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    Clinical Trial Results:
    A randomised phase III trial to assess response adapted therapy using FDG-PET imaging in patients with newly diagnosed, advanced Hodgkin Lymphoma

    Summary
    EudraCT number
    		 2007-006064-30
    Trial protocol
    		 GB   IT   IE   SE   DK  
    Global end of trial date
    01 May 2024

    Results information
    Results version number
    		 v1(current)
    This version publication date
    27 May 2026
    First version publication date
    27 May 2026
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    UCL/07/146
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00678327
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Cancer Research UK & UCL Cancer Trials Centre
    Sponsor organisation address
    90 Tottenham Court Road, London, United Kingdom, W1T 4TJ
    Public contact
    RATHL Trial Manager, Cancer Research UK & UCL Cancer Trials Centre, 0044 020 7670 4696, rathl@ctc.ucl.ac.uk
    Scientific contact
    RATHL Trial Statistician, Cancer Research UK & UCL Cancer Trials Centre, 0044 0207 679 9231, rathl@ctc.ucl.ac.uk
    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 Nov 2015
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    01 May 2024
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The aim of this study is to evaluate prospectively the role of FDG-PET imaging after 2 cycles of ABVD chemotherapy in determining response assessment and subsequent management decisions for patients receiving first-line treatment for advanced Hodgkin lymphoma.
    Protection of trial subjects
    At the time of the RATHL study, six cycles of ABVD was considered the standard of care for patients with advanced Hodgkin’s lymphoma within the countries taking part in the RATHL trial. BEACOPP14 or escalated BEACOPP represented a safe and effective alternative adopted as standard of care in other European countries based on trials conducted by the German Hodgkin Study Group. The RATHL study tested both the efficacy of two cycles of ABVD followed by up to six cycles of BEACOPP14 or four cycles of escalated BEACOPP in patients with interval PET-positive disease; as well as testing the comparative efficacy and toxicity of six cycles of ABVD compared to two cycles of ABVD followed by four cycles of AVD in patients with interval PET-negative disease, in a 1:1 randomisation. PET-CT scans after 2 cycles of ABVD were centrally reviewed with this review used to decide whether a patient was eligible for the dose de-escalation randomisation or should be escalated to BEACOPP14/escalated BEACOPP. Patients were closely monitored for toxicity and the protocol continuation criterion for therapy and dose modification. G-CSF was mandated during BEACOPP cycles and could be given at the investigator’s discretion within the ABVD/AVD arms. There was no data available for PET negative patients treated with AVD; however an independent data monitoring committee reviewed the trial data at least yearly and could halt the trial if there were any safety or efficacy concerns.
    Background therapy
    		 Supportive care was given as per local practise, specifically. Patients in need of urgent treatment are permitted to receive steroids up to a dose of 50mg of prednisolone or the equivalent for up to 7 days prior to their baseline trial PET-CT scan. Granulocyte colony stimulating factors are not indicated as a matter of routine for ABVD/AVD, but can be used at the discretion of the treating clinician, in accordance with local policy.
    Evidence for comparator
    		 Evidence for PET as a prognostic factor Several studies have assessed the role of PET imaging in response assessment in HL: the largest being collective data from the Italian and Danish groups which prospectively evaluated and compared the prognostic role of FDG-PET and the International Prognostic Score (IPS) in 260 newly diagnosed patients with advanced HL, treated with conventional ABVD and consolidation radiotherapy if indicated. FDG-PET scan was performed at baseline and after two courses of ABVD, with no treatment change allowed on the basis of the PET-2 results. After a median follow-up of 2.19 years (range, 0.32 to 5.18 years), 205 patients were in continued complete remission, 2 patients were in partial remission, 43 patients progressed during therapy or immediately after and 10 patients had relapsed. The 2-year PFS for patients with positive PET-2 results was 12.8% and for patients with negative PET-2 results was 95% (P < .0001). In multivariate analyses, only PET-2 results were significant (P < .0001). Based on this data it was felt that it was safe to de-escalate treatment (to AVD) for patients who were PET2 negative and that patients who were PE2 positive so switch to a more intensive regimen. Evidence for BEACOPP. The BEACOPP regimen devised by the German Hodgkin Lymphoma Study Group substitutes etoposide for dacarbazine and vinblastine and encompasses two main intensification principles: dose escalation of the putative most important drugs (cyclophosphamide, etoposide, and doxorubicin) and time intensification accomplished by shortening the respective chemotherapy cycles from 4 to 3 weeks. Within the randomized multicentre HD9 trial, it was demonstrated that the BEACOPP led to a significantly lower progression rate and an improved failure-free and overall survival as compared with standard COPP/ABVD. At 34 months, freedom from treatment failure (FFTF) rates were 90% and 81% for BEACOPP-escalated and BEACOPP-21 respectively.
    Actual start date of recruitment
    29 Aug 2008
    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
    Norway: 75
    Country: Number of subjects enrolled
    Sweden: 51
    Country: Number of subjects enrolled
    United Kingdom: 854
    Country: Number of subjects enrolled
    Denmark: 11
    Country: Number of subjects enrolled
    Italy: 128
    Country: Number of subjects enrolled
    Australia: 70
    Country: Number of subjects enrolled
    New Zealand: 14
    Worldwide total number of subjects
    1203
    EEA total number of subjects
    265
    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)
    1152
    From 65 to 84 years
    51
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 29/08/2008 - 21/12/2012 from 7 countries and 138 recruiting centres.

