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    Clinical Trial Results:
    Rituximab with or without Ibrutinib for untreated patients with advanced follicular lymphoma in need of therapy.

    Summary
    EudraCT number
    		 2015-001487-19
    Trial protocol
    		 NO   DK   SE   FI   AT  
    Global end of trial date
    15 Jul 2023

    Results information
    Results version number
    		 v1(current)
    This version publication date
    05 Oct 2024
    First version publication date
    05 Oct 2024
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    SAKK 35/14
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02451111
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 SNCTP No: SNCTP000001327
    Sponsors
    Sponsor organisation name
    Swiss Group For Clinical Cancer Research (SAKK)
    Sponsor organisation address
    Effingerstrasse 33, Bern, Switzerland, 3008
    Public contact
    Head Regulatory Affairs, Swiss Group For Clinical Cancer Research (SAKK), +41 31389 91 91, sakkcc@sakk.ch
    Scientific contact
    Head Regulatory Affairs, Swiss Group For Clinical Cancer Research (SAKK), +41 31389 91 91, sakkcc@sakk.ch
    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
    17 Jun 2024
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    15 Jul 2023
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The objective of this trial is to study the activity and the safety of the 1st line treatment with Ibrutinib in combination with Rituximab for patients with advanced follicular lymphoma in need of therapy.
    Protection of trial subjects
    Protection of trial subjects was ensured by Safety Monitoring, i.e. assessment of adverse events, serious adverse events, adverse drug reactions, and the continous assessment of laboratory values and vital signs.
    Background therapy
    		 Not applicable.
    Evidence for comparator
    		 For symptomatic follicular lymphoma (fl) patients with more advanced tumor burden, in need of initial treatment, the combination of Rituximab and chemotherapy, possibly followed by Rituximab maintenance became a new standard in many countries [PMID: 23433739, PMID: 21176949]. In a setting of a chemotherapy-free strategy, the clinical study of Rituximab combinations with other immunotherapies or with novel targeted agents is obvious relevant. Promising results have also been reported with the combination of Rituximab and lenalidomide. The combination of Rituximab and Ibrutinib has been tested in clinical trials and appeared to be well tolerated and active [PMID: 25150798]. Since Ibrutinib seems to achieve better results when administered for prolonged time as shown in Chronic Lymphocytic Leukemia (CLL), it was chosen to compare its combination with Rituximab to the prolonged Rituximab-only schedule that was already shown to be very active in the SAKK 35/03 trial [see results for EudraCT No. 2004-002859-13].
    Actual start date of recruitment
    06 Nov 2015
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Efficacy
    Long term follow-up duration
    		 10 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Norway: 28
    Country: Number of subjects enrolled
    Sweden: 28
    Country: Number of subjects enrolled
    Austria: 1
    Country: Number of subjects enrolled
    Denmark: 16
    Country: Number of subjects enrolled
    Finland: 15
    Country: Number of subjects enrolled
    Switzerland: 104
    Worldwide total number of subjects
    192
    EEA total number of subjects
    88
    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)
    119
    From 65 to 84 years
    72
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 197 patients at 36 sites in Austria (1 site, 1 patient), Denmark (4 sites, 16 patients), Finland (3 sites, 15 patients), Norway (3 sites, 29 patients), Sweden (5 sites, 28 patients) and Switzerland (20 sites, 108 patients) were registered from 06-Nov-2015 to 22-Jun-2020. Of these, 196 patients were randomized; 192 patients received trial treatment.

    Pre-assignment
    Screening details
    		 Eligibility criteria of a patient were checked by the investigator. Once a patient fullfils all inclusion criteria and not any of the exclusion criteria, he/she was enrolled.

    Pre-assignment period milestones
    Number of subjects started
    		 203 [1]
    Number of subjects completed
    		 196

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    		 Screening failure: 6
    Reason: Number of subjects
    		 Not randomized: 1
    Notes
    [1] - The number of subjects reported to have started the pre-assignment period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: The worldwide number enrolled in the trial reflects patients being enrolled and receiving medication. The number of screened patients is 203, the number of registered patients is 197, the number of randomized patients is 196 and the number of patients receiving study medication is 192.
    Period 1
    Period 1 title
    Randomization
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Arm A | Rituximab + Placebo
    Arm description
    		 -
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Rituximab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Infusion
    Dosage and administration details
    Rituximab 375 mg/m2 was administered weekly for 4 infusions on day 1 of week 1, 2, 3 and 4 and afterwards in 8-weekly intervals for 12 further infusions. The administration mode could have been changed to s.c. (1400 mg) in the maintenance phase dependent on the local standard of care.

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo to Ibrutinib was taken orally as capsules for 24 months (104 weeks) daily at approximately the same time every day.

    Arm title
    		 Arm B | Rituximab + Ibrutinib
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Rituximab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Infusion
    Dosage and administration details
    Rituximab 375 mg/m2 was administered weekly for 4 infusions on day 1 of week 1, 2, 3 and 4 and afterwards in 8-weekly intervals for 12 further infusions. The administration mode could have been changed to s.c. (1400 mg) in the maintenance phase dependent on the local standard of care.

    Investigational medicinal product name
    Ibrutinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Ibrutinib was taken orally as capsules for 24 months (104 weeks) daily in a dose of 560 mg (4 x 140 mg capsules) at approximately the same time every day.

