects affected / exposed
    0 / 94 (0.00%)
    1 / 96 (1.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PLEURAL EFFUSION
         subjects affected / exposed
    0 / 94 (0.00%)
    1 / 96 (1.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PULMONARY EMBOLISM
         subjects affected / exposed
    0 / 94 (0.00%)
    4 / 96 (4.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PULMONARY MASS
         subjects affected / exposed
    1 / 94 (1.06%)
    0 / 96 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PULMONARY OEDEMA
         subjects affected / exposed
    1 / 94 (1.06%)
    0 / 96 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    RESPIRATORY FAILURE
         subjects affected / exposed
    2 / 94 (2.13%)
    0 / 96 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    DEPRESSION
         subjects affected / exposed
    0 / 94 (0.00%)
    1 / 96 (1.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    MANIA
         subjects affected / exposed
    1 / 94 (1.06%)
    0 / 96 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SUBSTANCE-INDUCED PSYCHOTIC DISORDER
         subjects affected / exposed
    0 / 94 (0.00%)
    1 / 96 (1.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    ALANINE AMINOTRANSFERASE INCREASED
         subjects affected / exposed
    0 / 94 (0.00%)
    1 / 96 (1.04%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ASPARTATE AMINOTRANSFERASE INCREASED
         subjects affected / exposed
    0 / 94 (0.00%)
    1 / 96 (1.04%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    WHITE BLOOD CELL COUNT DECREASED
         subjects affected / exposed
    1 / 94 (1.06%)
    0 / 96 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    ANKLE FRACTURE
         subjects affected / exposed
    1 / 94 (1.06%)
    0 / 96 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    FALL
         subjects affected / exposed
    1 / 94 (1.06%)
    0 / 96 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    FEMORAL NECK FRACTURE
         subjects affected / exposed
    0 / 94 (0.00%)
    1 / 96 (1.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    ACUTE CORONARY SYNDROME
         subjects affected / exposed
    0 / 94 (0.00%)
    1 / 96 (1.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ATRIAL FIBRILLATION
         subjects affected / exposed
    1 / 94 (1.06%)
    2 / 96 (2.08%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ATRIAL FLUTTER
         subjects affected / exposed
    1 / 94 (1.06%)
    0 / 96 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CARDIAC ARREST
         subjects affected / exposed
    1 / 94 (1.06%)
    1 / 96 (1.04%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    CARDIAC FAILURE
         subjects affected / exposed
    1 / 94 (1.06%)
    1 / 96 (1.04%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    MYOCARDITIS
         subjects affected / exposed
    1 / 94 (1.06%)
    0 / 96 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PERICARDIAL EFFUSION
         subjects affected / exposed
    2 / 94 (2.13%)
    0 / 96 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    ISCHAEMIC STROKE
         subjects affected / exposed
    1 / 94 (1.06%)
    0 / 96 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    POSTERIOR REVERSIBLE ENCEPHALOPATHY SYNDROME
         subjects affected / exposed
    1 / 94 (1.06%)
    0 / 96 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SEIZURE
         subjects affected / exposed
    1 / 94 (1.06%)
    0 / 96 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SYNCOPE
         subjects affected / exposed
    2 / 94 (2.13%)
    0 / 96 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    ANAEMIA
         subjects affected / exposed
    0 / 94 (0.00%)
    1 / 96 (1.04%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    COAGULOPATHY
         subjects affected / exposed
    0 / 94 (0.00%)
    1 / 96 (1.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    NEUTROPENIA
         subjects affected / exposed
    1 / 94 (1.06%)
    0 / 96 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    THROMBOTIC MICROANGIOPATHY
         subjects affected / exposed
    0 / 94 (0.00%)
    1 / 96 (1.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    DIPLOPIA
         subjects affected / exposed
    1 / 94 (1.06%)
    0 / 96 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    COLITIS
