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    Clinical Trial Results:
    HD16 for early stages in Hodgkins Lymphoma

    Summary
    EudraCT number
    		 2007-004474-24
    Trial protocol
    		 DE   NL   AT  
    Global end of trial date
    29 Dec 2020

    Results information
    Results version number
    		 v1(current)
    This version publication date
    02 Sep 2021
    First version publication date
    02 Sep 2021
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    Uni-Koeln-987
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00736320
    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
    06 Jul 2021
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    29 Dec 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The HD16 trial had 2 co-primary objectives regarding the treatment of early-stage favorable Hodgkin lymphoma (HL). The first question addressed whether radiotherapy could be omitted from standard combined-modality treatment (CMT) in patients with a negative PET after 2 cycles of ABVD (PET-2) without a clinically relevant loss of tumor control in terms of non-inferior progression-free survival (PFS). Second, the HD16 trial aimed to assess whether a positive PET-2 represented a risk factor for PFS among patients treated with CMT.
    Protection of trial subjects
    Written informed consent before study entry, frequent IDMC monitoring, central expert review of PET-2
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    25 Nov 2009
    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: 19
    Country: Number of subjects enrolled
    Austria: 43
    Country: Number of subjects enrolled
    Germany: 1025
    Country: Number of subjects enrolled
    Switzerland: 63
    Worldwide total number of subjects
    1150
    EEA total number of subjects
    1087
    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)
    1079
    From 65 to 84 years
    71
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 Between 25 Nov 2009 and 29 Dec 2015, 1150 patients were enrolled in 250 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, IIA, or IIB without pre-defined risk factors, ECOG performance status <= 2, and age at study entry 18-75 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, Data analyst, Assessor
    Blinding implementation details
    Patients and investigators as well as the central response assessment panel and data analysts were masked to treatment allocation until central review of the PET-2 examination had been completed.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Standard CMT
    Arm description
    		 Standard combined-modality treatment (CMT): Patients randomized to this arm were assigned to receive 2 cycles of ABVD chemotherapy followed by centrally reviewed PET/CT-based restaging (PET-2) and 20 Gy involved-field radiotherapy (IF-RT).
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Doxorubicin
    Investigational medicinal product code
    L01DB01
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    25 mg/m² BSA on day 1 and 15 of each 28-day cycle

    Investigational medicinal product name
    Bleomycin
    Investigational medicinal product code
    L01DC01
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous bolus use
    Dosage and administration details
    10 mg/m² BSA on day 1 and 15 of each 28-day cycle

    Investigational medicinal product name
    Vinblastine
    Investigational medicinal product code
    L01CA01
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous bolus use
    Dosage and administration details
    6 mg/m² BSA on day 1 and 15 of each 28-day cycle

    Investigational medicinal product name
    Dacarbazine
    Investigational medicinal product code
    L01AX04
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    375 mg/m² BSA on day 1 and 15 of each 28-day cycle

    Arm title
    		 PET-2-guided treatment
    Arm description
    		 PET-2-guided treatment: Patients randomized to this arm were assigned to receive 2 cycles of ABVD chemotherapy followed by centrally reviewed PET/CT-based restaging (PET-2). Only in case of a positive PET-2 in terms of a Deauville score of 3 or higher, chemotherapy was followed by consolidating 20 Gy IF-RT.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Doxorubicin
    Investigational medicinal product code
    L01DB01
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    25 mg/m² BSA on day 1 and 15 of each 28-day cycle

    Investigational medicinal product name
    Bleomycin
    Investigational medicinal product code
    L01DC01
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous bolus use
    Dosage and administration details
    10 mg/m² BSA on day 1 and 15 of each 28-day cycle

    Investigational medicinal product name
    Vinblastine
    Investigational medicinal product code
    L01CA01
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous bolus use
    Dosage and administration details
    6 mg/m² BSA on day 1 and 15 of each 28-day cycle

    Investigational medicinal product name
    Dacarbazine
    Investigational medicinal product code
    L01AX04
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    375 mg/m² BSA on day 1 and 15 of each 28-day cycle

