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    Clinical Trial Results:
    HD18 for advanced stages in Hodgkins Lymphoma

    Summary
    EudraCT number
    		 2007-003187-22
    Trial protocol
    		 DE   AT   CZ   NL  
    Global end of trial date
    18 Jul 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    24 Jul 2020
    First version publication date
    24 Jul 2020
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    Uni-Koeln-908
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00515554
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    University of Cologne
    Sponsor organisation address
    Albertus Magnus-Platz, Köln, Germany, 50923
    Public contact
    Trial Coordination Center of the German Hodgkin Study Group (GHSG), German Hodgkin Study Group (GHSG), 0049 22147888200, ghsg@uk-koeln.de
    Scientific contact
    Trial Coordination Center of the German Hodgkin Study Group (GHSG), German Hodgkin Study Group (GHSG), 0049 22147888200, ghsg@uk-koeln.de
    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
    13 Feb 2020
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    18 Jul 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The aim of the HD18 trial was to individualize treatment of patients with advanced-stage Hodgkin lymphoma (HL) by adapting it to early response. The HD18 trial comprises of two independent studies for patients with a positive or negative PET after 2 cycles of eBEACOPP (PET-2), respectively. The primary objective of the study in patients with positive PET-2 was to show superiority of the combined immuno-chemotherapy R-eBEACOPP compared with standard eBEACOPP in terms of progression-free survival (PFS). The primary objective of the study in patients with negative PET-2 was to show non-inferiority of treatment with a reduced number of cycles compared with standard treatment in terms of PFS.
    Protection of trial subjects
    Written informed consent before study entry, frequent DMC monitoring, hospitalization during first cycle and dexamethasone pre-treatment recommended for patients aged 40 years or older, mandatory prophylaxis during chemotherapy, dose reduction strategy in case of adverse events
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    14 May 2008
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Efficacy
    Long term follow-up duration
    		 5 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Netherlands: 37
    Country: Number of subjects enrolled
    Austria: 66
    Country: Number of subjects enrolled
    Czech Republic: 35
    Country: Number of subjects enrolled
    Germany: 1810
    Country: Number of subjects enrolled
    Switzerland: 153
    Worldwide total number of subjects
    2101
    EEA total number of subjects
    1948
    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)
    2101
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 Between 14 May 2008 and 18 July 2014, 2101 patients were enrolled in 301 trial sites in 5 European countries.

    Pre-assignment
    Screening details
    		 Enrolled patients received 2 cycles eBEACOPP followed by PET/CT-based response assessment. After central review of PET-2, patients were randomly assigned to a treatment group based on their PET-2 result. Patients dropping out before or during central PET review were not randomized.

    Pre-assignment period milestones
    Number of subjects started
    		 2101
    Number of subjects completed
    		 1964

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    		 Consent withdrawn by subject: 1
    Reason: Number of subjects
    		 Protocol deviation: 39
    Reason: Number of subjects
    		 Revision of HL diagnosis: 21
    Reason: Number of subjects
    		 Registration error: 1
    Reason: Number of subjects
    		 Violation of inclusion or exclusion criteria: 35
    Reason: Number of subjects
    		 Independent disease entity: 5
    Reason: Number of subjects
    		 Other: 9
    Reason: Number of subjects
    		 Progressive disease: 1
    Reason: Number of subjects
    		 Adverse event, serious fatal: 7
    Reason: Number of subjects
    		 Adverse event, non-fatal: 18
    Period 1
    Period 1 title
    Randomization
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    Not applicable

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Arm A: 8x eBEACOPP PET+
    Arm description
    		 Standard treatment for PET-2-positive patients pre amendment 2: 8x eBEACOPP in 21-day intervals; 30 Gy radiotherapy recommended for lesions of at least 2.5 cm in the largest diameter with residual ¹⁸F-FDG uptake after chemotherapy
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Bleomycin
    Investigational medicinal product code
    L01DC01
    Other name
    Pharmaceutical forms
    Powder for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    10 mg/m² BSA on day 8 of each cycle

    Investigational medicinal product name
    Etoposide
    Investigational medicinal product code
    L01CB01
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    200 mg/m² BSA on days 1-3 of each cycle

    Investigational medicinal product name
    Doxorubicine
    Investigational medicinal product code
    L01DB01
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    35 mg/m² BSA on day 1 of each cycle

    Investigational medicinal product name
    Cyclophosphamide
    Investigational medicinal product code
    L01AA01
    Other name
    Pharmaceutical forms
    Powder for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    1250 mg/m² BSA on day 1 of each cycle

    Investigational medicinal product name
    Vincristine
    Investigational medicinal product code
    L01CA02
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    1.4 mg/m² BSA on day 8 of each cycle

    Investigational medicinal product name
    Procarbazine
    Investigational medicinal product code
    L01XB01
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    100 mg/m² BSA on days 1-7 of each cycle

    Investigational medicinal product name
    Prednisone
    Investigational medicinal product code
    H02AB07
    Other name
    Pharmaceutical forms
    Oral drops
    Routes of administration
    Oral use
    Dosage and administration details
    40 mg/m² BSA on days 1-14 of each cycle

    Arm title
    		 Arm B: 8x R-eBEACOPP PET+
    Arm description
    		 Experimental treatment for PET-2-positive patients pre amendment 2: 8x R-eBEACOPP in 21-day intervals; 30 Gy radiotherapy recommended for lesions of at least 2.5 cm in the largest diameter with residual ¹⁸F-FDG uptake after chemotherapy
    Arm type
    		 Experimental

    Investigational medicinal product name
    Bleomycin
    Investigational medicinal product code
    L01DC01
    Other name
    Pharmaceutical forms
    Powder for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    10 mg/m² BSA on day 8 of each cycle

    Investigational medicinal product name
    Etoposide
    Investigational medicinal product code
    L01CB01
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    200 mg/m² BSA on days 1-3 of each cycle

    Investigational medicinal product name
    Doxorubicine
    Investigational medicinal product code
    L01DB01
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    35 mg/m² BSA on day 1 of each cycle

    Investigational medicinal product name
    Cyclophosphamide
    Investigational medicinal product code
    L01AA01
    Other name
    Pharmaceutical forms
    Powder for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    1250 mg/m² BSA on day 1 of each cycle

    Investigational medicinal product name
    Vincristine
    Investigational medicinal product code
    L01CA02
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    1.4 mg/m² BSA on day 8 of each cycle