         subjects affected / exposed
    0 / 94 (0.00%)
    1 / 96 (1.04%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DIARRHOEA
         subjects affected / exposed
    2 / 94 (2.13%)
    1 / 96 (1.04%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ENTERITIS
         subjects affected / exposed
    1 / 94 (1.06%)
    0 / 96 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    GASTROINTESTINAL HAEMORRHAGE
         subjects affected / exposed
    0 / 94 (0.00%)
    2 / 96 (2.08%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ILEUS
         subjects affected / exposed
    1 / 94 (1.06%)
    0 / 96 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    LARGE INTESTINE PERFORATION
         subjects affected / exposed
    1 / 94 (1.06%)
    0 / 96 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    LOWER GASTROINTESTINAL HAEMORRHAGE
         subjects affected / exposed
    0 / 94 (0.00%)
    1 / 96 (1.04%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    MELAENA
         subjects affected / exposed
    1 / 94 (1.06%)
    0 / 96 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PANCREATIC ENZYME ABNORMALITY
         subjects affected / exposed
    1 / 94 (1.06%)
    0 / 96 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SMALL INTESTINAL OBSTRUCTION
         subjects affected / exposed
    0 / 94 (0.00%)
    1 / 96 (1.04%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    VOMITING
         subjects affected / exposed
    1 / 94 (1.06%)
    0 / 96 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    CHOLECYSTITIS
         subjects affected / exposed
    1 / 94 (1.06%)
    1 / 96 (1.04%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HEPATIC CIRRHOSIS
         subjects affected / exposed
    1 / 94 (1.06%)
    0 / 96 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    ACUTE KIDNEY INJURY
         subjects affected / exposed
    1 / 94 (1.06%)
    2 / 96 (2.08%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CYSTITIS HAEMORRHAGIC
         subjects affected / exposed
    0 / 94 (0.00%)
    1 / 96 (1.04%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HAEMATURIA
         subjects affected / exposed
    2 / 94 (2.13%)
    0 / 96 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HYDRONEPHROSIS
         subjects affected / exposed
    1 / 94 (1.06%)
    1 / 96 (1.04%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    NEPHROLITHIASIS
         subjects affected / exposed
    0 / 94 (0.00%)
    1 / 96 (1.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    OBSTRUCTIVE NEPHROPATHY
         subjects affected / exposed
    1 / 94 (1.06%)
    0 / 96 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    RENAL FAILURE
         subjects affected / exposed
    0 / 94 (0.00%)
    1 / 96 (1.04%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    URETEROLITHIASIS
         subjects affected / exposed
    1 / 94 (1.06%)
    1 / 96 (1.04%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    URETHRAL STENOSIS
         subjects affected / exposed
    0 / 94 (0.00%)
    1 / 96 (1.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    MUSCLE ATROPHY
         subjects affected / exposed
    1 / 94 (1.06%)
    0 / 96 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    MYOPATHY
         subjects affected / exposed
    1 / 94 (1.06%)
    0 / 96 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    RHABDOMYOLYSIS
         subjects affected / exposed
    1 / 94 (1.06%)
    0 / 96 (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
    BACTERAEMIA
         subjects affected / exposed
    1 / 94 (1.06%)
    1 / 96 (1.04%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    BRONCHITIS
         subjects affected / exposed
    1 / 94 (1.06%)
    1 / 96 (1.04%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    COVID-19
         subjects affected / exposed
    2 / 94 (2.13%)
    0 / 96 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CELLULITIS
         subjects affected / exposed
    3 / 94 (3.19%)
    0 / 96 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CLOSTRIDIUM DIFFICILE INFECTION
         subjects affected / exposed
    0 / 94 (0.00%)
    1 / 96 (1.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CYTOMEGALOVIRUS COLITIS
         subjects affected / exposed
    0 / 94 (0.00%)
