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    Clinical Trial Results:
    Evaluation of anthroposophic supportive medicine on treatment-related toxicity in children receiving cancer therapy

    Summary
    EudraCT number
    		 2004-002711-83
    Trial protocol
    		 DE  
    Global end of trial date
    23 Mar 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    25 Apr 2022
    First version publication date
    25 Apr 2022
    Other versions
    Summary report(s)
    		 CSR Summary of Results

    Trial information

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    Trial identification
    Sponsor protocol code
    09-2004 PaedonkoChar
    Additional study identifiers
    ISRCTN number
    		 ISRCTN64676790
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Helixor Heilmittel GmbH
    Sponsor organisation address
    Fischermühle 1, Rosenfeld, Germany, 72348
    Public contact
    Sabine Rieger, Helixor Heilmittel GmbH, +49 7428 / 935 850, srieger@helixor.de
    Scientific contact
    Dr. rer. nat. Michael Schink, Helixor Heilmittel GmbH, +49 7428 / 935 860, mschink@helixor.de
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    21 Mar 2018
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    23 Mar 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    influence of an anthroposophic supportive therapy concept on the chemotherapy-associated toxicity was investigated by means of a toxicity sumscore consisting of the NCI-CTC-scales hematology, mucositis, general condition and the GPOH-modified scale for infection
    Protection of trial subjects
    - the study was conducted in accordance with all relevant laws and regulations relating to clinical studies and the protection of patients - the investigator ensured pseudonymity of the patients, signed patient informed consent and patient enrolment log were kept striktly confidential to enable patient identification at the site - minimisation of pain of subcutaneous injection by use of INJEX needle free injector (optional) - further measures were not necessary
    Background therapy
    		 participants of all groups received standard chemotherapy according to individual tumor type and stage
    Evidence for comparator
    		 -
    Actual start date of recruitment
    24 Nov 2005
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 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
    Germany: 340
    Worldwide total number of subjects
    340
    EEA total number of subjects
    340
    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)
    22
    Children (2-11 years)
    205
    Adolescents (12-17 years)
    113
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Recruitment period from 11/2005 until 11/2013 in 12 trial sites in Germany Patients were assigned to the verum or control group by stratified randomization according to tumor entities and chemotherapy protocols.

    Pre-assignment
    Screening details
    		 Fulfilment of inclusion and non-fulfilment of exclusion criteria. No further screening criteria defined. Latest possible date of randomisation was the 10th day after start of chemotherapy protocol. In total, 556 patients were screened.

    Period 1
    Period 1 title
    treatment period
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 control group
    Arm description
    		 standard therapy: chemotherapy according to underlying disease with standardised concomitant treatments
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 verum group
    Arm description
    		 anthroposophic supportive therapy in addition to standard therapy (chemotherapy according to underlying disease with standardised concomitant treatments)
    Arm type
    		 Experimental

    Investigational medicinal product name
    Helixor A
    Investigational medicinal product code
    L01CH01
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subcutaneous injections 2 times a week stepwise dose increase starting with 1 mg until occurence of local or systemic reaction to investigational drug maximum allowed dose: 100 mg

    Investigational medicinal product name
    Cichorium e planta tota 5% Globuli velati
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Pillules
    Routes of administration
    Oral use
    Dosage and administration details
    Dose for children < 4 years: 3x5 globules per day dose for children ≥ 4 years: 3x7 globules per day

    Investigational medicinal product name
    Oxalis Folium Rh D4 aqueous dilution
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral drops, solution
    Routes of administration
    Oral use
    Dosage and administration details
    Dose for children < 4 years: 3x5 drops per day dose for children ≥ 4 years: 3x7 drops per day

    Investigational medicinal product name
    Phosphorus D8 Globuli velati
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Pillules
    Routes of administration
    Oral use
    Dosage and administration details
    Dose for children < 4 years: 5 globules (in the morning) dose for children ≥ 4 years: 10 globules (in the morning)

    Investigational medicinal product name
    Phosphorus D30 Globuli velati
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Pillules
    Routes of administration
    Oral use
    Dosage and administration details
    Dose for children < 4 years: 5 globules (in the evening) dose for children ≥ 4 years: 10 globules (in the evening)

    Investigational medicinal product name
    Aurum/Prunus liquid dilution for injection
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    1 ampoule as an intravenous infusion before each chemotherapy

    Investigational medicinal product name
    Aurum Valeriana Globuli velati
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Pillules
    Routes of administration
    Oral use
    Dosage and administration details
    Dose for children < 4 years: 5 globules up to every 2 hours (except at night) dose for children ≥ 4 years: 10 globules up to every 2 hours (except at night)

