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    Clinical Trial Results:
    A multicentre, phase III, open-label, randomized study in patients with advanced follicular lymphoma evaluating the benefit of maintenance therapy with rituximab (Mabthéra® ) after induction of response with chemotherapy plus rituximab in comparison with no maintenance therapy.

    Summary
    EudraCT number
    		 2004-001756-36
    Trial protocol
    		 DK   FI   CZ   PT   GB   ES   BE  
    Global end of trial date
    31 Dec 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    29 Sep 2018
    First version publication date
    29 Sep 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    MO18264
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    LYSA
    Sponsor organisation address
    CH Lyon Sud - Service d'Hématologie - Bâtiment 1F - 3ème étage, Pierre Bénite, France, 69495
    Public contact
    Julie ASSEMAT, LYSARC, 33 472669333, julie.assemat@lysarc.org
    Scientific contact
    Pr Gilles SALLES, LYSA, 33 478864307, gilles.salles@chu-lyon.fr
    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
    31 Dec 2016
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    31 Dec 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the benefit of maintenance therapy with rituximab as measured by progression-free survival (PFS) in comparison with no maintenance therapy after induction of response with chemotherapy plus rituximab in patients with high tumor burden follicular lymphoma
    Protection of trial subjects
    New anti-lymphoma treatment is defined as any radiation therapy (even local), chemotherapy or immunotherapy, either alone or in combination. Any new, non-protocol anti-lymphoma treatment will be considered as an event for purposes of EFS assessment. New anti-lymphoma treatment should be considered: - if a patient does demonstrate disease progression during induction treatment; - at the discretion of the physician if a patient does not reach at least a partial response or a complete (either confirmed or unconfirmed) at the end of the induction treatment; - during the maintenance phase, for patients in both arms (rituximab maintenance or observation), at any time of documented disease progression if this progression is symptomatic and/or if the physician considers that a new treatment is necessary for patients benefit. - during the follow-up period, at any time of documented disease progression if this progression is symptomatic and/or if the physician considers that a new treatment is necessary for patients benefit.
    Background therapy
    		 The standard treatments used in this study are: - CHOP: Cyclophosphamide 750 mg/m2 day 1 Doxorubicin 50 mg/m2 day 1 Vincristine 1.4 mg/m2 (2 mg cap) day 1 Prednisone 100 mg/day (× 5 days) - CVP: Cyclophosphamide 750 mg/m2 day 1 Vincristine 1.4 mg/m2 (2 mg cap) day 1 Prednisone 40 mg/m2 (× 5 days) - FCM: Fludarabine 25 mg/m2 (× 3 days) Cyclophosphamide 200 mg/m2 (× 3 days) Mitoxantrone 6 mg/m2 day 1
    Evidence for comparator
    		 -
    Actual start date of recruitment
    24 Dec 2004
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Portugal: 16
    Country: Number of subjects enrolled
    Spain: 54
    Country: Number of subjects enrolled
    United Kingdom: 16
    Country: Number of subjects enrolled
    Belgium: 75
    Country: Number of subjects enrolled
    Czech Republic: 36
    Country: Number of subjects enrolled
    Denmark: 48
    Country: Number of subjects enrolled
    Finland: 24
    Country: Number of subjects enrolled
    France: 624
    Country: Number of subjects enrolled
    Argentina: 15
    Country: Number of subjects enrolled
    Australia: 132
    Country: Number of subjects enrolled
    Brazil: 13
    Country: Number of subjects enrolled
    China: 8
    Country: Number of subjects enrolled
    Colombia: 11
    Country: Number of subjects enrolled
    Croatia: 7
    Country: Number of subjects enrolled
    India: 14
    Country: Number of subjects enrolled
    Israel: 9
    Country: Number of subjects enrolled
    Netherlands: 18
    Country: Number of subjects enrolled
    New Zealand: 26
    Country: Number of subjects enrolled
    Peru: 10
    Country: Number of subjects enrolled
    Serbia: 9
    Country: Number of subjects enrolled
    Thailand: 18
    Country: Number of subjects enrolled
    Turkey: 7
    Country: Number of subjects enrolled
    Uruguay: 3
    Country: Number of subjects enrolled
    Venezuela, Bolivarian Republic of: 9
    Worldwide total number of subjects
    1202
    EEA total number of subjects
    918
    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)
    919
    From 65 to 84 years
    282
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 Be17/03/05 Fr24/12/04 UK06/07/06 Argent07/10/05 Aus01/07/05 NZ24/08/05 Brazil31/03/06 China09/05/06 Colombia03/08/05 Croatia30/12/05 Dmark31/05/05 Spa15/07/05 Finl 03/01/06 India21/10/05 Israel 25/04/06 NL 06/03/06 Peru 17/11/05 Portu 17/11/05 CZ 24/11/05 Serb 08/02/06 Thai 20/10/05 Turkey 30/11/05 Urug12/07/06 Venez 16/01/06