    Number of subjects in period 1
    		Arm A | Rituximab + Placebo Arm B | Rituximab + Ibrutinib
    Started
    98
    98
    Completed
    98
    94
    Not completed
    0
    4
         Not treated
    -
    4
    Period 2
    Period 2 title
    Baseline
    Is this the baseline period?
    		 Yes [2]
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Arm A | Rituximab + Placebo
    Arm description
    		 -
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Rituximab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Infusion
    Dosage and administration details
    Rituximab 375 mg/m2 was administered weekly for 4 infusions on day 1 of week 1, 2, 3 and 4 and afterwards in 8-weekly intervals for 12 further infusions. The administration mode could have been changed to s.c. (1400 mg) in the maintenance phase dependent on the local standard of care.

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo to Ibrutinib was taken orally as capsules for 24 months (104 weeks) daily at approximately the same time every day.

    Arm title
    		 Arm B | Rituximab + Ibrutinib
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Rituximab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Infusion
    Dosage and administration details
    Rituximab 375 mg/m2 was administered weekly for 4 infusions on day 1 of week 1, 2, 3 and 4 and afterwards in 8-weekly intervals for 12 further infusions. The administration mode could have been changed to s.c. (1400 mg) in the maintenance phase dependent on the local standard of care.

    Investigational medicinal product name
    Ibrutinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Ibrutinib was taken orally as capsules for 24 months (104 weeks) daily in a dose of 560 mg (4 x 140 mg capsules) at approximately the same time every day.

    Notes
    [2] - Period 1 is not the baseline period. It is expected that period 1 will be the baseline period.
    Justification: Four of the randomized patients did not recieve study treatment and thus were not included in the baseline period.
    Number of subjects in period 2
    		Arm A | Rituximab + Placebo Arm B | Rituximab + Ibrutinib
    Started
    98
    94
    Completed
    98
    94
    Period 3
    Period 3 title
    Treatment and FU phase
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Arm A | Rituximab + Placebo
    Arm description
    		 -
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Rituximab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Infusion
    Dosage and administration details
    Rituximab 375 mg/m2 was administered weekly for 4 infusions on day 1 of week 1, 2, 3 and 4 and afterwards in 8-weekly intervals for 12 further infusions. The administration mode could have been changed to s.c. (1400 mg) in the maintenance phase dependent on the local standard of care.

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo to Ibrutinib was taken orally as capsules for 24 months (104 weeks) daily at approximately the same time every day.

    Arm title
    		 Arm B | Rituximab + Ibrutinib
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Rituximab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Infusion
    Dosage and administration details
    Rituximab 375 mg/m2 was administered weekly for 4 infusions on day 1 of week 1, 2, 3 and 4 and afterwards in 8-weekly intervals for 12 further infusions. The administration mode could have been changed to s.c. (1400 mg) in the maintenance phase dependent on the local standard of care.

    Investigational medicinal product name
    Ibrutinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Ibrutinib was taken orally as capsules for 24 months (104 weeks) daily in a dose of 560 mg (4 x 140 mg capsules) at approximately the same time every day.

    Number of subjects in period 3
    		Arm A | Rituximab + Placebo Arm B | Rituximab + Ibrutinib
    Started
    98
    94
    Completed
    86
    84
    Not completed
    12
    10
         Consent withdrawn by subject
    -
    1
         Death
    9
    7
         Lost to follow-up
    3
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Arm A | Rituximab + Placebo
    Reporting group description
    		 -

    Reporting group title
    Arm B | Rituximab + Ibrutinib
    Reporting group description
    		 -

    Reporting group values
    		 Arm A | Rituximab + Placebo Arm B | Rituximab + Ibrutinib Total
    Number of subjects
    		 98 94 192
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 61 58 119
        From 65-84 years
    		 36 36 72
        85 years and over
    		 1 0 1
    Gender categorical
    Units: Subjects
        Female
    		 53 40 93
        Male
    		 45 54 99

    End points

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    End points reporting groups
    Reporting group title
    Arm A | Rituximab + Placebo
    Reporting group description
    		 -

    Reporting group title
    Arm B | Rituximab + Ibrutinib
    Reporting group description
    		 -
    Reporting group title
    Arm A | Rituximab + Placebo
    Reporting group description
    		 -

    Reporting group title
    Arm B | Rituximab + Ibrutinib
    Reporting group description
    		 -
    Reporting group title
    Arm A | Rituximab + Placebo
    Reporting group description
    		 -

    Reporting group title
    Arm B | Rituximab + Ibrutinib
    Reporting group description
    		 -

    Subject analysis set title
    Arm A | Rituximab + Placebo - FAS/PPS/SAF
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    There were no major protocol violations leading to an exclusion from one of the analysis sets. All randomized patients who started trial treatment qualified for inclusion in the Full Analysis Set (FAS), Per Protocol Set (PPS) and Safety Analysis Set (SAF).

    Subject analysis set title
    Arm B | Rituximab + Ibrutinib - FAS/PPS/SAF
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    There were no major protocol violations leading to an exclusion from one of the analysis sets. All randomized patients who started trial treatment qualified for inclusion in the Full Analysis Set (FAS), Per Protocol Set (PPS) and Safety Analysis Set (SAF).