    Investigational medicinal product name
    Procarbazine
    Investigational medicinal product code
    L01XB01
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    100 mg/m² BSA on days 1-7 of each cycle

    Investigational medicinal product name
    Prednisone
    Investigational medicinal product code
    H02AB07
    Other name
    Pharmaceutical forms
    Oral drops
    Routes of administration
    Oral use
    Dosage and administration details
    40 mg/m² BSA on days 1-14 of each cycle

    Investigational medicinal product name
    Rituximab
    Investigational medicinal product code
    L01XC02
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravascular use
    Dosage and administration details
    375 mg/m² BSA on days 0 and 3 of cycle 4; 375 mg/m² BSA on day 1 of cycles 5-8

    Arm title
    		 Arm A6: 6x eBEACOPP PET+
    Arm description
    		 Standard treatment for PET-2-positive patients post amendment 2: 6x eBEACOPP in 21-day intervals; 30 Gy radiotherapy recommended for lesions of at least 2.5 cm in the largest diameter with residual ¹⁸F-FDG uptake after chemotherapy
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Bleomycin
    Investigational medicinal product code
    L01DC01
    Other name
    Pharmaceutical forms
    Powder for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    10 mg/m² BSA on day 8 of each cycle

    Investigational medicinal product name
    Etoposide
    Investigational medicinal product code
    L01CB01
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    200 mg/m² BSA on days 1-3 of each cycle

    Investigational medicinal product name
    Doxorubicine
    Investigational medicinal product code
    L01DB01
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    35 mg/m² BSA on day 1 of each cycle

    Investigational medicinal product name
    Cyclophosphamide
    Investigational medicinal product code
    L01AA01
    Other name
    Pharmaceutical forms
    Powder for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    1250 mg/m² BSA on day 1 of each cycle

    Investigational medicinal product name
    Vincristine
    Investigational medicinal product code
    L01CA02
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    1.4 mg/m² BSA on day 8 of each cycle

    Investigational medicinal product name
    Procarbazine
    Investigational medicinal product code
    L01XB01
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    100 mg/m² BSA on days 1-7 of each cycle

    Investigational medicinal product name
    Prednisone
    Investigational medicinal product code
    H02AB07
    Other name
    Pharmaceutical forms
    Oral drops
    Routes of administration
    Oral use
    Dosage and administration details
    40 mg/m² BSA on days 1-14 of each cycle

    Arm title
    		 Arm C: 8/6x eBEACOPP PET-
    Arm description
    		 Standard treatment for PET-2-negative patients: 8x eBEACOPP pre amendment 2, 6x eBEACOPP post amendment 2, each in 21-day intervals; 30 Gy radiotherapy recommended for lesions of at least 2.5 cm in the largest diameter with residual ¹⁸F-FDG uptake after chemotherapy
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Bleomycin
    Investigational medicinal product code
    L01DC01
    Other name
    Pharmaceutical forms
    Powder for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    10 mg/m² BSA on day 8 of each cycle

    Investigational medicinal product name
    Etoposide
    Investigational medicinal product code
    L01CB01
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    200 mg/m² BSA on days 1-3 of each cycle

    Investigational medicinal product name
    Doxorubicine
    Investigational medicinal product code
    L01DB01
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    35 mg/m² BSA on day 1 of each cycle

    Investigational medicinal product name
    Cyclophosphamide
    Investigational medicinal product code
    L01AA01
    Other name
    Pharmaceutical forms
    Powder for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    1250 mg/m² BSA on day 1 of each cycle

    Investigational medicinal product name
    Vincristine
    Investigational medicinal product code
    L01CA02
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    1.4 mg/m² BSA on day 8 of each cycle

    Investigational medicinal product name
    Procarbazine
    Investigational medicinal product code
    L01XB01
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    100 mg/m² BSA on days 1-7 of each cycle

    Investigational medicinal product name
    Prednisone
    Investigational medicinal product code
    H02AB07
    Other name
    Pharmaceutical forms
    Oral drops
    Routes of administration
    Oral use
    Dosage and administration details
    40 mg/m² BSA on days 1-14 of each cycle

    Arm title
    		 Arm D: 4x eBEACOPP PET-
    Arm description
    		 Experimental treatment for PET-2-negative patients: 4x eBEACOPP in 21-day intervals; 30 Gy radiotherapy recommended for lesions of at least 2.5 cm in the largest diameter with residual ¹⁸F-FDG uptake after chemotherapy
    Arm type
    		 Experimental

    Investigational medicinal product name
    Bleomycin
    Investigational medicinal product code
    L01DC01
    Other name
    Pharmaceutical forms
    Powder for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    10 mg/m² BSA on day 8 of each cycle

    Investigational medicinal product name
    Etoposide
    Investigational medicinal product code
    L01CB01
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    200 mg/m² BSA on days 1-3 of each cycle

    Investigational medicinal product name
    Doxorubicine
    Investigational medicinal product code
    L01DB01
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    35 mg/m² BSA on day 1 of each cycle

    Investigational medicinal product name
    Cyclophosphamide
    Investigational medicinal product code
    L01AA01
    Other name
    Pharmaceutical forms
    Powder for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    1250 mg/m² BSA on day 1 of each cycle

    Investigational medicinal product name
    Vincristine
    Investigational medicinal product code
    L01CA02
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    1.4 mg/m² BSA on day 8 of each cycle

    Investigational medicinal product name
    Procarbazine
    Investigational medicinal product code
    L01XB01
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    100 mg/m² BSA on days 1-7 of each cycle

    Investigational medicinal product name
    Prednisone
    Investigational medicinal product code
    H02AB07
    Other name
    Pharmaceutical forms
    Oral drops
    Routes of administration
    Oral use
    Dosage and administration details
    40 mg/m² BSA on days 1-14 of each cycle

    Number of subjects in period 1
    		Arm A: 8x eBEACOPP PET+ Arm B: 8x R-eBEACOPP PET+ Arm A6: 6x eBEACOPP PET+ Arm C: 8/6x eBEACOPP PET- Arm D: 4x eBEACOPP PET-
    Started
    220
    220
    511
    508
    505
    Completed
    217
    217
    506
    504
    501
    Not completed
    3
    3
    5
    4
    4
         Revision of HL diagnosis
    1
    -
    2
    1
    2
         Adverse event, non-fatal
    1
    1
    -
    -
    -
         Violation of inclusion or exclusion criteria
    -
    -
    2
    1
    1
         Protocol deviation
    1
    2
    1
    2
    1
    Period 2
    Period 2 title
    Randomized treatment
    Is this the baseline period?
    		 Yes [1]
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    Not applicable