    Investigational medicinal product name
    Bryophyllum 5% solution for injection
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    In the recovery phase after sedation, anesthesia or punctures: dose for children < 4 years: 5 ml as an intravenous infusion dose for children ≥ 4 years: 10 ml as an intravenous infusion

    Investigational medicinal product name
    Bryophyllum 50%
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral powder
    Routes of administration
    Oral use
    Dosage and administration details
    For psychological and somatic side effects or at the end of steroid administration: 1 teaspoon 3 times a day; for sleep disorders daily: dose for children < 4 years: 1/2 teaspoon 3 times a day dose for children ≥ 4 years: 1 teaspoon 3 times a day

    Investigational medicinal product name
    Calendula (mother tincture)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral drops, solution
    Routes of administration
    Oral use
    Dosage and administration details
    Dose for children < 4 years: 5 drops 3 times a day Dose for children ≥ 4 years: 10 drops 3 times a day

    Investigational medicinal product name
    Nux vomica D4 liquid dilution for injection
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    1 ampoule as an intravenous infusion before each chemotherapy

    Investigational medicinal product name
    Nux vomica e semine D4 Globuli velati
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Pillules
    Routes of administration
    Oral use
    Dosage and administration details
    Dose for children < 4 years: 3 globules daily to hourly dose for children ≥ 4 years: 5 globules daily to hourly

    Investigational medicinal product name
    Oxalis ointment 30%
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Ointment
    Routes of administration
    Topical use
    Dosage and administration details
    if necessary or regularly moist warm wrap at noon

    Investigational medicinal product name
    Ratanhia comp.
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Mouthwash
    Routes of administration
    Oral use
    Dosage and administration details
    To be used only as a dilution (30 drops per 100 ml of water) Besides this mouthwash, no other conventional is allowed

    Investigational medicinal product name
    Solum Oil
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Pharmaceutical dose form not applicable
    Routes of administration
    Topical use
    Dosage and administration details
    Rubbing of individual body parts (for example extremities / back); if necessary, ideally in the evening

    Investigational medicinal product name
    Meteoreisen Globuli velati
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Pillules
    Routes of administration
    Oral use
    Dosage and administration details
    Dose for children < 4 years: 3x5 globules per day dose for children ≥ 4 years: 3x10 globules per day

    Investigational medicinal product name
    Argentum metallicum praeparatum D30 (liquid dilution for injection)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Dose for children < 4 years: 1 ampoule as an intravenous infusion once a day before intravenous antibiotic administration dose for children ≥ 4 years: 2 ampoules as an intravenous infusion once a day before intravenous antibiotic administration

    Investigational medicinal product name
    Gentiana Magen Globuli velati
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Pillules
    Routes of administration
    Oral use
    Dosage and administration details
    Dose for children < 4 years: 3x5 globules per day dose for children ≥ 4 years: 3x10 globules per day

    Investigational medicinal product name
    Lachesis D8 Dilution
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Pillules
    Routes of administration
    Oral use
    Dosage and administration details
    Dose for children < 4 years: 3x5 drops per day (to be diluted) dose for children ≥ 4 years: 3x7 drops per day (to be diluted)

    Number of subjects in period 1
    		control group verum group
    Started
    170
    170
    Completed
    149
    139
    Not completed
    21
    31
         Protocol deviation
    21
    31
    Period 2
    Period 2 title
    follow-up period
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Follow-up control group
    Arm description
    		 Patients who have finished at least the first observation period of chemotherapy were observed up to five years no limitations for treatment during follow-up period after conclusion of standard therapy
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 Follow-up verum group
    Arm description
    		 Patients, who have finished at least the first observation period of chemotherapy and have received basic remedies at least during this period, were observed up to five years no limitations for treatment during follow-up period after conclusion of standard therapy
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 2
    		Follow-up control group Follow-up verum group
    Started
    149
    139
    Completed
    135
    135
    Not completed
    14
    4
         Lost to follow-up
    14
    4

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    control group
    Reporting group description
    		 standard therapy: chemotherapy according to underlying disease with standardised concomitant treatments

    Reporting group title
    verum group
    Reporting group description
    		 anthroposophic supportive therapy in addition to standard therapy (chemotherapy according to underlying disease with standardised concomitant treatments)

    Reporting group values
    		 control group verum group Total
    Number of subjects
    		 170 170 340
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 12 10 22
        Children (2-11 years)
    		 104 101 205
        Adolescents (12-17 years)
    		 54 59 113
        Adults (18-64 years)
    		 0 0 0
        From 65-84 years
    		 0 0 0
        85 years and over
    		 0 0 0
    Gender categorical
    Units: Subjects
        Female
    		 82 59 141
        Male
    		 88 111 199

    End points

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    End points reporting groups
    Reporting group title
    control group
    Reporting group description
    		 standard therapy: chemotherapy according to underlying disease with standardised concomitant treatments