    Primary: PE | Complete response at 24 months (PET/CT)

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    End point title
    		 PE | Complete response at 24 months (PET/CT)
    End point description
    The primary endpoint is the proportion of patients with complete response (CR) at 24 months determined by PET/CT scan by the (independent response review) IRR panel. Progressive disease (PD) or death observed and the PD or death date ≤ 24 months after randomization >>> Non-CR No CR observed and last known non-PD and non-CR status date > 24 months >>> Non-CR 1st CR date ≤ 24 months ≤ last CR date >>> CR
    End point type
    Primary
    End point timeframe
    At 24 months
    End point values
    		 Arm A | Rituximab + Placebo - FAS/PPS/SAF Arm B | Rituximab + Ibrutinib - FAS/PPS/SAF
    Number of subjects analysed
    98
    94
    Units: patients with CR (%)
        number (confidence interval 95%)
    35.7 (26.3 to 46.0)
    40.4 (30.4 to 51.0)
    Statistical analysis title
    		 Stratified logistic regression
    Statistical analysis description
    Comparsion of CR at 24 months (by PET/CT) between treatment arms.
    Comparison groups
    Arm A | Rituximab + Placebo - FAS/PPS/SAF v Arm B | Rituximab + Ibrutinib - FAS/PPS/SAF
    Number of subjects included in analysis
    192
    Analysis specification
    Pre-specified
    Analysis type
    		 other [1]
    P-value
    		 = 0.233 [2]
    Method
    		 stratified logistic regression
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.799
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.44
         upper limit
    		 1.46
    Notes
    [1] - Arm A vs B
    [2] - One-sided

    Primary: PE | Complete response at 24 months (PET/CT) - Sensitivity analyses

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    End point title
    		 PE | Complete response at 24 months (PET/CT) - Sensitivity analyses
    End point description
    The results for CR at 24 months as assessed by the (independent response review) IRR panel based on CT and PET alone are shown in Table 36 and Table 37. The analysis of the primary endpoint CR at 24 months was repeated with the response assessments entered by local investigators.
    End point type
    Primary
    End point timeframe
    At 24 months.
    End point values
    		 Arm A | Rituximab + Placebo - FAS/PPS/SAF Arm B | Rituximab + Ibrutinib - FAS/PPS/SAF
    Number of subjects analysed
    98
    94
    Units: patients with CR (%)
    number (confidence interval 95%)
        CT alone
    16.3 (9.6 to 25.2)
    20.2 (12.6 to 29.8)
        PET alone
    35.7 (26.3 to 46.0)
    36.2 (26.5 to 46.7)
        PET/CT by local investigators
    15.3 (8.8 to 24.0)
    22.3 (14.4 to 32.1)
    Statistical analysis title
    		 Stratified logistic regression - CT
    Statistical analysis description
    Comparsion of CR at 24 months (by CT) between treatment arms
    Comparison groups
    Arm A | Rituximab + Placebo - FAS/PPS/SAF v Arm B | Rituximab + Ibrutinib - FAS/PPS/SAF
    Number of subjects included in analysis
    192
    Analysis specification
    Pre-specified
    Analysis type
    		 other [3]
    P-value
    		 = 0.241 [4]
    Method
    		 stratified logistic regression
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.766
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.36
         upper limit
    		 1.61
    Notes
    [3] - Arm A vs B
    [4] - One-sided
    Statistical analysis title
    		 Stratified logistic regression - PET
    Statistical analysis description
    Comparsion of CR at 24 months (by PET) between treatment arms
    Comparison groups
    Arm A | Rituximab + Placebo - FAS/PPS/SAF v Arm B | Rituximab + Ibrutinib - FAS/PPS/SAF
    Number of subjects included in analysis
    192
    Analysis specification
    Pre-specified
    Analysis type
    		 other [5]
    P-value
    		 = 0.464 [6]
    Method
    		 stratified logistic regression
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.972
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.53
         upper limit
    		 1.8
    Notes
    [5] - Arm A vs B
    [6] - One-sided
    Statistical analysis title
    		 Stratified logistic regression - local inv.
    Statistical analysis description
    Comparsion of CR at 24 months (by local investigators) between treatment arms
    Comparison groups
    Arm A | Rituximab + Placebo - FAS/PPS/SAF v Arm B | Rituximab + Ibrutinib - FAS/PPS/SAF
    Number of subjects included in analysis
    192
    Analysis specification
    Pre-specified
    Analysis type
    		 other [7]
    P-value
    		 = 0.099 [8]
    Method
    		 stratified logistic regression
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.613
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.29
         upper limit
    		 1.29
    Notes
    [7] - Arm A vs B
    [8] - One-sided

    Secondary: SE | Complete response at 30 months (PET/CT)

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    End point title
    		 SE | Complete response at 30 months (PET/CT)
    End point description
    Any assessment within a window of week 126 to week 142 (inclusive) was considered as the 30 months response assessment for determining the CR status. The same rules as described for the primary endpoint were used for determination of CR status at 30 months.
    End point type
    Secondary
    End point timeframe
    At 30 months.
    End point values
    		 Arm A | Rituximab + Placebo - FAS/PPS/SAF Arm B | Rituximab + Ibrutinib - FAS/PPS/SAF
    Number of subjects analysed
    98
    94
    Units: patients (%) with CR
        number (confidence interval 95%)
    28.6 (19.9 to 38.6)
    34.0 (24.6 to 44.5)
    Statistical analysis title
    		 Stratified logistic regression
    Statistical analysis description
    Between arm comparison of CR at 30 months
    Comparison groups
    Arm A | Rituximab + Placebo - FAS/PPS/SAF v Arm B | Rituximab + Ibrutinib - FAS/PPS/SAF
    Number of subjects included in analysis
    192
    Analysis specification
    Pre-specified
    Analysis type
    		 other [9]
    P-value
    		 = 0.427
    Method
    		 stratified logistic regression
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.77
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.41
         upper limit
    		 1.46
    Notes
    [9] - Arm A vs B