    Number of subjects in period 1
    		Standard CMT PET-2-guided treatment
    Started
    575
    575
    Completed
    573
    566
    Not completed
    2
    9
         Consent withdrawn by subject
    -
    1
         Disconfirmation of diagnosis
    2
    8
    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, Data analyst, Assessor
    Blinding implementation details
    Patients and investigators as well as the central response assessment panel and data analysts were masked to treatment allocation until central review of the PET-2 examination had been completed.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Standard CMT
    Arm description
    		 Standard combined-modality treatment (CMT): Patients randomized to this arm were assigned to receive 2 cycles of ABVD chemotherapy followed by centrally reviewed PET/CT-based restaging (PET-2) and 20 Gy involved-field radiotherapy (IF-RT).
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Doxorubicin
    Investigational medicinal product code
    L01DB01
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    25 mg/m² BSA on day 1 and 15 of each 28-day cycle

    Investigational medicinal product name
    Bleomycin
    Investigational medicinal product code
    L01DC01
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous bolus use
    Dosage and administration details
    10 mg/m² BSA on day 1 and 15 of each 28-day cycle

    Investigational medicinal product name
    Vinblastine
    Investigational medicinal product code
    L01CA01
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous bolus use
    Dosage and administration details
    6 mg/m² BSA on day 1 and 15 of each 28-day cycle

    Investigational medicinal product name
    Dacarbazine
    Investigational medicinal product code
    L01AX04
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    375 mg/m² BSA on day 1 and 15 of each 28-day cycle

    Arm title
    		 PET-2-guided treatment
    Arm description
    		 PET-2-guided treatment: Patients randomized to this arm were assigned to receive 2 cycles of ABVD chemotherapy followed by centrally reviewed PET/CT-based restaging (PET-2). Only in case of a positive PET-2 in terms of a Deauville score of 3 or higher, chemotherapy was followed by consolidating 20 Gy IF-RT.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Doxorubicin
    Investigational medicinal product code
    L01DB01
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    25 mg/m² BSA on day 1 and 15 of each 28-day cycle

    Investigational medicinal product name
    Bleomycin
    Investigational medicinal product code
    L01DC01
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous bolus use
    Dosage and administration details
    10 mg/m² BSA on day 1 and 15 of each 28-day cycle

    Investigational medicinal product name
    Vinblastine
    Investigational medicinal product code
    L01CA01
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous bolus use
    Dosage and administration details
    6 mg/m² BSA on day 1 and 15 of each 28-day cycle

    Investigational medicinal product name
    Dacarbazine
    Investigational medicinal product code
    L01AX04
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    375 mg/m² BSA on day 1 and 15 of each 28-day 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 those who did not start study treatment were excluded from all analyses including baseline characteristics.
    Number of subjects in period 2 [2]
    		Standard CMT PET-2-guided treatment
    Started
    573
    566
    Completed
    501
    506
    Not completed
    72
    60
         Consent withdrawn by subject
    4
    2
         Lack of efficacy
    1
    -
         Protocol deviation
    67
    58
    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

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    Baseline characteristics reporting groups
    Reporting group title
    Standard CMT
    Reporting group description
    		 Standard combined-modality treatment (CMT): Patients randomized to this arm were assigned to receive 2 cycles of ABVD chemotherapy followed by centrally reviewed PET/CT-based restaging (PET-2) and 20 Gy involved-field radiotherapy (IF-RT).

    Reporting group title
    PET-2-guided treatment
    Reporting group description
    		 PET-2-guided treatment: Patients randomized to this arm were assigned to receive 2 cycles of ABVD chemotherapy followed by centrally reviewed PET/CT-based restaging (PET-2). Only in case of a positive PET-2 in terms of a Deauville score of 3 or higher, chemotherapy was followed by consolidating 20 Gy IF-RT.