    Pre-assignment
    Screening details
    		 ICF, Medical history, examination, Height, weight, BSA, B-Symptoms, ECOG, Ann Arbor Staging, Spleen and Liver evaluation, haematology, biochemistry,Serum immunoglobulins, Pregnancy test, echocardiography or left VEF, CT-SCAN, Tumor lesion measurements, BOM, QoL, tumor biopsy and serum samples for additional studies. 1202 included, 1022 randomized

    Period 1
    Period 1 title
    Baseline period
    Is this the baseline period?
    		 Yes
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 Rituximab
    Arm description
    		 R-CHOP 6 cycles of 21 days during induction period: Rituximab 375 mg/ m2 Cyclophosphamide 750 mg/m2 day 1 Doxorubicin 50 mg/m2 day 1 Vincristine 1.4 mg/m2 (2 mg cap) day 1 R-CVP 8 cycles of 21 days during induction period: Rituximab 375 mg/ m2 Cyclophosphamide 750 mg/m2 day 1 Vincristine 1.4 mg/m2 (2 mg cap) day 1 Prednisone 40 mg/m2 (× 5 days) Prednisone 100 mg/day (× 5 days) R-FCM 6 cycles of 28 days during induction period: Rituximab 375 mg/ m2 Fludarabine 25 mg/m2 (× 3 days) Cyclophosphamide 200 mg/m2 (× 3 days) Mitoxantrone 6 mg/m2 day 1
    Arm type
    		 Experimental

    Investigational medicinal product name
    Rituximab
    Investigational medicinal product code
    R
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Dilution of 2mG/mL Induction period: Patients will receive 375 mg/m2 rituximab, administered by IV infusion, at each Day 1 of each cycle (6 or 8 cycles) + 2 additional rituximab infusions for R-CHOP (cycle 7 and 8) and R-FCM (day 15 of cycle 1 and cycle 4) Maintenance period: Patients will receive 375 mg/m2 rituximab, administered by IV infusion every 8 weeks starting 8 weeks ± 7 days after the last induction treatment every 8 weeks for a total of 12 cycles (2 years) or observation (without rituximab) for 2 years

    Arm title
    		 observation
    Arm description
    		 -
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 1
    		Rituximab observation
    Started
    596
    606
    Completed
    501
    508
    Not completed
    95
    98
         Adverse event, serious fatal
    1
    -
         Adverse event, non-fatal
    4
    5
         Non evaluable patients
    90
    -
         non evaluable
    -
    93
    Period 2
    Period 2 title
    overall-trial
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 Observation
    Arm description
    		 -
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 Rituximab
    Arm description
    		 R-CHOP 6 cycles of 21 days + 2 additional R cycles 7 and 8 or R-CVP 8 cycles of 21 days or R-FCM 6 cycles of 28 days + 2 additional R on D15 of cycles 1 and 4
    Arm type
    		 Experimental