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Arm A: 8x eBEACOPP PET+
    Arm description
    		 Standard treatment for PET-2-positive patients pre amendment 2: 8x eBEACOPP in 21-day intervals; 30 Gy radiotherapy recommended for lesions of at least 2.5 cm in the largest diameter with residual ¹⁸F-FDG uptake after chemotherapy
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Bleomycin
    Investigational medicinal product code
    L01DC01
    Other name
    Pharmaceutical forms
    Powder for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    10 mg/m² BSA on day 8 of each cycle

    Investigational medicinal product name
    Etoposide
    Investigational medicinal product code
    L01CB01
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    200 mg/m² BSA on days 1-3 of each cycle

    Investigational medicinal product name
    Doxorubicine
    Investigational medicinal product code
    L01DB01
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    35 mg/m² BSA on day 1 of each cycle

    Investigational medicinal product name
    Cyclophosphamide
    Investigational medicinal product code
    L01AA01
    Other name
    Pharmaceutical forms
    Powder for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    1250 mg/m² BSA on day 1 of each cycle

    Investigational medicinal product name
    Vincristine
    Investigational medicinal product code
    L01CA02
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    1.4 mg/m² BSA on day 8 of each cycle

    Investigational medicinal product name
    Procarbazine
    Investigational medicinal product code
    L01XB01
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    100 mg/m² BSA on days 1-7 of each cycle

    Investigational medicinal product name
    Prednisone
    Investigational medicinal product code
    H02AB07
    Other name
    Pharmaceutical forms
    Oral drops
    Routes of administration
    Oral use
    Dosage and administration details
    40 mg/m² BSA on days 1-14 of each cycle

    Arm title
    		 Arm B: 8x R-eBEACOPP PET+
    Arm description
    		 Experimental treatment for PET-2-positive patients pre amendment 2: 8x R-eBEACOPP in 21-day intervals; 30 Gy radiotherapy recommended for lesions of at least 2.5 cm in the largest diameter with residual ¹⁸F-FDG uptake after chemotherapy
    Arm type
    		 Experimental

    Investigational medicinal product name
    Bleomycin
    Investigational medicinal product code
    L01DC01
    Other name
    Pharmaceutical forms
    Powder for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    10 mg/m² BSA on day 8 of each cycle

    Investigational medicinal product name
    Etoposide
    Investigational medicinal product code
    L01CB01
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    200 mg/m² BSA on days 1-3 of each cycle

    Investigational medicinal product name
    Doxorubicine
    Investigational medicinal product code
    L01DB01
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    35 mg/m² BSA on day 1 of each cycle

    Investigational medicinal product name
    Cyclophosphamide
    Investigational medicinal product code
    L01AA01
    Other name
    Pharmaceutical forms
    Powder for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    1250 mg/m² BSA on day 1 of each cycle

    Investigational medicinal product name
    Vincristine
    Investigational medicinal product code
    L01CA02
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    1.4 mg/m² BSA on day 8 of each cycle

    Investigational medicinal product name
    Procarbazine
    Investigational medicinal product code
    L01XB01
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    100 mg/m² BSA on days 1-7 of each cycle

    Investigational medicinal product name
    Prednisone
    Investigational medicinal product code
    H02AB07
    Other name
    Pharmaceutical forms
    Oral drops
    Routes of administration
    Oral use
    Dosage and administration details
    40 mg/m² BSA on days 1-14 of each cycle

    Investigational medicinal product name
    Rituximab
    Investigational medicinal product code
    L01XC02
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravascular use
    Dosage and administration details
    375 mg/m² BSA on days 0 and 3 of cycle 4; 375 mg/m² BSA on day 1 of cycles 5-8

    Arm title
    		 Arm A6: 6x eBEACOPP PET+
    Arm description
    		 Standard treatment for PET-2-positive patients post amendment 2: 6x eBEACOPP in 21-day intervals; 30 Gy radiotherapy recommended for lesions of at least 2.5 cm in the largest diameter with residual ¹⁸F-FDG uptake after chemotherapy
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Bleomycin
    Investigational medicinal product code
    L01DC01
    Other name
    Pharmaceutical forms
    Powder for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    10 mg/m² BSA on day 8 of each cycle

    Investigational medicinal product name
    Etoposide
    Investigational medicinal product code
    L01CB01
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    200 mg/m² BSA on days 1-3 of each cycle

    Investigational medicinal product name
    Doxorubicine
    Investigational medicinal product code
    L01DB01
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    35 mg/m² BSA on day 1 of each cycle

    Investigational medicinal product name
    Cyclophosphamide
    Investigational medicinal product code
    L01AA01
    Other name
    Pharmaceutical forms
    Powder for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    1250 mg/m² BSA on day 1 of each cycle

    Investigational medicinal product name
    Vincristine
    Investigational medicinal product code
    L01CA02
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    1.4 mg/m² BSA on day 8 of each cycle

    Investigational medicinal product name
    Procarbazine
    Investigational medicinal product code
    L01XB01
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    100 mg/m² BSA on days 1-7 of each cycle

    Investigational medicinal product name
    Prednisone
    Investigational medicinal product code
    H02AB07
    Other name
    Pharmaceutical forms
    Oral drops
    Routes of administration
    Oral use
    Dosage and administration details
    40 mg/m² BSA on days 1-14 of each cycle

    Arm title
    		 Arm C: 8/6x eBEACOPP PET-
    Arm description
    		 Standard treatment for PET-2-negative patients: 8x eBEACOPP pre amendment 2, 6x eBEACOPP post amendment 2, each in 21-day intervals; 30 Gy radiotherapy recommended for lesions of at least 2.5 cm in the largest diameter with residual ¹⁸F-FDG uptake after chemotherapy
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Bleomycin
    Investigational medicinal product code
    L01DC01
    Other name
    Pharmaceutical forms
    Powder for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    10 mg/m² BSA on day 8 of each cycle

    Investigational medicinal product name
    Etoposide
    Investigational medicinal product code
    L01CB01
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    200 mg/m² BSA on days 1-3 of each cycle

    Investigational medicinal product name
    Doxorubicine
    Investigational medicinal product code
    L01DB01
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    35 mg/m² BSA on day 1 of each cycle

    Investigational medicinal product name
    Cyclophosphamide
    Investigational medicinal product code
    L01AA01
    Other name
    Pharmaceutical forms
    Powder for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    1250 mg/m² BSA on day 1 of each cycle

