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    Clinical Trial Results:
    EWING 2008

    Summary
    EudraCT number
    2008-003658-13
    Trial protocol
    DE   AT   BE   NL   SE   HU   FI   LT   PL  
    Global end of trial date
    30 Jun 2019

    Results information
    Results version number
    v1(current)
    This version publication date
    12 Jan 2020
    First version publication date
    12 Jan 2020
    Other versions

    Trial information

    Close Top of page
    Trial identification
    Sponsor protocol code
    EWING2008
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    -
    WHO universal trial number (UTN)
    -
    Other trial identifiers
    ClinicalTrials.gov: NCT00824083
    Sponsors
    Sponsor organisation name
    Universitätsklinikum Münster
    Sponsor organisation address
    Albert-Schweitzer-Campus 1, Gebäude D5, Münster, Germany, 48149
    Public contact
    EWING 2008 Trial Office, Universitätsklinikum Münster, 49 2017238082, ewing@uk-essen.de
    Scientific contact
    EWING 2008 Trial Office, Universitätsklinikum Münster, 49 2017238082, ewing@uk-essen.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?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    30 Jun 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    30 Jun 2019
    Global end of trial reached?
    Yes
    Global end of trial date
    30 Jun 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Randomised trial to test for superiority regarding event-free survival (EFS) Standard Risk R1: in localised Ewing tumour (ET) with good histological response or initial tumour volume <200ml: fenretinide or bisphosphonates or bisphosphonates+fenretinide add-on to induction and maintenance chemotherapy versus no add-on treatment. High Risk R2: in localised Ewing tumour with unfavourable histological response or tumour volume>200ml (R2loc): busulfan/melphalan high dose chemotherapy (HDT) and autologous stem cell reinfusion versus standard chemotherapy. In pulmonary metastases: busulfan/melphalan HDT and autologous stem cell reinfusion (SCT) versus standard chemotherapy plus whole lung irradiation (R2pulm). Very High Risk R3: in primary disseminated disease: treosulfan-melphalan HDT and autologous SCT add-on to 8 cycles of standard adjuvant chemotherapy versus 8 cycles of standard adjuvant chemotherapy alone.
    Protection of trial subjects
    This study is conducted in accordance with applicable laws and regulations including, but not limited to, the ethical principles that have their origins in the Declaration of Helsinki and the International Conference on Harmonisation Guideline for Good Clinical Practice (GCP). Before any subjects are enrolled competent authorities and ethics committees concerned must grant authorisation and approval of this clinical trial. Before any procedures specified in this protocol are performed, the subject or subject’s parent(s)/legal guardian must sign and date the approved informed consent form according to requirements stated in national law.
    Background therapy
    Sufficient hydration (~ 2-3 L/m²/d), with appropriate electrolyte supplementation, during chemotherapy. Antiemetic therapy was administered according to institutional policy, e.g., ondansetron 5 mg/m² BSA (maximum single dose 8 mg) orally or IV every 12 hours for 5 days. Radiation of Blood Products: Due to the risk of graft-versus-host reactions in patients under chemotherapy, especially in case of high-dose therapy, all blood products (except fresh frozen plasma) were irradiated with at least 20 Gy prior to transfusion, according to national policies. The use of leukocyte filters for leukocyte depletion (CMV negativity) was advised. Red blood cells: Haemoglobin should be kept above 6 g/dl (haematocrit above 20 %). Platelets: Platelet substitution was advised when platelets are <10,000/μL or with clinical evidence of bleeding. Central Lines: The use of central lines was strongly recommended. In HDT patients, multi-lumen central lines should be used for PBPC sampling and supportive care. Pneumocystis carinii prophylaxis according to the recommendations of the national groups was mandatory. Treatment of Infections (especially neutropenic infection) according to accepted general principles of supportive care.
    Evidence for comparator
    EWING 2008 is a phase 3, open label, multi-centre, randomised controlled trial of international study groups with the intention of optimising treatment and treatment results in patients with localised and advanced Ewing sarcomas. The primary objective was to assess whether either of the randomised treatments is superior regarding 3-year event-free survival. The treatment was stratified according to prognostic factors as determined by previous studies. All patients received VIDE chemotherapy as induction treatment. Disease assessment was performed prior to treatment and after the 2nd (latest 3rd) and 5th (latest 6th) cycle of VIDE chemotherapy. Depending on the presentation at the time of diagnosis and on the histological response to induction chemotherapy, patients were stratified into to the risk groups.
    Actual start date of recruitment
    01 Oct 2009
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Efficacy, Safety
    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: 81
    Country: Number of subjects enrolled
    Poland: 8
    Country: Number of subjects enrolled
    Sweden: 19
    Country: Number of subjects enrolled
    Austria: 57
    Country: Number of subjects enrolled
    Belgium: 38
    Country: Number of subjects enrolled
    Czech Republic: 41
    Country: Number of subjects enrolled
    Finland: 7
    Country: Number of subjects enrolled
    Germany: 585
    Country: Number of subjects enrolled
    Hungary: 21
    Country: Number of subjects enrolled
    Lithuania: 1
    Country: Number of subjects enrolled
    Switzerland: 19
    Country: Number of subjects enrolled
    Australia: 30
    Worldwide total number of subjects
    907
    EEA total number of subjects
    858
    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)
    251
    Adolescents (12-17 years)
    399
    Adults (18-64 years)
    257
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

    Close Top of page
    Recruitment
    Recruitment details
    The patients were recruited from 120 trial sites in 12 countries. The recruitment period was from October 2009 to March 2018.

    Pre-assignment
    Screening details
    The study included patients with histologically confirmed Ewing sarcoma of bone or soft tissue, either sex and age > 48 months (for Germany) and < 50 years at the date of diagnostic biopsy.

    Pre-assignment period milestones
    Number of subjects started
    907
    Number of subjects completed
    441

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    Other: 85
    Reason: Number of subjects
    Medical contraindication/toxicity: 47
    Reason: Number of subjects
    Organisational reasons: 40
    Reason: Number of subjects
    Progress: 20
    Reason: Number of subjects
    Not available: 2
    Reason: Number of subjects
    Consent withdrawn by patient/parents: 172
    Reason: Number of subjects
    Physician decision: 100
    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    R1 Add-on
    Arm description
    Patients with localised disease and good histological response at surgery after induction chemotherapy and patients with initial surgery or in whom surgery was not feasible and who have small tumours < 200 mL at diagnosis were included in the risk group Standard Risk R1. Patients who were randomized into the R1 Add-on arm received 6 courses of vincristine, ifosfamide, doxorubicin, and etoposide (VIDE) as intensive induction chemotherapy followed by 8 cycles of either VAI (vincristine, actinomycin-D, ifosfamide) or VAC (vincristine, actinomycin-D, cyclophosphamide). In addition to induction and maintenance chemotherapy, patients were treated with zoledronic acid (Add-on treatment).
    Arm type
    Experimental

    Investigational medicinal product name
    Vincristine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    VIDE chemotherapy (cycles 1-6 at 21-day intervals): Vincristine is given on day 1 in a dose of 1.5 mg/m²/d per cycle. VAI chemotherapy (cycles 7-14 at 21-day intervals): Vincristine is given on day 1 in a dose of 1.5 mg/m²/d per cycle. VAC chemotherapy (cycles 7-14 at 21-day intervals): Vincristine is given on day 1 in a dose of 1.5 mg/m²/d per cycle.

    Investigational medicinal product name
    Ifosfamide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    VIDE chemotherapy (cycles 1-6 at 21-day intervals): Ifosfamide is given on day 1,2 and 3 in a dose of 3.0 g/m²/d per cycle. VAI chemotherapy (cycles 7-14 at 21-day intervals): Ifosfamide is given on day 1 and 2 in a dose of 3.0 g/m²/d per cycle.

    Investigational medicinal product name
    Doxorubicin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    VIDE chemotherapy (cycles 1-6 at 21-day intervals): Doxorubicin is given on day 1, 2 an 3 in a dose of 20 mg/m²/d per cycle.

    Investigational medicinal product name
    Etoposide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    VIDE chemotherapy (cycles 1-6 at 21-day intervals): Etoposide is given on day 1, 2 an 3 in a dose of 150 mg/m²/d per cycle.

    Investigational medicinal product name
    Actinomycin D
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    VAI chemotherapy (cycles 7-14 at 21-day intervals): Actinomycin D is given on day 1 and 2 in a dose of 1.5 mg/m²/d per cycle. VAC chemotherapy (cycles 7-14 at 21-day intervals): Actinomycin D is given on day 1 and 2 in a dose of 1.5 mg/m²/d per cycle.

    Investigational medicinal product name
    Cyclophosphamide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    VAC chemotherapy (cycles 7-14 at 21-day intervals):Cyclophosphamide is given on day 1 in a dose of 1500 mg/m²/d per cycle.

    Investigational medicinal product name
    Zoledronic acid
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for injection
    Routes of administration
    Intracavernous use
    Dosage and administration details
    Patients randomised for zoledronic acid received zoledronic acid at 28-day intervals beginning with cycle 6 of VAC/VAI consolidation chemotherapy (cycle 12 from start of chemotherapy) for a maximum of nine cycles. Patients < 18 years received 0.05 mg/kg BW by IV infusion 30 min-1 h. In patients >= 18 years zoledronic acid was dosed according to body weight: Patients > 40kg received 4 mg by IV infusion 30 min–1 h. Patients 20-40 kg received 2 mg by IV infusion 30 min–1 h.

    Arm title
    R1 No Add-on
    Arm description
    Patients with localised disease and good histological response at surgery after induction chemotherapy and patients with initial surgery or in whom surgery was not feasible and who have small tumours < 200 mL at diagnosis were included in the risk group Standard Risk R1. Patients who were randomized into the R1 No Add-on arm received only 6 courses of vincristine, ifosfamide, doxorubicin, and etoposide (VIDE) as intensive induction chemotherapy followed by 8 cycles of either VAI (vincristine, actinomycin-D, Ifosfamide) or VAC (vincristine, actinomycin-D, Cyclophosphamide). No additional treatment with zoledronic acid was administered to the patients (No Add-on treatment).
    Arm type
    Active comparator

    Investigational medicinal product name
    Vincristine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    VIDE chemotherapy (cycles 1-6 at 21-day intervals): Vincristine is given on day 1 in a dose of 1.5 mg/m²/d per cycle. VAI chemotherapy (cycles 7-14 at 21-day intervals): Vincristine is given on day 1 in a dose of 1.5 mg/m²/d per cycle. VAC chemotherapy (cycles 7-14 at 21-day intervals): Vincristine is given on day 1 in a dose of 1.5 mg/m²/d per cycle.

    Investigational medicinal product name
    Ifosfamide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    VIDE chemotherapy (cycles 1-6 at 21-day intervals): Ifosfamide is given on day 1,2 and 3 in a dose of 3.0 g/m²/d per cycle. VAI chemotherapy (cycles 7-14 at 21-day intervals): Ifosfamide is given on day 1 and 2 in a dose of 3.0 g/m²/d per cycle.