    Pre-assignment
    Screening details
    		 Previously untreated patients 18 years of age or older with advanced classic Hodgkin’s lymphoma that was confirmed by histologic analysis were eligible if they were fit to receive a full course of combination chemotherapy.

    Period 1
    Period 1 title
    Registration
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded
    Blinding implementation details
    N/A, registration has no arms.

    Arms
    Arm title
    		 ABVD (Cycle 1 and Cycle 2)
    Arm description
    		 All patients treated with 2 cycles of ABVD chemotherapy after registration, as per standard of care.
    Arm type
    		 See description

    Investigational medicinal product name
    ABVD
    Investigational medicinal product code
    Other name
    Doxorubicin, Bleomycin, Vinblastine and Dacarbazine
    Pharmaceutical forms
    Powder for solution for infusion, Powder for solution for injection, Powder for solution for injection/infusion, Solution for infusion, Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    All patients will receive 2 cycles of ABVD according to the following schedule which should be repeated every 28 days: Doxorubicin 25 mg/m2 IV Days 1 & 15 Bleomycin 10,000 IU/m2 IV Days 1 & 15 Vinblastine 6 mg/m2 IV Days 1 & 15 Dacarbazine 375 mg/m2 IV Days 1 & 15

    Number of subjects in period 1
    		ABVD (Cycle 1 and Cycle 2)
    Started
    1203
    Completed
    1135
    Not completed
    68
         Consent withdrawn by subject
    3
         Physician decision
    2
         PET CT scan error
    53
         Adverse event, non-fatal
    6
         Death
    1
         Treatment delays
    1
         Moved
    1
         Larceny and drug abuse
    1
    Period 2
    Period 2 title
    PET-negative randomisation
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    N/A

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 PET negative ABVD
    Arm description
    		 4 further cycles of ABVD chemotherapy.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    ABVD
    Investigational medicinal product code
    Other name
    Doxorubicin, Bleomycin, Vinblastine and Dacarbazine
    Pharmaceutical forms
    Powder for solution for infusion, Powder for solution for injection, Powder for solution for injection/infusion, Solution for infusion, Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    ABVD (repeated every 28 days for 4 cycles) Doxorubicin 25 mg/m2 IV Days 1 & 15 Bleomycin 10,000 IU/m2 IV Days 1 & 15 Vinblastine 6 mg/m2 IV Days 1 & 15 Dacarbazine 375 mg/m2 IV Days 1 & 15

    Arm title
    		 PET negative AVD
    Arm description
    		 4 cycles of AVD chemotherapy.
    Arm type
    		 Experimental

    Investigational medicinal product name
    ABVD
    Investigational medicinal product code
    Other name
    Doxorubicin, Bleomycin, Vinblastine and Dacarbazine
    Pharmaceutical forms
    Powder for solution for infusion, Powder for solution for injection/infusion, Solution for infusion, Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    ABVD (repeated every 28 days for 4 cycles) Doxorubicin 25 mg/m2 IV Days 1 & 15 Bleomycin 10,000 IU/m2 IV Days 1 & 15 Vinblastine 6 mg/m2 IV Days 1 & 15 Dacarbazine 375 mg/m2 IV Days 1 & 15

    Number of subjects in period 2 [1]
    		PET negative ABVD PET negative AVD
    Started
    468
    457
    Completed
    458
    446
    Not completed
    10
    11
         Consent withdrawn by subject
    2
    1
         Physician decision
    -
    1
         Adverse event, non-fatal
    3
    7
         Death
    1
    -
         was treated at center with vinblastine shortage
    -
    1
         Other medical conditions
    2
    -
         Could not get to hospital
    1
    -
         Moved
    -
    1
         Was withdrawn owing to patient anxiety
    1
    -
    Notes
    [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: It is justified.
    Period 3
    Period 3 title
    PET-positive BEACOPP escalation
    Is this the baseline period?
    		 No
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    N/A

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 BEACOPP-14
    Arm description
    		 BEACOPP-14 chemotherapy.
    Arm type
    		 Experimental

    Investigational medicinal product name
    BEACOPP-14
    Investigational medicinal product code
    Other name
    Doxorubicin, Cyclophosphamide, Etoposide, Procarbazine, Prednisolone, Bleomycin, Vincristine and G-CSF
    Pharmaceutical forms
    Concentrate for solution for infusion, Powder for solution for injection, Powder for solution for injection/infusion, Solution for infusion, Solution for injection, Tablet
    Routes of administration
    Intravenous use, Oral use
    Dosage and administration details
    BEACOPP-14 (repeated every 14 days for 4 to 6 cycles – see section 1.2 of RATHL protocol v6.0 21.06.2022) Doxorubicin 25mg/m2 iv Day 1 Cyclophosphamide 650mg/m2 iv Day 1 Etoposide 100mg/m2 iv Days 1-3 Procarbazine (or Natulan) 100mg/m2 po Days 1-7 Prednisolone 80mg/m2 po Days 1-7 Bleomycin 10,000units/m2 iv Day 8 Vincristine* 1.4mg/m2 iv Day 8 G-CSF 263/300mcg or equivalent PEG-Filgrastim single dose Day 9-13

    Arm title
    		 esc-BEACOPP
    Arm description
    		 escalated BEACOPP
    Arm type
    		 Experimental