    Reporting group title
    verum group
    Reporting group description
    		 anthroposophic supportive therapy in addition to standard therapy (chemotherapy according to underlying disease with standardised concomitant treatments)
    Reporting group title
    Follow-up control group
    Reporting group description
    		 Patients who have finished at least the first observation period of chemotherapy were observed up to five years no limitations for treatment during follow-up period after conclusion of standard therapy

    Reporting group title
    Follow-up verum group
    Reporting group description
    		 Patients, who have finished at least the first observation period of chemotherapy and have received basic remedies at least during this period, were observed up to five years no limitations for treatment during follow-up period after conclusion of standard therapy

    Subject analysis set title
    control group ITT subset
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    This ITT population includes all patients enrolled in the study who have been randomised, regardless of protocol violations in the course of the study

    Subject analysis set title
    verum group ITT subset
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    This ITT population includes all patients enrolled in the study who have been randomised and who have received basic medications at least during one complete observation period, regardless of protocol violations in the course of the study.

    Subject analysis set title
    Follow-up control group EFS
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    This modified ITT-population includes all patients enrolled in the study and randomised into the control group • with complete remission (CR) at the end of the intensive phase of chemotherapy (main study) • for which a follow-up documentation sheet is available 5 years after diagnosis. This documentation sheet must contain an indication (yes or no) on relapse, death and second malignancy

    Subject analysis set title
    Follow-up verum group EFS
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    This modified ITT-population includes all patients enrolled in the study and randomised into the verum group • with complete remission (CR) at the end of the intensive phase of chemotherapy (main study) • for which a follow-up documentation sheet is available 5 years after diagnosis. This documentation sheet must contain an indication (yes or no) on relapse, death and second malignancy

    Subject analysis set title
    Follow-up control group OS
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    This modified ITT-population includes all patients enrolled in the study and randomised into the control group for whom a follow-up documentation form has been completed 5 years after diagnosis

    Subject analysis set title
    Follow-up verum group OS
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    This modified ITT-population includes all patients enrolled in the study and randomised into the verum group for whom a follow-up documentation form has been completed 5 years after diagnosis

    Subject analysis set title
    control group PP subset
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The PP population includes all patients enrolled in the study who have been randomised and have gone through all chemotherapy units until conclusion of last chemotherapy unit without occurrence of serious protocol violations.

    Subject analysis set title
    verum group PP subset
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The PP population includes all patients enrolled in the study who have been randomised and have gone through all chemotherapy units until conclusion of last chemotherapy unit without occurrence of serious protocol violations. Additionally at least 75% of basic remedies of study medication have been administered.

    Primary: Reduction of toxicity sum score of selected NCI-CTC-scales

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    End point title
    		 Reduction of toxicity sum score of selected NCI-CTC-scales
    End point description
    influence of an anthroposophic supportive therapy concept on the chemotherapy-associated toxicity was investigated by means of a toxicity sumscore consisting of the NCI-CTC-scales hematology, mucositis, general condition and the GPOH-modified scale for infection
    End point type
    Primary
    End point timeframe
    Depending on the chosen chemotherapy schedule time frame lasted from beginning of first chemotherapy treatment unit until 28 days after termination of last chemotherapy treatment unit.
    End point values
    		 control group ITT subset verum group ITT subset control group PP subset verum group PP subset
    Number of subjects analysed
    140
    139
    126
    82
    Units: unit(s)
        arithmetic mean (standard deviation)
    11.8 ( 4.54 )
    12.1 ( 3.92 )
    11.5 ( 4.33 )
    11.4 ( 3.58 )
    Statistical analysis title
    		 Comparison of toxicity sum score ITT group
    Comparison groups
    control group ITT subset v verum group ITT subset
    Number of subjects included in analysis
    279
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 = 0.257
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    		 Comparison of toxicity sum score PP group
    Comparison groups
    control group PP subset v verum group PP subset
    Number of subjects included in analysis
    208
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 = 0.716
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: ALL-Non-HR; overall survival

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    End point title
    		 ALL-Non-HR; overall survival
    End point description
    Overall survival within a period of 5 years
    End point type
    Secondary
    End point timeframe
    Date of initial diagnosis until date of death or end of 5-years observation period
    End point values
    		 Follow-up control group OS Follow-up verum group OS
    Number of subjects analysed
    54
    47
    Units: months
        arithmetic mean (standard deviation)
    56.9 ( 10.2 )
    59.0 ( 5.61 )
    Statistical analysis title
    		 Comparison of overall survival
    Comparison groups
    Follow-up control group OS v Follow-up verum group OS
    Number of subjects included in analysis
    101
    Analysis specification
    Post-hoc
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.185
    Method
    		 Logrank
    Confidence interval