    Investigational medicinal product name
    Doxorubicin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    VIDE chemotherapy (cycles 1-6 at 21-day intervals): Doxorubicin is given on day 1, 2 an 3 in a dose of 20 mg/m²/d per cycle.

    Investigational medicinal product name
    Etoposide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    VIDE chemotherapy (cycles 1-6 at 21-day intervals): Etoposide is given on day 1, 2 an 3 in a dose of 150 mg/m²/d per cycle.

    Investigational medicinal product name
    Actinomycin D
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    VAI chemotherapy (cycles 7-14 at 21-day intervals): Actinomycin D is given on day 1 and 2 in a dose of 1.5 mg/m²/d per cycle. VAC chemotherapy (cycles 7-14 at 21-day intervals): Actinomycin D is given on day 1 and 2 in a dose of 1.5 mg/m²/d per cycle.

    Investigational medicinal product name
    Cyclophosphamide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    VAC chemotherapy (cycles 7-14 at 21-day intervals):Cyclophosphamide is given on day 1 in a dose of 1500 mg/m²/d per cycle.

    Arm title
    R2loc VAI
    Arm description
    Patients with localised disease and poor histological response at surgery after induction chemotherapy and patients with initial surgery or in whom surgery was not feasible and who have large tumours > 200 mL at diagnosis were included in the risk group High Risk localised disease R2loc. Patients who were randomized into the R2loc VAI arm received 6 courses of vincristine, ifosfamide, doxorubicin, and etoposide (VIDE) as intensive induction chemotherapy followed by 8 cycles of standard chemotherapy VAI (vincristine, actinomycin-D, ifosfamide).
    Arm type
    Active comparator

    Investigational medicinal product name
    Vincristine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    VIDE chemotherapy (cycles 1-6 at 21-day intervals): Vincristine is given on day 1 in a dose of 1.5 mg/m²/d per cycle. VAI chemotherapy (cycles 7-14 at 21-day intervals): Vincristine is given on day 1 in a dose of 1.5 mg/m²/d per cycle.

    Investigational medicinal product name
    Ifosfamide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    VIDE chemotherapy (cycles 1-6 at 21-day intervals): Ifosfamide is given on day 1,2 and 3 in a dose of 3.0 g/m²/d per cycle. VAI chemotherapy (cycles 7-14 at 21-day intervals): Ifosfamide is given on day 1 and 2 in a dose of 3.0 g/m²/d per cycle.

    Investigational medicinal product name
    Doxorubicin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    VIDE chemotherapy (cycles 1-6 at 21-day intervals): Doxorubicin is given on day 1, 2 an 3 in a dose of 20 mg/m²/d per cycle.

    Investigational medicinal product name
    Etoposide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    VIDE chemotherapy (cycles 1-6 at 21-day intervals): Etoposide is given on day 1, 2 an 3 in a dose of 150 mg/m²/d per cycle.

    Investigational medicinal product name
    Actinomycin D
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    VAI chemotherapy (cycles 7-14 at 21-day intervals): Actinomycin D is given onday 1 and 2 in a dose of 1.5 mg/m²/d per cycle.

    Arm title
    R2loc Bu-Mel
    Arm description
    Patients with localised disease and poor histological response at surgery after induction chemotherapy and patients with initial surgery or in whom surgery was not feasible and who have large tumours > 200 mL at diagnosis were included in the risk group High Risk localised disease R2loc. Patients who were randomized into the R2loc Bu-Mel arm received 6 courses of vincristine, ifosfamide, doxorubicin, and etoposide (VIDE) as intensive induction chemotherapy followed by high-dose chemotherapy using busulfan-melphalan with autologous stem cell reinfusion.
    Arm type
    Experimental

    Investigational medicinal product name
    Vincristine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    VIDE chemotherapy (cycles 1-6 at 21-day intervals): Vincristine is given on day 1 in a dose of 1.5 mg/m²/d per cycle.

    Investigational medicinal product name
    Ifosfamide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    VIDE chemotherapy (cycles 1-6 at 21-day intervals): Ifosfamide is given on day 1,2 and 3 in a dose of 3.0 g/m²/d per cycle.

    Investigational medicinal product name
    Doxorubicin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    VIDE chemotherapy (cycles 1-6 at 21-day intervals): Doxorubicin is given on day 1, 2 an 3 in a dose of 20 mg/m²/d per cycle.

    Investigational medicinal product name
    Etoposide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    VIDE chemotherapy (cycles 1-6 at 21-day intervals): Etoposide is given on day 1, 2 an 3 in a dose of 150 mg/m²/d per cycle.

    Investigational medicinal product name
    Busulfan
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Busulfan–Melphalan High-Dose Chemotherapy with autologous stem cell reinfusion (cycle 8): Busulfan is given on day -6, -5, -4 and -3 before Stem cell reinfusion. Adults: 0.8 mg/kg body weight (BW), children and adolescents: <9 kg = 1 mg/kg BW, 9-<16 kg = 1.2 mg/kg BW, 16-23 kg = 1.1 mg/kg BW, >23-34 kg = 0.95 mg/kg BW, >34 kg = 0.8 mg/kg BW.

    Investigational medicinal product name
    Melphalan
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Busulfan–Melphalan High-Dose Chemotherapy with autologous stem cell reinfusion (cycle 8): Melphalan is given on day -2 before Stem cell reinfusion (140 mg/m² IV infusion, 30 min.).

    Investigational medicinal product name
    Adult haematopoietic stem cells
    Investigational medicinal product code
    Other name
    Autologous adult haematopoietic stem cells
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Busulfan–Melphalan High-Dose Chemotherapy with autologous stem cell reinfusion (cycle 8): Stem cell reinfusion (min. 3 x 1000000/kg CD 34+) after busulfan–melphalan Treatment (d 0).

    Arm title
    R2pulm VAI
    Arm description
    Patients with a Ewing sarcoma metastatic to the lungs and/or pleura, but not to any other sites, at the time of diagnosis were included in the risk group High Risk primary lung metastases R2pulm. Patients who were randomized into the R2pulm VAI arm received 6 courses of vincristine, ifosfamide, doxorubicin, and etoposide (VIDE) as intensive induction chemotherapy followed by 8 cycles of standard chemotherapy VAI (vincristine, actinomycin-D, ifosfamide) plus whole lung irradiation.
    Arm type
    Active comparator

    Investigational medicinal product name
    Vincristine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    VIDE chemotherapy (cycles 1-6 at 21-day intervals): Vincristine is given on day 1 in a dose of 1.5 mg/m²/d per cycle. VAI chemotherapy (cycles 7-14 at 21-day intervals): Vincristine is given on day 1 in a dose of 1.5 mg/m²/d per cycle.

    Investigational medicinal product name
    Ifosfamide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    VIDE chemotherapy (cycles 1-6 at 21-day intervals): Ifosfamide is given on day 1,2 and 3 in a dose of 3.0 g/m²/d per cycle. VAI chemotherapy (cycles 7-14 at 21-day intervals): Ifosfamide is given on day 1 and 2 in a dose of 3.0 g/m²/d per cycle.

    Investigational medicinal product name
    Doxorubicin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    VIDE chemotherapy (cycles 1-6 at 21-day intervals): Doxorubicin is given on day 1, 2 an 3 in a dose of 20 mg/m²/d per cycle.

    Investigational medicinal product name
    Etoposide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    VIDE chemotherapy (cycles 1-6 at 21-day intervals): Etoposide is given on day 1, 2 an 3 in a dose of 150 mg/m²/d per cycle.

    Investigational medicinal product name
    Actinomycin D
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    VAI chemotherapy (cycles 7-14 at 21-day intervals): Actinomycin D is given on day 1 and 2 in a dose of 1.5 mg/m²/d per cycle.

    Arm title
    R2pulm Bu-Mel
    Arm description
    Patients with a Ewing sarcoma metastatic to the lungs and/or pleura, but not to any other sites, at the time of diagnosis were included in the risk group High Risk primary lung metastases R2pulm. Patients who were randomized into the R2pulm Bu-Mel arm received 6 courses of vincristine, ifosfamide, doxorubicin, and etoposide (VIDE) as intensive induction chemotherapy followed by high dose busulfan-melphalan chemotherapy with autologous stem cell reinfusion.
    Arm type
    Experimental

    Investigational medicinal product name
    Vincristine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    VIDE chemotherapy (cycles 1-6 at 21-day intervals): Vincristine is given on day 1 in a dose of 1.5 mg/m²/d per cycle.

    Investigational medicinal product name
    Ifosfamide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    VIDE chemotherapy (cycles 1-6 at 21-day intervals): Ifosfamide is given on day 1,2 and 3 in a dose of 3.0 g/m²/d per cycle.

    Investigational medicinal product name
    Doxorubicin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    VIDE chemotherapy (cycles 1-6 at 21-day intervals): Doxorubicin is given on day 1, 2 an 3 in a dose of 20 mg/m²/d per cycle.

    Investigational medicinal product name
    Etoposide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    VIDE chemotherapy (cycles 1-6 at 21-day intervals): Etoposide is given on day 1, 2 an 3 in a dose of 150 mg/m²/d per cycle.

    Investigational medicinal product name
    Busulfan
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Busulfan–Melphalan High-Dose Chemotherapy with autologous stem cell reinfusion (cycle 8): Busulfan is given on day -6, -5, -4 and -3 before Stem cell reinfusion. Adults: 0.8 mg/kg body weight (BW), children and adolescents: <9 kg = 1 mg/kg BW, 9-<16 kg = 1.2 mg/kg BW, 16-23 kg = 1.1 mg/kg BW, >23-34 kg = 0.95 mg/kg BW, >34 kg = 0.8 mg/kg BW.

    Investigational medicinal product name
    Melphalan
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Busulfan–Melphalan High-Dose Chemotherapy with autologous stem cell reinfusion (cycle 8): Melphalan is given on day -2 before Stem cell reinfusion (140 mg/m² IV infusion, 30 min.).

    Investigational medicinal product name
    Adult haematopoietic stem cells
    Investigational medicinal product code
    Other name
    Autologous adult haematopoietic stem cells
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Busulfan–Melphalan High-Dose Chemotherapy with autologous stem cell reinfusion (cycle 8): Stem cell reinfusion (min. 3 x 1000000/kg CD 34+) after busulfan–melphalan Treatment (d 0).

    Arm title
    R3 VAC
    Arm description
    Patients with metastatic disease not confined to the lungs and/or pleura, i.e. patients with bone metastases, bone marrow metastases or other metastases (e.g. lymph nodes, liver, CNS, etc) with and without additional pulmonary metastases at the time of diagnosis were included in the risk group Very High Risk R3. Patients who were randomized into the R3 VAC arm received 6 courses of vincristine, ifosfamide, doxorubicin, and etoposide (VIDE) as intensive induction chemotherapy followed by 8 cycles of VAC (vincristine, actinomycin-D, cyclophosphamide).
    Arm type
    Active comparator

    Investigational medicinal product name
    Vincristine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    VIDE chemotherapy (cycles 1-6 at 21-day intervals): Vincristine is given on day 1 in a dose of 1.5 mg/m²/d per cycle. VAC chemotherapy (cycles 7-14 at 21-day intervals): Vincristine is given on day 1 in a dose of 1.5 mg/m²/d per cycle.