    Investigational medicinal product name
    Vincristine
    Investigational medicinal product code
    L01CA02
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    1.4 mg/m² BSA on day 8 of each cycle

    Investigational medicinal product name
    Procarbazine
    Investigational medicinal product code
    L01XB01
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    100 mg/m² BSA on days 1-7 of each cycle

    Investigational medicinal product name
    Prednisone
    Investigational medicinal product code
    H02AB07
    Other name
    Pharmaceutical forms
    Oral drops
    Routes of administration
    Oral use
    Dosage and administration details
    40 mg/m² BSA on days 1-14 of each cycle

    Arm title
    		 Arm D: 4x eBEACOPP PET-
    Arm description
    		 Experimental treatment for PET-2-negative patients: 4x eBEACOPP in 21-day intervals; 30 Gy radiotherapy recommended for lesions of at least 2.5 cm in the largest diameter with residual ¹⁸F-FDG uptake after chemotherapy
    Arm type
    		 Experimental

    Investigational medicinal product name
    Bleomycin
    Investigational medicinal product code
    L01DC01
    Other name
    Pharmaceutical forms
    Powder for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    10 mg/m² BSA on day 8 of each cycle

    Investigational medicinal product name
    Etoposide
    Investigational medicinal product code
    L01CB01
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    200 mg/m² BSA on days 1-3 of each cycle

    Investigational medicinal product name
    Doxorubicine
    Investigational medicinal product code
    L01DB01
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    35 mg/m² BSA on day 1 of each cycle

    Investigational medicinal product name
    Cyclophosphamide
    Investigational medicinal product code
    L01AA01
    Other name
    Pharmaceutical forms
    Powder for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    1250 mg/m² BSA on day 1 of each cycle

    Investigational medicinal product name
    Vincristine
    Investigational medicinal product code
    L01CA02
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    1.4 mg/m² BSA on day 8 of each cycle

    Investigational medicinal product name
    Procarbazine
    Investigational medicinal product code
    L01XB01
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    100 mg/m² BSA on days 1-7 of each cycle

    Investigational medicinal product name
    Prednisone
    Investigational medicinal product code
    H02AB07
    Other name
    Pharmaceutical forms
    Oral drops
    Routes of administration
    Oral use
    Dosage and administration details
    40 mg/m² BSA on days 1-14 of each cycle

    Notes
    [1] - Period 1 is not the baseline period. It is expected that period 1 will be the baseline period.
    Justification: In the HD18 trial, all patients received initial 2 cycles of chemotherapy and were then randomized into one of two parallel treatment arms according to their PET-result. The baseline period only includes those patients who received randomized treatment within the study and are included in the efficacy analyses. Patients who dropped out before randomization are not included.
    Number of subjects in period 2 [2]
    		Arm A: 8x eBEACOPP PET+ Arm B: 8x R-eBEACOPP PET+ Arm A6: 6x eBEACOPP PET+ Arm C: 8/6x eBEACOPP PET- Arm D: 4x eBEACOPP PET-
    Started
    217
    217
    506
    504
    501
    Completed
    186
    180
    442
    446
    474
    Not completed
    31
    37
    64
    58
    27
         Adverse event, serious fatal
    -
    -
    -
    1
    -
         Consent withdrawn by subject
    3
    2
    1
    1
    1
         Physician decision
    -
    1
    3
    -
    2
         Adverse event, non-fatal
    4
    10
    3
    10
    2
         Incomplete documentation
    6
    9
    20
    14
    11
         Violation of inclusion or exclusion criteria
    1
    1
    2
    2
    1
         Not specified
    -
    -
    -
    1
    1
         Independent disease entity
    1
    -
    4
    -
    -
         Patients' wish
    4
    3
    6
    23
    6
         Lack of efficacy
    2
    2
    2
    -
    -
         Protocol deviation
    10
    9
    23
    6
    3
    Notes
    [2] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: In HD18, all patients received 2 cycles of chemotherapy and were then randomized into one of two parallel treatment arms according to their PET result. All randomized patients are included in period 1 ("Randomization"). However, there were a small number of patients randomized despite prior protocol violation. These did not receive randomized treatment and have not been included in the efficacy analyses. Thus, the baseline period only includes patients receiving randomized treatment.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Arm A: 8x eBEACOPP PET+
    Reporting group description
    		 Standard treatment for PET-2-positive patients pre amendment 2: 8x eBEACOPP in 21-day intervals; 30 Gy radiotherapy recommended for lesions of at least 2.5 cm in the largest diameter with residual ¹⁸F-FDG uptake after chemotherapy

    Reporting group title
    Arm B: 8x R-eBEACOPP PET+
    Reporting group description
    		 Experimental treatment for PET-2-positive patients pre amendment 2: 8x R-eBEACOPP in 21-day intervals; 30 Gy radiotherapy recommended for lesions of at least 2.5 cm in the largest diameter with residual ¹⁸F-FDG uptake after chemotherapy

    Reporting group title
    Arm A6: 6x eBEACOPP PET+
    Reporting group description
    		 Standard treatment for PET-2-positive patients post amendment 2: 6x eBEACOPP in 21-day intervals; 30 Gy radiotherapy recommended for lesions of at least 2.5 cm in the largest diameter with residual ¹⁸F-FDG uptake after chemotherapy

    Reporting group title
    Arm C: 8/6x eBEACOPP PET-
    Reporting group description
    		 Standard treatment for PET-2-negative patients: 8x eBEACOPP pre amendment 2, 6x eBEACOPP post amendment 2, each in 21-day intervals; 30 Gy radiotherapy recommended for lesions of at least 2.5 cm in the largest diameter with residual ¹⁸F-FDG uptake after chemotherapy

    Reporting group title
    Arm D: 4x eBEACOPP PET-
    Reporting group description
    		 Experimental treatment for PET-2-negative patients: 4x eBEACOPP in 21-day intervals; 30 Gy radiotherapy recommended for lesions of at least 2.5 cm in the largest diameter with residual ¹⁸F-FDG uptake after chemotherapy

