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    Clinical Trial Results:
    A Multicenter, Open-Label, Phase 2 Study of the Bruton’s Tyrosine Kinase (BTK) Inhibitor, Ibrutinib, in Subjects with Relapsed/Refractory Marginal Zone Lymphoma

    Summary
    EudraCT number
    2013-003561-34
    Trial protocol
    BE   DE   GB  
    Global end of trial date
    02 Oct 2017

    Results information
    Results version number
    v2(current)
    This version publication date
    12 Dec 2018
    First version publication date
    21 Oct 2017
    Other versions
    v1
    Version creation reason
    • New data added to full data set
    final analysis with last subject last visit 02 October 2017

    Trial information

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    Trial identification
    Sponsor protocol code
    PCYC-1121-CA
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01980628
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Pharmacyclics LLC
    Sponsor organisation address
    999 E Arques Ave, Sunnyvale, United States, 94085
    Public contact
    Thorsten Graef, Pharmacyclics LLC, +1 408) 215 2127, medinfo@pcyc.com
    Scientific contact
    Clinical Trial information, Pharmacyclics LLC, +1 408774 0330, medinfo@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?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    02 Oct 2017
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    02 Oct 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the efficacy of ibrutinib therapy in subjects with marginal zone lymphoma (MZL) using the overall response rate (ORR) as assessed by an Independent Review Committee (IRC)
    Protection of trial subjects
    This study was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki and that are consistent with Good Clinical Practice (GCP)
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    05 Dec 2013
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 4
    Country: Number of subjects enrolled
    Belgium: 1
    Country: Number of subjects enrolled
    France: 13
    Country: Number of subjects enrolled
    Germany: 1
    Country: Number of subjects enrolled
    United States: 44
    Worldwide total number of subjects
    63
    EEA total number of subjects
    19
    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)
    27
    From 65 to 84 years
    36
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    This was a Phase 2, open-label, non-randomized, multicenter, monotherapy study assessing the safety and efficacy of ibrutinib in subjects with relapsed/refractory MZL. The study had a Simon’s optimal design to test the null hypothesis that the ORR was ≤ 25%.

    Pre-assignment
    Screening details
    Histologically documented evidence of MZL including splenic, nodal, and extranodal MZL subtypes with at least 1 measurable lesion and a history of 1 or more prior lines of therapy including at least 1 CD20-directed regimen either as monotherapy or as CIT with disease progression or failure of response reported after the last therapy.

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

    Arms
    Arm title
    Overall Trial
    Arm description
    Overall trial
    Arm type
    overall

    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 was provided as size-0, hard gelatin capsules each containing 140 mg of active drug for oral administration

    Number of subjects in period 1
    Overall Trial
    Started
    63
    Completed
    59
    Not completed
    4
         Consent withdrawn by subject
    4

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall trial
    Reporting group description
    -

    Reporting group values
    Overall trial Total
    Number of subjects
    63 63
    Age categorical
    Units: Subjects
        In utero
    0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0
        Newborns (0-27 days)
    0 0
        Infants and toddlers (28 days-23 months)
    0 0
        Children (2-11 years)
    0 0
        Adolescents (12-17 years)
    0 0
        Adults (18-64 years)
    27 27
        From 65-84 years
    36 36
        85 years and over
    0 0
    Age continuous
    Units: years
        median (full range (min-max))
    66 (30 to 92) -
    Gender categorical
    Units: Subjects
        Female
    27 27
        Male
    36 36

    End points

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    End points reporting groups
    Reporting group title
    Overall Trial
    Reporting group description
    Overall trial

    Subject analysis set title
    Efficacy analysis set
    Subject analysis set type
    Modified intention-to-treat
    Subject analysis set description
    At baseline, 3 subjects in this study were reported with non-measurable disease by IRC assessment but with measurable disease per investigator assessment.