    Investigational medicinal product name
    Ifosfamide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    VIDE chemotherapy (cycles 1-6 at 21-day intervals): Ifosfamide is given on day 1,2 and 3 in a dose of 3.0 g/m²/d per cycle.

    Investigational medicinal product name
    Doxorubicin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    VIDE chemotherapy (cycles 1-6 at 21-day intervals): Doxorubicin is given on day 1, 2 an 3 in a dose of 20 mg/m²/d per cycle.

    Investigational medicinal product name
    Etoposide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    VIDE chemotherapy (cycles 1-6 at 21-day intervals): Etoposide is given on day 1, 2 an 3 in a dose of 150 mg/m²/d per cycle.

    Investigational medicinal product name
    Actinomycin D
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    VAC chemotherapy (cycles 7-14 at 21-day intervals): Actinomycin D is given on day 1 and 2 in a dose of 1.5 mg/m²/d per cycle.

    Investigational medicinal product name
    Cyclophosphamide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    VAC chemotherapy (cycles 7-14 at 21-day intervals):Cyclophosphamide is given on day 1 in a dose of 1500 mg/m²/d per cycle.

    Arm title
    R3 Treo-Mel
    Arm description
    Patients with metastatic disease not confined to the lungs and/or pleura, i.e. patients with bone metastases, bone marrow metastases or other metastases (e.g. lymph nodes, liver, CNS, etc) with and without additional pulmonary metastases at the time of diagnosis were included in the risk group Very High Risk R3. Patients who were randomized into the R3 Treo-Mel arm received 6 courses of vincristine, ifosfamide, doxorubicin, and etoposide (VIDE) as intensive induction chemotherapy followed by high dose chemotherapy using treosulfan-melphalan and autologous stem cell reinfusion.
    Arm type
    Experimental

    Investigational medicinal product name
    Vincristine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    VIDE chemotherapy (cycles 1-6 at 21-day intervals): Vincristine is given on day 1 in a dose of 1.5 mg/m²/d per cycle.

    Investigational medicinal product name
    Ifosfamide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    VIDE chemotherapy (cycles 1-6 at 21-day intervals): Ifosfamide is given on day 1,2 and 3 in a dose of 3.0 g/m²/d per cycle.

    Investigational medicinal product name
    Doxorubicin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    VIDE chemotherapy (cycles 1-6 at 21-day intervals): Doxorubicin is given on day 1, 2 an 3 in a dose of 20 mg/m²/d per cycle.

    Investigational medicinal product name
    Etoposide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    VIDE chemotherapy (cycles 1-6 at 21-day intervals): Etoposide is given on day 1, 2 an 3 in a dose of 150 mg/m²/d per cycle.

    Investigational medicinal product name
    Treosulfan
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Treosulfan–Melphalan High-Dose Chemotherapy with autologous stem cell reinfusion: Treosulfan (12 g/m²/dose IV infusion, 2 hours) is given on day -5, -4 and -3 before Stem cell reinfusion.

    Investigational medicinal product name
    Melphalan
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Treosulfan–Melphalan High-Dose Chemotherapy with autologous stem cell reinfusion (cycle 8): Melphalan is given on day -2 before Stem cell reinfusion (140 mg/m² IV infusion, 30 min.).

    Investigational medicinal product name
    Adult haematopoietic stem cells
    Investigational medicinal product code
    Other name
    Autologous adult haematopoietic stem cells
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Treosulfan–Melphalan High-Dose Chemotherapy with autologous stem cell reinfusion (cycle 8): Stem cell reinfusion (min. 3 x 1000000/kg CD 34+) after treosulfan–melphalan Treatment (d 0).

    Number of subjects in period 1 [1]
    R1 Add-on R1 No Add-on R2loc VAI R2loc Bu-Mel R2pulm VAI R2pulm Bu-Mel R3 VAC R3 Treo-Mel
    Started
    142
    142
    12
    14
    11
    11
    54
    55
    Completed
    101
    135
    11
    7
    10
    8
    46
    41
    Not completed
    41
    7
    1
    7
    1
    3
    8
    14
         Protocol deviation
    41
    7
    1
    7
    1
    3
    8
    14
    Notes
    [1] - 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: 907 patients were eligible for the study and therefore study patients. Since 466 patients were not eligible for randomization or could not be randomized, only 441 started the randomized study. These patients are reported in the baseline period.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    R1 Add-on
    Reporting group description
    Patients with localised disease and good histological response at surgery after induction chemotherapy and patients with initial surgery or in whom surgery was not feasible and who have small tumours < 200 mL at diagnosis were included in the risk group Standard Risk R1. Patients who were randomized into the R1 Add-on arm received 6 courses of vincristine, ifosfamide, doxorubicin, and etoposide (VIDE) as intensive induction chemotherapy followed by 8 cycles of either VAI (vincristine, actinomycin-D, ifosfamide) or VAC (vincristine, actinomycin-D, cyclophosphamide). In addition to induction and maintenance chemotherapy, patients were treated with zoledronic acid (Add-on treatment).

    Reporting group title
    R1 No Add-on
    Reporting group description
    Patients with localised disease and good histological response at surgery after induction chemotherapy and patients with initial surgery or in whom surgery was not feasible and who have small tumours < 200 mL at diagnosis were included in the risk group Standard Risk R1. Patients who were randomized into the R1 No Add-on arm received only 6 courses of vincristine, ifosfamide, doxorubicin, and etoposide (VIDE) as intensive induction chemotherapy followed by 8 cycles of either VAI (vincristine, actinomycin-D, Ifosfamide) or VAC (vincristine, actinomycin-D, Cyclophosphamide). No additional treatment with zoledronic acid was administered to the patients (No Add-on treatment).

    Reporting group title
    R2loc VAI
    Reporting group description
    Patients with localised disease and poor histological response at surgery after induction chemotherapy and patients with initial surgery or in whom surgery was not feasible and who have large tumours > 200 mL at diagnosis were included in the risk group High Risk localised disease R2loc. Patients who were randomized into the R2loc VAI arm received 6 courses of vincristine, ifosfamide, doxorubicin, and etoposide (VIDE) as intensive induction chemotherapy followed by 8 cycles of standard chemotherapy VAI (vincristine, actinomycin-D, ifosfamide).

    Reporting group title
    R2loc Bu-Mel
    Reporting group description
    Patients with localised disease and poor histological response at surgery after induction chemotherapy and patients with initial surgery or in whom surgery was not feasible and who have large tumours > 200 mL at diagnosis were included in the risk group High Risk localised disease R2loc. Patients who were randomized into the R2loc Bu-Mel arm received 6 courses of vincristine, ifosfamide, doxorubicin, and etoposide (VIDE) as intensive induction chemotherapy followed by high-dose chemotherapy using busulfan-melphalan with autologous stem cell reinfusion.

    Reporting group title
    R2pulm VAI
    Reporting group description
    Patients with a Ewing sarcoma metastatic to the lungs and/or pleura, but not to any other sites, at the time of diagnosis were included in the risk group High Risk primary lung metastases R2pulm. Patients who were randomized into the R2pulm VAI arm received 6 courses of vincristine, ifosfamide, doxorubicin, and etoposide (VIDE) as intensive induction chemotherapy followed by 8 cycles of standard chemotherapy VAI (vincristine, actinomycin-D, ifosfamide) plus whole lung irradiation.

    Reporting group title
    R2pulm Bu-Mel
    Reporting group description
    Patients with a Ewing sarcoma metastatic to the lungs and/or pleura, but not to any other sites, at the time of diagnosis were included in the risk group High Risk primary lung metastases R2pulm. Patients who were randomized into the R2pulm Bu-Mel arm received 6 courses of vincristine, ifosfamide, doxorubicin, and etoposide (VIDE) as intensive induction chemotherapy followed by high dose busulfan-melphalan chemotherapy with autologous stem cell reinfusion.

    Reporting group title
    R3 VAC
    Reporting group description
    Patients with metastatic disease not confined to the lungs and/or pleura, i.e. patients with bone metastases, bone marrow metastases or other metastases (e.g. lymph nodes, liver, CNS, etc) with and without additional pulmonary metastases at the time of diagnosis were included in the risk group Very High Risk R3. Patients who were randomized into the R3 VAC arm received 6 courses of vincristine, ifosfamide, doxorubicin, and etoposide (VIDE) as intensive induction chemotherapy followed by 8 cycles of VAC (vincristine, actinomycin-D, cyclophosphamide).

    Reporting group title
    R3 Treo-Mel
    Reporting group description
    Patients with metastatic disease not confined to the lungs and/or pleura, i.e. patients with bone metastases, bone marrow metastases or other metastases (e.g. lymph nodes, liver, CNS, etc) with and without additional pulmonary metastases at the time of diagnosis were included in the risk group Very High Risk R3. Patients who were randomized into the R3 Treo-Mel arm received 6 courses of vincristine, ifosfamide, doxorubicin, and etoposide (VIDE) as intensive induction chemotherapy followed by high dose chemotherapy using treosulfan-melphalan and autologous stem cell reinfusion.

    Reporting group values
    R1 Add-on R1 No Add-on R2loc VAI R2loc Bu-Mel R2pulm VAI R2pulm Bu-Mel R3 VAC R3 Treo-Mel Total
    Number of subjects
    142 142 12 14 11 11 54 55 441
    Age categorical
    Units: Subjects
        In utero
    0 0 0 0 0 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0 0 0 0 0 0 0 0
        Newborns (0-27 days)
    0 0 0 0 0 0 0 0 0
        Infants and toddlers (28 days-23 months)
    0 0 0 0 0 0 0 0 0
        Children (2-11 years)
    59 48 1 4 0 3 12 13 140
        Adolescents (12-17 years)
    50 66 6 3 5 5 24 23 182
        Adults (18-64 years)
    33 28 5 7 6 3 18 19 119
        From 65-84 years
    0 0 0 0 0 0 0 0 0
        85 years and over
    0 0 0 0 0 0 0 0 0
    Gender categorical
    Units: Subjects
        Female
    60 66 5 4 3 3 31 24 196
        Male
    82 76 7 10 8 8 23 31 245

    End points

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    End points reporting groups
    Reporting group title
    R1 Add-on
    Reporting group description
    Patients with localised disease and good histological response at surgery after induction chemotherapy and patients with initial surgery or in whom surgery was not feasible and who have small tumours < 200 mL at diagnosis were included in the risk group Standard Risk R1. Patients who were randomized into the R1 Add-on arm received 6 courses of vincristine, ifosfamide, doxorubicin, and etoposide (VIDE) as intensive induction chemotherapy followed by 8 cycles of either VAI (vincristine, actinomycin-D, ifosfamide) or VAC (vincristine, actinomycin-D, cyclophosphamide). In addition to induction and maintenance chemotherapy, patients were treated with zoledronic acid (Add-on treatment).