    Secondary: ALL-HR; overall survival

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    End point title
    		 ALL-HR; overall survival
    End point description
    Overall survival within a period of 5 years
    End point type
    Secondary
    End point timeframe
    Date of initial diagnosis until date of death or end of 5-years observation period
    End point values
    		 Follow-up control group OS Follow-up verum group OS
    Number of subjects analysed
    3
    5
    Units: months
        arithmetic mean (standard deviation)
    60.0 ( 0 )
    57.6 ( 5.37 )
    Statistical analysis title
    		 Comparison of overall survival
    Comparison groups
    Follow-up control group OS v Follow-up verum group OS
    Number of subjects included in analysis
    8
    Analysis specification
    Post-hoc
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.439
    Method
    		 Logrank
    Confidence interval

    Secondary: COALL-HR; overall survival

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    End point title
    		 COALL-HR; overall survival
    End point description
    Overall survival within a period of 5 years
    End point type
    Secondary
    End point timeframe
    Date of initial diagnosis until date of death or end of 5-years observation period
    End point values
    		 Follow-up control group OS Follow-up verum group OS
    Number of subjects analysed
    7
    9
    Units: months
        arithmetic mean (standard deviation)
    53.0 ( 13.7 )
    55.3 ( 9.27 )
    Statistical analysis title
    		 Comparison of overall survival
    Comparison groups
    Follow-up control group OS v Follow-up verum group OS
    Number of subjects included in analysis
    16
    Analysis specification
    Post-hoc
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.756
    Method
    		 Logrank
    Confidence interval

    Secondary: ALL-Rez; overall survival

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    End point title
    		 ALL-Rez; overall survival
    End point description
    Overall survival within a period of 5 years
    End point type
    Secondary
    End point timeframe
    Date of initial diagnosis until date of death or end of 5-years observation period
    End point values
    		 Follow-up control group OS Follow-up verum group OS
    Number of subjects analysed
    6
    6
    Units: months
        arithmetic mean (standard deviation)
    50.2 ( 22.7 )
    46.2 ( 21.8 )
    Statistical analysis title
    		 Comparison of overall survival
    Comparison groups
    Follow-up control group OS v Follow-up verum group OS
    Number of subjects included in analysis
    12
    Analysis specification
    Post-hoc
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.992
    Method
    		 Logrank
    Confidence interval

    Secondary: AML; overall survival

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    End point title
    		 AML; overall survival
    End point description
    Overall survival within a period of 5 years
    End point type
    Secondary
    End point timeframe
    Date of initial diagnosis until date of death or end of 5-years observation period
    End point values
    		 Follow-up control group OS Follow-up verum group OS
    Number of subjects analysed
    9
    8
    Units: months
        arithmetic mean (standard deviation)
    55.3 ( 14.0 )
    46.8 ( 20.1 )
    Statistical analysis title
    		 Comparison of overall survival
    Comparison groups
    Follow-up control group OS v Follow-up verum group OS
    Number of subjects included in analysis
    17
    Analysis specification
    Post-hoc
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.229
    Method
    		 Logrank
    Confidence interval

    Secondary: B-NHL; overall survival

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    End point title
    		 B-NHL; overall survival
    End point description
    Overall survival within a period of 5 years
    End point type
    Secondary
    End point timeframe
    Date of initial diagnosis until date of death or end of 5-years observation period
    End point values
    		 Follow-up control group OS Follow-up verum group OS
    Number of subjects analysed
    8
    8
    Units: months
        arithmetic mean (standard deviation)
    57.6 ( 6.72 )
    40.4 ( 27.2 )
    Statistical analysis title
    		 Comparison of overall survival
    Comparison groups
    Follow-up control group OS v Follow-up verum group OS
    Number of subjects included in analysis
    16
    Analysis specification
    Post-hoc
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.063
    Method
    		 Logrank
    Confidence interval

    Secondary: Rhabdomyosarcoma; overall survival

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    End point title
    		 Rhabdomyosarcoma; overall survival
    End point description
    Overall survival within a period of 5 years
    End point type
    Secondary
    End point timeframe
    Date of initial diagnosis until date of death or end of 5-years observation period
    End point values
    		 Follow-up control group OS Follow-up verum group OS
    Number of subjects analysed
    3
    2
    Units: months
        arithmetic mean (standard deviation)
    60.0 ( 0 )
    34.0 ( 0 )
    Statistical analysis title
    		 Comparison of overall survival
    Comparison groups
    Follow-up control group OS v Follow-up verum group OS
    Number of subjects included in analysis
    5
    Analysis specification
    Post-hoc
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.221
    Method
    		 Logrank
    Confidence interval