    Reporting group values
    		 Arm A: 8x eBEACOPP PET+ Arm B: 8x R-eBEACOPP PET+ Arm A6: 6x eBEACOPP PET+ Arm C: 8/6x eBEACOPP PET- Arm D: 4x eBEACOPP PET- Total
    Number of subjects
    		 217 217 506 504 501 1945
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0 0 0
        Adults (18-64 years)
    		 217 217 506 504 501 1945
        From 65-84 years
    		 0 0 0 0 0 0
        85 years and over
    		 0 0 0 0 0 0
    Gender categorical
    Units: Subjects
        Female
    		 88 86 211 189 188 762
        Male
    		 129 131 295 315 313 1183
    Ann Arbor Stage
    Units: Subjects
        IIA
    		 0 1 0 0 0 1
        IIB
    		 49 54 96 40 42 281
        IIIA
    		 41 29 93 156 156 475
        IIIB
    		 58 51 118 131 122 480
        IVA
    		 20 26 63 59 60 228
        IVB
    		 49 56 136 118 121 480
    ECOG Performance Status
    Units: Subjects
        ECOG 0
    		 110 106 302 319 314 1151
        ECOG 1
    		 101 104 185 174 181 745
        ECOG 2
    		 6 7 19 11 6 49
    Large Mediastinal Mass
    Units: Subjects
        No
    		 122 117 306 425 413 1383
        Yes
    		 95 100 199 79 88 561
        Missing
    		 0 0 1 0 0 1
    Extranodal disease
    Units: Subjects
        No
    		 151 168 382 424 441 1566
        Yes
    		 66 49 124 80 60 379
    IPS
    Units: Subjects
        0-1
    		 58 62 129 177 174 600
        2-3
    		 131 108 284 254 257 1034
        4-7
    		 27 45 93 71 68 304
        Missing
    		 1 2 0 2 2 7
    HL subtype
    Units: Subjects
        Classical HL
    		 184 173 326 365 364 1412
        Nodular lymphocyte-predominant HL
    		 4 12 15 26 27 84
        Missing
    		 29 32 165 113 110 449

    End points

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    End points reporting groups
    Reporting group title
    Arm A: 8x eBEACOPP PET+
    Reporting group description
    		 Standard treatment for PET-2-positive patients pre amendment 2: 8x eBEACOPP in 21-day intervals; 30 Gy radiotherapy recommended for lesions of at least 2.5 cm in the largest diameter with residual ¹⁸F-FDG uptake after chemotherapy

    Reporting group title
    Arm B: 8x R-eBEACOPP PET+
    Reporting group description
    		 Experimental treatment for PET-2-positive patients pre amendment 2: 8x R-eBEACOPP in 21-day intervals; 30 Gy radiotherapy recommended for lesions of at least 2.5 cm in the largest diameter with residual ¹⁸F-FDG uptake after chemotherapy

    Reporting group title
    Arm A6: 6x eBEACOPP PET+
    Reporting group description
    		 Standard treatment for PET-2-positive patients post amendment 2: 6x eBEACOPP in 21-day intervals; 30 Gy radiotherapy recommended for lesions of at least 2.5 cm in the largest diameter with residual ¹⁸F-FDG uptake after chemotherapy

    Reporting group title
    Arm C: 8/6x eBEACOPP PET-
    Reporting group description
    		 Standard treatment for PET-2-negative patients: 8x eBEACOPP pre amendment 2, 6x eBEACOPP post amendment 2, each in 21-day intervals; 30 Gy radiotherapy recommended for lesions of at least 2.5 cm in the largest diameter with residual ¹⁸F-FDG uptake after chemotherapy

    Reporting group title
    Arm D: 4x eBEACOPP PET-
    Reporting group description
    		 Experimental treatment for PET-2-negative patients: 4x eBEACOPP in 21-day intervals; 30 Gy radiotherapy recommended for lesions of at least 2.5 cm in the largest diameter with residual ¹⁸F-FDG uptake after chemotherapy
    Reporting group title
    Arm A: 8x eBEACOPP PET+
    Reporting group description
    		 Standard treatment for PET-2-positive patients pre amendment 2: 8x eBEACOPP in 21-day intervals; 30 Gy radiotherapy recommended for lesions of at least 2.5 cm in the largest diameter with residual ¹⁸F-FDG uptake after chemotherapy

    Reporting group title
    Arm B: 8x R-eBEACOPP PET+
    Reporting group description
    		 Experimental treatment for PET-2-positive patients pre amendment 2: 8x R-eBEACOPP in 21-day intervals; 30 Gy radiotherapy recommended for lesions of at least 2.5 cm in the largest diameter with residual ¹⁸F-FDG uptake after chemotherapy

    Reporting group title
    Arm A6: 6x eBEACOPP PET+
    Reporting group description
    		 Standard treatment for PET-2-positive patients post amendment 2: 6x eBEACOPP in 21-day intervals; 30 Gy radiotherapy recommended for lesions of at least 2.5 cm in the largest diameter with residual ¹⁸F-FDG uptake after chemotherapy

    Reporting group title
    Arm C: 8/6x eBEACOPP PET-
    Reporting group description
    		 Standard treatment for PET-2-negative patients: 8x eBEACOPP pre amendment 2, 6x eBEACOPP post amendment 2, each in 21-day intervals; 30 Gy radiotherapy recommended for lesions of at least 2.5 cm in the largest diameter with residual ¹⁸F-FDG uptake after chemotherapy

    Reporting group title
    Arm D: 4x eBEACOPP PET-
    Reporting group description
    		 Experimental treatment for PET-2-negative patients: 4x eBEACOPP in 21-day intervals; 30 Gy radiotherapy recommended for lesions of at least 2.5 cm in the largest diameter with residual ¹⁸F-FDG uptake after chemotherapy