    Investigational medicinal product name
    BEACOPP-escalated
    Investigational medicinal product code
    Other name
    Doxorubicin, Cyclophosphamide, Etoposide, Procarbazine, Prednisolone, Bleomycin, Vincristine and G-CSF
    Pharmaceutical forms
    Capsule, Concentrate for solution for infusion, Powder for solution for injection, Solution for infusion, Solution for injection, Tablet
    Routes of administration
    Intravenous use, Oral use
    Dosage and administration details
    Level 1- escalated dose Cyclophosphamide -1250mg/m2 Level 2- escalated dose Cyclophosphamide -1100mg/m2 Level 3- escalated dose Cyclophosphamide -950mg/m2 Level 4- escalated dose Cyclophosphamide -800mg/m2 Level 5- escalated dose Cyclophosphamide -650mg/m2 Level 1- escalated dose Etoposide -200mg/m2 Level 2- escalated dose Etoposide -175mg/m2 Level 3- escalated dose Etoposide -150mg/m2 Level 4- escalated dose Etoposide -125mg/m2 Level 5- escalated dose Etoposide -100mg/m2

    Number of subjects in period 3 [2]
    		BEACOPP-14 esc-BEACOPP
    Started
    94
    78
    Completed
    76
    66
    Not completed
    18
    12
         Consent withdrawn by subject
    3
    2
         Physician decision
    1
    -
         Disease progression
    1
    1
         Transferred Hospital
    1
    -
         Adverse event, non-fatal
    5
    2
         Death
    1
    2
         Unknown
    -
    3
         Other medical conditions
    -
    2
         Medical conditions
    2
    -
         Lack of efficacy
    3
    -
         Protocol deviation
    1
    -
    Notes
    [2] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: It is justified.

    Baseline characteristics

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

    Reporting group values
    		 Registration Total
    Number of subjects
    		 1203 1203
    Age categorical
    Units: Subjects
        18-24
    		 299 299
        25-44
    		 576 576
        45-59
    		 213 213
        60 years and over
    		 115 115
    Age continuous
    Units: years
        median (full range (min-max))
    		 33 (18 to 79) -
    Gender categorical
    Units: Subjects
        Female
    		 547 547
        Male
    		 656 656
    ECOG
    Units: Subjects
        Zero
    		 889 889
        One
    		 271 271
        Two
    		 28 28
        Three
    		 14 14
        Missing
    		 1 1
    Ann Arbor stage
    Units: Subjects
        II
    		 500 500
        III
    		 363 363
        IV
    		 340 340
    International prognostic score
    Units: Subjects
        0 or 1
    		 404 404
        2 or 3
    		 579 579
        ≥4
    		 209 209
        Missing
    		 11 11
    Subject analysis sets

    Subject analysis set title
    PET2 negative ABVD randomised patients
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    All eligible patients randomised to ABVD.

    Subject analysis set title
    PET2 negative AVD randomised patients
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    All eligible AVD randomised patients.

    Subject analysis set title
    PET2 positive patients
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    PET2 positive patients who were treated with BEACOPP.

    Subject analysis sets values
    		 PET2 negative ABVD randomised patients PET2 negative AVD randomised patients PET2 positive patients
    Number of subjects
    470
    465
    172
    Age categorical
    Units: Subjects
        18-24
    121
    117
    47
        25-44
    231
    223
    75
        45-59
    80
    81
    32
        60 years and over
    38
    44
    18
    Age continuous
    Units: years
        median (full range (min-max))
    32 (18 to 79)
    33 (18 to 76)
    32 (18 to 70)
    Gender categorical
    Units: Subjects
        Female
    209
    213
    80
        Male
    261
    252
    92
    ECOG
    Units: Subjects
        Zero
    340
    354
    123
        One
    113
    96
    40
        Two
    11
    9
    6
        Three
    6
    6
    2
        Missing
    0
    0
    1
    Ann Arbor stage
    Units: Subjects
        II
    195
    197
    73
        III
    157
    140
    34
        IV
    118
    128
    65
    International prognostic score
    Units: Subjects
        0 or 1
    170
    172
    34
        2 or 3
    219
    224
    84
        ≥4
    75
    67
    52
        Missing
    6
    2
    2

    End points

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    End points reporting groups
    Reporting group title
    ABVD (Cycle 1 and Cycle 2)
    Reporting group description
    		 All patients treated with 2 cycles of ABVD chemotherapy after registration, as per standard of care.
    Reporting group title
    PET negative ABVD
    Reporting group description
    		 4 further cycles of ABVD chemotherapy.

    Reporting group title
    PET negative AVD
    Reporting group description
    		 4 cycles of AVD chemotherapy.
    Reporting group title
    BEACOPP-14
    Reporting group description
    		 BEACOPP-14 chemotherapy.

    Reporting group title
    esc-BEACOPP
    Reporting group description
    		 escalated BEACOPP

    Subject analysis set title
    PET2 negative ABVD randomised patients
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    All eligible patients randomised to ABVD.

    Subject analysis set title
    PET2 negative AVD randomised patients
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    All eligible AVD randomised patients.

    Subject analysis set title
    PET2 positive patients
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    PET2 positive patients who were treated with BEACOPP.