    Reporting group values
    		 Standard CMT PET-2-guided treatment Total
    Number of subjects
    		 573 566 1139
    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)
    		 543 528 1071
        From 65-84 years
    		 30 38 68
        85 years and over
    		 0 0 0
    Age continuous
    Units: years
        median (full range (min-max))
    		 38 (18 to 75) 37 (18 to 75) -
    Gender categorical
    Units: Subjects
        Female
    		 241 244 485
        Male
    		 332 322 654
    Ann Arbor stage
    Units: Subjects
        IA
    		 164 145 309
        IB
    		 24 22 46
        IIA
    		 358 367 725
        IIB
    		 27 32 59
    ECOG performance status
    Units: Subjects
        ECOG 0
    		 529 519 1048
        ECOG 1
    		 43 47 90
        ECOG 2
    		 1 0 1
    Histologic subtype
    Units: Subjects
        Classical HL
    		 433 409 842
        Nodular lymphocyte-predominant HL
    		 43 54 97
        Not done
    		 97 103 200

    End points

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    End points reporting groups
    Reporting group title
    Standard CMT
    Reporting group description
    		 Standard combined-modality treatment (CMT): Patients randomized to this arm were assigned to receive 2 cycles of ABVD chemotherapy followed by centrally reviewed PET/CT-based restaging (PET-2) and 20 Gy involved-field radiotherapy (IF-RT).

    Reporting group title
    PET-2-guided treatment
    Reporting group description
    		 PET-2-guided treatment: Patients randomized to this arm were assigned to receive 2 cycles of ABVD chemotherapy followed by centrally reviewed PET/CT-based restaging (PET-2). Only in case of a positive PET-2 in terms of a Deauville score of 3 or higher, chemotherapy was followed by consolidating 20 Gy IF-RT.
    Reporting group title
    Standard CMT
    Reporting group description
    		 Standard combined-modality treatment (CMT): Patients randomized to this arm were assigned to receive 2 cycles of ABVD chemotherapy followed by centrally reviewed PET/CT-based restaging (PET-2) and 20 Gy involved-field radiotherapy (IF-RT).

    Reporting group title
    PET-2-guided treatment
    Reporting group description
    		 PET-2-guided treatment: Patients randomized to this arm were assigned to receive 2 cycles of ABVD chemotherapy followed by centrally reviewed PET/CT-based restaging (PET-2). Only in case of a positive PET-2 in terms of a Deauville score of 3 or higher, chemotherapy was followed by consolidating 20 Gy IF-RT.

    Subject analysis set title
    Standard CMT - PET-2-negative PP
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Per-protocol population of patients assigned to the standard CMT group with negative PET-2 in terms of Deauville score 1-2. These patients received standard CMT with 2 cycles of ABVD chemotherapy and 20 Gy involved-field radiotherapy.

    Subject analysis set title
    PET-2-guided treatment - PET-2-negative PP
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Per-protocol population of patients assigned to the PET-2-guided treatment group with negative PET-2 in terms of Deauville score 1-2. These patients received 2 cycles of ABVD chemotherapy alone.

    Subject analysis set title
    CMT cohort with negative PET-2
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Patients with a negative PET-2 (in terms of a Deauville score of 1-2) assigned to receive CMT (i.e. only from the standard CMT group)

    Subject analysis set title
    CMT cohort with positive PET-2
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Patients with a positive PET-2 in terms of a Deauville score of 3 or higher assigned to receive CMT (i.e. from both the standard CMT and PET-2-guided treatment groups)