    Investigational medicinal product name
    Rituximab
    Investigational medicinal product code
    R
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Dosage: 375mg/m2 dilution of 2mg/mL

    Number of subjects in period 2
    		Observation Rituximab
    Started
    513
    506
    Completed
    508
    501
    Not completed
    5
    5
         Adverse event, serious fatal
    -
    1
         Adverse event, non-fatal
    5
    4

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Baseline period
    Reporting group description
    		 -

    Reporting group values
    		 Baseline period Total
    Number of subjects
    		 1202 1202
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0
        Newborns (0-27 days)
    		 0
        Infants and toddlers (28 days-23 months)
    		 0
        Children (2-11 years)
    		 0
        Adolescents (12-17 years)
    		 0
        Adults (18-64 years)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    A similar proportion of male and female patients were randomized to the maintenance/observation phase (52% vs 48%, respectively), and the study arms were well balanced with respect to gender. The median age of patients at randomization to the maintenance/observation phase was 57.0 years (range, 2385 years). The study arms were also balanced in terms of other baseline characteristics such as height, weight, and body surface area.
    Units: years
        median (full range (min-max))
    		 57 (23 to 85) -
    Gender categorical
    Units: Subjects
        Female
    		 577 577
        Male
    		 625 625

    End points

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    End points reporting groups
    Reporting group title
    Rituximab
    Reporting group description
    		 R-CHOP 6 cycles of 21 days during induction period: Rituximab 375 mg/ m2 Cyclophosphamide 750 mg/m2 day 1 Doxorubicin 50 mg/m2 day 1 Vincristine 1.4 mg/m2 (2 mg cap) day 1 R-CVP 8 cycles of 21 days during induction period: Rituximab 375 mg/ m2 Cyclophosphamide 750 mg/m2 day 1 Vincristine 1.4 mg/m2 (2 mg cap) day 1 Prednisone 40 mg/m2 (× 5 days) Prednisone 100 mg/day (× 5 days) R-FCM 6 cycles of 28 days during induction period: Rituximab 375 mg/ m2 Fludarabine 25 mg/m2 (× 3 days) Cyclophosphamide 200 mg/m2 (× 3 days) Mitoxantrone 6 mg/m2 day 1

    Reporting group title
    observation
    Reporting group description
    		 -
    Reporting group title
    Observation
    Reporting group description
    		 -

    Reporting group title
    Rituximab
    Reporting group description
    		 R-CHOP 6 cycles of 21 days + 2 additional R cycles 7 and 8 or R-CVP 8 cycles of 21 days or R-FCM 6 cycles of 28 days + 2 additional R on D15 of cycles 1 and 4

    Primary: Progression free survival

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    End point title
    		 Progression free survival
    End point description
    End point type
    Primary
    End point timeframe
    two years from randomization
    End point values
    		 Observation Rituximab
    Number of subjects analysed
    513
    506
    Units: median
        median (confidence interval 95%)
    4.06 (3.45 to 4.67)
    10.49 (9.88 to 11.1)
    Statistical analysis title
    		 Progression Free Survival
    Comparison groups
    Rituximab v Observation
    Number of subjects included in analysis
    1019
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [1]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.61
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.52
         upper limit
    		 0.73
    Variability estimate
    Standard deviation
    Notes
    [1] - Stratified

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    During induction treatment, adverse events will be recorded until 30 days after the administration of the last treatment dose. During the maintenance phase, adverse events will be recorded until 6 months after the administration of the last treatment dose
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    1
    Reporting groups
    Reporting group title
    Observation
    Reporting group description
    		 AE description in the observation arm

    Reporting group title
    Rituximab
    Reporting group description
    		 AE description on the rituximab arm