    Primary: Progression Free Survival

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    End point title
    		 Progression Free Survival
    End point description
    End point type
    Primary
    End point timeframe
    3 years after registration.
    End point values
    		 ABVD (Cycle 1 and Cycle 2) PET2 negative ABVD randomised patients PET2 negative AVD randomised patients PET2 positive patients
    Number of subjects analysed
    1203
    470
    465
    172
    Units: percentage
        number (confidence interval 95%)
    82.6 (80.2 to 84.7)
    85.7 (82.1 to 88.6)
    84.4 (80.7 to 87.5)
    67.5 (59.7 to 74.2)
    Attachments
    		 Untitled (Filename: RATHL_KM_plot_PFS_ALL.tif)
    Untitled (Filename: RATHL_KM_plot_PFS_BEACOPP.tif)
    Untitled (Filename: RATHL_KM_plot_PFS_randomisedITT.tif)
    Statistical analysis title
    		 PFS at 3 yrs in PET2 negative randomised patients
    Statistical analysis description
    This is the primary endpoint for the randomised comparison and is based on the 3 year rates in the 2 arms and the hazard ratio. ABVD: 85.7% (95% CI: 82.1 - 88.6) AVD: 84.4% (95% CI: 80.7 - 87.5) Hazard Ratio: 1.13 (95%CI : 0.81 - 1.57)
    Comparison groups
    PET2 negative ABVD randomised patients v PET2 negative AVD randomised patients
    Number of subjects included in analysis
    935
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    Method
    Parameter type
    		 Risk difference (RD)
    Point estimate
    1.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.2
         upper limit
    		 5.3
    Variability estimate
    Standard error of the mean
    Statistical analysis title
    		 Hazard ratio for PFS in PET2 randomised patients
    Comparison groups
    PET2 negative AVD randomised patients v PET2 negative ABVD randomised patients
    Number of subjects included in analysis
    935
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.48 [1]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.13
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.81
         upper limit
    		 1.57
    Variability estimate
    Standard error of the mean
    Notes
    [1] - Two-tailed P = 0.48 for the null hypothesis of a hazard ratio of 1.00; one-tailed P = 0.11 for the null hypothesis of a hazard ratio of ≥1.39 [i.e., a difference of 5 percentage points from 80.7% to 85.7%] vs. the alternative hazard ratio of <1.39)

    Secondary: Overall Survival

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    End point title
    		 Overall Survival
    End point description
    End point type
    Secondary
    End point timeframe
    3 years after registration.
    End point values
    		 ABVD (Cycle 1 and Cycle 2) PET2 negative ABVD randomised patients PET2 negative AVD randomised patients PET2 positive patients
    Number of subjects analysed
    1203
    470
    465
    172
    Units: percentage
        number (confidence interval 95%)
    95.8 (94.4 to 96.8)
    97.2 (95.1 to 98.4)
    97.6 (95.6 to 98.7)
    87.8 (81.5 to 92.1)
    Attachments
    		 Untitled (Filename: RATHL_KM_plot_OS_randomisedITT.tif)
    Untitled (Filename: RATHL_KM_plot_OS_BEACOPP.tif)
    Untitled (Filename: RATHL_KM_plot_OS_ALL.tif)
    Statistical analysis title
    		 OS comparing PET2 randomised arms
    Comparison groups
    PET2 negative AVD randomised patients v PET2 negative ABVD randomised patients
    Number of subjects included in analysis
    935
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.76
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.47
         upper limit
    		 1.74
    Variability estimate
    Standard error of the mean

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All adverse events that occur between informed consent and 30 days post last trial treatment administration.
    Adverse event reporting additional description
    Severity of each adverse event will be determined by using the Common Terminology Criteria for Adverse Events (CTCAE) v3.0 as a guideline, wherever possible.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 CTCAE
    Dictionary version
    3.0
    Reporting groups
    Reporting group title
    ABVD (Cycle 1 and Cycle 2)
    Reporting group description
    		 All patients treated with 2 cycles of ABVD chemotherapy after registration.

    Reporting group title
    Cycles 3 - 6 ABVD
    Reporting group description
    		 All PET 2 negative eligible patients who started ABVD cycles 3 to 6. For non-serious adverse events only patients with an AE form returned are included and only grades 3-5 reported. SAEs are also are also included within the AE reporting numbers i.e. these are the total number of all grade 3-5 events.

    Reporting group title
    Cycles 3 - 6 AVD
    Reporting group description
    		 All PET 2 negative eligible patients who started AVD cycles 3 to 6. For non-serious adverse events only patients with an AE form returned are included and only grades 3-5 reported. SAEs are also are also included within the AE reporting numbers i.e. these are the total number of all grade 3-5 events.

    Reporting group title
    Cycles 1 - 6 BEACOPP-14
    Reporting group description
    		 All PET 2 positive eligible patients who started BEACOPP-14 who started cycles 1 to 6. For non-serious adverse events only patients with an AE form returned are included and only grades 3-5 reported. SAEs are also are also included within the AE reporting numbers i.e. these are the total number of all grade 3-5 events.

    Reporting group title
    Cycles 1 - 4 BEACOPP-ESC
    Reporting group description
    		 All PET 2 positive eligible patients who started BEACOPP-ESC cycles 1 to 4. For non-serious adverse events only patients with an AE form returned are included and only grades 3-5 reported. SAEs are also are also included within the AE reporting numbers i.e. these are the total number of all grade 3-5 events.

