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    Clinical Trial Results:
    HD17 for Intermediate Stage Hodgkin Lymphoma - Treatment Optimization Trial in the First-Line Treatment of intermediate Stage Hodgkin lymhoma; Therapy stratification by means of FDG-PET

    Summary
    EudraCT number
    		 2007-005920-34
    Trial protocol
    		 DE   NL   AT  
    Global end of trial date
    21 Mar 2020

    Results information
    Results version number
    		 v1(current)
    This version publication date
    24 Mar 2021
    First version publication date
    24 Mar 2021
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    Uni-Koeln-1014
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01356680
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    University of Cologne
    Sponsor organisation address
    Albertus Magnus-Platz, Köln, Germany, 50923
    Public contact
    German Hodgkin Study Group (GHSG), Trial Coordination Center of the German Hodgkin Study Group (GHSG), 0049 22147888200, ghsg@uk-koeln.de
    Scientific contact
    German Hodgkin Study Group (GHSG), Trial Coordination Center of the 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
    30 Oct 2020
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    21 Mar 2020
    Global end of trial reached?
    Yes
    Global end of trial date
    21 Mar 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The aim of the HD17 trial was to individualize the treatment of patients with intermediate-stage Hodgkin lymphoma (HL) by PET-guided treatmet, omitting radiotherapy in PET-negative patients after completion of 4 chemotherapy cycles (PET4). The primary objective of the study was to show non-inferiority of the PET-guided strategy in terms of progression-free survival (PFS). The second objective of the study was to confirm PET4-positivity as risk factor for PFS in patients treated with combined modality treatment (CMT).
    Protection of trial subjects
    Written informed consent before study entry, frequent DMC monitoring, hospitalization during first cycle, mandatory prophylaxis during chemotherapy, dose reduction strategy in case of adverse events
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    13 Jan 2012
    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
    Switzerland: 84
    Country: Number of subjects enrolled
    Netherlands: 8
    Country: Number of subjects enrolled
    Austria: 45
    Country: Number of subjects enrolled
    Germany: 963
    Worldwide total number of subjects
    1100
    EEA total number of subjects
    1016
    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)
    1100
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 Between 13 January 2012 and 21 March 2017, 1100 patients were recruited in 224 trial sites in 4 European countries.

    Pre-assignment
    Screening details
    		 Main entry criteria were histologically proven primary Hodgkin lymphoma (HL), clinical stages (CS) IA, IB, or IIA with pre-defined risk factor, ECOG performance status <= 2, and age at study entry 18-60 years.

    Period 1
    Period 1 title
    Randomization
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Assessor
    Blinding implementation details
    Patients and investigators as well as the central response assessment committee were masked to treatment allocation until central review of the PET4 examination had been completed.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 A: Standard CMT
    Arm description
    		 Standard CMT = combined modality treatment (chemotherapy followed by consolidating radiotherapy) Patients randomized to arm A were assigned to receive 2+2 chemotherapy (2 cycles eBEACOPP followed by 2 cycles ABVD) and 30 Gy IFRT (involved-field radiotherapy)
    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
    Powder for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    200 mg/m2 BSA on days 1-3 of each eBEACOPP 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 eBEACOPP 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 eBEACOPP 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 on day 8 of each eBEACOPP 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 on days 1-7 of each eBEACOPP 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 eBEACOPP cycle

    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
    Doxorubicine
    Investigational medicinal product code
    L01DB01
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    25 mg/m2 BSA on days 1+15 of each ABVD cycle

    Investigational medicinal product name
    Vinblastine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    6 mg/m2 BSA on days 1+15 of each ABVD cycle

    Investigational medicinal product name
    Dacarbazine
    Investigational medicinal product code
    Other name
    DTIC
    Pharmaceutical forms
    Powder for solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    375 mg/m2 BSA on days 1+15 of each ABVD cycle

    Arm title
    		 B: PET4-stratified treatment
    Arm description
    		 PET4-stratified treatment= chemotherapy only in case of PET4-negativity and standard CMT in case of PET4-positivity at the restaging after chemotherapy Patients randomized to arm B were assigned to receive standard 2+2 chemotherapy (2 cycles eBEACOPP followed by 2 cycles ABVD) and - in case of PET4-positivity - followed by consolidating 30 GY INRT (involved-node radiotherapy). PET4-positivity was defined as Deauville score (DS) 3 or 4 at the PET/CT-based restaging 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
    Powder for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    200 mg/m2 BSA on days 1-3 of each eBEACOPP 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 eBEACOPP 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 eBEACOPP 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 on day 8 of each eBEACOPP 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 on days 1-7 of each eBEACOPP 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 eBEACOPP cycle