    Secondary: Osteosarcoma; overall survival

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    End point title
    		 Osteosarcoma; overall survival
    End point description
    Overall survival within a period of 5 years
    End point type
    Secondary
    End point timeframe
    Date of initial diagnosis until date of death or end of 5-years observation period
    End point values
    		 Follow-up control group OS Follow-up verum group OS
    Number of subjects analysed
    4
    3
    Units: months
        arithmetic mean (standard deviation)
    56.8 ( 6.50 )
    42.3 ( 30.6 )
    Statistical analysis title
    		 Comparison of overall survival
    Comparison groups
    Follow-up control group OS v Follow-up verum group OS
    Number of subjects included in analysis
    7
    Analysis specification
    Post-hoc
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.728
    Method
    		 Logrank
    Confidence interval

    Secondary: Morbus Hodgkin; overall survival

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    End point title
    		 Morbus Hodgkin; overall survival
    End point description
    Overall survival within a period of 5 years
    End point type
    Secondary
    End point timeframe
    Date of initial diagnosis until date of death or end of 5-years observation period
    End point values
    		 Follow-up control group OS Follow-up verum group OS
    Number of subjects analysed
    17
    11
    Units: months
        arithmetic mean (standard deviation)
    55.1 ( 11.0 )
    59.4 ( 2.11 )
    Statistical analysis title
    		 Comparison of overall survival
    Comparison groups
    Follow-up control group OS v Follow-up verum group OS
    Number of subjects included in analysis
    28
    Analysis specification
    Post-hoc
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.407
    Method
    		 Logrank
    Confidence interval

    Secondary: Ewing-Sarcoma; overall survival

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    End point title
    		 Ewing-Sarcoma; overall survival
    End point description
    Overall survival within a period of 5 years
    End point type
    Secondary
    End point timeframe
    Date of initial diagnosis until date of death or end of 5-years observation period
    End point values
    		 Follow-up control group OS Follow-up verum group OS
    Number of subjects analysed
    11
    10
    Units: months
        arithmetic mean (standard deviation)
    56.9 ( 6.89 )
    47.4 ( 21.7 )
    Statistical analysis title
    		 Comparison of overall survival
    Comparison groups
    Follow-up control group OS v Follow-up verum group OS
    Number of subjects included in analysis
    21
    Analysis specification
    Post-hoc
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.441
    Method
    		 Logrank
    Confidence interval

    Secondary: Medulloblastoma/Ependymoma; overall survival

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    End point title
    		 Medulloblastoma/Ependymoma; overall survival
    End point description
    Overall survival within a period of 5 years
    End point type
    Secondary
    End point timeframe
    Date of initial diagnosis until date of death or end of 5-years observation period
    End point values
    		 Follow-up control group OS Follow-up verum group OS
    Number of subjects analysed
    1
    3
    Units: months
        arithmetic mean (standard deviation)
    60.0 ( 0 )
    29.0 ( 11.5 )
    Statistical analysis title
    		 Comparison of overall survival
    Comparison groups
    Follow-up control group OS v Follow-up verum group OS
    Number of subjects included in analysis
    4
    Analysis specification
    Post-hoc
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.182
    Method
    		 Logrank
    Confidence interval

    Secondary: Neuroblastoma; overall survival

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    End point title
    		 Neuroblastoma; overall survival
    End point description
    Overall survival within a period of 5 years
    End point type
    Secondary
    End point timeframe
    Date of initial diagnosis until date of death or end of 5-years observation period
    End point values
    		 Follow-up control group OS Follow-up verum group OS
    Number of subjects analysed
    7
    7
    Units: months
        arithmetic mean (standard deviation)
    48.4 ( 20.2 )
    33.0 ( 18.2 )
    Statistical analysis title
    		 Comparison of overall survival
    Comparison groups
    Follow-up control group OS v Follow-up verum group OS
    Number of subjects included in analysis
    14
    Analysis specification
    Post-hoc
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.025
    Method
    		 Logrank
    Confidence interval

    Secondary: ALL-Non-HR; event-free survival

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    End point title
    		 ALL-Non-HR; event-free survival
    End point description
    Event-free survival within a period of 5 years
    End point type
    Secondary
    End point timeframe
    Date of initial diagnosis until date of event (relapse, death or second malignancy) or end of 5-years observation period
    End point values
    		 Follow-up control group EFS Follow-up verum group EFS
    Number of subjects analysed
    49
    44
    Units: months
        arithmetic mean (standard deviation)
    54.9 ( 13.4 )
    55.7 ( 12.5 )
    Statistical analysis title
    		 Comparion of event free survival
    Comparison groups
    Follow-up control group EFS v Follow-up verum group EFS
    Number of subjects included in analysis
    93
    Analysis specification
    Post-hoc
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.686
    Method
    		 Logrank
    Confidence interval