    Primary: Progression-free survival

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    End point title
    		 Progression-free survival
    End point description
    Progression-free survival was defined as the time from completion of staging until progression, relapse, or death from any cause. If none of these events had occurred, progression-free survival was censored at the date of last information on the disease status. Progression-free survival was analyzed according to Kaplan-Meier. Analyses are based on the final data status after end of study and results may thus slightly differ from published values. Median observation time for progression-free survival for the entire study was 64 months. 5-year estimates and the respective 95% CIs will be reported.
    End point type
    Primary
    End point timeframe
    5 years
    End point values
    		 Arm A: 8x eBEACOPP PET+ Arm B: 8x R-eBEACOPP PET+ Arm A6: 6x eBEACOPP PET+ Arm C: 8/6x eBEACOPP PET- Arm D: 4x eBEACOPP PET-
    Number of subjects analysed
    217
    217
    506
    446 [1]
    474 [2]
    Units: percent
        number (confidence interval 95%)
    89.9 (85.7 to 94.1)
    87.7 (83.1 to 92.4)
    90.1 (87.2 to 92.9)
    91.2 (88.4 to 93.9)
    93.0 (90.6 to 95.4)
    Notes
    [1] - PET-2-negative study: per-protocol analysis, severe protocol deviations excluded
    [2] - PET-2-negative study: per-protocol analysis, severe protocol deviations excluded
    Statistical analysis title
    		 PET-2-positive study, superiority test
    Statistical analysis description
    The primary objective of the study in patients with positive PET-2 was to show superiority of 8x R-eBEACOPP over 8x eBEACOPP. The trial was designed to detect an improvement of at least 15% in 5-year progression-free survival with a power of 80% and a two-sided significance level of 5%. Only patients with a positive PET-2 randomized to arms A and B (i.e. before amendment 2) are analyzed. PET-2-positive patients treated according to arm A6 post amendment 2 were separately analyzed descriptively.
    Comparison groups
    Arm A: 8x eBEACOPP PET+ v Arm B: 8x R-eBEACOPP PET+
    Number of subjects included in analysis
    434
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [3]
    P-value
    		 = 0.4 [4]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.29
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.72
         upper limit
    		 2.32
    Notes
    [3] - Superiority was tested using log-rank test on a 2-sided significance level of 5%.
    [4] - Conclusion: The favourable outcome of patients treated with eBEACOPP could not be improved by adding rituximab after positive PET-2.
    Statistical analysis title
    		 PET-2-negative study, non-inferiority test
    Statistical analysis description
    The primary objective of the study in patients with negative PET-2 was to show non-inferiority of 4x eBEACOPP over combined 8/6x eBEACOPP. We defined non-inferiority as an absolute difference of 6% in the 5-year progression-free survival estimates. The trial was designed to perform a per-protocol analysis (excluding severe protocol deviations) with a power of 80%.
    Comparison groups
    Arm C: 8/6x eBEACOPP PET- v Arm D: 4x eBEACOPP PET-
    Number of subjects included in analysis
    920
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [5]
    Method
    Parameter type
    		 Difference in 5-year estimates
    Point estimate
    1.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.8
         upper limit
    		 5.5
    Notes
    [5] - Non-inferiority would be established if the lower limit of the 2-sided 95% CI for the difference in 5-year progression-free survival was above -6%. As the 95% CI for the 5-year difference excluded the predefined non-inferiority margin of -6%, non-inferiority of the shorter regimen could be concluded.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    AEs of CTCAE grades 3/4 were assessed on the therapy administration CRFs for the duration of chemotherapy. SAEs were additionally assessed on specific forms, from first dose until 28 days after last dose unless at least possibly related.
    Adverse event reporting additional description
    Please note that SAEs may be reported twice, on the therapy administration CRF and again on the SAE form. Thus, the "non-serious" AEs and the SAEs might include duplicate events and do not add up to a total number of AEs.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    10.1
    Reporting groups
    Reporting group title
    Arm A: 8x eBEACOPP PET+
    Reporting group description
    		 Standard treatment for PET-2-positive patients pre amendment 2: 8x eBEACOPP in 21-day intervals; 30 Gy radiotherapy recommended for lesions of at least 2.5 cm in the largest diameter with residual ¹⁸F-FDG uptake after chemotherapy

    Reporting group title
    Arm B: 8x R-eBEACOPP PET+
    Reporting group description
    		 Experimental treatment for PET-2-positive patients pre amendment 2: 8x R-eBEACOPP in 21-day intervals; 30 Gy radiotherapy recommended for lesions of at least 2.5 cm in the largest diameter with residual ¹⁸F-FDG uptake after chemotherapy

    Reporting group title
    Arm A6: 6x eBEACOPP PET+
    Reporting group description
    		 Standard treatment for PET-2-positive patients post amendment 2: 6x eBEACOPP in 21-day intervals; 30 Gy radiotherapy recommended for lesions of at least 2.5 cm in the largest diameter with residual ¹⁸F-FDG uptake after chemotherapy

    Reporting group title
    Arm C: 8/6x eBEACOPP PET-
    Reporting group description
    		 Standard treatment for PET-2-negative patients: 8x eBEACOPP pre amendment 2, 6x eBEACOPP post amendment 2, each in 21-day intervals; 30 Gy radiotherapy recommended for lesions of at least 2.5 cm in the largest diameter with residual ¹⁸F-FDG uptake after chemotherapy

    Reporting group title
    Arm D: 4x eBEACOPP PET-
    Reporting group description
    		 Experimental treatment for PET-2-negative patients: 4x eBEACOPP in 21-day intervals; 30 Gy radiotherapy recommended for lesions of at least 2.5 cm in the largest diameter with residual ¹⁸F-FDG uptake after chemotherapy

    Reporting group title
    Arm 0: Non-randomized patients
    Reporting group description
    		 In HD18, patients were randomized after the second cycle of eBEACOPP. Thus, also non-randomized patients might have received study treatment and were analyzed for safety. Out of 137 non-randomized patients, 102 have received study treatment.