    1 / 96 (1.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CYTOMEGALOVIRUS INFECTION REACTIVATION
         subjects affected / exposed
    1 / 94 (1.06%)
    1 / 96 (1.04%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DACRYOCYSTITIS
         subjects affected / exposed
    1 / 94 (1.06%)
    0 / 96 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DIVERTICULITIS
         subjects affected / exposed
    1 / 94 (1.06%)
    0 / 96 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ENCEPHALITIS
         subjects affected / exposed
    1 / 94 (1.06%)
    0 / 96 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    EPSTEIN-BARR VIRUS INFECTION REACTIVATION
         subjects affected / exposed
    1 / 94 (1.06%)
    0 / 96 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    EYE INFECTION
         subjects affected / exposed
    0 / 94 (0.00%)
    1 / 96 (1.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HAEMOPHILUS INFECTION
         subjects affected / exposed
    0 / 94 (0.00%)
    1 / 96 (1.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    INFLUENZA
         subjects affected / exposed
    4 / 94 (4.26%)
    4 / 96 (4.17%)
         occurrences causally related to treatment / all
    0 / 4
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    KLEBSIELLA BACTERAEMIA
         subjects affected / exposed
    1 / 94 (1.06%)
    0 / 96 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    KLEBSIELLA SEPSIS
         subjects affected / exposed
    0 / 94 (0.00%)
    1 / 96 (1.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    LOWER RESPIRATORY TRACT INFECTION
         subjects affected / exposed
    0 / 94 (0.00%)
    1 / 96 (1.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    MASTOIDITIS
         subjects affected / exposed
    1 / 94 (1.06%)
    0 / 96 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    MEDIASTINITIS
         subjects affected / exposed
    1 / 94 (1.06%)
    0 / 96 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    METAPNEUMOVIRUS INFECTION
         subjects affected / exposed
    0 / 94 (0.00%)
    1 / 96 (1.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PARAINFLUENZAE VIRUS INFECTION
         subjects affected / exposed
    1 / 94 (1.06%)
    1 / 96 (1.04%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PAROTITIS
         subjects affected / exposed
    0 / 94 (0.00%)
    1 / 96 (1.04%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PERIORBITAL CELLULITIS
         subjects affected / exposed
    1 / 94 (1.06%)
    0 / 96 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PERITONITIS
         subjects affected / exposed
    0 / 94 (0.00%)
    1 / 96 (1.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PNEUMOCYSTIS JIROVECII PNEUMONIA
         subjects affected / exposed
    1 / 94 (1.06%)
    0 / 96 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PNEUMONIA
         subjects affected / exposed
    6 / 94 (6.38%)
    9 / 96 (9.38%)
         occurrences causally related to treatment / all
    2 / 8
    4 / 10
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    PNEUMONIA CYTOMEGALOVIRAL
         subjects affected / exposed
    1 / 94 (1.06%)
    0 / 96 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PNEUMONIA FUNGAL
         subjects affected / exposed
    1 / 94 (1.06%)
    0 / 96 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    PNEUMONIA LEGIONELLA
         subjects affected / exposed
    1 / 94 (1.06%)
    0 / 96 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PNEUMONIA PARAINFLUENZAE VIRAL
         subjects affected / exposed
    0 / 94 (0.00%)
    1 / 96 (1.04%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PNEUMONIA RESPIRATORY SYNCYTIAL VIRAL
         subjects affected / exposed
    0 / 94 (0.00%)
    2 / 96 (2.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PNEUMONIA VIRAL
         subjects affected / exposed
    0 / 94 (0.00%)
    1 / 96 (1.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    RESPIRATORY SYNCYTIAL VIRUS INFECTION
         subjects affected / exposed
    0 / 94 (0.00%)
    1 / 96 (1.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    RESPIRATORY TRACT INFECTION
         subjects affected / exposed
    1 / 94 (1.06%)
    0 / 96 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SEPSIS
         subjects affected / exposed
    1 / 94 (1.06%)
    2 / 96 (2.08%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 2