    Reporting group title
    R1 No Add-on
    Reporting group description
    Patients with localised disease and good histological response at surgery after induction chemotherapy and patients with initial surgery or in whom surgery was not feasible and who have small tumours < 200 mL at diagnosis were included in the risk group Standard Risk R1. Patients who were randomized into the R1 No Add-on arm received only 6 courses of vincristine, ifosfamide, doxorubicin, and etoposide (VIDE) as intensive induction chemotherapy followed by 8 cycles of either VAI (vincristine, actinomycin-D, Ifosfamide) or VAC (vincristine, actinomycin-D, Cyclophosphamide). No additional treatment with zoledronic acid was administered to the patients (No Add-on treatment).

    Reporting group title
    R2loc VAI
    Reporting group description
    Patients with localised disease and poor histological response at surgery after induction chemotherapy and patients with initial surgery or in whom surgery was not feasible and who have large tumours > 200 mL at diagnosis were included in the risk group High Risk localised disease R2loc. Patients who were randomized into the R2loc VAI arm received 6 courses of vincristine, ifosfamide, doxorubicin, and etoposide (VIDE) as intensive induction chemotherapy followed by 8 cycles of standard chemotherapy VAI (vincristine, actinomycin-D, ifosfamide).

    Reporting group title
    R2loc Bu-Mel
    Reporting group description
    Patients with localised disease and poor histological response at surgery after induction chemotherapy and patients with initial surgery or in whom surgery was not feasible and who have large tumours > 200 mL at diagnosis were included in the risk group High Risk localised disease R2loc. Patients who were randomized into the R2loc Bu-Mel arm received 6 courses of vincristine, ifosfamide, doxorubicin, and etoposide (VIDE) as intensive induction chemotherapy followed by high-dose chemotherapy using busulfan-melphalan with autologous stem cell reinfusion.

    Reporting group title
    R2pulm VAI
    Reporting group description
    Patients with a Ewing sarcoma metastatic to the lungs and/or pleura, but not to any other sites, at the time of diagnosis were included in the risk group High Risk primary lung metastases R2pulm. Patients who were randomized into the R2pulm VAI arm received 6 courses of vincristine, ifosfamide, doxorubicin, and etoposide (VIDE) as intensive induction chemotherapy followed by 8 cycles of standard chemotherapy VAI (vincristine, actinomycin-D, ifosfamide) plus whole lung irradiation.

    Reporting group title
    R2pulm Bu-Mel
    Reporting group description
    Patients with a Ewing sarcoma metastatic to the lungs and/or pleura, but not to any other sites, at the time of diagnosis were included in the risk group High Risk primary lung metastases R2pulm. Patients who were randomized into the R2pulm Bu-Mel arm received 6 courses of vincristine, ifosfamide, doxorubicin, and etoposide (VIDE) as intensive induction chemotherapy followed by high dose busulfan-melphalan chemotherapy with autologous stem cell reinfusion.

    Reporting group title
    R3 VAC
    Reporting group description
    Patients with metastatic disease not confined to the lungs and/or pleura, i.e. patients with bone metastases, bone marrow metastases or other metastases (e.g. lymph nodes, liver, CNS, etc) with and without additional pulmonary metastases at the time of diagnosis were included in the risk group Very High Risk R3. Patients who were randomized into the R3 VAC arm received 6 courses of vincristine, ifosfamide, doxorubicin, and etoposide (VIDE) as intensive induction chemotherapy followed by 8 cycles of VAC (vincristine, actinomycin-D, cyclophosphamide).

    Reporting group title
    R3 Treo-Mel
    Reporting group description
    Patients with metastatic disease not confined to the lungs and/or pleura, i.e. patients with bone metastases, bone marrow metastases or other metastases (e.g. lymph nodes, liver, CNS, etc) with and without additional pulmonary metastases at the time of diagnosis were included in the risk group Very High Risk R3. Patients who were randomized into the R3 Treo-Mel arm received 6 courses of vincristine, ifosfamide, doxorubicin, and etoposide (VIDE) as intensive induction chemotherapy followed by high dose chemotherapy using treosulfan-melphalan and autologous stem cell reinfusion.

    Subject analysis set title
    R1 Add-on (First interim analysis)
    Subject analysis set type
    Full analysis
    Subject analysis set description
    The first interim analysis was performed after observing 17 events of 121 randomized patients in the Add-on group.

    Subject analysis set title
    R1 No Add-on (First interim analysis)
    Subject analysis set type
    Full analysis
    Subject analysis set description
    The first interim analysis was performed after observing 16 events of 121 randomized patients in the no Add-on group.

    Subject analysis set title
    R3 VAC (First interim analysis)
    Subject analysis set type
    Full analysis
    Subject analysis set description
    The first interim analysis was performed after observing 19 events of 32 randomized patients in the R3 VAC Group.

    Subject analysis set title
    R3 Treo-Mel (First interim analysis)
    Subject analysis set type
    Full analysis
    Subject analysis set description
    The first interim analysis was performed after observing 9 events of 30 randomized patients in the R3 Treo-Mel Group.

    Subject analysis set title
    R1 Add-on (Per protocol)
    Subject analysis set type
    Per protocol
    Subject analysis set description
    The per protocol collective is defined as all R1 Add-on patients completing the study without major protocol deviations.

    Subject analysis set title
    R1 No Add-on (Per protocol)
    Subject analysis set type
    Per protocol
    Subject analysis set description
    The per protocol collective is defined as all R1 No Add-on patients completing the study without major protocol deviations.

    Subject analysis set title
    R3 VAC (Per Protocol)
    Subject analysis set type
    Per protocol
    Subject analysis set description
    The per protocol collective is defined as all R3 VAC patients completing the study without major protocol deviations.

    Subject analysis set title
    R3 Treo-Mel (Per protocol)
    Subject analysis set type
    Per protocol
    Subject analysis set description
    The per protocol collective is defined as all R3 Treo-Mel patients completing the study without major protocol deviations.

    Primary: R1: Event-free survival (EFS)

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    End point title
    R1: Event-free survival (EFS) [1]
    End point description
    The primary endpoint of event-free survival (EFS) was estimated according to the method of Kaplan and Meier (1958). EFS time starts at the date of randomisation and ends at the date of first event (progression of disease, relapse of disease, diagnosis of secondary malignancy, or death of the patient irrespective of its cause) or at the date of the patient's most recent consultation. Patients lost to follow-up without event were censored at the date of their last consultation. Progression of disease is defined as recurrent disease under active oncological therapy. Relapse of disease is defined as recurrent disease in patients with complete clinical remission after completion of active oncological therapy. The Primary Analysis was performed according to the Intention-to-treat (ITT) principle in the full analysis set.
    End point type
    Primary
    End point timeframe
    From randomisation to first event or last follow-up in case of no event.
    Notes
    [1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The R2 randomization of the EURO-E.W.I.N.G. 99 trial was continued in the EWING2008 Trial. The EWING2008 R2 data were transferred to the EURO-E.W.I.N.G. 99 data center and was analyzed by the EURO-E.W.I.N.G. Group. The results were already published (see online references).
    End point values
    R1 Add-on R1 No Add-on R1 Add-on (First interim analysis) R1 No Add-on (First interim analysis) R1 Add-on (Per protocol) R1 No Add-on (Per protocol)
    Number of subjects analysed
    142
    142
    121
    121
    101
    135
    Units: Events
    22
    30
    17
    16
    14
    28
    Statistical analysis title
    Final analysis (superiority)
    Statistical analysis description
    Because the number of the initially planned number of events (n=146) could not be reached, an adaptive design change was performed based on the data from the 1st interim analysis, according to which only an additional analysis is planned. The conditional rejection error probability (CREP) (Müller & Schäfer 2001) was calculated for each direction of the null hypothesis (superiority of Add-on ϵ+=0.0086 and inferiority of Add-on ϵ-=0.0126). The CREPs were used as new local significance levels.
    Comparison groups
    R1 Add-on v R1 No Add-on
    Number of subjects included in analysis
    284
    Analysis specification
    Pre-specified
    Analysis type
    superiority [2]
    P-value
    = 0.0242 [3]
    Method
    Increment of the logrank test statistic
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.735
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.424
         upper limit
    1.275
    Notes
    [2] - In the final analysis the one-sided null hypotheses was tested by calculating the approximately normally distributed independent increment of the logrank test statistic. The independent increment of the logrank test statistic was -1.0987, leading to the one-sided single-stage p-values p_end+=0.0242> 0.0086=ϵ+ and p_end-=0.9758> 0.0126=ϵ-.
    [3] - The independent increment of the logrank test statistic was -1.0987, leading to the one-sided single-stage p-values p_end+=0.0242> 0.0086=ϵ+ and p_end-=0.9758> 0.0126=ϵ-.
    Statistical analysis title
    First interim analysis
    Statistical analysis description
    The primary endpoint is event-free survival (EFS) starts at the date of randomization and ends at the date of first compound event (progression of disease, relapse of disease, diagnosis of secondary malignancy, or death of the patient irrespective of its cause) or at the date of the patient's most recent consultation. The EFS was analyzed using the intention-to-treat principle in the full-analysis set. A multiple type 1 error rate (significance level) of α = 5% (two-sided) was controlled.
    Comparison groups
    R1 Add-on (First interim analysis) v R1 No Add-on (First interim analysis)
    Number of subjects included in analysis
    242
    Analysis specification
    Pre-specified
    Analysis type
    superiority [4]
    P-value
    = 0.9058 [5]
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    1.042
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.526
         upper limit
    2.064
    Notes
    [4] - An adaptive two-sided group sequential design with four equally weighted stages using an inverse normal combination function and O’Brien & Fleming boundaries was applied (Wassmer 2006, O’Brien & Fleming 1979). The first interim analysis was performed based on data from 20 March 2017 after observing 33 events.
    [5] - Stage I two-sided p-value is reported. Stage I p-value (one-sided) for superiority (H1: HR < 1) p=0.5471 and for inferiority (H1: HR > 1) p=0.4529.
    Statistical analysis title
    Final analysis (inferiority)
    Statistical analysis description
    Because the number of the initially planned number of events (n=146) could not be reached, an adaptive design change was performed based on the data from the 1st interim analysis, according to which only an additional analysis is planned. The conditional rejection error probability (CREP) (Müller & Schäfer 2001) was calculated for each direction of the null hypothesis (superiority of Add-on ϵ+=0.0086 and inferiority of Add-on ϵ-=0.0126). The CREPs were used as new local significance levels.
    Comparison groups
    R1 Add-on v R1 No Add-on
    Number of subjects included in analysis
    284
    Analysis specification
    Pre-specified
    Analysis type
    other [6]
    P-value
    = 0.0126 [7]
    Method
    Increment of the logrank test statistic
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.735
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.424
         upper limit
    1.275
    Notes
    [6] - In the final analysis the one-sided null hypotheses was tested by calculating the approximately normally distributed independent increment of the logrank test statistic. The independent increment of the logrank test statistic was -1.0987, leading to the one-sided single-stage p-values p_end+=0.0242> 0.0086=ϵ+ and p_end-=0.9758> 0.0126=ϵ-.
    [7] - The independent increment of the logrank test statistic was -1.0987, leading to the one-sided single-stage p-values p_end+=0.0242> 0.0086=ϵ+ and p_end-=0.9758> 0.0126=ϵ-.
    Statistical analysis title
    Final analysis (Per protocol)
    Comparison groups
    R1 Add-on (Per protocol) v R1 No Add-on (Per protocol)
    Number of subjects included in analysis
    236
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.1794
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.65
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.34
         upper limit
    1.23