    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 days 1+15 of each ABVD 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
    25 mg/m2 BSA on days 1+15 of each ABVD cycle

    Investigational medicinal product name
    Vinblastine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    6 mg/m2 BSA on days 1+15 of each ABVD cycle

    Investigational medicinal product name
    Dacarbazine
    Investigational medicinal product code
    Other name
    DTIC
    Pharmaceutical forms
    Powder for solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    375 mg/m2 BSA on days 1+15 of each ABVD cycle

    Number of subjects in period 1
    		A: Standard CMT B: PET4-stratified treatment
    Started
    548
    552
    Completed
    546
    550
    Not completed
    2
    2
         withdrawal before start of treatment
    1
    1
         Hodgkin lymphoma diagnosis disconfirmed
    1
    1
    Period 2
    Period 2 title
    ITT
    Is this the baseline period?
    		 Yes [1]
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 A: Standard CMT
    Arm description
    		 Standard CMT = combined modality treatment (chemotherapy followed by consolidating radiotherapy) Patients randomized to arm A were assigned to receive 2+2 chemotherapy (2 cycles eBEACOPP followed by 2 cycles ABVD) and 30 Gy IFRT (involved-field radiotherapy)
    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
    Powder for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    200 mg/m2 BSA on days 1-3 of each eBEACOPP 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 eBEACOPP 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 eBEACOPP 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 on day 8 of each eBEACOPP 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 on days 1-7 of each eBEACOPP 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 eBEACOPP cycle

    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
    Doxorubicine
    Investigational medicinal product code
    L01DB01
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    25 mg/m2 BSA on days 1+15 of each ABVD cycle

    Investigational medicinal product name
    Vinblastine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    6 mg/m2 BSA on days 1+15 of each ABVD cycle

    Investigational medicinal product name
    Dacarbazine
    Investigational medicinal product code
    Other name
    DTIC
    Pharmaceutical forms
    Powder for solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    375 mg/m2 BSA on days 1+15 of each ABVD cycle

    Arm title
    		 B: PET4-stratified treatment
    Arm description
    		 PET4-stratified treatment= chemotherapy only in case of PET4-negativity and standard CMT in case of PET4-positivity at the restaging after chemotherapy Patients randomized to arm B were assigned to receive standard 2+2 chemotherapy (2 cycles eBEACOPP followed by 2 cycles ABVD) and - in case of PET4-positivity - followed by consolidating 30 GY INRT (involved-node radiotherapy). PET4-positivity was defined as Deauville score (DS) 3 or 4 at the PET/CT-based restaging 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
    Powder for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    200 mg/m2 BSA on days 1-3 of each eBEACOPP 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 eBEACOPP 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 eBEACOPP 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 on day 8 of each eBEACOPP 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 on days 1-7 of each eBEACOPP 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 eBEACOPP cycle

    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 days 1+15 of each ABVD 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
    25 mg/m2 BSA on days 1+15 of each ABVD cycle

    Investigational medicinal product name
    Vinblastine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    6 mg/m2 BSA on days 1+15 of each ABVD cycle

    Investigational medicinal product name
    Dacarbazine
    Investigational medicinal product code
    Other name
    DTIC
    Pharmaceutical forms
    Powder for solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    375 mg/m2 BSA on days 1+15 of each ABVD cycle

    Notes
    [1] - Period 1 is not the baseline period. It is expected that period 1 will be the baseline period.
    Justification: Randomized patients with disconfirmed HL or who did not start study treatment were excluded from all analyses and are not reported.
    Number of subjects in period 2 [2]
    		A: Standard CMT B: PET4-stratified treatment
    Started
    546
    550
    Completed
    428
    477
    Not completed
    118
    73
         Adverse event, serious fatal
    -
    1
         acute toxicity of chemotherapy
    2
    1
         early-stage or advanced-stage HL
    49
    39
         violation of other inclusion criteria
    2
    2
         no PET4 for other reasons
    5
    11
         Protocol deviation
    60
    19
    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: Patients with disconfirmed HL diagnosis and those who did not receive any study treatment were excluded from all analyses are not reported in the baseline period.