    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 all staging examinations 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 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.
    End point type
    Primary
    End point timeframe
    5 years
    End point values
    		 Standard CMT - PET-2-negative PP PET-2-guided treatment - PET-2-negative PP CMT cohort with negative PET-2 CMT cohort with positive PET-2
    Number of subjects analysed
    328
    300
    353
    340
    Units: Percent
        number (confidence interval 95%)
    94.2 (91.6 to 96.9)
    86.7 (82.5 to 90.9)
    94.0 (91.4 to 96.6)
    90.3 (86.9 to 93.6)
    Statistical analysis title
    		 Non-inferiority of PET-2-guided treatment
    Statistical analysis description
    Non-inferiority analysis regarding the omission of radiotherapy in patients with a negative PET-2: Non-inferiority of ABVD alone over standard CMT would be established if the upper limit of the 2-sided 95% CI for the hazard ratio was below the pre-defined non-inferiority margin of 3.01 in a per-protocol analysis of the PET-2-negative patient population. Hazard ratio and 95% CI were obtained from univariate Cox regression.
    Comparison groups
    PET-2-guided treatment - PET-2-negative PP v Standard CMT - PET-2-negative PP
    Number of subjects included in analysis
    628
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    2.05
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.2
         upper limit
    		 3.51
    Statistical analysis title
    		 Prognostic impact of PET-2
    Statistical analysis description
    Analysis of the prognostic impact of PET-2: A two-sided log-rank test regarding progression-free survival on a significance level of 5% was to be performed comparing groups defined by PET-2 result (i.e. Deauville score 1-2 vs. Deauville score 3 or higher) among all patients assigned to receive CMT.
    Comparison groups
    CMT cohort with positive PET-2 v CMT cohort with negative PET-2
    Number of subjects included in analysis
    693
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.013 [1]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.96
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.16
         upper limit
    		 3.32
    Notes
    [1] - Sensitivity analysis: Cox regression model adjusted for the stratification factors age, sex, B symptoms, disease localization, albumin level and bulky disease, HR=1.96, 95% CI 1.16-3.32, p=0.012.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events (AEs) of CTCAE grades 3/4 were assessed on the therapy administraion CRFs for the duration of study therapy. 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, non-serious AEs and 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
    Standard CMT
    Reporting group description
    		 Standard combined-modality treatment (CMT): Patients randomized to this arm were assigned to receive 2 cycles of ABVD chemotherapy followed by centrally reviewed PET/CT-based restaging (PET-2) and 20 Gy involved-field radiotherapy (IF-RT).

    Reporting group title
    PET-2-guided treatment
    Reporting group description
    		 PET-2-guided treatment: Patients randomized to this arm were assigned to receive 2 cycles of ABVD chemotherapy followed by centrally reviewed PET/CT-based restaging (PET-2). Only in case of a positive PET-2 in terms of a Deauville score of 3 or higher, chemotherapy was followed by consolidating 20 Gy IF-RT.