    Primary: R3 trial: Event-free survival (EFS)

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    End point title
    R3 trial: Event-free survival (EFS) [8]
    End point description
    The primary endpoint of event-free survival (EFS) was estimated according to the method of Kaplan and Meier (1958). EFS time starts at the date of randomisation and ends at the date of first event (progression of disease, relapse of disease, diagnosis of secondary malignancy, or death of the patient irrespective of its cause) or at the date of the patient's most recent consultation. Patients lost to follow-up without event were censored at the date of their last consultation. Progression of disease is defined as recurrent disease under active oncological therapy. Relapse of disease is defined as recurrent disease in patients with complete clinical remission after completion of active oncological therapy. The Primary Analysis was performed according to the Intention-to-treat (ITT) principle in the full analysis set.
    End point type
    Primary
    End point timeframe
    From randomisation to first event or last follow-up in case of no event.
    Notes
    [8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The R2 randomization of the EURO-E.W.I.N.G. 99 trial was continued in the EWING2008 Trial. The EWING2008 R2 data were transferred to the EURO-E.W.I.N.G. 99 data center and was analyzed by the EURO-E.W.I.N.G. Group. The results were already published (see online references).
    End point values
    R3 VAC R3 Treo-Mel R3 VAC (First interim analysis) R3 Treo-Mel (First interim analysis) R3 VAC (Per Protocol) R3 Treo-Mel (Per protocol)
    Number of subjects analysed
    54
    55
    32
    30
    46
    41
    Units: Events
    43
    39
    19
    9
    35
    31
    Statistical analysis title
    Final analysis
    Statistical analysis description
    Because the number of the initially planned number of events (n=155) could not be reached, an adaptive design change was performed based on the data from the 1st interim analysis, according to which only an additional analysis is planned. The conditional rejection error probability (CREP) (Müller & Schäfer 2001) was calculated for the one-sided null hypothesis, resulting in ϵ+=0.0116. The CREP was used as new local significance level for the final analysis of the remaining trial.
    Comparison groups
    R3 Treo-Mel v R3 VAC
    Number of subjects included in analysis
    109
    Analysis specification
    Pre-specified
    Analysis type
    superiority [9]
    P-value
    = 0.1195 [10]
    Method
    Increment of the logrank test statistic
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.821
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.532
         upper limit
    1.268
    Notes
    [9] - In the final analysis the one-sided null hypothesis was tested by calculating the approximately normally distributed independent increment of the logrank test statistic (Wassmer 2006). The final analysis was performed on data from 30th June 2019.
    [10] - The independent increment of the logrank test statistic was -0.889, leading to the one-sided single-stage p-value p_end+=0.1195> 0.0116=ϵ+
    Statistical analysis title
    First interim analysis
    Statistical analysis description
    The primary endpoint is event-free survival (EFS) starts at the date of randomization and ends at the date of first compound event (progression of disease, relapse of disease, diagnosis of secondary malignancy, or death of the patient irrespective of its cause) or at the date of the patient's most recent consultation. The EFS was analyzed using the intention-to-treat principle in the full-analysis set. A multiple type 1 error rate (significance level) of α = 2.5% (one-sided) was controlled.
    Comparison groups
    R3 VAC (First interim analysis) v R3 Treo-Mel (First interim analysis)
    Number of subjects included in analysis
    62
    Analysis specification
    Pre-specified
    Analysis type
    superiority [11]
    P-value
    = 0.4737 [12]
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.979
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.52
         upper limit
    1.842
    Notes
    [11] - An adaptive one-sided group sequential design with four stages using an inverse normal combination function, O’Brien & Fleming boundaries, and equally spaced weights was applied (Wassmer 2006, O’Brien & Fleming 1979).
    [12] - Stage I one-sided p-value is reported. The hypotheses that the randomization arm ‘R3: Treo-Mel’ differs in the full-analysis set from the randomization arm ‘R3: VAC' with respect to EFS could not be rejected.
    Statistical analysis title
    Final analysis (Per protocol)
    Comparison groups
    R3 VAC (Per Protocol) v R3 Treo-Mel (Per protocol)
    Number of subjects included in analysis
    87
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.4463
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.83
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.51
         upper limit
    1.35

    Secondary: R1 trial: Overall survival (OS)

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    End point title
    R1 trial: Overall survival (OS) [13]
    End point description
    Overall survival time (OS) starts at the date of randomisation and ends at the date of death of the patient (irrespective of its cause) or at the date of the patient's most recent consultation. Patients lost to follow-up are censored at the date of their last consultation.
    End point type
    Secondary
    End point timeframe
    From randomisation to death.
    Notes
    [13] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The R2 randomization of the EURO-E.W.I.N.G. 99 trial was continued in the EWING2008 Trial. The EWING2008 R2 data were transferred to the EURO-E.W.I.N.G. 99 data center and was analyzed by the EURO-E.W.I.N.G. Group. The results were already published (see online references).
    End point values
    R1 Add-on R1 No Add-on R1 Add-on (Per protocol) R1 No Add-on (Per protocol)
    Number of subjects analysed
    142
    142
    101
    135
    Units: Deaths
    13
    12
    9
    10
    Statistical analysis title
    R1 trial: OS (full analysis set)
    Statistical analysis description
    Comparision of overall survival between R1: Add-on and R1: No Add-on in the full analysis set (ITT principle).
    Comparison groups
    R1 Add-on v R1 No Add-on
    Number of subjects included in analysis
    284
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.8445
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    1.08
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.49
         upper limit
    2.37
    Statistical analysis title
    R1 trial: OS (Per protocol)
    Comparison groups
    R1 Add-on (Per protocol) v R1 No Add-on (Per protocol)
    Number of subjects included in analysis
    236
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.7441
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    1.16
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.47
         upper limit
    2.86

    Secondary: R3 trial: Overall survival (OS)

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    End point title
    R3 trial: Overall survival (OS) [14]
    End point description
    Overall survival time (OS) starts at the date of randomisation and ends at the date of death of the patient (irrespective of its cause) or at the date of the patient's most recent consultation. Patients lost to follow-up are censored at the date of their last consultation.
    End point type
    Secondary
    End point timeframe
    From randomisation to death or last follow-up.
    Notes
    [14] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The R2 randomization of the EURO-E.W.I.N.G. 99 trial was continued in the EWING2008 Trial. The EWING2008 R2 data were transferred to the EURO-E.W.I.N.G. 99 data center and was analyzed by the EURO-E.W.I.N.G. Group. The results were already published (see online references).
    End point values
    R3 VAC R3 Treo-Mel R3 VAC (Per Protocol) R3 Treo-Mel (Per protocol)
    Number of subjects analysed
    54
    55
    46
    41
    Units: Deaths
    31
    30
    23
    23
    Statistical analysis title
    R3 trial: OS (full analysis set)
    Statistical analysis description
    Comparision of overall survival between R3: Treo-Mel and R3: VAC in the full analysis set (ITT principle).
    Comparison groups
    R3 VAC v R3 Treo-Mel
    Number of subjects included in analysis
    109
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.868
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.96
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.58
         upper limit
    1.58
    Statistical analysis title
    R3 trial: OS (Per protocol)
    Comparison groups
    R3 VAC (Per Protocol) v R3 Treo-Mel (Per protocol)
    Number of subjects included in analysis
    87
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.8779
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    1.05
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.59
         upper limit
    1.87

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    from treatment initiation until 3 months following completion of active oncological therapy.
    Adverse event reporting additional description
    Expected toxicities, both severe (CTC grade >=3, hematologic: CTC grade = 4) and non-severe (CTC grade 1-2, hematologic: CTC grade 1-3), were recorded as pre-specified items according to CTCAE in the CRF. Severe toxicities were documented as SAE and non-severe toxicities as non-SAE. Toxicities collected as free text in the CRF were not documented.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    CTCAE
    Dictionary version
    3.0
    Reporting groups
    Reporting group title
    Safety: R1 Add-on
    Reporting group description
    All randomized patients who received R1 add-on treatment (Safety set, as-treated). In this reporting group, 11 deaths occurred with the following causes: Cancer = 9, Secondary malignancy = 1, Pneumonia = 1. Because the deaths could not be assigned to any specific toxicity, 0 was entered under „Serious adverse event details and values“ for both „Fatalities number“ and „Fatalities causally related to treatment number“.

    Reporting group title
    Safety: R1 no Add-on
    Reporting group description
    All randomized patients who received R1 no Add-on treatment (Safety set, as-treated). In this reporting group, 14 deaths occurred with the following causes: Cancer = 14. Because the deaths could not be assigned to any specific toxicity, 0 was entered under „Serious adverse event details and values“ for both „Fatalities number“ and „Fatalities causally related to treatment number“.

    Reporting group title
    Safety: R2loc VAI
    Reporting group description
    All randomized patients who received R2loc VAI treatment (Safety set, as-treated). In this reporting group, 2 deaths occurred with the following causes: Cancer = 2. Because the deaths could not be assigned to any specific toxicity, 0 was entered under „Serious adverse event details and values“ for both „Fatalities number“ and „Fatalities causally related to treatment number“.

    Reporting group title
    Safety: R2loc Bu-Mel
    Reporting group description
    All randomized patients who received R2loc Bu-Mel treatment (Safety set, as-treated). In this reporting group, 1 death occurred with the following cause: Cancer = 1. Because the deaths could not be assigned to any specific toxicity, 0 was entered under „Serious adverse event details and values“ for both „Fatalities number“ and „Fatalities causally related to treatment number“.

    Reporting group title
    Safety: R2pulm VAI
    Reporting group description
    All randomized patients who received R2pulm VAI treatment (Safety set, as-treated). In this reporting group, 4 deaths occurred with the following causes: Cancer = 4. Because the deaths could not be assigned to any specific toxicity, 0 was entered under „Serious adverse event details and values“ for both „Fatalities number“ and „Fatalities causally related to treatment number“.