    Baseline characteristics

    		 Close Top of page
    Baseline characteristics reporting groups
    Reporting group title
    A: Standard CMT
    Reporting group description
    		 Standard CMT = combined modality treatment (chemotherapy followed by consolidating radiotherapy) Patients randomized to arm A were assigned to receive 2+2 chemotherapy (2 cycles eBEACOPP followed by 2 cycles ABVD) and 30 Gy IFRT (involved-field radiotherapy)

    Reporting group title
    B: PET4-stratified treatment
    Reporting group description
    		 PET4-stratified treatment= chemotherapy only in case of PET4-negativity and standard CMT in case of PET4-positivity at the restaging after chemotherapy Patients randomized to arm B were assigned to receive standard 2+2 chemotherapy (2 cycles eBEACOPP followed by 2 cycles ABVD) and - in case of PET4-positivity - followed by consolidating 30 GY INRT (involved-node radiotherapy). PET4-positivity was defined as Deauville score (DS) 3 or 4 at the PET/CT-based restaging after chemotherapy.

    Reporting group values
    		 A: Standard CMT B: PET4-stratified treatment Total
    Number of subjects
    		 546 550 1096
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 546 550 1096
        From 65-84 years
    		 0 0 0
        85 years and over
    		 0 0 0
    Gender categorical
    Units: Subjects
        Female
    		 294 294 588
        Male
    		 252 256 508
    Ann Arbor Stage
    Units: Subjects
        IA
    		 20 18 38
        IB
    		 18 12 30
        IIA
    		 374 376 750
        IIB
    		 134 143 277
        IIIA
    		 0 1 1
    ECOG Performance
    Units: Subjects
        ECOG: 0
    		 448 444 892
        ECOG:1
    		 98 102 200
        ECOG: 2
    		 0 4 4
        ECOG: >2
    		 0 0 0
    Large mediastinal mass
    Units: Subjects
        No
    		 448 449 897
        Yes
    		 98 101 199
    Elevated erythrocyte sedimentation rate
    Units: Subjects
        No
    		 303 298 601
        Yes
    		 243 252 495
    >= 3 nodal areas involved
    Units: Subjects
        No
    		 153 150 303
        Yes
    		 393 400 793
    Infra-diaphragmatic disease
    Units: Subjects
        No
    		 511 517 1028
        Yes
    		 35 33 68
    Bulky disease
    Units: Subjects
        No
    		 263 245 508
        Yes
    		 283 305 588
    Histologic subtype
    Units: Subjects
        Nodular sclerosis
    		 210 211 421
        Mixed cellularity
    		 54 46 100
        Lymphocyte-depleted
    		 1 0 1
        Lymphocyte-rich
    		 8 7 15
        unspecified classical HL
    		 59 52 111
        Nodular lymphocyte-predominant HL
    		 7 7 14
        not recorded
    		 207 227 434

    End points

    		 Close Top of page
    End points reporting groups
    Reporting group title
    A: Standard CMT
    Reporting group description
    		 Standard CMT = combined modality treatment (chemotherapy followed by consolidating radiotherapy) Patients randomized to arm A were assigned to receive 2+2 chemotherapy (2 cycles eBEACOPP followed by 2 cycles ABVD) and 30 Gy IFRT (involved-field radiotherapy)

    Reporting group title
    B: PET4-stratified treatment
    Reporting group description
    		 PET4-stratified treatment= chemotherapy only in case of PET4-negativity and standard CMT in case of PET4-positivity at the restaging after chemotherapy Patients randomized to arm B were assigned to receive standard 2+2 chemotherapy (2 cycles eBEACOPP followed by 2 cycles ABVD) and - in case of PET4-positivity - followed by consolidating 30 GY INRT (involved-node radiotherapy). PET4-positivity was defined as Deauville score (DS) 3 or 4 at the PET/CT-based restaging after chemotherapy.
    Reporting group title
    A: Standard CMT
    Reporting group description
    		 Standard CMT = combined modality treatment (chemotherapy followed by consolidating radiotherapy) Patients randomized to arm A were assigned to receive 2+2 chemotherapy (2 cycles eBEACOPP followed by 2 cycles ABVD) and 30 Gy IFRT (involved-field radiotherapy)

    Reporting group title
    B: PET4-stratified treatment
    Reporting group description
    		 PET4-stratified treatment= chemotherapy only in case of PET4-negativity and standard CMT in case of PET4-positivity at the restaging after chemotherapy Patients randomized to arm B were assigned to receive standard 2+2 chemotherapy (2 cycles eBEACOPP followed by 2 cycles ABVD) and - in case of PET4-positivity - followed by consolidating 30 GY INRT (involved-node radiotherapy). PET4-positivity was defined as Deauville score (DS) 3 or 4 at the PET/CT-based restaging after chemotherapy.