    Serious adverse events
    		 Arm A: 8x eBEACOPP PET+ Arm B: 8x R-eBEACOPP PET+ Arm A6: 6x eBEACOPP PET+ Arm C: 8/6x eBEACOPP PET- Arm D: 4x eBEACOPP PET- Arm 0: Non-randomized patients
    Total subjects affected by serious adverse events
         subjects affected / exposed
    101 / 219 (46.12%)
    95 / 220 (43.18%)
    194 / 509 (38.11%)
    190 / 507 (37.48%)
    147 / 502 (29.28%)
    39 / 102 (38.24%)
         number of deaths (all causes)
    9
    17
    15
    29
    11
    9
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    alternative assessment type: Systematic
         subjects affected / exposed
    4 / 219 (1.83%)
    1 / 220 (0.45%)
    2 / 509 (0.39%)
    4 / 507 (0.79%)
    4 / 502 (0.80%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    4 / 4
    1 / 1
    2 / 2
    3 / 4
    4 / 4
    1 / 1
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    1 / 1
    1 / 1
    0 / 0
    Vascular disorders
    Vascular disorders
    alternative assessment type: Systematic
         subjects affected / exposed
    7 / 219 (3.20%)
    10 / 220 (4.55%)
    17 / 509 (3.34%)
    26 / 507 (5.13%)
    18 / 502 (3.59%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    6 / 8
    7 / 10
    15 / 19
    22 / 29
    15 / 20
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Surgical and medical procedures
    Surgical and medical procedures
    alternative assessment type: Systematic
         subjects affected / exposed
    2 / 219 (0.91%)
    0 / 220 (0.00%)
    0 / 509 (0.00%)
    2 / 507 (0.39%)
    0 / 502 (0.00%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    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
    0 / 0
    General disorders and administration site conditions
    General disorders and administration site conditions
    alternative assessment type: Systematic
         subjects affected / exposed
    22 / 219 (10.05%)
    17 / 220 (7.73%)
    27 / 509 (5.30%)
    26 / 507 (5.13%)
    27 / 502 (5.38%)
    2 / 102 (1.96%)
         occurrences causally related to treatment / all
    23 / 26
    17 / 19
    23 / 28
    30 / 31
    26 / 28
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    Immune system disorders
    Immune system disorders
    alternative assessment type: Systematic
         subjects affected / exposed
    2 / 219 (0.91%)
    1 / 220 (0.45%)
    7 / 509 (1.38%)
    8 / 507 (1.58%)
    4 / 502 (0.80%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
    4 / 7
    7 / 8
    2 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Reproductive system and breast disorders
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 219 (0.00%)
    0 / 220 (0.00%)
    1 / 509 (0.20%)
    0 / 507 (0.00%)
    1 / 502 (0.20%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Respiratory, thoracic and mediastinal disorders
    alternative assessment type: Systematic
         subjects affected / exposed
    6 / 219 (2.74%)
    9 / 220 (4.09%)
    8 / 509 (1.57%)
    22 / 507 (4.34%)
    4 / 502 (0.80%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    6 / 6
    8 / 9
    8 / 8
    20 / 23
    3 / 4
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    Psychiatric disorders
    Psychiatric disorders
    alternative assessment type: Systematic
         subjects affected / exposed
    2 / 219 (0.91%)
    3 / 220 (1.36%)
    3 / 509 (0.59%)
    0 / 507 (0.00%)
    3 / 502 (0.60%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    2 / 2
    3 / 3
    2 / 3
    0 / 0
    1 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Investigations
    alternative assessment type: Systematic
         subjects affected / exposed
    3 / 219 (1.37%)
    0 / 220 (0.00%)
    3 / 509 (0.59%)
    4 / 507 (0.79%)
    5 / 502 (1.00%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
    3 / 3
    4 / 4
    5 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Injury, poisioning and procedural complications
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 219 (0.46%)
    2 / 220 (0.91%)
    1 / 509 (0.20%)
    1 / 507 (0.20%)
    2 / 502 (0.40%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 2
    1 / 1
    1 / 1
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiac disorders
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 219 (0.00%)
    3 / 220 (1.36%)
    4 / 509 (0.79%)
    6 / 507 (1.18%)
    3 / 502 (0.60%)
    3 / 102 (2.94%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 4
    3 / 4
    7 / 7
    2 / 6
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Nervous system disorders
    alternative assessment type: Systematic
         subjects affected / exposed
    2 / 219 (0.91%)
    4 / 220 (1.82%)
    6 / 509 (1.18%)
    7 / 507 (1.38%)
    3 / 502 (0.60%)
    2 / 102 (1.96%)
         occurrences causally related to treatment / all
    1 / 2
    3 / 4
    5 / 6
    7 / 7
    2 / 4
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Blood and lymphatic system disorders
    alternative assessment type: Systematic
         subjects affected / exposed
    42 / 219 (19.18%)
    37 / 220 (16.82%)
    78 / 509 (15.32%)
    68 / 507 (13.41%)
    65 / 502 (12.95%)
    10 / 102 (9.80%)
         occurrences causally related to treatment / all
    54 / 56
    48 / 50
    98 / 98
    83 / 84
    79 / 79
    11 / 11
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Ear and labyrinth disorders
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 219 (0.00%)
    1 / 220 (0.45%)
    0 / 509 (0.00%)
    0 / 507 (0.00%)
    0 / 502 (0.00%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 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
    0 / 0
    Eye disorders
    Eye disorders
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 219 (0.00%)
    0 / 220 (0.00%)
    0 / 509 (0.00%)
    0 / 507 (0.00%)
    0 / 502 (0.00%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Gastrointestinal disorders
    alternative assessment type: Systematic
         subjects affected / exposed
    17 / 219 (7.76%)
    12 / 220 (5.45%)
    24 / 509 (4.72%)
    33 / 507 (6.51%)
    15 / 502 (2.99%)
    4 / 102 (3.92%)
         occurrences causally related to treatment / all
    17 / 18
    11 / 13
    22 / 29
    35 / 35
    13 / 15
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hepatobiliary disorders
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 219 (0.46%)
    1 / 220 (0.45%)
    0 / 509 (0.00%)
    0 / 507 (0.00%)
    0 / 502 (0.00%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 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
    0 / 0
    Skin and subcutaneous tissue disorders
    Skin and subcutaneous tissue disorders
    alternative assessment type: Systematic
         subjects affected / exposed
    3 / 219 (1.37%)
    2 / 220 (0.91%)
    3 / 509 (0.59%)
    6 / 507 (1.18%)
    2 / 502 (0.40%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    2 / 2
    3 / 3
    7 / 10
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal and urinary disorders
    alternative assessment type: Systematic
         subjects affected / exposed
    3 / 219 (1.37%)
    1 / 220 (0.45%)
    1 / 509 (0.20%)
    2 / 507 (0.39%)
    5 / 502 (1.00%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    1 / 1
    1 / 1
    2 / 2
    3 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Endocrine disorders
    Endocrine disorders
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 219 (0.00%)
    0 / 220 (0.00%)
    1 / 509 (0.20%)
    0 / 507 (0.00%)
    0 / 502 (0.00%)
    2 / 102 (1.96%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Musculoskeletal and connective tissue disorders
    alternative assessment type: Systematic
         subjects affected / exposed
    4 / 219 (1.83%)
    6 / 220 (2.73%)
    13 / 509 (2.55%)
    11 / 507 (2.17%)
    7 / 502 (1.39%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    1 / 5
    2 / 6
    4 / 15
    3 / 12
    1 / 7
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Infections and infestations
    alternative assessment type: Systematic
         subjects affected / exposed
    31 / 219 (14.16%)
    36 / 220 (16.36%)
    77 / 509 (15.13%)
    67 / 507 (13.21%)
    29 / 502 (5.78%)
    18 / 102 (17.65%)
         occurrences causally related to treatment / all
    36 / 37
    43 / 43
    91 / 92
    72 / 77
    29 / 31
    18 / 18
         deaths causally related to treatment / all
    1 / 1
    3 / 3
    0 / 0
    5 / 5
    0 / 0
    5 / 5
    Metabolism and nutrition disorders
    Metabolism and nutrition disorders
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 219 (0.46%)
    0 / 220 (0.00%)
    1 / 509 (0.20%)
    2 / 507 (0.39%)
    0 / 502 (0.00%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Arm A: 8x eBEACOPP PET+ Arm B: 8x R-eBEACOPP PET+ Arm A6: 6x eBEACOPP PET+ Arm C: 8/6x eBEACOPP PET- Arm D: 4x eBEACOPP PET- Arm 0: Non-randomized patients
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    214 / 219 (97.72%)
    213 / 220 (96.82%)
    486 / 509 (95.48%)
    491 / 507 (96.84%)
    461 / 502 (91.83%)
    89 / 102 (87.25%)
    Nervous system disorders
    Nervous system disorder
    alternative dictionary used: NCI CTCAE 3.0
         subjects affected / exposed [1]
    20 / 218 (9.17%)
    21 / 220 (9.55%)
    49 / 505 (9.70%)
    52 / 505 (10.30%)
    17 / 499 (3.41%)
    0 / 84 (0.00%)
         occurrences all number
    38
    36
    87
    96
    25
    0
    Blood and lymphatic system disorders
    Leukopenia
    alternative dictionary used: NCI CTCAE 3.0
         subjects affected / exposed [2]
    207 / 218 (94.95%)
    211 / 220 (95.91%)
    470 / 505 (93.07%)
    469 / 505 (92.87%)
    439 / 499 (87.98%)
    66 / 84 (78.57%)
         occurrences all number
    1054
    1128
    1933
    2249
    1296
    110
    Anaemia
    alternative dictionary used: NCI CTCAE 3.0
         subjects affected / exposed [3]
    115 / 218 (52.75%)
    134 / 220 (60.91%)
    261 / 505 (51.68%)
    276 / 505 (54.65%)
    195 / 499 (39.08%)
    18 / 84 (21.43%)
         occurrences all number
    315
    382
    622
    662
    345
    25
    Thrombocytopenia
    alternative dictionary used: NCI CTCAE 3.0
         subjects affected / exposed [4]
    158 / 218 (72.48%)
    167 / 220 (75.91%)
    327 / 505 (64.75%)
    364 / 505 (72.08%)
    286 / 499 (57.31%)
    36 / 84 (42.86%)
         occurrences all number
    532
    606
    1023
    1360
    617
    48
    Gastrointestinal disorders
    Nausea or vomiting
    alternative dictionary used: NCI CTCAE 3.0
         subjects affected / exposed [5]
    19 / 218 (8.72%)
    22 / 220 (10.00%)
    33 / 505 (6.53%)
    49 / 505 (9.70%)
    32 / 499 (6.41%)
    9 / 84 (10.71%)
         occurrences all number
    25
    50
    53
    83
    42
    10
    Mucositis
    alternative dictionary used: NCI CTCAE 3.0
         subjects affected / exposed [6]
    20 / 218 (9.17%)
    16 / 220 (7.27%)
    25 / 505 (4.95%)
    39 / 505 (7.72%)
    28 / 499 (5.61%)
    7 / 84 (8.33%)
         occurrences all number
    30
    23
    27
    56
    38
    8
    Infections and infestations
    Infection
    alternative dictionary used: NCI CTCAE 3.0
         subjects affected / exposed [7]
    51 / 218 (23.39%)
    43 / 220 (19.55%)
    56 / 505 (11.09%)
    75 / 505 (14.85%)
    40 / 499 (8.02%)
    11 / 84 (13.10%)
         occurrences all number
    67
    57
    69
    104
    51
    11
    Notes
    [1] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: Non-serious AEs were documented on the same CRF reporting treatment administration. This CRF is missing in a small number of patients. As we do not have any information on (non-serious) AEs in these patients, they have been excluded from the "exposed" cohort.
    [2] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: Non-serious AEs were documented on the same CRF reporting treatment administration. This CRF is missing in a small number of patients. As we do not have any information on (non-serious) AEs in these patients, they have been excluded from the "exposed" cohort.
    [3] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: Non-serious AEs were documented on the same CRF reporting treatment administration. This CRF is missing in a small number of patients. As we do not have any information on (non-serious) AEs in these patients, they have been excluded from the "exposed" cohort.
    [4] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: Non-serious AEs were documented on the same CRF reporting treatment administration. This CRF is missing in a small number of patients. As we do not have any information on (non-serious) AEs in these patients, they have been excluded from the "exposed" cohort.
    [5] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: Non-serious AEs were documented on the same CRF reporting treatment administration. This CRF is missing in a small number of patients. As we do not have any information on (non-serious) AEs in these patients, they have been excluded from the "exposed" cohort.
    [6] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: Non-serious AEs were documented on the same CRF reporting treatment administration. This CRF is missing in a small number of patients. As we do not have any information on (non-serious) AEs in these patients, they have been excluded from the "exposed" cohort.
    [7] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: Non-serious AEs were documented on the same CRF reporting treatment administration. This CRF is missing in a small number of patients. As we do not have any information on (non-serious) AEs in these patients, they have been excluded from the "exposed" cohort.