    Reporting group title
    Safety: R2pulm Bu-Mel
    Reporting group description
    All randomized patients who received R2pulm Bu-Mel treatment (Safety set, as-treated). In this reporting group, 2 deaths occurred with the following causes: Cancer = 1, Pulmonary veno-occlusive disease (Treatment-related) = 1. Because the deaths could not be assigned to any specific toxicity, 0 was entered under „Serious adverse event details and values“ for both „Fatalities number“ and „Fatalities causally related to treatment number“.

    Reporting group title
    Safety: R3 VAC
    Reporting group description
    All randomized patients who received R3 VAC treatment (Safety set, as-treated). In this reporting group, 35 deaths occurred with the following causes: Cancer = 34, Acute pulmonary embolism = 1. Because the deaths could not be assigned to any specific toxicity, 0 was entered under „Serious adverse event details and values“ for both „Fatalities number“ and „Fatalities causally related to treatment number“.

    Reporting group title
    Safety: R3 Treo-Mel
    Reporting group description
    All randomized patients who received R3 Treo-Mel treatment (Safety set, as-treated). In this reporting group, 25 deaths occurred with the following causes: Cancer = 24, Secondary malignancy = 1. Because the deaths could not be assigned to any specific toxicity, 0 was entered under „Serious adverse event details and values“ for both „Fatalities number“ and „Fatalities causally related to treatment number“.