    Subject analysis set title
    Arm A (PP)
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Arm A: standard combined modality treatment (PP)

    Subject analysis set title
    Arm B (PP)
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Arm B: experimental PET4-stratified treatment

    Subject analysis set title
    Arm A - PET4-negative (PP)
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Arm A: standard CMT ( 2+2 chemotherapy followed by consolidating 30 Gy IF-RT)

    Subject analysis set title
    Arm B - PET4-negative (PP)
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Arm B: experimental treatment omitting consolidating radiotherapy for PET4-negative patients

    Subject analysis set title
    CMT PET4-negative (ITT)
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    PET4-negative arm A patients: combined modality treatment PET4-negativity was defined as Deauville Score (DS) <3 in the trial protocol.

    Subject analysis set title
    CMT PET4-positive (ITT)
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All PET4-positive patients. All received combined modality treatment. Arm A: 2+2 followed by 30 Gy IF-RT Arm B: 2+2 followed by 30 Gy IN-RT PET4-positivity was defined as Deauville Score (DS) 3 or 4 in the trial protocol.

    Primary: Progression-free survival (PFS) - PP analysis

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    End point title
    		 Progression-free survival (PFS) - PP analysis
    End point description
    This is a per-protocol analysis of Progression-free survival (PFS). Patients without regular PET4 review or with protocol violation after the PET4 result had been documented where excluded. PFS was defined as the time from study entry until progression, relapse, or death from any cause. If none of these events had occurred, PFS was censored at the date of last information on disease status. PFS 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 was months. 5-year estimates and the rspective 95% CIs will be reported.
    End point type
    Primary
    End point timeframe
    5 years
    End point values
    		 Arm A (PP) Arm B (PP)
    Number of subjects analysed
    435 [1]
    479 [2]
    Units: percent
        number (confidence interval 95%)
    97.4 (95.0 to 98.7)
    94.5 (91.5 to 96.5)
    Notes
    [1] - Patients in arm A received standard CMT (2 x eBEACOPP + 2 x ABVD, followed by 30 Gy IF-RT)
    [2] - PET4-stratified treatment (2+2 chemotherapy for all. Omission of 30 Gy IN-RT if PET4-negative)
    Statistical analysis title
    		 Non-inferiority test
    Statistical analysis description
    Non-inferiority would be established if the lower limit of the 2-sided 95%-CI for the difference in 5-year PFS was above -8%.
    Comparison groups
    Arm A (PP) v Arm B (PP)
    Number of subjects included in analysis
    914
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [3]
    Method
    Parameter type
    		 Difference in 5-year estimates
    Point estimate
    -2.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.8
         upper limit
    		 0.1
    Notes
    [3] - Non-inferiority would be established if the lower limit of the 2-sided 95%-CI for the difference in 5-year PFS was above -8%. As the 95%-CI for the 5-year difference excluded the pedefined non-inferiority margin of -8%, non-inferiority of the PET4-stratified treatment strategy could be concluded

    Primary: Progression-free survival (PFS)- PP analysis of PET4-negative patients

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    End point title
    		 Progression-free survival (PFS)- PP analysis of PET4-negative patients
    End point description
    The second primary objective of the trial was to demonstrate non-inferiority of 2+2-chemotherapy over combined modality treatment (2+2 + IF-RT) for patients with a complete metabolic response after chemotherapy (PET4-negative patients).
    End point type
    Primary
    End point timeframe
    5-years
    End point values
    		 Arm A - PET4-negative (PP) Arm B - PET4-negative (PP)
    Number of subjects analysed
    318
    333
    Units: percent
        number (confidence interval 95%)
    97.9 (94.9 to 99.1)
    94.9 (91.2 to 97.0)
    Statistical analysis title
    		 Non-inferiority test for PET4-negative patients
    Comparison groups
    Arm A - PET4-negative (PP) v Arm B - PET4-negative (PP)
    Number of subjects included in analysis
    651
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [4]
    Method
    Parameter type
    		 Difference in 5-year estimates
    Point estimate
    -3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.4
         upper limit
    		 0.3
    Notes
    [4] - As the 95%-CI for the 5-year difference excluded the predefined non-inferiority margin of -8%, non-inferiority of 2+2 over CMT could be concluded for PET4-negative patients