    Secondary: SE | Evaluation of minimal residual disease (MRD) - bone marrow

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    End point title
    		 SE | Evaluation of minimal residual disease (MRD) - bone marrow
    End point description
    MRD evaluation was performed using real-time PCR (polymerase chain reaction) based methods in peripheral blood and bone marrow at baseline and week 106. The proportion of patients achieving MRD negativity at week 106 was calculated separately for bone marrow and peripheral blood. Only patients with positive MRD at baseline were considered for this analysis. Due to the low sample sizes, no statistical comparison (logistic regression) between treatment arms has been performed.
    End point type
    Secondary
    End point timeframe
    At week 106.
    End point values
    		 Arm A | Rituximab + Placebo - FAS/PPS/SAF Arm B | Rituximab + Ibrutinib - FAS/PPS/SAF
    Number of subjects analysed
    3 [10]
    6 [11]
    Units: patients (%) with MRD negativity
    number (not applicable)
        negative
    100.0
    83.3
        positive
    0.0
    16.7
    Notes
    [10] - Only for patients with data at baseline and week 106.
    [11] - Only for patients with data at baseline and week 106.
    No statistical analyses for this end point

    Secondary: SE | Evaluation of minimal residual disease (MRD) - peripheral blood

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    End point title
    		 SE | Evaluation of minimal residual disease (MRD) - peripheral blood
    End point description
    MRD evaluation was performed using real-time PCR (polymerase chain reaction) based methods in peripheral blood and bone marrow at baseline and week 106. The proportion of patients achieving MRD negativity at week 106 was calculated separately for bone marrow and peripheral blood. Only patients with positive MRD at baseline were considered for this analysis. Due to the low sample sizes, no statistical comparison (logistic regression) between treatment arms has been performed.
    End point type
    Secondary
    End point timeframe
    At week 106.
    End point values
    		 Arm A | Rituximab + Placebo - FAS/PPS/SAF Arm B | Rituximab + Ibrutinib - FAS/PPS/SAF
    Number of subjects analysed
    23 [12]
    25 [13]
    Units: patients (%) with MRD negativity
    number (not applicable)
        Negative
    100.0
    96.0
        Positive
    0.0
    4.0
    Notes
    [12] - Only for patients with data at baseline and week 106.
    [13] - Only for patients with data at baseline and week 106.
    No statistical analyses for this end point

    Secondary: SE | Overall response (OR) at 24 weeks

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    End point title
    		 SE | Overall response (OR) at 24 weeks
    End point description
    Overall response (OR) is defined as either: - the disappearance of all evidence of disease (CR) - the regression of measurable disease with no new sites (PR) Any assessment within a window of 21 to 27 weeks (inclusive) was considered as the 24 weeks response assessment for determining the OR status. Similar rules as described for the primary endpoint were used for determination of OR status at 24 weeks in case of missing assessment within a window of 21 to 27 weeks. For this endpoint, data entered by the local investigators were used.
    End point type
    Secondary
    End point timeframe
    At 24 weeks.
    End point values
    		 Arm A | Rituximab + Placebo - FAS/PPS/SAF Arm B | Rituximab + Ibrutinib - FAS/PPS/SAF
    Number of subjects analysed
    98
    94
    Units: patients (%) with OR
        number (confidence interval 95%)
    59.2 (48.8 to 69.0)
    73.4 (63.3 to 82.0)
    Statistical analysis title
    		 Stratified logistic regression
    Statistical analysis description
    Between arm comparison of OR at 24 weeks
    Comparison groups
    Arm A | Rituximab + Placebo - FAS/PPS/SAF v Arm B | Rituximab + Ibrutinib - FAS/PPS/SAF
    Number of subjects included in analysis
    192
    Analysis specification
    Pre-specified
    Analysis type
    		 other [14]
    P-value
    		 = 0.046
    Method
    		 stratified logistic regression
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.53
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.28
         upper limit
    		 0.99
    Notes
    [14] - Arm A vs B

    Secondary: SE | Duration of complete response (DUR)

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    End point title
    		 SE | Duration of complete response (DUR)
    End point description
    Kaplan-Meier analysis. DUR was calculated from when the criteria for CR (according to local assessments recorded on the tumor form) were met, until documentation of relapse thereafter. Only patients with a CR (n=56) were included in this analysis. Patients without any documentation of relapse thereafter were censored at the last time they were known to be without relapse (i.e. last date of tumor assessment without relapse) and before the start of a new anti-lymphoma treatment, if any. A total of 9 patients experienced an event in Arm A and 6 in Arm B. Note: Median and upper 95% confidence intervall were note reached for both arms. Dummy data ("9999") entered due to database restrictions.
    End point type
    Secondary
    End point timeframe
    From achieving criteria for CR until documentation of relapse thereafter.
    End point values
    		 Arm A | Rituximab + Placebo - FAS/PPS/SAF Arm B | Rituximab + Ibrutinib - FAS/PPS/SAF
    Number of subjects analysed
    26 [15]
    32 [16]
    Units: months
        median (confidence interval 95%)
    9999 (20.8 to 9999)
    9999 (49.4 to 9999)
    Notes
    [15] - Only for patients achieving CR.
    [16] - Only for patients achieving CR.
    Statistical analysis title
    		 Stratified Cox proportional hazards model
    Statistical analysis description
    Between arm comparison of DUR months.
    Comparison groups
    Arm A | Rituximab + Placebo - FAS/PPS/SAF v Arm B | Rituximab + Ibrutinib - FAS/PPS/SAF
    Number of subjects included in analysis
    58
    Analysis specification
    Pre-specified
    Analysis type
    		 other [17]
    P-value
    		 = 0.454
    Method
    		 Regression, Cox
    Parameter type
    		 Cox proportional hazard
    Point estimate
    0.64
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.2
         upper limit
    		 2.06
    Notes
    [17] - Arm B vs A

    Secondary: SE | Progression-free survival (PFS)