    Serious adverse events
    Safety: R1 Add-on Safety: R1 no Add-on Safety: R2loc VAI Safety: R2loc Bu-Mel Safety: R2pulm VAI Safety: R2pulm Bu-Mel Safety: R3 VAC Safety: R3 Treo-Mel
    Total subjects affected by serious adverse events
         subjects affected / exposed
    124 / 124 (100.00%)
    157 / 160 (98.13%)
    18 / 18 (100.00%)
    7 / 7 (100.00%)
    12 / 12 (100.00%)
    9 / 9 (100.00%)
    62 / 64 (96.88%)
    44 / 44 (100.00%)
         number of deaths (all causes)
    11
    14
    2
    1
    4
    2
    35
    25
         number of deaths resulting from adverse events
    Investigations
    Hemoglobin
         subjects affected / exposed
    66 / 124 (53.23%)
    85 / 160 (53.13%)
    8 / 18 (44.44%)
    3 / 7 (42.86%)
    7 / 12 (58.33%)
    5 / 9 (55.56%)
    31 / 64 (48.44%)
    31 / 44 (70.45%)
         occurrences causally related to treatment / all
    145 / 145
    180 / 180
    14 / 14
    3 / 3
    13 / 13
    9 / 9
    64 / 64
    66 / 66
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Leukocytes
         subjects affected / exposed
    123 / 124 (99.19%)
    155 / 160 (96.88%)
    15 / 18 (83.33%)
    7 / 7 (100.00%)
    12 / 12 (100.00%)
    9 / 9 (100.00%)
    58 / 64 (90.63%)
    44 / 44 (100.00%)
         occurrences causally related to treatment / all
    1337 / 1337
    1390 / 1390
    125 / 125
    41 / 41
    86 / 86
    58 / 58
    504 / 504
    425 / 425
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Granulocytes
         subjects affected / exposed
    114 / 124 (91.94%)
    148 / 160 (92.50%)
    15 / 18 (83.33%)
    5 / 7 (71.43%)
    10 / 12 (83.33%)
    9 / 9 (100.00%)
    55 / 64 (85.94%)
    40 / 44 (90.91%)
         occurrences causally related to treatment / all
    1307 / 1307
    1334 / 1334
    107 / 107
    25 / 25
    81 / 81
    57 / 57
    459 / 459
    393 / 393
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Platelets
         subjects affected / exposed
    107 / 124 (86.29%)
    136 / 160 (85.00%)
    11 / 18 (61.11%)
    6 / 7 (85.71%)
    11 / 12 (91.67%)
    9 / 9 (100.00%)
    54 / 64 (84.38%)
    42 / 44 (95.45%)
         occurrences causally related to treatment / all
    652 / 652
    711 / 711
    62 / 62
    23 / 23
    41 / 41
    33 / 33
    269 / 269
    256 / 256
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fever
         subjects affected / exposed
    9 / 124 (7.26%)
    19 / 160 (11.88%)
    1 / 18 (5.56%)
    0 / 7 (0.00%)
    0 / 12 (0.00%)
    1 / 9 (11.11%)
    5 / 64 (7.81%)
    5 / 44 (11.36%)
         occurrences causally related to treatment / all
    10 / 10
    28 / 28
    1 / 1
    0 / 0
    0 / 0
    1 / 1
    5 / 5
    5 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Creatinine
         subjects affected / exposed
    2 / 124 (1.61%)
    2 / 160 (1.25%)
    0 / 18 (0.00%)
    0 / 7 (0.00%)
    0 / 12 (0.00%)
    0 / 9 (0.00%)
    1 / 64 (1.56%)
    7 / 44 (15.91%)
         occurrences causally related to treatment / all
    2 / 2
    7 / 7
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    10 / 10
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Proteinuria
         subjects affected / exposed
    0 / 124 (0.00%)
    2 / 160 (1.25%)
    0 / 18 (0.00%)
    0 / 7 (0.00%)
    0 / 12 (0.00%)
    0 / 9 (0.00%)
    0 / 64 (0.00%)
    2 / 44 (4.55%)
         occurrences causally related to treatment / all
    0 / 0
    4 / 4
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hematuria
         subjects affected / exposed
    2 / 124 (1.61%)
    0 / 160 (0.00%)
    0 / 18 (0.00%)
    1 / 7 (14.29%)
    0 / 12 (0.00%)
    0 / 9 (0.00%)
    1 / 64 (1.56%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Glumerular filtration rate
         subjects affected / exposed
    1 / 124 (0.81%)
    1 / 160 (0.63%)
    0 / 18 (0.00%)
    1 / 7 (14.29%)
    0 / 12 (0.00%)
    0 / 9 (0.00%)
    0 / 64 (0.00%)
    2 / 44 (4.55%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tubular phosphate reabsorption
         subjects affected / exposed
    19 / 124 (15.32%)
    5 / 160 (3.13%)
    0 / 18 (0.00%)
    0 / 7 (0.00%)
    0 / 12 (0.00%)
    0 / 9 (0.00%)
    2 / 64 (3.13%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    71 / 71
    15 / 15
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bilirubin
         subjects affected / exposed
    2 / 124 (1.61%)
    1 / 160 (0.63%)
    2 / 18 (11.11%)
    0 / 7 (0.00%)
    0 / 12 (0.00%)
    0 / 9 (0.00%)
    1 / 64 (1.56%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    1 / 1
    3 / 3
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    S-GOT/S-GPT
         subjects affected / exposed
    16 / 124 (12.90%)
    24 / 160 (15.00%)
    3 / 18 (16.67%)
    2 / 7 (28.57%)
    2 / 12 (16.67%)
    1 / 9 (11.11%)
    12 / 64 (18.75%)
    6 / 44 (13.64%)
         occurrences causally related to treatment / all
    41 / 41
    45 / 45
    6 / 6
    2 / 2
    6 / 6
    1 / 1
    19 / 19
    10 / 10
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac function test
         subjects affected / exposed
    1 / 124 (0.81%)
    2 / 160 (1.25%)
    0 / 18 (0.00%)
    0 / 7 (0.00%)
    0 / 12 (0.00%)
    0 / 9 (0.00%)
    1 / 64 (1.56%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    ECHO: LV-SF
         subjects affected / exposed
    6 / 124 (4.84%)
    4 / 160 (2.50%)
    0 / 18 (0.00%)
    0 / 7 (0.00%)
    1 / 12 (8.33%)
    2 / 9 (22.22%)
    3 / 64 (4.69%)
    3 / 44 (6.82%)
         occurrences causally related to treatment / all
    7 / 7
    9 / 9
    0 / 0
    0 / 0
    1 / 1
    2 / 2
    7 / 7
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Mucous membrane
         subjects affected / exposed
    0 / 124 (0.00%)
    0 / 160 (0.00%)
    1 / 18 (5.56%)
    0 / 7 (0.00%)
    0 / 12 (0.00%)
    0 / 9 (0.00%)
    1 / 64 (1.56%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Salivary gland
         subjects affected / exposed
    1 / 124 (0.81%)
    0 / 160 (0.00%)
    0 / 18 (0.00%)
    0 / 7 (0.00%)
    0 / 12 (0.00%)
    0 / 9 (0.00%)
    0 / 64 (0.00%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Pharynx and oesophagus
         subjects affected / exposed
    1 / 124 (0.81%)
    2 / 160 (1.25%)
    0 / 18 (0.00%)
    0 / 7 (0.00%)
    0 / 12 (0.00%)
    0 / 9 (0.00%)
    1 / 64 (1.56%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Larynx
         subjects affected / exposed
    0 / 124 (0.00%)
    0 / 160 (0.00%)
    1 / 18 (5.56%)
    0 / 7 (0.00%)
    0 / 12 (0.00%)
    0 / 9 (0.00%)
    0 / 64 (0.00%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    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
    0 / 0
    0 / 0
    Upper gastrointestinal tract
         subjects affected / exposed
    0 / 124 (0.00%)
    1 / 160 (0.63%)
    2 / 18 (11.11%)
    0 / 7 (0.00%)
    0 / 12 (0.00%)
    0 / 9 (0.00%)
    0 / 64 (0.00%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    2 / 2
    0 / 0
    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
    0 / 0
    0 / 0
    Lung
         subjects affected / exposed
    0 / 124 (0.00%)
    0 / 160 (0.00%)
    0 / 18 (0.00%)
    0 / 7 (0.00%)
    0 / 12 (0.00%)
    0 / 9 (0.00%)
    1 / 64 (1.56%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Central neurotoxicity
         subjects affected / exposed
    3 / 124 (2.42%)
    4 / 160 (2.50%)
    1 / 18 (5.56%)
    0 / 7 (0.00%)
    0 / 12 (0.00%)
    0 / 9 (0.00%)
    1 / 64 (1.56%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    4 / 4
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    6 / 124 (4.84%)
    7 / 160 (4.38%)
    1 / 18 (5.56%)
    0 / 7 (0.00%)
    0 / 12 (0.00%)
    1 / 9 (11.11%)
    2 / 64 (3.13%)
    1 / 44 (2.27%)
         occurrences causally related to treatment / all
    6 / 6
    8 / 8
    1 / 1
    0 / 0
    0 / 0
    1 / 1
    2 / 2
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peripheral neurotoxicity
         subjects affected / exposed
    2 / 124 (1.61%)
    5 / 160 (3.13%)
    0 / 18 (0.00%)
    0 / 7 (0.00%)
    0 / 12 (0.00%)
    0 / 9 (0.00%)
    1 / 64 (1.56%)
    2 / 44 (4.55%)
         occurrences causally related to treatment / all
    8 / 8
    14 / 14
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    General physical condition
         subjects affected / exposed
    26 / 124 (20.97%)
    43 / 160 (26.88%)
    4 / 18 (22.22%)
    0 / 7 (0.00%)
    2 / 12 (16.67%)
    5 / 9 (55.56%)
    18 / 64 (28.13%)
    18 / 44 (40.91%)
         occurrences causally related to treatment / all
    81 / 81
    106 / 106
    7 / 7
    0 / 0
    2 / 2
    8 / 8
    24 / 24
    43 / 43
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    0 / 124 (0.00%)
    1 / 160 (0.63%)
    0 / 18 (0.00%)
    0 / 7 (0.00%)
    0 / 12 (0.00%)
    0 / 9 (0.00%)
    0 / 64 (0.00%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Stomatitis
         subjects affected / exposed
    39 / 124 (31.45%)
    50 / 160 (31.25%)
    3 / 18 (16.67%)
    5 / 7 (71.43%)
    4 / 12 (33.33%)
    6 / 9 (66.67%)
    19 / 64 (29.69%)
    21 / 44 (47.73%)
         occurrences causally related to treatment / all
    87 / 87
    137 / 137
    3 / 3
    6 / 6
    8 / 8
    15 / 15
    35 / 35
    40 / 40
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    20 / 124 (16.13%)
    30 / 160 (18.75%)
    2 / 18 (11.11%)
    1 / 7 (14.29%)
    1 / 12 (8.33%)
    1 / 9 (11.11%)
    13 / 64 (20.31%)
    5 / 44 (11.36%)
         occurrences causally related to treatment / all
    27 / 27
    69 / 69
    4 / 4
    2 / 2
    1 / 1
    1 / 1
    19 / 19
    10 / 10
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    7 / 124 (5.65%)
    15 / 160 (9.38%)
    0 / 18 (0.00%)
    1 / 7 (14.29%)
    1 / 12 (8.33%)
    3 / 9 (33.33%)
    7 / 64 (10.94%)
    5 / 44 (11.36%)
         occurrences causally related to treatment / all
    10 / 10
    17 / 17
    0 / 0
    1 / 1
    1 / 1
    3 / 3
    9 / 9
    7 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Changes in the skin
         subjects affected / exposed
    7 / 124 (5.65%)
    9 / 160 (5.63%)
    3 / 18 (16.67%)
    0 / 7 (0.00%)
    1 / 12 (8.33%)
    0 / 9 (0.00%)
    3 / 64 (4.69%)
    7 / 44 (15.91%)
         occurrences causally related to treatment / all
    10 / 10
    13 / 13
    6 / 6
    0 / 0
    1 / 1
    0 / 0
    3 / 3
    10 / 10
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Infection
         subjects affected / exposed
    45 / 124 (36.29%)
    67 / 160 (41.88%)
    8 / 18 (44.44%)
    1 / 7 (14.29%)
    5 / 12 (41.67%)
    6 / 9 (66.67%)
    27 / 64 (42.19%)
    23 / 44 (52.27%)
         occurrences causally related to treatment / all
    97 / 97
    122 / 122
    12 / 12
    2 / 2
    6 / 6
    8 / 8
    45 / 45
    39 / 39
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    Safety: R1 Add-on Safety: R1 no Add-on Safety: R2loc VAI Safety: R2loc Bu-Mel Safety: R2pulm VAI Safety: R2pulm Bu-Mel Safety: R3 VAC Safety: R3 Treo-Mel
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    124 / 124 (100.00%)
    160 / 160 (100.00%)
    18 / 18 (100.00%)
    7 / 7 (100.00%)
    12 / 12 (100.00%)
    9 / 9 (100.00%)
    63 / 64 (98.44%)
    44 / 44 (100.00%)
    Investigations
    Hemoglobin
         subjects affected / exposed
    58 / 124 (46.77%)
    75 / 160 (46.88%)
    10 / 18 (55.56%)
    4 / 7 (57.14%)
    5 / 12 (41.67%)
    4 / 9 (44.44%)
    32 / 64 (50.00%)
    13 / 44 (29.55%)
         occurrences all number
    1900
    1865
    207
    47
    130
    55
    675
    494
    Leukocytes
         subjects affected / exposed
    1 / 124 (0.81%)
    4 / 160 (2.50%)
    3 / 18 (16.67%)
    0 / 7 (0.00%)
    0 / 12 (0.00%)
    0 / 9 (0.00%)
    5 / 64 (7.81%)
    0 / 44 (0.00%)
         occurrences all number
    807
    662
    91
    12
    55
    12
    204
    137
    Granulocytes
         subjects affected / exposed
    6 / 124 (4.84%)
    5 / 160 (3.13%)
    1 / 18 (5.56%)
    1 / 7 (14.29%)
    0 / 12 (0.00%)
    0 / 9 (0.00%)
    3 / 64 (4.69%)
    0 / 44 (0.00%)
         occurrences all number
    461
    403
    51
    12
    32
    4
    113
    69
    Platelets
         subjects affected / exposed
    17 / 124 (13.71%)
    22 / 160 (13.75%)
    6 / 18 (33.33%)
    1 / 7 (14.29%)
    1 / 12 (8.33%)
    0 / 9 (0.00%)
    8 / 64 (12.50%)
    2 / 44 (4.55%)
         occurrences all number
    867
    913
    90
    21
    78
    23
    282
    219
    Fever
         subjects affected / exposed
    109 / 124 (87.90%)
    131 / 160 (81.88%)
    15 / 18 (83.33%)
    7 / 7 (100.00%)
    11 / 12 (91.67%)
    8 / 9 (88.89%)
    55 / 64 (85.94%)
    38 / 44 (86.36%)
         occurrences all number
    875
    991
    73
    19
    52
    42
    322
    284
    Creatinine
         subjects affected / exposed
    28 / 124 (22.58%)
    34 / 160 (21.25%)
    4 / 18 (22.22%)
    2 / 7 (28.57%)
    4 / 12 (33.33%)
    0 / 9 (0.00%)
    6 / 64 (9.38%)
    12 / 44 (27.27%)
         occurrences all number
    100
    83
    7
    3
    9
    0
    10
    38
    Proteinuria
         subjects affected / exposed
    61 / 124 (49.19%)
    60 / 160 (37.50%)
    3 / 18 (16.67%)
    2 / 7 (28.57%)
    5 / 12 (41.67%)
    4 / 9 (44.44%)
    28 / 64 (43.75%)
    18 / 44 (40.91%)
         occurrences all number
    238
    194
    5
    2
    9
    8
    62
    52
    Hematuria
         subjects affected / exposed
    59 / 124 (47.58%)
    65 / 160 (40.63%)
    5 / 18 (27.78%)
    1 / 7 (14.29%)
    5 / 12 (41.67%)
    4 / 9 (44.44%)
    26 / 64 (40.63%)
    19 / 44 (43.18%)
         occurrences all number
    186
    143
    5
    4
    9
    6
    80
    63
    Glumerular filtration rate
         subjects affected / exposed
    30 / 124 (24.19%)
    26 / 160 (16.25%)
    2 / 18 (11.11%)
    1 / 7 (14.29%)
    2 / 12 (16.67%)
    1 / 9 (11.11%)
    2 / 64 (3.13%)
    6 / 44 (13.64%)
         occurrences all number
    104
    92
    3
    6
    2
    4
    14
    36
    Tubular phosphate reabsorption
         subjects affected / exposed
    20 / 124 (16.13%)
    29 / 160 (18.13%)
    2 / 18 (11.11%)
    2 / 7 (28.57%)
    3 / 12 (25.00%)
    1 / 9 (11.11%)
    7 / 64 (10.94%)
    6 / 44 (13.64%)
         occurrences all number
    141
    67
    3
    2
    4
    1
    17
    8
    Bilirubin
         subjects affected / exposed
    28 / 124 (22.58%)
    40 / 160 (25.00%)
    2 / 18 (11.11%)
    1 / 7 (14.29%)
    3 / 12 (25.00%)
    3 / 9 (33.33%)
    17 / 64 (26.56%)
    12 / 44 (27.27%)
         occurrences all number
    84
    79
    12
    1
    6
    3
    41
    23
    S-GOT/S-GPT
         subjects affected / exposed
    97 / 124 (78.23%)
    120 / 160 (75.00%)
    15 / 18 (83.33%)
    3 / 7 (42.86%)
    10 / 12 (83.33%)
    8 / 9 (88.89%)
    48 / 64 (75.00%)
    37 / 44 (84.09%)
         occurrences all number
    1071
    996
    104
    29
    78
    58
    318
    248
    ECHO: LV-SF
         subjects affected / exposed
    13 / 124 (10.48%)
    17 / 160 (10.63%)
    1 / 18 (5.56%)
    0 / 7 (0.00%)
    0 / 12 (0.00%)
    0 / 9 (0.00%)
    1 / 64 (1.56%)
    3 / 44 (6.82%)
         occurrences all number
    33
    45
    1
    0
    0
    2
    6
    8
    ureter and bladder
         subjects affected / exposed
    1 / 124 (0.81%)
    2 / 160 (1.25%)
    0 / 18 (0.00%)
    0 / 7 (0.00%)
    0 / 12 (0.00%)
    0 / 9 (0.00%)
    2 / 64 (3.13%)
    2 / 44 (4.55%)
         occurrences all number
    1
    2
    0
    0
    0
    0
    2
    4
    Mucous membrane
         subjects affected / exposed
    5 / 124 (4.03%)
    7 / 160 (4.38%)
    1 / 18 (5.56%)
    0 / 7 (0.00%)
    0 / 12 (0.00%)
    0 / 9 (0.00%)
    3 / 64 (4.69%)
    1 / 44 (2.27%)
         occurrences all number
    5
    8
    1
    0
    0
    0
    5
    1
    Salivary gland
         subjects affected / exposed
    1 / 124 (0.81%)
    1 / 160 (0.63%)
    0 / 18 (0.00%)
    0 / 7 (0.00%)
    0 / 12 (0.00%)
    1 / 9 (11.11%)
    0 / 64 (0.00%)
    0 / 44 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    1
    0
    0
    Pharynx and oesophagus
         subjects affected / exposed
    2 / 124 (1.61%)
    7 / 160 (4.38%)
    1 / 18 (5.56%)
    0 / 7 (0.00%)
    0 / 12 (0.00%)
    0 / 9 (0.00%)
    3 / 64 (4.69%)
    1 / 44 (2.27%)
         occurrences all number
    2
    8
    1
    0
    0
    0
    4
    2
    Larynx
         subjects affected / exposed
    2 / 124 (1.61%)
    3 / 160 (1.88%)
    0 / 18 (0.00%)
    0 / 7 (0.00%)
    1 / 12 (8.33%)
    0 / 9 (0.00%)
    0 / 64 (0.00%)
    0 / 44 (0.00%)
         occurrences all number
    2
    3
    0
    0
    1
    0
    0
    0
    Upper gastrointestinal tract
         subjects affected / exposed
    4 / 124 (3.23%)
    7 / 160 (4.38%)
    1 / 18 (5.56%)
    0 / 7 (0.00%)
    2 / 12 (16.67%)
    0 / 9 (0.00%)
    9 / 64 (14.06%)
    8 / 44 (18.18%)
         occurrences all number
    5
    7
    1
    0
    2
    0
    15
    14
    Lower gastrointestinal tract including pelvis
         subjects affected / exposed
    1 / 124 (0.81%)
    5 / 160 (3.13%)
    0 / 18 (0.00%)
    0 / 7 (0.00%)
    2 / 12 (16.67%)
    1 / 9 (11.11%)
    8 / 64 (12.50%)
    7 / 44 (15.91%)
         occurrences all number
    1
    5
    0
    0
    2
    1
    16
    14
    Lung
         subjects affected / exposed
    2 / 124 (1.61%)
    4 / 160 (2.50%)
    0 / 18 (0.00%)
    0 / 7 (0.00%)
    0 / 12 (0.00%)
    2 / 9 (22.22%)
    3 / 64 (4.69%)
    1 / 44 (2.27%)
         occurrences all number
    4
    5
    0
    0
    0
    2
    3
    1
    Cardiac disorders
    Cardiac function test
         subjects affected / exposed
    13 / 124 (10.48%)
    18 / 160 (11.25%)
    1 / 18 (5.56%)
    0 / 7 (0.00%)
    2 / 12 (16.67%)
    2 / 9 (22.22%)
    6 / 64 (9.38%)
    6 / 44 (13.64%)
         occurrences all number
    32
    40
    2
    0
    2
    2
    12
    9
    Nervous system disorders
    Cantral neurotoxicity
         subjects affected / exposed
    19 / 124 (15.32%)
    20 / 160 (12.50%)
    2 / 18 (11.11%)
    2 / 7 (28.57%)
    0 / 12 (0.00%)
    0 / 9 (0.00%)
    17 / 64 (26.56%)
    7 / 44 (15.91%)
         occurrences all number
    53
    48
    4
    7
    0
    0
    36
    10
    Seizure
         subjects affected / exposed
    12 / 124 (9.68%)
    8 / 160 (5.00%)
    0 / 18 (0.00%)
    0 / 7 (0.00%)
    0 / 12 (0.00%)
    0 / 9 (0.00%)
    8 / 64 (12.50%)
    2 / 44 (4.55%)
         occurrences all number
    17
    9
    0
    0
    0
    0
    9
    2
    Peripheral neurotoxicity
         subjects affected / exposed
    63 / 124 (50.81%)
    50 / 160 (31.25%)
    9 / 18 (50.00%)
    2 / 7 (28.57%)
    5 / 12 (41.67%)
    3 / 9 (33.33%)
    22 / 64 (34.38%)
    18 / 44 (40.91%)
         occurrences all number
    290
    144
    51
    9
    17
    6
    85
    75
    General disorders and administration site conditions
    General physical condition
         subjects affected / exposed
    89 / 124 (71.77%)
    108 / 160 (67.50%)
    13 / 18 (72.22%)
    6 / 7 (85.71%)
    9 / 12 (75.00%)
    4 / 9 (44.44%)
    44 / 64 (68.75%)
    23 / 44 (52.27%)
         occurrences all number
    1404
    1443
    173
    34
    106
    50
    598
    410
    Headache
         subjects affected / exposed
    3 / 124 (2.42%)
    2 / 160 (1.25%)
    1 / 18 (5.56%)
    0 / 7 (0.00%)
    0 / 12 (0.00%)
    0 / 9 (0.00%)
    2 / 64 (3.13%)
    3 / 44 (6.82%)
         occurrences all number
    4
    2
    1
    0
    0
    0
    2
    5
    Stomatitis
         subjects affected / exposed
    63 / 124 (50.81%)
    83 / 160 (51.88%)
    8 / 18 (44.44%)
    2 / 7 (28.57%)
    5 / 12 (41.67%)
    3 / 9 (33.33%)
    33 / 64 (51.56%)
    22 / 44 (50.00%)
         occurrences all number
    407
    469
    45
    16
    35
    8
    172
    149
    Vomiting
         subjects affected / exposed
    91 / 124 (73.39%)
    98 / 160 (61.25%)
    9 / 18 (50.00%)
    3 / 7 (42.86%)
    8 / 12 (66.67%)
    7 / 9 (77.78%)
    38 / 64 (59.38%)
    37 / 44 (84.09%)
         occurrences all number
    672
    634
    41
    15
    54
    23
    226
    214
    Diarrhoea
         subjects affected / exposed
    72 / 124 (58.06%)
    66 / 160 (41.25%)
    7 / 18 (38.89%)
    2 / 7 (28.57%)
    9 / 12 (75.00%)
    3 / 9 (33.33%)
    31 / 64 (48.44%)
    27 / 44 (61.36%)
         occurrences all number
    214
    199
    12
    3
    23
    12
    90
    87
    Hepatobiliary disorders
    VOD Bearman
         subjects affected / exposed
    0 / 124 (0.00%)
    0 / 160 (0.00%)
    0 / 18 (0.00%)
    1 / 7 (14.29%)
    0 / 12 (0.00%)
    0 / 9 (0.00%)
    0 / 64 (0.00%)
    0 / 44 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    Skin and subcutaneous tissue disorders
    Changes in the skin
         subjects affected / exposed
    80 / 124 (64.52%)
    85 / 160 (53.13%)
    9 / 18 (50.00%)
    5 / 7 (71.43%)
    5 / 12 (41.67%)
    4 / 9 (44.44%)
    38 / 64 (59.38%)
    29 / 44 (65.91%)
         occurrences all number
    263
    221
    36
    11
    18
    7
    126
    98
    Infections and infestations
    Infection
         subjects affected / exposed
    75 / 124 (60.48%)
    83 / 160 (51.88%)
    9 / 18 (50.00%)
    5 / 7 (71.43%)
    7 / 12 (58.33%)
    3 / 9 (33.33%)
    32 / 64 (50.00%)
    20 / 44 (45.45%)
         occurrences all number
    667
    788
    52
    18
    52
    25
    220
    216