    Serious adverse events
    		 ABVD (Cycle 1 and Cycle 2) Cycles 3 - 6 ABVD Cycles 3 - 6 AVD Cycles 1 - 6 BEACOPP-14 Cycles 1 - 4 BEACOPP-ESC
    Total subjects affected by serious adverse events
         subjects affected / exposed
    90 / 1203 (7.48%)
    70 / 468 (14.96%)
    53 / 457 (11.60%)
    40 / 94 (42.55%)
    36 / 78 (46.15%)
         number of deaths (all causes)
    1
    1
    0
    0
    1
         number of deaths resulting from adverse events
    0
    Vascular disorders
    Thrombosis
         subjects affected / exposed
    6 / 1203 (0.50%)
    7 / 468 (1.50%)
    4 / 457 (0.88%)
    5 / 94 (5.32%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 7
    0 / 4
    0 / 5
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Embolism
         subjects affected / exposed
    0 / 1203 (0.00%)
    3 / 468 (0.64%)
    0 / 457 (0.00%)
    0 / 94 (0.00%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    Other - pregnancy with multiple dysmorphic features and congenital abnormalities
         subjects affected / exposed
    0 / 1203 (0.00%)
    1 / 468 (0.21%)
    0 / 457 (0.00%)
    0 / 94 (0.00%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    0 / 1203 (0.00%)
    0 / 468 (0.00%)
    2 / 457 (0.44%)
    0 / 94 (0.00%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fever
         subjects affected / exposed
    2 / 1203 (0.17%)
    0 / 468 (0.00%)
    4 / 457 (0.88%)
    0 / 94 (0.00%)
    2 / 78 (2.56%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 4
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Insomnia
         subjects affected / exposed
    1 / 1203 (0.08%)
    0 / 468 (0.00%)
    0 / 457 (0.00%)
    0 / 94 (0.00%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    1 / 1203 (0.08%)
    0 / 468 (0.00%)
    0 / 457 (0.00%)
    0 / 94 (0.00%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    3 / 1203 (0.25%)
    0 / 468 (0.00%)
    0 / 457 (0.00%)
    1 / 94 (1.06%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    1 / 1203 (0.08%)
    0 / 468 (0.00%)
    0 / 457 (0.00%)
    0 / 94 (0.00%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oedema
         subjects affected / exposed
    0 / 1203 (0.00%)
    1 / 468 (0.21%)
    1 / 457 (0.22%)
    0 / 94 (0.00%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Allergic reaction
         subjects affected / exposed
    0 / 1203 (0.00%)
    1 / 468 (0.21%)
    0 / 457 (0.00%)
    0 / 94 (0.00%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Infertility
         subjects affected / exposed
    0 / 1203 (0.00%)
    0 / 468 (0.00%)
    0 / 457 (0.00%)
    1 / 94 (1.06%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pulmonary fibrosis
         subjects affected / exposed
    0 / 1203 (0.00%)
    1 / 468 (0.21%)
    0 / 457 (0.00%)
    0 / 94 (0.00%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    0 / 1203 (0.00%)
    3 / 468 (0.64%)
    1 / 457 (0.22%)
    0 / 94 (0.00%)
    2 / 78 (2.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    1 / 1203 (0.08%)
    0 / 468 (0.00%)
    0 / 457 (0.00%)
    0 / 94 (0.00%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    2 / 1203 (0.17%)
    4 / 468 (0.85%)
    0 / 457 (0.00%)
    1 / 94 (1.06%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 4
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cough
         subjects affected / exposed
    0 / 1203 (0.00%)
    0 / 468 (0.00%)
    0 / 457 (0.00%)
    1 / 94 (1.06%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    upper respiratory pain
         subjects affected / exposed
    0 / 1203 (0.00%)
    1 / 468 (0.21%)
    0 / 457 (0.00%)
    0 / 94 (0.00%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    chest wall pain
         subjects affected / exposed
    0 / 1203 (0.00%)
    1 / 468 (0.21%)
    0 / 457 (0.00%)
    0 / 94 (0.00%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 1203 (0.00%)
    0 / 468 (0.00%)
    1 / 457 (0.22%)
    2 / 94 (2.13%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 1203 (0.00%)
    1 / 468 (0.21%)
    2 / 457 (0.44%)
    1 / 94 (1.06%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Depression
         subjects affected / exposed
    1 / 1203 (0.08%)
    0 / 468 (0.00%)
    1 / 457 (0.22%)
    0 / 94 (0.00%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Anxiety
         subjects affected / exposed
    1 / 1203 (0.08%)
    0 / 468 (0.00%)
    0 / 457 (0.00%)
    0 / 94 (0.00%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Agitation
         subjects affected / exposed
    1 / 1203 (0.08%)
    0 / 468 (0.00%)
    0 / 457 (0.00%)
    0 / 94 (0.00%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    1 / 1203 (0.08%)
    0 / 468 (0.00%)
    0 / 457 (0.00%)
    0 / 94 (0.00%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac Troponin I
         subjects affected / exposed
    0 / 1203 (0.00%)
    1 / 468 (0.21%)
    1 / 457 (0.22%)
    0 / 94 (0.00%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac troponin T
         subjects affected / exposed
    0 / 1203 (0.00%)
    0 / 468 (0.00%)
    0 / 457 (0.00%)
    1 / 94 (1.06%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pericardial effusion
         subjects affected / exposed
    3 / 1203 (0.25%)
    0 / 468 (0.00%)
    0 / 457 (0.00%)
    0 / 94 (0.00%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    vasovagal episode
         subjects affected / exposed
    0 / 1203 (0.00%)
    1 / 468 (0.21%)
    0 / 457 (0.00%)
    0 / 94 (0.00%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac ischemia/infarction
         subjects affected / exposed
    2 / 1203 (0.17%)
    0 / 468 (0.00%)
    0 / 457 (0.00%)
    0 / 94 (0.00%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac Arrhythmia - Other - left ventricular systolic dysfunction
         subjects affected / exposed
    0 / 1203 (0.00%)
    1 / 468 (0.21%)
    0 / 457 (0.00%)
    0 / 94 (0.00%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Supraventricular arrhythmia NOS
         subjects affected / exposed
    1 / 1203 (0.08%)