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    End point title
    		 SE | Progression-free survival (PFS)
    End point description
    Kaplan-Meier analysis. Progression-free survival (PFS) was calculated from randomization until the first event of interest: - disease progression or relapse - death from any cause Patients not experiencing an event, including patients receiving a subsequent anti-lymphoma therapy without documented disease progression or relapse, were censored at the last time they were known to be without progression (i.e. last date of tumor assessment without progression) and before the start of a new anti-lymphoma treatment, if any. A total of 48 patients experienced a PFS event in Arm A and 36 in Arm B. Note: Upper 95%-CI for arm B was not reached. Dummy data ("9999") entered due to database restrictions.
    End point type
    Secondary
    End point timeframe
    From baseline until disease progression or relapse or death from any cause.
    End point values
    		 Arm A | Rituximab + Placebo - FAS/PPS/SAF Arm B | Rituximab + Ibrutinib - FAS/PPS/SAF
    Number of subjects analysed
    98
    94
    Units: months
        median (confidence interval 95%)
    32.7 (24.6 to 55.0)
    61.9 (33.1 to 9999)
    Statistical analysis title
    		 Stratified Cox proportional hazards model
    Statistical analysis description
    Between arm comparison of PFS months.
    Comparison groups
    Arm A | Rituximab + Placebo - FAS/PPS/SAF v Arm B | Rituximab + Ibrutinib - FAS/PPS/SAF
    Number of subjects included in analysis
    192
    Analysis specification
    Pre-specified
    Analysis type
    		 other [18]
    P-value
    		 = 0.057
    Method
    		 Regression, Cox
    Parameter type
    		 Cox proportional hazard
    Point estimate
    0.64
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.4
         upper limit
    		 1.01
    Notes
    [18] - Arm B vs A

    Secondary: SE | Event-free survival (EFS)

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    End point title
    		 SE | Event-free survival (EFS)
    End point description
    Kaplan-Meier analysis. Event-free survival (time to treatment failure) was calculated from randomization to premature discontinuation of trial treatment for any reason (e.g., insufficient response at first, second or third restaging at 12, 24 or 52 weeks, progressive disease, toxicity, patient preference, initiation of new anti-lymphoma treatment without documented progression, secondary malignancy or death). After completion of trial therapy the following was considered as event: progressive disease, death, initiation of new anti-lymphoma treatment without documented progression or secondary malignancy. Patients not experiencing an event will were censored at the last date they were known to be alive. A total of 70 patients experienced an EFS event in Arm A and 56 in Arm B.
    End point type
    Secondary
    End point timeframe
    From randomization to premature discontinuation of trial treatment for any reason.
    End point values
    		 Arm A | Rituximab + Placebo - FAS/PPS/SAF Arm B | Rituximab + Ibrutinib - FAS/PPS/SAF
    Number of subjects analysed
    98
    94
    Units: months
        median (confidence interval 95%)
    21.6 (11.1 to 24.8)
    30.2 (17.9 to 61.0)
    Statistical analysis title
    		 Stratified Cox proportional hazards model
    Statistical analysis description
    Between arm comparison of EFS months.
    Comparison groups
    Arm A | Rituximab + Placebo - FAS/PPS/SAF v Arm B | Rituximab + Ibrutinib - FAS/PPS/SAF
    Number of subjects included in analysis
    192
    Analysis specification
    Pre-specified
    Analysis type
    		 other [19]
    P-value
    		 = 0.053
    Method
    		 Regression, Cox
    Parameter type
    		 Cox proportional hazard
    Point estimate
    0.69
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.47
         upper limit
    		 1
    Notes
    [19] - Arm B vs A

    Secondary: SE | Time to next anti-lymphoma therapy (TTNT)

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    End point title
    		 SE | Time to next anti-lymphoma therapy (TTNT)
    End point description
    Kaplan-Meier analysis. Time to next anti-lymphoma therapy (TTNT) was calculated from randomization until the start of the first off-trial anti-lymphoma treatment. Patients not receiving any off-trial anti-lymphoma treatment were censored at the last follow-up visit. A total of 52 patients experienced a TTNT event in Arm A and 43 in Arm B. Note: Upper 95%-CI not reached for arm A and B. Dummy data ("9999") entered due to database restrictions.
    End point type
    Secondary
    End point timeframe
    From randomization until the start of the first off-trial anti-lymphoma treatment.
    End point values
    		 Arm A | Rituximab + Placebo - FAS/PPS/SAF Arm B | Rituximab + Ibrutinib - FAS/PPS/SAF
    Number of subjects analysed
    98
    94
    Units: months
        median (confidence interval 95%)
    41.2 (24.0 to 9999)
    73.8 (33.1 to 9999)
    Statistical analysis title
    		 Stratified Cox proportional hazards model
    Statistical analysis description
    Between arm comparison of TTNT months.
    Comparison groups
    Arm B | Rituximab + Ibrutinib - FAS/PPS/SAF v Arm A | Rituximab + Placebo - FAS/PPS/SAF
    Number of subjects included in analysis
    192
    Analysis specification
    Pre-specified
    Analysis type
    		 other [20]
    P-value
    		 = 0.112
    Method
    		 Regression, Cox
    Parameter type
    		 Cox proportional hazard
    Point estimate
    0.71
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.46
         upper limit
    		 1.09
    Notes
    [20] - Arm B vs A

    Secondary: SE | Overall survival (OS)