         deaths causally related to treatment / all
    1 / 1
    0 / 1
    SEPTIC SHOCK
         subjects affected / exposed
    2 / 94 (2.13%)
    1 / 96 (1.04%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 1
         deaths causally related to treatment / all
    1 / 1
    0 / 1
    SINUSITIS
         subjects affected / exposed
    0 / 94 (0.00%)
    1 / 96 (1.04%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SINUSITIS FUNGAL
         subjects affected / exposed
    1 / 94 (1.06%)
    0 / 96 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SKIN INFECTION
         subjects affected / exposed
    0 / 94 (0.00%)
    1 / 96 (1.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    STAPHYLOCOCCAL BACTERAEMIA
         subjects affected / exposed
    0 / 94 (0.00%)
    1 / 96 (1.04%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    STAPHYLOCOCCAL SEPSIS
         subjects affected / exposed
    1 / 94 (1.06%)
    0 / 96 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    URINARY TRACT INFECTION
         subjects affected / exposed
    1 / 94 (1.06%)
    1 / 96 (1.04%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    URINARY TRACT INFECTION BACTERIAL
         subjects affected / exposed
    1 / 94 (1.06%)
    0 / 96 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    UROSEPSIS
         subjects affected / exposed
    1 / 94 (1.06%)
    0 / 96 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    WOUND INFECTION
         subjects affected / exposed
    1 / 94 (1.06%)
    0 / 96 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    DIABETES MELLITUS INADEQUATE CONTROL
         subjects affected / exposed
    0 / 94 (0.00%)
    1 / 96 (1.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HYPERGLYCAEMIA
         subjects affected / exposed
    2 / 94 (2.13%)
    2 / 96 (2.08%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HYPONATRAEMIA
         subjects affected / exposed
    0 / 94 (0.00%)
    2 / 96 (2.08%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    STEROID DIABETES
         subjects affected / exposed
    0 / 94 (0.00%)
    2 / 96 (2.08%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Ibrutinib Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    88 / 94 (93.62%)
    92 / 96 (95.83%)
    Vascular disorders
    HYPERTENSION
         subjects affected / exposed
    10 / 94 (10.64%)
    13 / 96 (13.54%)
         occurrences all number
    16
    14
    General disorders and administration site conditions
    ASTHENIA
         subjects affected / exposed
    5 / 94 (5.32%)
    6 / 96 (6.25%)
         occurrences all number
    7
    7
    FATIGUE
         subjects affected / exposed
    17 / 94 (18.09%)
    18 / 96 (18.75%)
         occurrences all number
    22
    30
    INFLUENZA LIKE ILLNESS
         subjects affected / exposed
    5 / 94 (5.32%)
    1 / 96 (1.04%)
         occurrences all number
    6
    1
    OEDEMA PERIPHERAL
         subjects affected / exposed
    25 / 94 (26.60%)
    13 / 96 (13.54%)
         occurrences all number
    37
    17
    PYREXIA
         subjects affected / exposed
    7 / 94 (7.45%)
    16 / 96 (16.67%)
         occurrences all number
    7
    22
    Immune system disorders
    HYPOGAMMAGLOBULINAEMIA
         subjects affected / exposed
    5 / 94 (5.32%)
    3 / 96 (3.13%)
         occurrences all number
    5
    3
    Respiratory, thoracic and mediastinal disorders
    COUGH
         subjects affected / exposed
    21 / 94 (22.34%)
    29 / 96 (30.21%)
         occurrences all number
    24
    37
    DYSPNOEA
         subjects affected / exposed
    9 / 94 (9.57%)
    14 / 96 (14.58%)
         occurrences all number
    12
    16
    DYSPNOEA EXERTIONAL
         subjects affected / exposed
    2 / 94 (2.13%)
    5 / 96 (5.21%)
         occurrences all number
    2
    6
    EPISTAXIS
         subjects affected / exposed
    7 / 94 (7.45%)
    4 / 96 (4.17%)
         occurrences all number
    8
    5
    OROPHARYNGEAL PAIN
         subjects affected / exposed
    5 / 94 (5.32%)
    3 / 96 (3.13%)
         occurrences all number
    6
    3
    PRODUCTIVE COUGH
         subjects affected / exposed
    5 / 94 (5.32%)
    3 / 96 (3.13%)
         occurrences all number
    8
    3
    RHINORRHOEA
         subjects affected / exposed
    3 / 94 (3.19%)
    8 / 96 (8.33%)