    0 / 468 (0.00%)
    0 / 457 (0.00%)
    0 / 94 (0.00%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Headache
         subjects affected / exposed
    0 / 1203 (0.00%)
    0 / 468 (0.00%)
    0 / 457 (0.00%)
    0 / 94 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    0 / 1203 (0.00%)
    0 / 468 (0.00%)
    1 / 457 (0.22%)
    0 / 94 (0.00%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cerebrovascular ischemia
         subjects affected / exposed
    2 / 1203 (0.17%)
    0 / 468 (0.00%)
    0 / 457 (0.00%)
    1 / 94 (1.06%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    1 / 1203 (0.08%)
    0 / 468 (0.00%)
    0 / 457 (0.00%)
    0 / 94 (0.00%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    2 / 1203 (0.17%)
    0 / 468 (0.00%)
    0 / 457 (0.00%)
    0 / 94 (0.00%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sensory neuropathy
         subjects affected / exposed
    0 / 1203 (0.00%)
    1 / 468 (0.21%)
    0 / 457 (0.00%)
    0 / 94 (0.00%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Motor neuropathy
         subjects affected / exposed
    0 / 1203 (0.00%)
    0 / 468 (0.00%)
    1 / 457 (0.22%)
    0 / 94 (0.00%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    CSF leak
         subjects affected / exposed
    0 / 1203 (0.00%)
    0 / 468 (0.00%)
    1 / 457 (0.22%)
    0 / 94 (0.00%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 1203 (0.00%)
    0 / 468 (0.00%)
    1 / 457 (0.22%)
    4 / 94 (4.26%)
    2 / 78 (2.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Leucopenia
         subjects affected / exposed
    0 / 1203 (0.00%)
    1 / 468 (0.21%)
    4 / 457 (0.88%)
    0 / 94 (0.00%)
    3 / 78 (3.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 4
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    14 / 1203 (1.16%)
    6 / 468 (1.28%)
    17 / 457 (3.72%)
    9 / 94 (9.57%)
    11 / 78 (14.10%)
         occurrences causally related to treatment / all
    0 / 14
    0 / 6
    0 / 17
    0 / 9
    0 / 11
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    16 / 1203 (1.33%)
    6 / 468 (1.28%)
    15 / 457 (3.28%)
    18 / 94 (19.15%)
    33 / 78 (42.31%)
         occurrences causally related to treatment / all
    0 / 16
    0 / 6
    0 / 15
    0 / 18
    0 / 33
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Colitis
         subjects affected / exposed
    0 / 1203 (0.00%)
    1 / 468 (0.21%)
    0 / 457 (0.00%)
    1 / 94 (1.06%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    1 / 1203 (0.08%)
    1 / 468 (0.21%)
    0 / 457 (0.00%)
    0 / 94 (0.00%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    1 / 1203 (0.08%)
    0 / 468 (0.00%)
    0 / 457 (0.00%)
    0 / 94 (0.00%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    1 / 1203 (0.08%)
    0 / 468 (0.00%)
    0 / 457 (0.00%)
    2 / 94 (2.13%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    0 / 1203 (0.00%)
    0 / 468 (0.00%)
    1 / 457 (0.22%)
    0 / 94 (0.00%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    1 / 1203 (0.08%)
    1 / 468 (0.21%)
    0 / 457 (0.00%)
    1 / 94 (1.06%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Obstruction, GI - Rectum
         subjects affected / exposed
    1 / 1203 (0.08%)
    0 / 468 (0.00%)
    0 / 457 (0.00%)
    0 / 94 (0.00%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    3 / 1203 (0.25%)
    2 / 468 (0.43%)
    1 / 457 (0.22%)
    2 / 94 (2.13%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
    0 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 1203 (0.00%)
    0 / 468 (0.00%)
    0 / 457 (0.00%)
    1 / 94 (1.06%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lower gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 1203 (0.00%)
    0 / 468 (0.00%)
    0 / 457 (0.00%)
    1 / 94 (1.06%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    rectal pain
         subjects affected / exposed
    1 / 1203 (0.08%)
    0 / 468 (0.00%)
    0 / 457 (0.00%)
    1 / 94 (1.06%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    AST increased
         subjects affected / exposed
    1 / 1203 (0.08%)
    0 / 468 (0.00%)
    0 / 457 (0.00%)
    0 / 94 (0.00%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    2 / 1203 (0.17%)
    0 / 468 (0.00%)
    0 / 457 (0.00%)
    0 / 94 (0.00%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 1203 (0.08%)
    0 / 468 (0.00%)
    0 / 457 (0.00%)
    0 / 94 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bone pain
         subjects affected / exposed
    0 / 1203 (0.00%)
    0 / 468 (0.00%)
    0 / 457 (0.00%)
    2 / 94 (2.13%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    0 / 1203 (0.00%)
    0 / 468 (0.00%)
    0 / 457 (0.00%)
    0 / 94 (0.00%)
    4 / 78 (5.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myalgia
         subjects affected / exposed
    1 / 1203 (0.08%)
    0 / 468 (0.00%)
    1 / 457 (0.22%)
    0 / 94 (0.00%)
    2 / 78 (2.56%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Muscle weakness
         subjects affected / exposed
    1 / 1203 (0.08%)
    0 / 468 (0.00%)
    0 / 457 (0.00%)
    0 / 94 (0.00%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Soft tissue injury
         subjects affected / exposed
    1 / 1203 (0.08%)
    0 / 468 (0.00%)
    0 / 457 (0.00%)
    1 / 94 (1.06%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Ear infection
         subjects affected / exposed
    0 / 1203 (0.00%)
    0 / 468 (0.00%)
    1 / 457 (0.22%)
    0 / 94 (0.00%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    0 / 1203 (0.00%)
    0 / 468 (0.00%)
    0 / 457 (0.00%)
    1 / 94 (1.06%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    16 / 1203 (1.33%)
    16 / 468 (3.42%)
    8 / 457 (1.75%)
    8 / 94 (8.51%)
    16 / 78 (20.51%)
         occurrences causally related to treatment / all
    0 / 16
    0 / 16
    0 / 8
    0 / 8
    0 / 16
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 1203 (0.00%)
    3 / 468 (0.64%)
    0 / 457 (0.00%)