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    End point title
    		 SE | Overall survival (OS)
    End point description
    Kaplan-Meier analysis. OS was calculated from randomization until death. Patients not experiencing an event were censored at the last date they were known to be alive. A total of 9 patients died in Arm A and 7 in Arm B. Note: Median and upper 95%-CI for arm A and B, and additionally the lower 95%-CI for arm A were not reached. Dummy data ("9999") entered due to database restrictions.
    End point type
    Secondary
    End point timeframe
    From randomization until death.
    End point values
    		 Arm A | Rituximab + Placebo - FAS/PPS/SAF Arm B | Rituximab + Ibrutinib - FAS/PPS/SAF
    Number of subjects analysed
    98
    94
    Units: months
        median (confidence interval 95%)
    9999 (9999 to 9999)
    9999 (75.3 to 9999)
    Statistical analysis title
    		 Stratified Cox proportional hazards model
    Statistical analysis description
    Between arm comparison of OS months.
    Comparison groups
    Arm A | Rituximab + Placebo - FAS/PPS/SAF v Arm B | Rituximab + Ibrutinib - FAS/PPS/SAF
    Number of subjects included in analysis
    192
    Analysis specification
    Pre-specified
    Analysis type
    		 other [21]
    P-value
    		 = 0.81
    Method
    		 Regression, Cox
    Parameter type
    		 Cox proportional hazard
    Point estimate
    0.88
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.3
         upper limit
    		 2.56
    Notes
    [21] - Arm B vs A

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    AE reporting period is from registration into the trial until 30 days after end of treatment (or immediately prior to next off-trial treatment, whichever occurs first).
    Adverse event reporting additional description
    Ongoing AEs need to be followed-up until resolution or permanent sequelae or start of new therapy.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    27.0
    Reporting groups
    Reporting group title
    Arm A | Rituximab + Placebo
    Reporting group description
    		 -

    Reporting group title
    Arm B | Rituximab + Ibrutinib
    Reporting group description
    		 -