         occurrences all number
    5
    8
    Psychiatric disorders
    ANXIETY
         subjects affected / exposed
    5 / 94 (5.32%)
    7 / 96 (7.29%)
         occurrences all number
    5
    8
    DEPRESSION
         subjects affected / exposed
    5 / 94 (5.32%)
    2 / 96 (2.08%)
         occurrences all number
    6
    2
    INSOMNIA
         subjects affected / exposed
    26 / 94 (27.66%)
    18 / 96 (18.75%)
         occurrences all number
    28
    20
    Investigations
    ALANINE AMINOTRANSFERASE INCREASED
         subjects affected / exposed
    7 / 94 (7.45%)
    16 / 96 (16.67%)
         occurrences all number
    11
    29
    ASPARTATE AMINOTRANSFERASE INCREASED
         subjects affected / exposed
    1 / 94 (1.06%)
    13 / 96 (13.54%)
         occurrences all number
    1
    17
    BLOOD ALKALINE PHOSPHATASE INCREASED
         subjects affected / exposed
    3 / 94 (3.19%)
    6 / 96 (6.25%)
         occurrences all number
    3
    12
    BLOOD CREATININE INCREASED
         subjects affected / exposed
    5 / 94 (5.32%)
    6 / 96 (6.25%)
         occurrences all number
    8
    7
    PLATELET COUNT DECREASED
         subjects affected / exposed
    7 / 94 (7.45%)
    6 / 96 (6.25%)
         occurrences all number
    13
    10
    WEIGHT DECREASED
         subjects affected / exposed
    6 / 94 (6.38%)
    4 / 96 (4.17%)
         occurrences all number
    6
    4
    WEIGHT INCREASED
         subjects affected / exposed
    5 / 94 (5.32%)
    6 / 96 (6.25%)
         occurrences all number
    7
    6
    Injury, poisoning and procedural complications
    CONTUSION
         subjects affected / exposed
    10 / 94 (10.64%)
    4 / 96 (4.17%)
         occurrences all number
    11
    5
    FALL
         subjects affected / exposed
    3 / 94 (3.19%)
    7 / 96 (7.29%)
         occurrences all number
    4
    7
    Cardiac disorders
    PALPITATIONS
         subjects affected / exposed
    5 / 94 (5.32%)
    3 / 96 (3.13%)
         occurrences all number
    5
    3
    Nervous system disorders
    DIZZINESS
         subjects affected / exposed
    10 / 94 (10.64%)
    11 / 96 (11.46%)
         occurrences all number
    10
    16
    HEADACHE
         subjects affected / exposed
    13 / 94 (13.83%)
    12 / 96 (12.50%)
         occurrences all number
    19
    17
    PERIPHERAL SENSORY NEUROPATHY
         subjects affected / exposed
    6 / 94 (6.38%)
    2 / 96 (2.08%)
         occurrences all number
    7
    5
    TREMOR
         subjects affected / exposed
    5 / 94 (5.32%)
    9 / 96 (9.38%)
         occurrences all number
    5
    10
    Blood and lymphatic system disorders
    ANAEMIA
         subjects affected / exposed
    4 / 94 (4.26%)
    11 / 96 (11.46%)
         occurrences all number
    17
    21
    INCREASED TENDENCY TO BRUISE
         subjects affected / exposed
    9 / 94 (9.57%)
    8 / 96 (8.33%)
         occurrences all number
    10
    8
    NEUTROPENIA
         subjects affected / exposed
    1 / 94 (1.06%)
    6 / 96 (6.25%)
         occurrences all number
    1
    11
    THROMBOCYTOPENIA
         subjects affected / exposed
    18 / 94 (19.15%)
    15 / 96 (15.63%)
         occurrences all number
    30
    25
    Eye disorders
    CATARACT
         subjects affected / exposed
    2 / 94 (2.13%)
    7 / 96 (7.29%)
         occurrences all number
    3
    8
    VISION BLURRED
         subjects affected / exposed
    7 / 94 (7.45%)
    9 / 96 (9.38%)
         occurrences all number
    7
    10
    DRY EYE
         subjects affected / exposed
    5 / 94 (5.32%)
    4 / 96 (4.17%)
         occurrences all number
    6
    4
    Gastrointestinal disorders
    ABDOMINAL PAIN
         subjects affected / exposed
    8 / 94 (8.51%)
    6 / 96 (6.25%)
         occurrences all number
    10
    6
    CONSTIPATION
         subjects affected / exposed
    7 / 94 (7.45%)
    14 / 96 (14.58%)
         occurrences all number
    7
    15
    DYSPEPSIA
         subjects affected / exposed
    7 / 94 (7.45%)
    4 / 96 (4.17%)
         occurrences all number
    7
    4
    DIARRHOEA
         subjects affected / exposed
    14 / 94 (14.89%)
    13 / 96 (13.54%)
         occurrences all number
    20
    19
    NAUSEA
         subjects affected / exposed
    13 / 94 (13.83%)
    13 / 96 (13.54%)
         occurrences all number
    20
    15
    VOMITING