    Primary: Progression-free survival (PFS) - ITT analysis of CMT-treated patients

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    End point title
    		 Progression-free survival (PFS) - ITT analysis of CMT-treated patients
    End point description
    The third primary objective of the trial was do demonstrate the negative-prognostic value of PET4-positivity in an ITT-analysis of all PET4-positive arm A and arm B patients and PET-negative arm B patients (all assigned to combined modality treatment).
    End point type
    Primary
    End point timeframe
    5-years
    End point values
    		 CMT PET4-negative (ITT) CMT PET4-positive (ITT)
    Number of subjects analysed
    318
    328
    Units: percent
        number (confidence interval 95%)
    97.9 (94.9 to 99.1)
    94.7 (91.0 to 96.9)
    Statistical analysis title
    		 Comparison of PET4-negative and PET4-positive pts.
    Comparison groups
    CMT PET4-negative (ITT) v CMT PET4-positive (ITT)
    Number of subjects included in analysis
    646
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [5]
    P-value
    		 = 0.01
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    3.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.2
         upper limit
    		 9
    Notes
    [5] - Kaplan-Meier analysis of PFS-curves : Comparison of PET4-positive and PET4-negative patients treated with 2+2 followed by consolidating radiotherapy.

    Secondary: Progression-free survival (PFS) - ITT analysis

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    End point title
    		 Progression-free survival (PFS) - ITT analysis
    End point description
    This is an intention-to treat analysis of Progression-free survival (PFS) which was defined as the time from study entry until progression, relapse, or death from any cause. If none of these events had occurred, PFS was censored at the date of last information on disease status. PFS 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 was 52 months. 5-year estimates and the respective 95% CIs will be reported.
    End point type
    Secondary
    End point timeframe
    5 years
    End point values
    		 A: Standard CMT B: PET4-stratified treatment
    Number of subjects analysed
    546 [6]
    550 [7]
    Units: percent
        number (confidence interval 95%)
    96.7 (94.4 to 98.0)
    94.0 (91.2 to 95.9)
    Notes
    [6] - ITT analysis
    [7] - ITT
    No statistical analyses for this end point

    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 administraion CRFs for the duration of chemotherapy. SAEs were addditionally 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 administraion 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 - Safety Set
    Reporting group description
    		 Patients randomized to standard treatment (2+2 chemotherapy + 30 Gy IF-RT). Patients with disconfirmed HL diagnosis or without documented chemotherapy-CRF were excluded from analysis.

    Reporting group title
    Arm B - Safety set
    Reporting group description
    		 Patients randomized to PET4-stratified treatment (2+2 chemotherapy followed by 30Gy INRT only in case of PET4-positivity). Patients with disconfirmed HL diagnosis or without documented chemotherapy-CRF were excluded from analysis.