    Secondary: ALL-HR; event-free survival

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    End point title
    		 ALL-HR; event-free survival
    End point description
    Event-free survival within a period of 5 years
    End point type
    Secondary
    End point timeframe
    Date of initial diagnosis until date of event (relapse, death or second malignancy) or end of 5-years observation period
    End point values
    		 Follow-up control group EFS Follow-up verum group EFS
    Number of subjects analysed
    3
    5
    Units: months
        arithmetic mean (standard deviation)
    60.0 ( 0 )
    57.2 ( 6.26 )
    Statistical analysis title
    		 Comparion of event free survival
    Comparison groups
    Follow-up control group EFS v Follow-up verum group EFS
    Number of subjects included in analysis
    8
    Analysis specification
    Post-hoc
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.436
    Method
    		 Logrank
    Confidence interval

    Secondary: COALL-Non-HR; event-free survival

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    End point title
    		 COALL-Non-HR; event-free survival
    End point description
    Event-free survival within a period of 5 years
    End point type
    Secondary
    End point timeframe
    Date of initial diagnosis until date of event (relapse, death or second malignancy) or end of 5-years observation period
    End point values
    		 Follow-up control group EFS Follow-up verum group EFS
    Number of subjects analysed
    9
    9
    Units: months
        arithmetic mean (standard deviation)
    57.9 ( 6.33 )
    58.9 ( 3.33 )
    Statistical analysis title
    		 Comparion of event free survival
    Comparison groups
    Follow-up control group EFS v Follow-up verum group EFS
    Number of subjects included in analysis
    18
    Analysis specification
    Post-hoc
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.967
    Method
    		 Logrank
    Confidence interval

    Secondary: COALL-HR; event-free survival

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    End point title
    		 COALL-HR; event-free survival
    End point description
    Event-free survival within a period of 5 years
    End point type
    Secondary
    End point timeframe
    Date of initial diagnosis until date of event (relapse, death or second malignancy) or end of 5-years observation period
    End point values
    		 Follow-up control group EFS Follow-up verum group EFS
    Number of subjects analysed
    4
    9
    Units: months
        arithmetic mean (standard deviation)
    60.0 ( 0 )
    53.8 ( 12.8 )
    Statistical analysis title
    		 Comparion of event free survival
    Comparison groups
    Follow-up control group EFS v Follow-up verum group EFS
    Number of subjects included in analysis
    13
    Analysis specification
    Post-hoc
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.331
    Method
    		 Logrank
    Confidence interval

    Secondary: ALL-Rez; event-free survival

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    End point title
    		 ALL-Rez; event-free survival
    End point description
    Event-free survival within a period of 5 years
    End point type
    Secondary
    End point timeframe
    Date of initial diagnosis until date of event (relapse, death or second malignancy) or end of 5-years observation period
    End point values
    		 Follow-up control group EFS Follow-up verum group EFS
    Number of subjects analysed
    3
    4
    Units: months
        arithmetic mean (standard deviation)
    59.0 ( 1.73 )
    50.8 ( 18.5 )
    Statistical analysis title
    		 Comparion of event free survival
    Comparison groups
    Follow-up control group EFS v Follow-up verum group EFS
    Number of subjects included in analysis
    7
    Analysis specification
    Post-hoc
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.919
    Method
    		 Logrank
    Confidence interval

    Secondary: AML; event-free survival

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    End point title
    		 AML; event-free survival
    End point description
    Event-free survival within a period of 5 years
    End point type
    Secondary
    End point timeframe
    Date of initial diagnosis until date of event (relapse, death or second malignancy) or end of 5-years observation period
    End point values
    		 Follow-up control group EFS Follow-up verum group EFS
    Number of subjects analysed
    8
    4
    Units: months
        arithmetic mean (standard deviation)
    49.9 ( 19.6 )
    50.8 ( 18.5 )
    Statistical analysis title
    		 Comparion of event free survival
    Comparison groups
    Follow-up control group EFS v Follow-up verum group EFS
    Number of subjects included in analysis
    12
    Analysis specification
    Post-hoc
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.306
    Method
    		 Logrank
    Confidence interval

    Secondary: B-NHL; event-free survival

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    End point title
    		 B-NHL; event-free survival
    End point description
    Event-free survival within a period of 5 years
    End point type
    Secondary
    End point timeframe
    Date of initial diagnosis until date of event (relapse, death or second malignancy) or end of 5-years observation period
    End point values
    		 Follow-up control group EFS Follow-up verum group EFS
    Number of subjects analysed
    7
    6
    Units: months
        arithmetic mean (standard deviation)
    60.0 ( 0 )
    51.5 ( 20.8 )
    Statistical analysis title
    		 Comparion of event free survival
    Comparison groups
    Follow-up control group EFS v Follow-up verum group EFS
    Number of subjects included in analysis
    13
    Analysis specification
    Post-hoc
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.28
    Method
    		 Logrank
    Confidence interval