    Serious adverse events
    		 Observation Rituximab
    Total subjects affected by serious adverse events
         subjects affected / exposed
    68 / 508 (13.39%)
    106 / 501 (21.16%)
         number of deaths (all causes)
    83
    84
         number of deaths resulting from adverse events
    0
    2
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Cancer
         subjects affected / exposed
    21 / 508 (4.13%)
    22 / 501 (4.39%)
         occurrences causally related to treatment / all
    0 / 21
    0 / 25
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Vascular
         subjects affected / exposed
    2 / 508 (0.39%)
    3 / 501 (0.60%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Surgical
         subjects affected / exposed
    1 / 508 (0.20%)
    2 / 501 (0.40%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    Pregnancy
         subjects affected / exposed
    3 / 508 (0.59%)
    4 / 501 (0.80%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    General disorders
         subjects affected / exposed
    4 / 508 (0.79%)
    4 / 501 (0.80%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Social circumstances
    Social
         subjects affected / exposed
    0 / 508 (0.00%)
    1 / 501 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Reproductive
         subjects affected / exposed
    0 / 508 (0.00%)
    1 / 501 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Respiratory
         subjects affected / exposed
    1 / 508 (0.20%)
    4 / 501 (0.80%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Psychiatric
         subjects affected / exposed
    6 / 508 (1.18%)
    5 / 501 (1.00%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Product issues
    Product
         subjects affected / exposed
    0 / 508 (0.00%)
    1 / 501 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Injury
         subjects affected / exposed
    9 / 508 (1.77%)
    3 / 501 (0.60%)
         occurrences causally related to treatment / all
    0 / 9
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiac
         subjects affected / exposed
    2 / 508 (0.39%)
    13 / 501 (2.59%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 13
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Nervous system
         subjects affected / exposed
    9 / 508 (1.77%)
    10 / 501 (2.00%)
         occurrences causally related to treatment / all
    0 / 9
    0 / 10
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Blood
         subjects affected / exposed
    2 / 508 (0.39%)
    2 / 501 (0.40%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Ear
         subjects affected / exposed
    1 / 508 (0.20%)
    1 / 501 (0.20%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Eye
         subjects affected / exposed
    1 / 508 (0.20%)
    3 / 501 (0.60%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Gastrointestinal
         subjects affected / exposed
    3 / 508 (0.59%)
    10 / 501 (2.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 10
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Liver
         subjects affected / exposed
    1 / 508 (0.20%)
    2 / 501 (0.40%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Kidney
         subjects affected / exposed
    3 / 508 (0.59%)
    3 / 501 (0.60%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Endocrine
         subjects affected / exposed
    0 / 508 (0.00%)
    1 / 501 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Muscles and tissue
         subjects affected / exposed
    3 / 508 (0.59%)
    6 / 501 (1.20%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Infections
         subjects affected / exposed
    6 / 508 (1.18%)
    26 / 501 (5.19%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 27
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Observation Rituximab
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    194 / 508 (38.19%)
    285 / 501 (56.89%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Cancers
         subjects affected / exposed
    23 / 508 (4.53%)
    24 / 501 (4.79%)
         occurrences all number
    23
    28
    Vascular disorders
    Vascular
         subjects affected / exposed
    6 / 508 (1.18%)
    6 / 501 (1.20%)
         occurrences all number
    6
    6
    Surgical and medical procedures
    Surgical
         subjects affected / exposed
    1 / 508 (0.20%)
    5 / 501 (1.00%)
         occurrences all number
    1
    5