    Primary: ORR

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    End point title
    ORR [1]
    End point description
    The primary endpoint of this study was ORR (defined as the proportion of subjects with evidence of disease at baseline having partial response [PR] or better) per IRC assessment. Secondary endpoints included DOR and PFS per IRC assessment, OS, and safety and PK evaluation. Exploratory endpoints included biomarker evaluation.
    End point type
    Primary
    End point timeframe
    overall trial
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: This has been an open-label, uncontrolled Phase II study. No formal statistical analysis was therefore conducted.
    End point values
    Efficacy analysis set
    Number of subjects analysed
    60
    Units: percent
        number (confidence interval 95%)
    48.3 (35.3 to 61.7)
    No statistical analyses for this end point

    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
    Adverse event reporting additional description
    Subjects who receieved at least one dose of study medication
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    19.0
    Reporting groups
    Reporting group title
    Overall trial
    Reporting group description
    -

    Serious adverse events
    Overall trial
    Total subjects affected by serious adverse events
         subjects affected / exposed
    28 / 63 (44.44%)
         number of deaths (all causes)
    3
         number of deaths resulting from adverse events
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Lymphoma
         subjects affected / exposed
    1 / 63 (1.59%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Marginal zone lymphoma
         subjects affected / exposed
    1 / 63 (1.59%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Vascular disorders
    Hypotension
         subjects affected / exposed
    1 / 63 (1.59%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    1 / 63 (1.59%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    1 / 63 (1.59%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 63 (1.59%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pyrexia
         subjects affected / exposed
    1 / 63 (1.59%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pneumothorax
         subjects affected / exposed
    2 / 63 (3.17%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Dyspnoea
         subjects affected / exposed
    1 / 63 (1.59%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Eosinophilic pneumonia
         subjects affected / exposed
    1 / 63 (1.59%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Hypoxia
         subjects affected / exposed
    1 / 63 (1.59%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pleural effusion
         subjects affected / exposed
    1 / 63 (1.59%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pneumonitis
         subjects affected / exposed
    1 / 63 (1.59%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    1 / 63 (1.59%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory failure
         subjects affected / exposed
    1 / 63 (1.59%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Injury, poisoning and procedural complications
    Ankle fracture
         subjects affected / exposed
    1 / 63 (1.59%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    1 / 63 (1.59%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Pericardial effusion
         subjects affected / exposed
    1 / 63 (1.59%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Nervous system disorders
    Cerebral haemorrhage
         subjects affected / exposed
    1 / 63 (1.59%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Cervical radiculopathy
         subjects affected / exposed
    1 / 63 (1.59%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    1 / 63 (1.59%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Blood and lymphatic system disorders
    Autoimmune haemolytic anaemia
         subjects affected / exposed
    2 / 63 (3.17%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Haemolytic anaemia
         subjects affected / exposed
    1 / 63 (1.59%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Pancreatitis
         subjects affected / exposed
    1 / 63 (1.59%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Stomatitis
         subjects affected / exposed
    1 / 63 (1.59%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Hepatobiliary disorders
    Cholelithiasis
         subjects affected / exposed
    1 / 63 (1.59%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    1 / 63 (1.59%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    5 / 63 (7.94%)
         occurrences causally related to treatment / all
    5 / 6
         deaths causally related to treatment / all
    0 / 0
    Cellulitis
         subjects affected / exposed
    2 / 63 (3.17%)
         occurrences causally related to treatment / all
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    Sepsis
         subjects affected / exposed
    2 / 63 (3.17%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Escherichia sepsis
         subjects affected / exposed
    1 / 63 (1.59%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infection
         subjects affected / exposed
    1 / 63 (1.59%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Influenza
         subjects affected / exposed
    1 / 63 (1.59%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Listeria sepsis
         subjects affected / exposed
    1 / 63 (1.59%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Lung infection
         subjects affected / exposed
    1 / 63 (1.59%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Parainfluenzae virus infection
         subjects affected / exposed
    1 / 63 (1.59%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    1 / 63 (1.59%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Fluid overload
         subjects affected / exposed
    1 / 63 (1.59%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Overall trial
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    63 / 63 (100.00%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    8 / 63 (12.70%)
         occurrences all number
    11
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    28 / 63 (44.44%)
         occurrences all number
    42
    Oedema peripheral
         subjects affected / exposed
    15 / 63 (23.81%)
         occurrences all number
    26
    Pyrexia
         subjects affected / exposed
    10 / 63 (15.87%)
         occurrences all number
    18
    Asthenia
         subjects affected / exposed
    6 / 63 (9.52%)
         occurrences all number
    6
    Reproductive system and breast disorders
    Cough
         subjects affected / exposed
    14 / 63 (22.22%)