    Serious adverse events
    		 Arm A | Rituximab + Placebo Arm B | Rituximab + Ibrutinib
    Total subjects affected by serious adverse events
         subjects affected / exposed
    25 / 98 (25.51%)
    37 / 94 (39.36%)
         number of deaths (all causes)
    9
    7
         number of deaths resulting from adverse events
    0
    1
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Acute myeloid leukaemia
         subjects affected / exposed
    0 / 98 (0.00%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Basal cell carcinoma
         subjects affected / exposed
    2 / 98 (2.04%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Breast cancer
         subjects affected / exposed
    1 / 98 (1.02%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colon cancer
         subjects affected / exposed
    1 / 98 (1.02%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymphoma transformation
    Additional description: Arm A: 6 events for 6 patients (Diffuse large B-cell lymphoma) | Arm B: 8 events for 8 patients (Diffuse large B-cell lymphoma), 1 event for 1 patient (High-grade B-cell lymphoma), 2 events for 2 patients (Hodgkin's disease).
         subjects affected / exposed
    6 / 98 (6.12%)
    11 / 94 (11.70%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 11
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Lung adenocarcinoma
         subjects affected / exposed
    0 / 98 (0.00%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malignant sweat gland neoplasm
         subjects affected / exposed
    1 / 98 (1.02%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Non-small cell lung cancer
         subjects affected / exposed
    0 / 98 (0.00%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Prostate cancer
         subjects affected / exposed
    0 / 98 (0.00%)
    2 / 94 (2.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Plasma cell myeloma
         subjects affected / exposed
    1 / 98 (1.02%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Squamous cell carcinoma
         subjects affected / exposed
    1 / 98 (1.02%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    T-cell lymphoma
         subjects affected / exposed
    0 / 98 (0.00%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thyroid cancer
         subjects affected / exposed
    0 / 98 (0.00%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bladder transitional cell carcinoma
         subjects affected / exposed
    0 / 98 (0.00%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Hypertension
         subjects affected / exposed
    0 / 98 (0.00%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Embolism
         subjects affected / exposed
    0 / 98 (0.00%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vasculitis
         subjects affected / exposed
    1 / 98 (1.02%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Cyst removal
    Additional description: Removal of branchial cleft cyst (right side).
         subjects affected / exposed
    1 / 98 (1.02%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tonsillectomy
    Additional description: Tonsillectomy and biopsy of throat cyst.
         subjects affected / exposed
    1 / 98 (1.02%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    0 / 98 (0.00%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza like illness
         subjects affected / exposed
    1 / 98 (1.02%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    0 / 98 (0.00%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cytokine release syndrome
         subjects affected / exposed
    1 / 98 (1.02%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Serum sickness
         subjects affected / exposed
    1 / 98 (1.02%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Chylothorax
         subjects affected / exposed
    1 / 98 (1.02%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    1 / 98 (1.02%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Hepatic enzyme increased
    Additional description: Aspartate aminotransferase and alanine aminotransferase increased increased for both patients.
         subjects affected / exposed
    1 / 98 (1.02%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Infusion related reaction
         subjects affected / exposed
    1 / 98 (1.02%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    1 / 98 (1.02%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal fracture
         subjects affected / exposed
    0 / 98 (0.00%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    1 / 98 (1.02%)
    3 / 94 (3.19%)
         occurrences causally related to treatment / all
    1 / 1
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial flutter
         subjects affected / exposed
    1 / 98 (1.02%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    0 / 98 (0.00%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinus node dysfunction
         subjects affected / exposed
    0 / 98 (0.00%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ventricular tachycardia
         subjects affected / exposed
    1 / 98 (1.02%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    0 / 98 (0.00%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 98 (0.00%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    1 / 98 (1.02%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Febrile neutropenia
         subjects affected / exposed
    1 / 98 (1.02%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    1 / 1
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 98 (1.02%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileal perforation
         subjects affected / exposed
    0 / 98 (0.00%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    1 / 98 (1.02%)
    0 / 94 (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 / 98 (1.02%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Hyperthyroidism
         subjects affected / exposed
    1 / 98 (1.02%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthritis
         subjects affected / exposed
    1 / 98 (1.02%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteonecrosis
         subjects affected / exposed
    0 / 98 (0.00%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    0 / 98 (0.00%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    1 / 98 (1.02%)
    0 / 94 (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
    Abdominal infection
         subjects affected / exposed
    0 / 98 (0.00%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    COVID-19
         subjects affected / exposed
    1 / 98 (1.02%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Kidney infection
         subjects affected / exposed
    1 / 98 (1.02%)
    0 / 94 (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
    0 / 98 (0.00%)
    4 / 94 (4.26%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lyme disease
         subjects affected / exposed
    0 / 98 (0.00%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin infection
         subjects affected / exposed
    1 / 98 (1.02%)
    2 / 94 (2.13%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stomatitis
         subjects affected / exposed
    0 / 98 (0.00%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 98 (0.00%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    0 / 98 (0.00%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Arm A | Rituximab + Placebo Arm B | Rituximab + Ibrutinib
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    98 / 98 (100.00%)
    94 / 94 (100.00%)
    Vascular disorders
    Haematoma
         subjects affected / exposed
    6 / 98 (6.12%)
    11 / 94 (11.70%)
         occurrences all number
    6
    12
    Hypertension
         subjects affected / exposed
    11 / 98 (11.22%)
    11 / 94 (11.70%)
         occurrences all number
    21
    19
    General disorders and administration site conditions
    Oedema peripheral
         subjects affected / exposed
    11 / 98 (11.22%)
    4 / 94 (4.26%)
         occurrences all number
    13
    4
    Fatigue
         subjects affected / exposed
    32 / 98 (32.65%)
    34 / 94 (36.17%)
         occurrences all number
    39
    47
    Pyrexia
         subjects affected / exposed
    7 / 98 (7.14%)
    9 / 94 (9.57%)
         occurrences all number
    7
    9
    Influenza like illness
         subjects affected / exposed
    16 / 98 (16.33%)
    18 / 94 (19.15%)
         occurrences all number
    23
    22
    Pain
         subjects affected / exposed
    9 / 98 (9.18%)
    12 / 94 (12.77%)
         occurrences all number
    11
    18
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    18 / 98 (18.37%)
    29 / 94 (30.85%)
         occurrences all number
    27
    38
    Dyspnoea
         subjects affected / exposed
    11 / 98 (11.22%)
    6 / 94 (6.38%)
         occurrences all number
    11
    7
    Epistaxis
         subjects affected / exposed
    1 / 98 (1.02%)
    9 / 94 (9.57%)
         occurrences all number
    2
    9
    Oropharyngeal pain
         subjects affected / exposed
    6 / 98 (6.12%)
    6 / 94 (6.38%)
         occurrences all number
    10
    7
    Psychiatric disorders
    Depression
         subjects affected / exposed
    3 / 98 (3.06%)
    6 / 94 (6.38%)
         occurrences all number
    3
    6
    Insomnia
         subjects affected / exposed
    8 / 98 (8.16%)
    7 / 94 (7.45%)
         occurrences all number
    8
    12
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    29 / 98 (29.59%)
    24 / 94 (25.53%)
         occurrences all number
    158
    85
    Blood alkaline phosphatase increased
         subjects affected / exposed
    29 / 98 (29.59%)
    20 / 94 (21.28%)
         occurrences all number
    153
    82
    Aspartate aminotransferase increased
         subjects affected / exposed
    32 / 98 (32.65%)
    31 / 94 (32.98%)
         occurrences all number
    129
    98
    Blood bilirubin increased
         subjects affected / exposed
    12 / 98 (12.24%)
    25 / 94 (26.60%)
         occurrences all number
    39
    187
    Blood creatinine increased
         subjects affected / exposed
    34 / 98 (34.69%)
    29 / 94 (30.85%)
         occurrences all number
    166
    232
    Lymphocyte count decreased
         subjects affected / exposed
    59 / 98 (60.20%)
    49 / 94 (52.13%)
         occurrences all number
    470
    387
    Neutrophil count decreased
         subjects affected / exposed
    16 / 98 (16.33%)
    34 / 94 (36.17%)
         occurrences all number
    38
    61
    Platelet count decreased
         subjects affected / exposed
    26 / 98 (26.53%)
    45 / 94 (47.87%)
         occurrences all number
    128
    424
    White blood cell count decreased
         subjects affected / exposed
    19 / 98 (19.39%)
    16 / 94 (17.02%)
         occurrences all number
    49
    27
    Injury, poisoning and procedural complications
    Infusion related reaction
         subjects affected / exposed
    12 / 98 (12.24%)
    4 / 94 (4.26%)
         occurrences all number
    17
    4
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    10 / 98 (10.20%)
    7 / 94 (7.45%)
         occurrences all number
    13
    7
    Dysgeusia
         subjects affected / exposed
    5 / 98 (5.10%)
    1 / 94 (1.06%)
         occurrences all number
    5
    1
    Headache
         subjects affected / exposed
    15 / 98 (15.31%)
    21 / 94 (22.34%)
         occurrences all number
    27
    30
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    42 / 98 (42.86%)
    41 / 94 (43.62%)
         occurrences all number
    220
    215
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    3 / 98 (3.06%)
    6 / 94 (6.38%)
         occurrences all number
    3
    7
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    14 / 98 (14.29%)
    12 / 94 (12.77%)
         occurrences all number
    21
    22
    Constipation
         subjects affected / exposed
    5 / 98 (5.10%)
    10 / 94 (10.64%)
         occurrences all number
    6
    11
    Diarrhoea
         subjects affected / exposed
    27 / 98 (27.55%)
    30 / 94 (31.91%)
         occurrences all number
    40
    52
    Dry mouth
         subjects affected / exposed
    6 / 98 (6.12%)
    7 / 94 (7.45%)
         occurrences all number
    6
    7
    Dyspepsia
         subjects affected / exposed
    3 / 98 (3.06%)
    10 / 94 (10.64%)
         occurrences all number
    3
    12
    Gastritis
         subjects affected / exposed
    0 / 98 (0.00%)
    7 / 94 (7.45%)
         occurrences all number
    0
    7
    Gastrooesophageal reflux disease
         subjects affected / exposed
    1 / 98 (1.02%)
    7 / 94 (7.45%)
         occurrences all number
    1
    7
    Stomatitis
         subjects affected / exposed
    3 / 98 (3.06%)
    6 / 94 (6.38%)
         occurrences all number
    3
    9
    Nausea
         subjects affected / exposed
    19 / 98 (19.39%)
    20 / 94 (21.28%)
         occurrences all number
    32
    34
    Abdominal pain upper
         subjects affected / exposed
    9 / 98 (9.18%)
    3 / 94 (3.19%)
         occurrences all number
    10
    5
    Vomiting
         subjects affected / exposed
    6 / 98 (6.12%)
    6 / 94 (6.38%)
         occurrences all number
    6
    9
    Skin and subcutaneous tissue disorders
    Dry skin
         subjects affected / exposed
    6 / 98 (6.12%)
    8 / 94 (8.51%)
         occurrences all number
    7
    9
    Pruritus
         subjects affected / exposed
    5 / 98 (5.10%)
    5 / 94 (5.32%)
         occurrences all number
    7
    7
    Rash maculo-papular
         subjects affected / exposed
    8 / 98 (8.16%)
    21 / 94 (22.34%)
         occurrences all number
    10
    28
    Renal and urinary disorders
    Chronic kidney disease
         subjects affected / exposed
    75 / 98 (76.53%)
    83 / 94 (88.30%)
         occurrences all number
    1140
    1256
    Pollakiuria
         subjects affected / exposed
    4 / 98 (4.08%)
    5 / 94 (5.32%)
         occurrences all number
    4
    6
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    13 / 98 (13.27%)
    7 / 94 (7.45%)
         occurrences all number
    17
    7
    Back pain
         subjects affected / exposed
    14 / 98 (14.29%)
    15 / 94 (15.96%)
         occurrences all number
    17
    20
    Muscle spasms
         subjects affected / exposed
    2 / 98 (2.04%)
    9 / 94 (9.57%)
         occurrences all number
    2
    13
    Myalgia
         subjects affected / exposed
    5 / 98 (5.10%)
    4 / 94 (4.26%)
         occurrences all number
    6
    5
    Pain in extremity
         subjects affected / exposed
    10 / 98 (10.20%)
    14 / 94 (14.89%)
         occurrences all number
    10
    17
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    2 / 98 (2.04%)
    5 / 94 (5.32%)
         occurrences all number
    2
    6
    COVID-19
         subjects affected / exposed
    5 / 98 (5.10%)
    3 / 94 (3.19%)
         occurrences all number
    6
    4
    Lip infection
         subjects affected / exposed
    3 / 98 (3.06%)
    5 / 94 (5.32%)
         occurrences all number
    6
    6
    Pneumonia
         subjects affected / exposed
    0 / 98 (0.00%)
    5 / 94 (5.32%)
         occurrences all number
    0
    6
    Nail infection
         subjects affected / exposed
    1 / 98 (1.02%)
    5 / 94 (5.32%)
         occurrences all number
    1
    5
    Rhinitis
         subjects affected / exposed
    3 / 98 (3.06%)
    5 / 94 (5.32%)
         occurrences all number
    4
    6
    Skin infection
         subjects affected / exposed
    2 / 98 (2.04%)
    7 / 94 (7.45%)
         occurrences all number
    2
    7
    Upper respiratory tract infection
         subjects affected / exposed
    13 / 98 (13.27%)
    10 / 94 (10.64%)
         occurrences all number
    14
    13
    Urinary tract infection
         subjects affected / exposed
    5 / 98 (5.10%)
    4 / 94 (4.26%)
         occurrences all number
    10
    7
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    8 / 98 (8.16%)
    9 / 94 (9.57%)
         occurrences all number
    8
    10