    0 / 94 (0.00%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Clostridium difficile colitis
         subjects affected / exposed
    0 / 1203 (0.00%)
    0 / 468 (0.00%)
    0 / 457 (0.00%)
    1 / 94 (1.06%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 1203 (0.00%)
    1 / 468 (0.21%)
    0 / 457 (0.00%)
    1 / 94 (1.06%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Perianal infection
         subjects affected / exposed
    0 / 1203 (0.00%)
    1 / 468 (0.21%)
    0 / 457 (0.00%)
    1 / 94 (1.06%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lymphatic infection
         subjects affected / exposed
    0 / 1203 (0.00%)
    0 / 468 (0.00%)
    1 / 457 (0.22%)
    0 / 94 (0.00%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal infection
         subjects affected / exposed
    0 / 1203 (0.00%)
    1 / 468 (0.21%)
    0 / 457 (0.00%)
    0 / 94 (0.00%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Soft tissue infection
         subjects affected / exposed
    0 / 1203 (0.00%)
    0 / 468 (0.00%)
    0 / 457 (0.00%)
    0 / 94 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    not specified
         subjects affected / exposed
    13 / 1203 (1.08%)
    11 / 468 (2.35%)
    6 / 457 (1.31%)
    5 / 94 (5.32%)
    6 / 78 (7.69%)
         occurrences causally related to treatment / all
    0 / 13
    0 / 11
    0 / 6
    0 / 5
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chest infection
         subjects affected / exposed
    1 / 1203 (0.08%)
    0 / 468 (0.00%)
    0 / 457 (0.00%)
    1 / 94 (1.06%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Upper respiratory infection
         subjects affected / exposed
    1 / 1203 (0.08%)
    3 / 468 (0.64%)
    1 / 457 (0.22%)
    1 / 94 (1.06%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infection NOS
         subjects affected / exposed
    17 / 1203 (1.41%)
    6 / 468 (1.28%)
    8 / 457 (1.75%)
    5 / 94 (5.32%)
    4 / 78 (5.13%)
         occurrences causally related to treatment / all
    0 / 17
    0 / 6
    0 / 8
    0 / 5
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neutropenic infection G3-G4
         subjects affected / exposed
    7 / 1203 (0.58%)
    6 / 468 (1.28%)
    6 / 457 (1.31%)
    9 / 94 (9.57%)
    5 / 78 (6.41%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 6
    0 / 6
    0 / 9
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hyperglycaemia
         subjects affected / exposed
    1 / 1203 (0.08%)
    0 / 468 (0.00%)
    0 / 457 (0.00%)
    0 / 94 (0.00%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    1 / 1203 (0.08%)
    0 / 468 (0.00%)
    0 / 457 (0.00%)
    1 / 94 (1.06%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    1 / 1203 (0.08%)
    0 / 468 (0.00%)
    0 / 457 (0.00%)
    1 / 94 (1.06%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 ABVD (Cycle 1 and Cycle 2) Cycles 3 - 6 ABVD Cycles 3 - 6 AVD Cycles 1 - 6 BEACOPP-14 Cycles 1 - 4 BEACOPP-ESC
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    771 / 1203 (64.09%)
    322 / 468 (68.80%)
    299 / 457 (65.43%)
    75 / 94 (79.79%)
    65 / 78 (83.33%)
    Vascular disorders
    Thrombosis/Thrombus/embolism
         subjects affected / exposed
    14 / 1203 (1.16%)
    20 / 468 (4.27%)
    11 / 457 (2.41%)
    8 / 94 (8.51%)
    2 / 78 (2.56%)
         occurrences all number
    14
    20
    11
    8
    2
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    8 / 1203 (0.67%)
    7 / 468 (1.50%)
    4 / 457 (0.88%)
    32 / 94 (34.04%)
    18 / 78 (23.08%)
         occurrences all number
    8
    7
    4
    32
    18
    Leucopenia
         subjects affected / exposed
    162 / 1203 (13.47%)
    107 / 468 (22.86%)
    100 / 457 (21.88%)
    25 / 94 (26.60%)
    6 / 78 (7.69%)
         occurrences all number
    162
    107
    100
    25
    6
    Neutropenia
         subjects affected / exposed
    694 / 1203 (57.69%)
    275 / 468 (58.76%)
    269 / 457 (58.86%)
    59 / 94 (62.77%)
    52 / 78 (66.67%)
         occurrences all number
    694
    275
    269
    59
    52
    Thrombocytopenia
         subjects affected / exposed
    16 / 1203 (1.33%)
    6 / 468 (1.28%)
    15 / 457 (3.28%)
    18 / 94 (19.15%)
    33 / 78 (42.31%)
         occurrences all number
    16
    6
    15
    18
    33
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    14 / 1203 (1.16%)
    14 / 468 (2.99%)
    5 / 457 (1.09%)
    8 / 94 (8.51%)
    3 / 78 (3.85%)
         occurrences all number
    14
    14
    5
    8
    3
    Fever
         subjects affected / exposed
    16 / 1203 (1.33%)
    4 / 468 (0.85%)
    7 / 457 (1.53%)
    2 / 94 (2.13%)
    9 / 78 (11.54%)
         occurrences all number
    16
    4
    7
    2
    9
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    4 / 1203 (0.33%)
    0 / 468 (0.00%)
    3 / 457 (0.66%)
    4 / 94 (4.26%)
    5 / 78 (6.41%)
         occurrences all number
    4
    0
    3
    4
    5
    Infections and infestations
    Febrile neutropenia
         subjects affected / exposed
    24 / 1203 (2.00%)
    22 / 468 (4.70%)
    10 / 457 (2.19%)
    10 / 94 (10.64%)
    20 / 78 (25.64%)
         occurrences all number
    24
    22
    10
    10
    20
    Infection - Not specified
         subjects affected / exposed
    57 / 1203 (4.74%)
    47 / 468 (10.04%)
    34 / 457 (7.44%)
    19 / 94 (20.21%)
    17 / 78 (21.79%)
         occurrences all number
    57
    47
    34
    19
    17
    Infection with G34 ANC
    Additional description: Infection with G34 ANC under infections and infestations.
         subjects affected / exposed
    7 / 1203 (0.58%)
    6 / 468 (1.28%)
    6 / 457 (1.31%)
    10 / 94 (10.64%)
    5 / 78 (6.41%)
         occurrences all number
    7
    6
    6
    10
    5
    Infection with normal ANC
    Additional description: under Infections and infestations.
         subjects affected / exposed
    17 / 1203 (1.41%)
    6 / 468 (1.28%)
    8 / 457 (1.75%)
    5 / 94 (5.32%)
    5 / 78 (6.41%)
         occurrences all number
    17
    6
    8
    5
    5