         subjects affected / exposed
    15 / 94 (15.96%)
    8 / 96 (8.33%)
         occurrences all number
    20
    8
    Hepatobiliary disorders
    HEPATIC FUNCTION ABNORMAL
         subjects affected / exposed
    6 / 94 (6.38%)
    6 / 96 (6.25%)
         occurrences all number
    19
    10
    Skin and subcutaneous tissue disorders
    PRURITUS
         subjects affected / exposed
    6 / 94 (6.38%)
    7 / 96 (7.29%)
         occurrences all number
    7
    10
    Renal and urinary disorders
    ACUTE KIDNEY INJURY
         subjects affected / exposed
    3 / 94 (3.19%)
    8 / 96 (8.33%)
         occurrences all number
    7
    9
    Endocrine disorders
    CUSHINGOID
         subjects affected / exposed
    3 / 94 (3.19%)
    6 / 96 (6.25%)
         occurrences all number
    3
    6
    Musculoskeletal and connective tissue disorders
    ARTHRALGIA
         subjects affected / exposed
    12 / 94 (12.77%)
    13 / 96 (13.54%)
         occurrences all number
    19
    16
    BACK PAIN
         subjects affected / exposed
    6 / 94 (6.38%)
    11 / 96 (11.46%)
         occurrences all number
    7
    12
    MUSCLE SPASMS
         subjects affected / exposed
    17 / 94 (18.09%)
    16 / 96 (16.67%)
         occurrences all number
    20
    27
    MUSCULAR WEAKNESS
         subjects affected / exposed
    5 / 94 (5.32%)
    9 / 96 (9.38%)
         occurrences all number
    7
    9
    MYALGIA
         subjects affected / exposed
    1 / 94 (1.06%)
    5 / 96 (5.21%)
         occurrences all number
    1
    6
    PAIN IN EXTREMITY
         subjects affected / exposed
    5 / 94 (5.32%)
    5 / 96 (5.21%)
         occurrences all number
    6
    5
    Infections and infestations
    BRONCHITIS
         subjects affected / exposed
    2 / 94 (2.13%)
    7 / 96 (7.29%)
         occurrences all number
    2
    8
    CONJUNCTIVITIS
         subjects affected / exposed
    4 / 94 (4.26%)
    5 / 96 (5.21%)
         occurrences all number
    5
    6
    HERPES ZOSTER
         subjects affected / exposed
    5 / 94 (5.32%)
    5 / 96 (5.21%)
         occurrences all number
    6
    5
    NASOPHARYNGITIS
         subjects affected / exposed
    6 / 94 (6.38%)
    8 / 96 (8.33%)
         occurrences all number
    6
    11
    INFLUENZA
         subjects affected / exposed
    5 / 94 (5.32%)
    6 / 96 (6.25%)
         occurrences all number
    5
    7
    PARONYCHIA
         subjects affected / exposed
    5 / 94 (5.32%)
    2 / 96 (2.08%)
         occurrences all number
    5
    2
    RHINOVIRUS INFECTION
         subjects affected / exposed
    1 / 94 (1.06%)
    7 / 96 (7.29%)
         occurrences all number
    1
    7
    SINUSITIS
         subjects affected / exposed
    1 / 94 (1.06%)
    5 / 96 (5.21%)
         occurrences all number
    1
    8
    UPPER RESPIRATORY TRACT INFECTION
         subjects affected / exposed
    15 / 94 (15.96%)
    15 / 96 (15.63%)
         occurrences all number
    24
    21
    Metabolism and nutrition disorders
    DECREASED APPETITE
         subjects affected / exposed
    7 / 94 (7.45%)
    7 / 96 (7.29%)
         occurrences all number
    8
    8
    HYPERGLYCAEMIA
         subjects affected / exposed
    4 / 94 (4.26%)
    13 / 96 (13.54%)
         occurrences all number
    6
    23
    HYPERKALAEMIA
         subjects affected / exposed
    3 / 94 (3.19%)
    8 / 96 (8.33%)
         occurrences all number
    3
    10
    HYPOKALAEMIA
         subjects affected / exposed
    11 / 94 (11.70%)
    14 / 96 (14.58%)
         occurrences all number
    21
    21
    HYPOMAGNESAEMIA
         subjects affected / exposed
    4 / 94 (4.26%)
    8 / 96 (8.33%)
         occurrences all number
    10
    11
    HYPONATRAEMIA
         subjects affected / exposed
    9 / 94 (9.57%)
    6 / 96 (6.25%)
         occurrences all number
    10
    9
    HYPOPHOSPHATAEMIA
         subjects affected / exposed
    3 / 94 (3.19%)
    9 / 96 (9.38%)
         occurrences all number
    5
    11

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    11 Aug 2016
    Original Protocol
    25 Oct 2016