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    12 Oct 2009
    Implementation of additional PET for PET-2-negative patients with residual lesions after end of chemotherapy; introduction of obligatory prephase treatment with dexamethasone for patients older than 40 years and extended prophylaxis
    22 Sep 2011
    Implementation of the results of the preceding GHSG HD15 trial: Therapy in the standard arms A and C was changed from 8 to 6 cycles eBEACOPP. Randomization for patients with positive PET-2 was stopped because the required sample size for superiority test was reached and PET-2-positive patients were subsequently treated with standard of 6x eBEACOPP.
    21 Dec 2012
    Recruitment of 500 additional patients in order to reach sufficient power for the analysis of PET-2-negative patients; current information regarding adjuvant medication (Levofloxacin) was taken into account.
    14 Apr 2014
    Adaption of the reference level for the evaluation of PET for radiotherapy recommendation
    11 Sep 2017
    Enable the documentation of follow-up data of all patients until the global end of the study.

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    19 Oct 2012
    Originally planned recruitment completed on 19-Oct-2012. Reassessment of assumptions - another 500 patients required in order to analyze the study question for PET-2-negative patients with sufficient power. Recruitment paused until amendment was approved.
    24 Jan 2013

    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/28236583
    http://www.ncbi.nlm.nih.gov/pubmed/29061295
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