    Secondary: Rhabdomyosarcoma; event-free survival

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    End point title
    		 Rhabdomyosarcoma; event-free survival
    End point description
    Event-free survival within a period of 5 years
    End point type
    Secondary
    End point timeframe
    Date of initial diagnosis until date of event (relapse, death or second malignancy) or end of 5-years observation period
    End point values
    		 Follow-up control group EFS Follow-up verum group EFS
    Number of subjects analysed
    2
    1
    Units: months
        arithmetic mean (standard deviation)
    60.0 ( 0 )
    9.0 ( 0 )
    Statistical analysis title
    		 Comparion of event free survival
    Comparison groups
    Follow-up control group EFS v Follow-up verum group EFS
    Number of subjects included in analysis
    3
    Analysis specification
    Post-hoc
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.157
    Method
    		 Logrank
    Confidence interval

    Secondary: Morbus Hodgkin; event-free survival

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    End point title
    		 Morbus Hodgkin; event-free survival
    End point description
    Event-free survival within a period of 5 years
    End point type
    Secondary
    End point timeframe
    Date of initial diagnosis until date of event (relapse, death or second malignancy) or end of 5-years observation period
    End point values
    		 Follow-up control group EFS Follow-up verum group EFS
    Number of subjects analysed
    6
    9
    Units: months
        arithmetic mean (standard deviation)
    53.5 ( 15.9 )
    52.0 ( 17.6 )
    Statistical analysis title
    		 Comparion of event free survival
    Comparison groups
    Follow-up control group EFS v Follow-up verum group EFS
    Number of subjects included in analysis
    15
    Analysis specification
    Post-hoc
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.802
    Method
    		 Logrank
    Confidence interval

    Secondary: Ewing-Sarcoma; event-free survival

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    End point title
    		 Ewing-Sarcoma; event-free survival
    End point description
    Event-free survival within a period of 5 years
    End point type
    Secondary
    End point timeframe
    Date of initial diagnosis until date of event (relapse, death or second malignancy) or end of 5-years observation period
    End point values
    		 Follow-up control group EFS Follow-up verum group EFS
    Number of subjects analysed
    10
    4
    Units: months
        arithmetic mean (standard deviation)
    56.0 ( 8.21 )
    55.0 ( 10.0 )
    Statistical analysis title
    		 Comparion of event free survival
    Comparison groups
    Follow-up control group EFS v Follow-up verum group EFS
    Number of subjects included in analysis
    14
    Analysis specification
    Post-hoc
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.897
    Method
    		 Logrank
    Confidence interval

    Secondary: Medulloblastoma/Ependymoma; event-free survival

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    End point title
    		 Medulloblastoma/Ependymoma; event-free survival
    End point description
    Event-free survival within a period of 5 years
    End point type
    Secondary
    End point timeframe
    Date of initial diagnosis until date of event (relapse, death or second malignancy) or end of 5-years observation period
    End point values
    		 Follow-up control group EFS Follow-up verum group EFS
    Number of subjects analysed
    1
    3
    Units: months
        arithmetic mean (standard deviation)
    60.0 ( 0 )
    22.7 ( 11.9 )
    Statistical analysis title
    		 Comparion of event free survival
    Comparison groups
    Follow-up verum group EFS v Follow-up control group EFS
    Number of subjects included in analysis
    4
    Analysis specification
    Post-hoc
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.182
    Method
    		 Logrank
    Confidence interval

    Secondary: Neuroblastoma; event-free survival

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    End point title
    		 Neuroblastoma; event-free survival
    End point description
    Event-free survival within a period of 5 years
    End point type
    Secondary
    End point timeframe
    Date of initial diagnosis until date of event (relapse, death or second malignancy) or end of 5-years observation period
    End point values
    		 Follow-up control group EFS Follow-up verum group EFS
    Number of subjects analysed
    3
    1
    Units: months
        arithmetic mean (standard deviation)
    60.0 ( 0 )
    41.0 ( 0 )
    Statistical analysis title
    		 Comparion of event free survival
    Comparison groups
    Follow-up control group EFS v Follow-up verum group EFS
    Number of subjects included in analysis
    4
    Analysis specification
    Post-hoc
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.083
    Method
    		 Logrank
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    continuous reporting of adverse events by investigator via remote data entry, assessment of reports yearly within framework of annual safety reports (serious adverse reactions assessed quarterly)
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    16.1
    Reporting groups
    Reporting group title
    safety population
    Reporting group description
    		 The safety population included all patients recruited into the study who were randomized and who received the basic medication at least once during the course of the study and/or on-demand remedies of the investigational medication. For this population adverse events (AE) and serious adverse events (SAEs) were assessed.