    · Inclusion criterion requirement for bilirubin was revised from "direct bilirubin 1.5 x ULN" to "total bilirubin 1.5 x ULN" and requirement for highly effective methods of birth control was revised from "for 30 days" to "for 90 days" after the last dose of study drug (ibrutinib/placebo). · Dose modification guidance changes included o Addition of text stating that AEs considered related to concomitant high dose steroids do not require dose modification or holding of ibrutinib. o Addition of text stating that for subjects who are at 140 mg on a CYP3A inhibitor, the subject may resume that dose on the second occurrence of a toxicity after resolution of that toxicity. Study drug (ibrutinib/placebo) will be discontinued after a third occurrence of that toxicity. o Revision of text for hepatic impaired subjects; ie, revised from "for subjects with direct bilirubin" to "for subjects with total bilirubin" >3 x ULN (Grade 3 CTCAE), ibrutinib will be held until the "total" bilirubin returns to 1.5 x ULN (Grade 1 CTCAE) or baseline. Added that subjects who are on 140 mg dose at the first occurrence of hepatic impairment, the subject may re-start at the 140 mg dose but will discontinue study drug (ibrutinib/placebo) at the second occurrence of hepatic impairment. · Summary of clinical safety was updated to align with current IB. · Infection surveillance monitoring guidance added that subjects should be monitored closely for signs or symptoms of aspergillus infection.
    03 Oct 2017
    ·Clarified that treatment can be discontinued after response in disease symptoms and withdrawal of other systemic immunosuppressants ·Inclusion criterion changed to allow "Total bilirubin of >1.5 x ULN to 3.0 x ULN if due to GVHD". ·Immunosuppressants dosing for treatment of aGVHD to be stable for 2 weeks prior to screening was removed ·Exclusion criteria updated to: o Allow subjects who received systemic corticosteroid treatment for cGVHD for a short period of time prior to signing consent o Exclude subjects with presence of single-organ, genito-urinary involvement with cGVHD as the only manifestation of cGVHD o Exclude only subjects with hepatic impairment Child Pugh Class C (previously excluded Class B or C) o Exclude subjects who had received a DLI 56 days before randomization o Clarify that subjects on secondary prophylaxis for fungal infections and some other low grade infections can be enrolled o Exclude subjects requiring treatment with a strong CYP3A inducer o Remove exclusion of subjects who are on strong CYP inhibitors ·Updated the dose modification guidelines for adverse reactions for subjects with hepatic impairment and for subjects using a CYP3A inhibitor ·Allowed prednisone to treat cGVHD to start prior to randomization ·Clarified restart of original blinded study therapy in the event of cGVHD worsening following ibrutinib/placebo withdrawal ·Clarified that the secondary endpoint of "withdrawal of all immunosuppressants at 48 weeks" was "time to withdrawal of all immunosuppressants"; revised DOR and Lee cGVHD Symptom Scale improvement from exploratory to secondary endpoints ·Updated the study evaluation requirements: added late effects surveillance for adolescents up to 5 years post randomization; simplified ECG procedure; clarified the overall response definition per NIH criteria. · Specified that tapering of an increased prednisone dose for flares should begin within 4 weeks · Updated statistical methods & analyis plans
    06 Feb 2019
    · The primary objective/primary endpoint revised from evaluating the efficacy based on response rate at 24 weeks, to evaluating the efficacy based on response rate at 48 weeks; evaluation of response rate at 24 weeks added as a secondary objective/endpoint. · Efficacy analyses were to be performed on the ITT population (all randomized subjects), rather than the mITT population (which excludes randomized subjects who had evidence of disease progression before randomization but was not identified until after randomization). · Clarified that cGVHD flares were expected but if they occurred during response assessments, the clinician had discretion to re-evaluate response when flare had resolved or disease had progressed. · Expected length of follow-up for adolescents (<22 years of age at the time of randomization) revised from 5 years after randomization to up to 5 years after randomization; however, the study may close after the last subject below 18 years of age has exited the study if all other participating subjects have completed a minimum of 1 year of follow-up.

    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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