         occurrences all number
    21
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    12 / 63 (19.05%)
         occurrences all number
    17
    Epistaxis
         subjects affected / exposed
    8 / 63 (12.70%)
         occurrences all number
    12
    Nasal congestion
         subjects affected / exposed
    5 / 63 (7.94%)
         occurrences all number
    6
    Oropharyngeal pain
         subjects affected / exposed
    4 / 63 (6.35%)
         occurrences all number
    5
    Productive cough
         subjects affected / exposed
    4 / 63 (6.35%)
         occurrences all number
    4
    Rhinorrhoea
         subjects affected / exposed
    4 / 63 (6.35%)
         occurrences all number
    4
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    10 / 63 (15.87%)
         occurrences all number
    11
    Depression
         subjects affected / exposed
    4 / 63 (6.35%)
         occurrences all number
    4
    Investigations
    Weight decreased
         subjects affected / exposed
    7 / 63 (11.11%)
         occurrences all number
    8
    Blood alkaline phosphatase increased
         subjects affected / exposed
    5 / 63 (7.94%)
         occurrences all number
    8
    Blood creatine increased
         subjects affected / exposed
    4 / 63 (6.35%)
         occurrences all number
    5
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    9 / 63 (14.29%)
         occurrences all number
    11
    Contusion
         subjects affected / exposed
    6 / 63 (9.52%)
         occurrences all number
    6
    Skin abrasion
         subjects affected / exposed
    6 / 63 (9.52%)
         occurrences all number
    7
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    4 / 63 (6.35%)
         occurrences all number
    4
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    12 / 63 (19.05%)
         occurrences all number
    18
    Headache
         subjects affected / exposed
    8 / 63 (12.70%)
         occurrences all number
    20
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    21 / 63 (33.33%)
         occurrences all number
    43
    Thrombocytopenia
         subjects affected / exposed
    15 / 63 (23.81%)
         occurrences all number
    31
    Increased tendency to bruise
         subjects affected / exposed
    12 / 63 (19.05%)
         occurrences all number
    15
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    27 / 63 (42.86%)
         occurrences all number
    51
    Nausea
         subjects affected / exposed
    16 / 63 (25.40%)
         occurrences all number
    25
    Dyspepsia
         subjects affected / exposed
    12 / 63 (19.05%)
         occurrences all number
    15
    Abdominal pain
         subjects affected / exposed
    10 / 63 (15.87%)
         occurrences all number
    11
    Constipation
         subjects affected / exposed
    9 / 63 (14.29%)
         occurrences all number
    11
    Abdominal pain upper
         subjects affected / exposed
    8 / 63 (12.70%)
         occurrences all number
    8
    Stomatitis
         subjects affected / exposed
    7 / 63 (11.11%)
         occurrences all number
    13
    Vomiting
         subjects affected / exposed
    7 / 63 (11.11%)
         occurrences all number
    9
    Abdominal discomfort
         subjects affected / exposed
    4 / 63 (6.35%)
         occurrences all number
    4
    Abdominal distension
         subjects affected / exposed
    4 / 63 (6.35%)
         occurrences all number
    5
    Skin and subcutaneous tissue disorders
    Rash maculo-papular
         subjects affected / exposed
    11 / 63 (17.46%)
         occurrences all number
    25
    Pruritus
         subjects affected / exposed
    9 / 63 (14.29%)
         occurrences all number
    11
    Ecchymosis
         subjects affected / exposed
    6 / 63 (9.52%)
         occurrences all number
    6
    Night sweats
         subjects affected / exposed
    5 / 63 (7.94%)
         occurrences all number
    6
    Alopecia
         subjects affected / exposed
    4 / 63 (6.35%)
         occurrences all number
    4
    Dry skin
         subjects affected / exposed
    4 / 63 (6.35%)
         occurrences all number
    6
    Erythema
         subjects affected / exposed
    4 / 63 (6.35%)
         occurrences all number
    4
    Rash erythematous
         subjects affected / exposed
    4 / 63 (6.35%)
         occurrences all number
    5
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    5 / 63 (7.94%)
         occurrences all number
    5
    Endocrine disorders
    Vision blurred
         subjects affected / exposed
    4 / 63 (6.35%)
         occurrences all number
    7
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    15 / 63 (23.81%)
         occurrences all number
    18
    Muscle spasms
         subjects affected / exposed
    12 / 63 (19.05%)
         occurrences all number
    13
    Pain in extremity
         subjects affected / exposed
    9 / 63 (14.29%)
         occurrences all number
    12
    Back pain
         subjects affected / exposed
    6 / 63 (9.52%)
         occurrences all number
    6
    Musculoskeletal pain
         subjects affected / exposed
    4 / 63 (6.35%)
         occurrences all number
    4
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    13 / 63 (20.63%)
         occurrences all number
    18
    Sinusitis
         subjects affected / exposed
    12 / 63 (19.05%)
         occurrences all number
    15
    Bronchitis
         subjects affected / exposed
    7 / 63 (11.11%)
         occurrences all number
    8
    Urinary tract infection
         subjects affected / exposed
    6 / 63 (9.52%)
         occurrences all number
    9
    Oral herpes
         subjects affected / exposed
    5 / 63 (7.94%)
         occurrences all number
    5
    Conjunctivitis
         subjects affected / exposed
    4 / 63 (6.35%)
         occurrences all number
    4
    Cystitis
         subjects affected / exposed
    4 / 63 (6.35%)
         occurrences all number
    5
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    10 / 63 (15.87%)
         occurrences all number
    13
    Hyperglycaemia
         subjects affected / exposed
    10 / 63 (15.87%)
         occurrences all number
    23
    Hyperuricaemia
         subjects affected / exposed
    10 / 63 (15.87%)
         occurrences all number
    16
    Hypoalbuminaemia
         subjects affected / exposed
    9 / 63 (14.29%)
         occurrences all number
    12
    Hypokalaemia
         subjects affected / exposed
    8 / 63 (12.70%)
         occurrences all number
    12
    Hypocalcaemia
         subjects affected / exposed
    6 / 63 (9.52%)
         occurrences all number
    12
    Hyponatraemia
         subjects affected / exposed
    5 / 63 (7.94%)
         occurrences all number
    8