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    21 Feb 2011
    - Member states were added: Belgium, Czech Republic and Spain joined study participation - Member state withdrawl trial participation: Slovenia - Changes in Datamanagement: Electronic data capture system is established. - Note regarding treatment with Treosulfan was added: In small children <20 kg BW the dose of treosulfan should be calculated per kg BW. 1 m² BSA = 30 kg BW - Changes in drug supply: In Germany study sites will be supplied with commercial drug from Novartis until 31 Dec 2011 - Changes in dosing of obese patients to ensure safety: In patients with BSA >2 m² dosing of chemotherapy may have to be adjusted to the individual patient’s requirements and tolerance. Note: Observe maximum single dose for vincristine: 2 mg. - Changes (due to typing error) in reportable AEs: Adverse Events not reportable on an SAE form are to be reported on the appropriate CRF (toxicity check list). This include: Neutropenia and neutropenic fever (CTCAE°1-4). Haematological toxicity: haemoglobin, WBC, granulocytes, platelets (CTCAE°1-4).
    23 Apr 2013
    - Changes in inclusion of patients: The option of registering patients to be observed is added into study design. These patients do not meet all inclusion criteria or meet one or more exclusion criteria. - Member states were added to participate in trial for recruiting patients to the R2 arm oft he trial: France, UK, USA - Member state was added: Hungary joined trial participation - Changes in Tresulfan IV administration: Infusion time was extended to 2 h - Changes in drug supply: In Germany study sites will be supplied with commercial drug from Novartis until 30 Sep 2013 - Clarification of drug administration which is relevant for patient safety: If SF remains below 29% then omit DOX and substitute ACT 0.75 mg/m2/d (d1, d2) (IV push) (1.5 mg/m2/cycle) (max. single dose/d: 1.5 mg/d).
    18 Sep 2013
    - Member states were added: Autralia and New Zealand joined trial participation. - Transformation of the original group sequential design into the corresponding inverse normal design: For the randomized risk groups R1 and R3 will be conducted, with 3 planned interim analyses and early stopping rules using the O’Brien and Fleming Design. For risk groups R2loc and R2pulm three interim analyses are intended to be performed using an inverse normal design corresponding to an equally spaced four step group sequential design according to O’Brien & Fleming (Wassmer 2006, O’Brien & Fleming 1979). After each interim analysis a data dependent sample size recalculation may be performed. Then, the accrual period, the observation time and the schedule of the next interim and final analysis (required number of events) can be adapted. If no adaptions are performed, the inverse normal design coincides with the underlying group sequential design. - Recommendation added for dose modifications of elderly patients to enhance paintent’s safety: Chemotherapy may have to be adjusted indivudual patient’s requirements. In these cases the EWING2008 Head Office should be contacted. - Recommandation added for dose medoifications in case of significant toxicities to enhance patient’s safety. Dose modicfications for ifosmamide, cyclophosphamide and actinomycin D
    08 Dec 2014
    - Member state was added: Finland joined trial participation. - Member state withdrawl trial participation: Spain - Changes in sample size, anticipated accrual time and recruitment period for risk groups: Recalculation of R2 (R2loc and R2pulm) with respect to conditional power was performed. - Clarification for patients who are not randomised and do not recieve the standard treatment was added: additional information for was provided each risk group in a guideline - Changes in drug supply: In Germany study sites will be supplied with commercial drug from Novartis until 31 Dec 2016 - SPC for all drugs are updated
    19 Feb 2016
    - Changes in study organisation: Retirement of Prof. Juergens; Prof. Dirksen is the new Coordinating Ivestigator - Changes in plannes study period: The overall study duration (incl. follow-up) was extended by one year as the accrual rate into the trials was slightly lower as expected. - Member state was added: Lithuania joined trial participation - Member state withdrawl trial participation: Slovakia - Changes in recruitment cohort: The study committee decided to close the R2loc arm and the R2pulm arm because of low accrual rate into the randomized arms. The study will be analyzed. - Changes in medication of Standard Risk R1 patients: Fenretinide will not be available, therefore the arm, that included fenretinide was deleted from the protocol for clarification. This results also on changes of the primary and secondary objecitves and oft he sample size. - Changes in inclusion criteria: for Germany patients either sex, age <48 months may be included. - Changes in Key time points: Response evaluation prior to add-on in R1 was changed to optional at the respective time points. - Changes in the staticital analysis: Transformation of the original group sequential design into the corresponding inverse normal design.
    06 Jul 2018
    - Update if trial conduct: R1 and R3 accrual was discontinued on April 1st 2018 - Statistical design has been adapted for final analysis: Adaption of the statistical analysis strategy for the final analysis of the primary endpoint, because the required number of events for the upcoming interim/final analyses cannot be reached. Due to the statistical design change, no further interim analyses will be performed. In the R1 and R3 trial the final analysis will be performed at the end of the trial. - Changes in drug supply: Zoledronic acid is no longer supplied by Novartis - Prophylaxis of ifosfamide-induced encephalopathy was changed: Methylene blue (50mg) should be given 4 times daily

    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/30188789
    http://www.ncbi.nlm.nih.gov/pubmed/31553693
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