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    16 May 2008
    First Approved Protocol
    18 Sep 2008
    Timing of PET scanning changed, timing of the response assessment clarified and a number of other administrative changes.
    10 Oct 2008
    PIS, GP Letter and consent form removed from protocol. Number of other minor changes.
    30 Nov 2009
    Inclusion criterion number 9 relating to pulmonary function test removed, Assessment times changed for bloods and other investigations. A number of other changes.
    10 Feb 2012
    Protocol restructured in line with current UCL CTC template. Key changes include: Updated trial contacts to include TMG details. Expanded study synopsis (section 1.1). More detailed site selection criteria (section 3). New section on informed consent (section 4). Pregnancy testing for women of childbearing potential added to baseline investigations (section 5.1). Inclusion criterion 12 updated to specify “approved PET-CT scanning facility” (section 5.3.1). Exclusion criterion 8 revised: now allows previous malignancies if disease-free ≥5 years; concurrent active malignancy remains exclusionary (section 5.3.2). Pathology specimens now sent directly to HMDS instead of UCL CTC (section 5.4). Guidance on contraception and fertility added (section 5.5). Additional detail on registration procedures (section 6). Clarified dose adjustments and capping; added info on Natulan use when UK-licensed procarbazine unavailable; updated pharmacy responsibilities (section 7). Clarified requirement for 3-month post-treatment CT scan (section 8.3). PV section (section 11) amended: now collecting all AEs, not just grade 3/4; expanded SAE exemptions; added overdose guidance; updated SAE/SUSAR processing and DSUR submission. Information added on incident reporting, serious breaches (section 12), and monitoring/oversight (section 13). Sponsorship and Indemnity section updated (section 18). Expanded publication policy (section 20), added references (section 21), and list of abbreviations (appendix 1). Expected AEs updated for ABVD, AVD, and BEACOPP regimens (appendix 3). Pregnancy test added to schedule of investigations (appendix 4). Change to PET scan uptake time (appendix 5). Minor typographical corrections made.
    22 Jun 2022
    • Section 8.4 has been updated to state annual follow-up will be collected via CRF and that annual follow-up will cease from sites if approval to collect data from a national registry is granted. • Section 15.1 has been updated to state the End of Trial will be declared once final data items for the trial are received. • A section has been added to the exploratory objectives which includes additional analyses of the PET scans.

    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.
    AEs: occurrences all number can't be provided as only highest grade are collected. Subjects affected is entered instead (only grade 3-4 reported). Treatment related death/relatedness to SAEs not available (0 entered). N = 11 ineligible pts excluded.

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/30220622
    http://www.ncbi.nlm.nih.gov/pubmed/33641019
    http://www.ncbi.nlm.nih.gov/pubmed/26747247
    http://www.ncbi.nlm.nih.gov/pubmed/38824206
    http://www.ncbi.nlm.nih.gov/pubmed/27332902
    http://www.ncbi.nlm.nih.gov/pubmed/41102172
    For support, Contact us.
    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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