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    19 Feb 2014
     Corrected language on ibrutinib dose as 560 mg (from 420 mg) orally once daily and removed requirement of dosing with meals.  Clarified that analysis of primary endpoint was per independent review radiographic review for analysis of primary and secondary efficacy endpoints  Updated/clarified eligibility criteria as it relates to prior treatments, prior therapies, exclusion of large cell transformation, the timing of PET scans, exclusionary concomitant medications and washout periods for strong CYP3A inhibitors.  Clarified the language on specific study assessments (ie, tumor assessments, pre-treatment bone marrow aspirate and biopsy, biomarkers testing, long-term follow-up, discontinuation of treatment, and study withdrawal).  Updated/added language for efficacy analysis, AE and SAE reporting requirements, and AEs of special interest.
    07 Oct 2014
    Revised the interim analysis for futility time point from 12 to 24 weeks post-enrollment of 19 subjects to align with anticipated response for an indolent disease, primary analysis time point from approximately 36 to 52 weeks after last patient  Clarified specific protocol management and safety reporting procedures  Updated information on ibrutinib to align with new version of Investigator’s Brochure.  Added guidelines regarding dose reductions, eye-related symptom assessment requirements and B-symptom assessment evaluations, and guidance on tumor flare assessments/ibrutinib dosing.  Defined conventions for lesion measurement.
    28 Dec 2015
     Updated information on ibrutinib to align with new version of Investigator’s Brochure.  Clarified specific protocol management and safety reporting procedures  Visit schedule changed from monthly to q12 weeks after 1 year of ibrutinib therapy  Added language to permit concomitant administration of prednisone for <14 days at doses that do not exceed 100 mg/day of prednisone or equivalent for treatment of autoimmune cytopenias
    05 Feb 2016
    Update the synopsis to correct the inconsistencies between the body of the protocol and the synopsis  Removed requirement for ECG to be performed in subjects who develop arrhythmic symptoms or new onset of dyspnea if clinically indicated

    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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