    Pregnancy, puerperium and perinatal conditions
    Pregnancy
         subjects affected / exposed
    3 / 508 (0.59%)
    4 / 501 (0.80%)
         occurrences all number
    3
    4
    General disorders and administration site conditions
    General disorders
         subjects affected / exposed
    9 / 508 (1.77%)
    10 / 501 (2.00%)
         occurrences all number
    10
    10
    Immune system disorders
    Immune
         subjects affected / exposed
    1 / 508 (0.20%)
    1 / 501 (0.20%)
         occurrences all number
    1
    1
    Social circumstances
    Social
         subjects affected / exposed
    0 / 508 (0.00%)
    1 / 501 (0.20%)
         occurrences all number
    0
    1
    Reproductive system and breast disorders
    Reproductive
         subjects affected / exposed
    2 / 508 (0.39%)
    4 / 501 (0.80%)
         occurrences all number
    2
    4
    Respiratory, thoracic and mediastinal disorders
    Respiratory
         subjects affected / exposed
    4 / 508 (0.79%)
    16 / 501 (3.19%)
         occurrences all number
    5
    16
    Psychiatric disorders
    Psychiatric
         subjects affected / exposed
    6 / 508 (1.18%)
    6 / 501 (1.20%)
         occurrences all number
    6
    6
    Product issues
    Products
         subjects affected / exposed
    0 / 508 (0.00%)
    1 / 501 (0.20%)
         occurrences all number
    0
    1
    Hepatobiliary disorders
    Liver
         subjects affected / exposed
    1 / 508 (0.20%)
    4 / 501 (0.80%)
         occurrences all number
    1
    4
    Investigations
    Investigations
         subjects affected / exposed
    5 / 508 (0.98%)
    5 / 501 (1.00%)
         occurrences all number
    5
    5
    Injury, poisoning and procedural complications
    Injury
         subjects affected / exposed
    10 / 508 (1.97%)
    5 / 501 (1.00%)
         occurrences all number
    10
    5
    Cardiac disorders
    Cardiac
         subjects affected / exposed
    6 / 508 (1.18%)
    17 / 501 (3.39%)
         occurrences all number
    6
    18
    Nervous system disorders
    Nervous system
         subjects affected / exposed
    13 / 508 (2.56%)
    14 / 501 (2.79%)
         occurrences all number
    13
    14
    Blood and lymphatic system disorders
    Blood
         subjects affected / exposed
    8 / 508 (1.57%)
    27 / 501 (5.39%)
         occurrences all number
    11
    35
    Ear and labyrinth disorders
    Ear
         subjects affected / exposed
    1 / 508 (0.20%)
    1 / 501 (0.20%)
         occurrences all number
    1
    1
    Eye disorders
    Eye
         subjects affected / exposed
    3 / 508 (0.59%)
    3 / 501 (0.60%)
         occurrences all number
    3
    3
    Gastrointestinal disorders
    Gastrointestinal
         subjects affected / exposed
    6 / 508 (1.18%)
    12 / 501 (2.40%)
         occurrences all number
    7
    13
    Skin and subcutaneous tissue disorders
    Skin
         subjects affected / exposed
    3 / 508 (0.59%)
    3 / 501 (0.60%)
         occurrences all number
    3
    3
    Renal and urinary disorders
    Kidney
         subjects affected / exposed
    3 / 508 (0.59%)
    5 / 501 (1.00%)
         occurrences all number
    3
    5
    Endocrine disorders
    Endocrine
         subjects affected / exposed
    1 / 508 (0.20%)
    2 / 501 (0.40%)
         occurrences all number
    1
    2
    Musculoskeletal and connective tissue disorders
    Muscles
         subjects affected / exposed
    9 / 508 (1.77%)
    10 / 501 (2.00%)
         occurrences all number
    9
    11
    Infections and infestations
    Infections
         subjects affected / exposed
    125 / 508 (24.61%)
    200 / 501 (39.92%)
         occurrences all number
    167
    305
    Metabolism and nutrition disorders
    Metabolism
         subjects affected / exposed
    4 / 508 (0.79%)
    4 / 501 (0.80%)
         occurrences all number
    4
    4

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    18 Apr 2006
    Extension of the number of recruited patients to 900
    17 Jun 2006
    Canceling of the first interim analysis after 50% of events (= 172 events)
    26 Sep 2006
    Modification of the primary criterion and increase of recruited patient from 900 to 1200
    15 Oct 2013
    Extension of the study regarding patients until December 2016

    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

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/21176949
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