    Serious adverse events
    		 Arm A - Safety Set Arm B - Safety set
    Total subjects affected by serious adverse events
         subjects affected / exposed
    161 / 544 (29.60%)
    164 / 543 (30.20%)
         number of deaths (all causes)
    5
    5
         number of deaths resulting from adverse events
    0
    1
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Neoplasms benign, malignant and unspecified
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 544 (0.18%)
    0 / 543 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Vascular disorders
    alternative assessment type: Systematic
         subjects affected / exposed
    11 / 544 (2.02%)
    18 / 543 (3.31%)
         occurrences causally related to treatment / all
    11 / 12
    14 / 18
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Surgical and medicalprocedures
    alternative assessment type: Systematic
         subjects affected / exposed
    3 / 544 (0.55%)
    0 / 543 (0.00%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    General disorders and administration site conditions
    alternative assessment type: Systematic
         subjects affected / exposed
    39 / 544 (7.17%)
    37 / 543 (6.81%)
         occurrences causally related to treatment / all
    40 / 44
    36 / 38
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Immune system disorder
    alternative assessment type: Systematic
         subjects affected / exposed
    5 / 544 (0.92%)
    5 / 543 (0.92%)
         occurrences causally related to treatment / all
    4 / 5
    3 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Respiratory, thoracic and mediastinal disorders
    alternative assessment type: Systematic
         subjects affected / exposed
    9 / 544 (1.65%)
    8 / 543 (1.47%)
         occurrences causally related to treatment / all
    10 / 11
    8 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Psychiatric disorder
    alternative assessment type: Systematic
         subjects affected / exposed
    2 / 544 (0.37%)
    1 / 543 (0.18%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Investigations
    alternative assessment type: Systematic
         subjects affected / exposed
    7 / 544 (1.29%)
    7 / 543 (1.29%)
         occurrences causally related to treatment / all
    5 / 7
    5 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Injury, poisoning and procedural complications
    alternative assessment type: Systematic
         subjects affected / exposed
    6 / 544 (1.10%)
    1 / 543 (0.18%)
         occurrences causally related to treatment / all
    2 / 7
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiac disorders
    alternative assessment type: Systematic
         subjects affected / exposed
    6 / 544 (1.10%)
    2 / 543 (0.37%)
         occurrences causally related to treatment / all
    5 / 7
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Nervous system disorders
    alternative assessment type: Systematic
         subjects affected / exposed
    5 / 544 (0.92%)
    4 / 543 (0.74%)
         occurrences causally related to treatment / all
    4 / 5
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Blood and lymphatic system disorders
    alternative assessment type: Systematic
         subjects affected / exposed
    56 / 544 (10.29%)
    64 / 543 (11.79%)
         occurrences causally related to treatment / all
    74 / 76
    82 / 82
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Eye disorder
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 544 (0.00%)
    1 / 543 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Gastrointestinal disorder
    alternative assessment type: Systematic
         subjects affected / exposed
    37 / 544 (6.80%)
    36 / 543 (6.63%)
         occurrences causally related to treatment / all
    39 / 46
    38 / 43
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hepatobiliary disorder
         subjects affected / exposed
    1 / 544 (0.18%)
    0 / 543 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Skin and subcutaneous tissue disorders
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 544 (0.18%)
    3 / 543 (0.55%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal and urinary disorders
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 544 (0.18%)
    2 / 543 (0.37%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Musculoskeletal and connective tissue disorders
    alternative assessment type: Systematic
         subjects affected / exposed
    7 / 544 (1.29%)
    9 / 543 (1.66%)
         occurrences causally related to treatment / all
    1 / 10
    3 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Infections and infestations
    alternative assessment type: Systematic
         subjects affected / exposed
    28 / 544 (5.15%)
    36 / 543 (6.63%)
         occurrences causally related to treatment / all
    32 / 35
    37 / 38
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Metabolism and nutrition disorders
    Metabolism and nutrion disorders
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 544 (0.18%)
    0 / 543 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0.05%
    Non-serious adverse events
    		 Arm A - Safety Set Arm B - Safety set
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    455 / 544 (83.64%)
    455 / 543 (83.79%)
    Blood and lymphatic system disorders
    Leukopenia
    alternative dictionary used: NCI CTCAE 3.0
         subjects affected / exposed [1]
    436 / 531 (82.11%)
    444 / 530 (83.77%)
         occurrences all number
    1006
    1027
    Anemia
    alternative dictionary used: NCI CTCAE 3.0
         subjects affected / exposed [2]
    46 / 531 (8.66%)
    64 / 530 (12.08%)
         occurrences all number
    63
    89
    Thrombocytopenia
    alternative dictionary used: NCI CTCAE 3.0
         subjects affected / exposed [3]
    139 / 531 (26.18%)
    176 / 530 (33.21%)
         occurrences all number
    208
    265
    Gastrointestinal disorders
    Nausea/Vomiting
    alternative dictionary used: NCI CTCAE 3.0
         subjects affected / exposed [4]
    38 / 531 (7.16%)
    29 / 530 (5.47%)
         occurrences all number
    52
    33
    Infections and infestations
    Infection
    alternative dictionary used: NCI CTCAE 3.0
         subjects affected / exposed [5]
    32 / 531 (6.03%)
    40 / 530 (7.55%)
         occurrences all number
    33
    43
    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 habe been excluded from te "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 for 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 for 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 for 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 for 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
    24 Jul 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? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/33539742
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