    Serious adverse events
    		 Standard CMT PET-2-guided treatment
    Total subjects affected by serious adverse events
         subjects affected / exposed
    71 / 571 (12.43%)
    51 / 561 (9.09%)
         number of deaths (all causes)
    14
    9
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Neoplasms benign, malignant and unspecified
         subjects affected / exposed
    0 / 571 (0.00%)
    1 / 561 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Vascular disorders
         subjects affected / exposed
    9 / 571 (1.58%)
    10 / 561 (1.78%)
         occurrences causally related to treatment / all
    8 / 9
    11 / 12
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    General disorders and administration site conditions
         subjects affected / exposed
    21 / 571 (3.68%)
    11 / 561 (1.96%)
         occurrences causally related to treatment / all
    21 / 23
    10 / 11
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Immune system disorderorders
         subjects affected / exposed
    0 / 571 (0.00%)
    1 / 561 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Reproductive system and breast disorders
         subjects affected / exposed
    0 / 571 (0.00%)
    1 / 561 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Respiratory, thoracic and mediastinal disorders
         subjects affected / exposed
    8 / 571 (1.40%)
    5 / 561 (0.89%)
         occurrences causally related to treatment / all
    6 / 8
    4 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Psychiatric disorders
         subjects affected / exposed
    2 / 571 (0.35%)
    1 / 561 (0.18%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Investigations
         subjects affected / exposed
    1 / 571 (0.18%)
    0 / 561 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Injury, poisoning and procedural complications
         subjects affected / exposed
    3 / 571 (0.53%)
    0 / 561 (0.00%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiac disorders
         subjects affected / exposed
    1 / 571 (0.18%)
    2 / 561 (0.36%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Nervous system disorders
         subjects affected / exposed
    2 / 571 (0.35%)
    1 / 561 (0.18%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Blood and lymphatic disorders
         subjects affected / exposed
    7 / 571 (1.23%)
    5 / 561 (0.89%)
         occurrences causally related to treatment / all
    6 / 7
    5 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Gastrointestinal disorders
         subjects affected / exposed
    11 / 571 (1.93%)
    4 / 561 (0.71%)
         occurrences causally related to treatment / all
    8 / 12
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Skin and subcutaneous tissue disorders
         subjects affected / exposed
    0 / 571 (0.00%)
    2 / 561 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal and urinary disorders
         subjects affected / exposed
    1 / 571 (0.18%)
    0 / 561 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Endocrine disorders
         subjects affected / exposed
    0 / 571 (0.00%)
    1 / 561 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Musculoskeletal and connective tissue disorders
         subjects affected / exposed
    7 / 571 (1.23%)
    3 / 561 (0.53%)
         occurrences causally related to treatment / all
    3 / 7
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Infections and infestations
         subjects affected / exposed
    10 / 571 (1.75%)
    13 / 561 (2.32%)
         occurrences causally related to treatment / all
    11 / 11
    15 / 15
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Metabolism and nutrition disorders
         subjects affected / exposed
    3 / 571 (0.53%)
    1 / 561 (0.18%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 1%
    Non-serious adverse events
    		 Standard CMT PET-2-guided treatment
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    156 / 571 (27.32%)
    141 / 561 (25.13%)
    Blood and lymphatic system disorders
    Leukopenia
    alternative dictionary used: NCI CTCAE 3.0
    alternative assessment type: Systematic
         subjects affected / exposed [1]
    103 / 554 (18.59%)
    100 / 542 (18.45%)
         occurrences all number
    131
    131
    General disorders and administration site conditions
    Nausea or vomiting
    alternative dictionary used: NCI CTCAE 3.0
    alternative assessment type: Systematic
         subjects affected / exposed [2]
    29 / 554 (5.23%)
    20 / 542 (3.69%)
         occurrences all number
    37
    23
    Gastrointestinal disorders
    Mucositis
    alternative dictionary used: NCI CTCAE 3.0
    alternative assessment type: Systematic
         subjects affected / exposed [3]
    9 / 554 (1.62%)
    3 / 542 (0.55%)
         occurrences all number
    9
    6
    Gastrointestinal disorder
    alternative dictionary used: NCI CTCAE 3.0
    alternative assessment type: Systematic
         subjects affected / exposed [4]
    9 / 554 (1.62%)
    9 / 542 (1.66%)
         occurrences all number
    11
    11
    Respiratory, thoracic and mediastinal disorders
    Respiratory disorder
    alternative dictionary used: NCI CTCAE 3.0
    alternative assessment type: Systematic
         subjects affected / exposed [5]
    10 / 554 (1.81%)
    12 / 542 (2.21%)
         occurrences all number
    10
    13
    Infections and infestations
    Infection
    alternative dictionary used: NCI CTCAE 3.0
    alternative assessment type: Systematic
         subjects affected / exposed [6]
    11 / 554 (1.99%)
    14 / 542 (2.58%)
         occurrences all number
    12
    16
    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 adverse events 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) adverse events 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 adverse events 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) adverse events 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 adverse events 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) adverse events 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 adverse events 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) adverse events 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 adverse events 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) adverse events 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 adverse events 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) adverse events in these patients, they have been excluded from the "exposed" cohort.

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    12 Oct 2009
    Reduction of radiotherapy dose from 30 Gy to 20 Gy based on the results of the GHSG HD10 trial
    17 Jul 2015
    Extension of recruitment period and sample size, rearrangement of statistical test hierarchy and adaption of test parameters for reasons of feasibility, all based on recommendations by the independent DMC
    14 Aug 2017
    Extension of individual follow-up period until the end of the study for all patients who would provide separate informed consent

    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/3149875
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