    Serious adverse events
    		 safety population
    Total subjects affected by serious adverse events
         subjects affected / exposed
    11 / 163 (6.75%)
         number of deaths (all causes)
    3
         number of deaths resulting from adverse events
    3
    Nervous system disorders
    Toxic encephalopathy
         subjects affected / exposed
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cerebral venous sinus thrombosis
         subjects affected / exposed
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Subarachnoid haemorrhage
         subjects affected / exposed
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pancreatitis
         subjects affected / exposed
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastric ulcer
         subjects affected / exposed
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Pneumonia viral
         subjects affected / exposed
    2 / 163 (1.23%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Sepsis
         subjects affected / exposed
    2 / 163 (1.23%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 2
    Neutropenic sepsis
         subjects affected / exposed
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Febrile infection
         subjects affected / exposed
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Soft tissue infection
         subjects affected / exposed
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Metabolism and nutrition disorders
    Type 1 diabetes mellitus
         subjects affected / exposed
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 safety population
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    123 / 163 (75.46%)
    Cardiac disorders
    Tachycardia paroxysmal
         subjects affected / exposed
    1 / 163 (0.61%)
         occurrences all number
    1
    Nervous system disorders
    Tremor
         subjects affected / exposed
    1 / 163 (0.61%)
         occurrences all number
    1
    General disorders and administration site conditions
    Injection site inflammation
         subjects affected / exposed
    106 / 163 (65.03%)
         occurrences all number
    453
    Inflammation
         subjects affected / exposed
    1 / 163 (0.61%)
         occurrences all number
    1
    Application site pain
         subjects affected / exposed
    6 / 163 (3.68%)
         occurrences all number
    9
    Injection site necrosis
         subjects affected / exposed
    1 / 163 (0.61%)
         occurrences all number
    1
    Pyrexia
         subjects affected / exposed
    32 / 163 (19.63%)
         occurrences all number
    81
    Blood and lymphatic system disorders
    Lymphadenopathy
         subjects affected / exposed
    1 / 163 (0.61%)
         occurrences all number
    1
    Immune system disorders
    Dermatitis allergic
         subjects affected / exposed
    17 / 163 (10.43%)
         occurrences all number
    27
    Hypersensitivity
         subjects affected / exposed
    8 / 163 (4.91%)
         occurrences all number
    9
    Urticaria
         subjects affected / exposed
    3 / 163 (1.84%)
         occurrences all number
    4
    Drug reaction with eosinophilia and systemic symptoms
         subjects affected / exposed
    4 / 163 (2.45%)
         occurrences all number
    6
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    1 / 163 (0.61%)
         occurrences all number
    1
    Vomiting
         subjects affected / exposed
    1 / 163 (0.61%)
         occurrences all number
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    1 / 163 (0.61%)
         occurrences all number
    1
    Lung infiltration
         subjects affected / exposed
    1 / 163 (0.61%)
         occurrences all number
    1
    Apnoea
         subjects affected / exposed
    1 / 163 (0.61%)
         occurrences all number
    1
    Dyspnoea
         subjects affected / exposed
    1 / 163 (0.61%)
         occurrences all number
    1
    Skin and subcutaneous tissue disorders
    Blister
         subjects affected / exposed
    4 / 163 (2.45%)
         occurrences all number
    4
    Pruritus
         subjects affected / exposed
    2 / 163 (1.23%)
         occurrences all number
    3

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    28 Aug 2006
    Essential changes were: - Updates, specifications and correction of chemotherapy protocols - Frequency of administration of an IV product - Addition of an investigation of mistletoe lectin-antibodies for a sample of n = 15 patients of verum group in order to get information about the application of Helixor® A - Specification for the early withdrawal of a patient from the study - Correction of expected end of study - Complete revision of the chapter on definition, recording and evaluation of adverse events
    01 Sep 2008
    Essential changes were: - Inclusion of new trial sites - Prolongation of recruitment time due to slow recruitment - Update of existing an new CT protocols - Specification of an exclusion criterion - Specification and supplementation of the analysis population - Supplement of side effects - Elimination of an additional analysis due to unsuitability
    18 Jan 2010
    Essential changes were: - Downsizing of the DSMC to exclude people directly involved in the study - Update and corrections of the CT protocols - Prolongation of recruitment time and study duration - Recruitment of further trial sites - Side effects: Adaption to SPC - Update of PIL and SPC - Supplement for control group regarding procedure after the end of the study - Specification of definition for follow up - Elimination of redundantinformation, statistical analysis: specification of analysis - Clear description for the documentation in case of early withdrawal of a patient

    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.
    The secondary endpoint Event-free Survival (EFS) could not be analysed for some subgroups due to too small analytical populations for valid comparison of verum vs control population
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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