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    29 Jun 2016
    A substantial amendment has been issued in order to adapt the Serious Adverse Event definition and reporting in the protocol. Further changes: - Risk changes: due to the new IB of Ibrutinib (Version 9, 30th June 2015) the chapter “drug related adverse events” (section 10.3) of the protocol was updated. - Adaptations to answer conditions issued by the Norwegian Medicines Agency - Administrative changes, clarifications and inconsistencies: correction of typos and wording
    23 Dec 2016
    A substantial amendment has been issued. The main reason for the amendment was the update of the risk section of the protocol and of the PIS/IC documents due to the release of the new IB of Ibrutinib (Version 10, 29th August 2016). Summary of changes: - Risk section: the chapter “drug related adverse events” (section 10.3) of the protocol was updated according to the new IB of Ibrutinib (Version 10, 29th August 2016). - Exclusion criteria: patient treatment with Aspirin up to 300 mg/daily is now allowed (section 6.2). - Translational research projects for the Biobank in Norway and Sweden: minor modifications were made concerning sample collections: amount and less time points (section 18.1). - Trial summary: has been integrated directly into the protocol. - Swiss Specific Appendix: description on how to order Rituximab provided by Roche in Switzerland. - Administrative changes, clarifications and inconsistencies: correction of typos and wording.

    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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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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