<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT03243461</url>
  </required_header>
  <id_info>
    <org_study_id>01153</org_study_id>
    <secondary_id>2013-004187-56</secondary_id>
    <nct_id>NCT03243461</nct_id>
  </id_info>
  <brief_title>International Cooperative Phase III Trial of the HIT-HGG Study Group (HIT-HGG-2013)</brief_title>
  <acronym>HIT-HGG-2013</acronym>
  <official_title>International Cooperative Phase III Trial of the HIT-HGG Study Group for the Treatment of High Grade Glioma, Diffuse Intrinsic Pontine Glioma, and Gliomatosis Cerebri in Children and Adolescents &lt; 18 Years.(HIT-HGG-2013)</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Göttingen</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Deutsche Kinderkrebsstiftung</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Hannover Medical School</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>University of Göttingen</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      The HIT-HGG-2013 trial offers an innovative high-quality diagnostics and science program for&#xD;
      children and adolescents &gt;3 years, suffering from one of the following types of high grade&#xD;
      gliomas:&#xD;
&#xD;
        1. glioblastoma WHO grade IV (GBM)&#xD;
&#xD;
        2. diffuse midlineglioma histone 3 K27M mutated WHO grade IV (DMG)&#xD;
&#xD;
        3. anaplastic astrocytoma WHO grade III (AA)&#xD;
&#xD;
        4. diffuse intrinsic pontine glioma (DIPG)&#xD;
&#xD;
        5. gliomatosis cerebri (GC) For 1.-3. diagnosis has to be confirmed by neuropathological&#xD;
           survey, for 4. and 5. diagnosis has to be confirmed by neuroradiological survey.&#xD;
&#xD;
      In addition to standard treatment (radiotherapy and temozolomide chemotherapy) the effect of&#xD;
      valproic acid which is traditionally used for treatment of seizure disorder, will be&#xD;
      investigated. The aim of the trial will be to investigate whether this drug may increase the&#xD;
      effects of radio- and chemotherapy, resulting in a better survival of the treated patients.&#xD;
      Scientific studies provided evidence for anti-tumoral effects of valproic acid: the drug&#xD;
      seems to be a so-called histondeacetylase inhibitor (HDAC inhibitor), controlling important&#xD;
      genetic processes of tumor growth.&#xD;
&#xD;
      Studies in cell culture, animals and first clinical trials in adults as well provided&#xD;
      evidence for efficacy of valproic acid in the treatment of glioblastoma. Due to this we hope&#xD;
      children and adolescents suffering from GBM, DMG, AA, DIPG und GC will benefit from the&#xD;
      treatment, too.&#xD;
&#xD;
      The aim of the HIT-HGG-2013 trial will be to compare the effects of Valproic acid with data&#xD;
      of the HIT-HGG-2007 trial (children and adolescents with same diseases, only treated with&#xD;
      simultaneous temozolomide radiochemotherapy).&#xD;
&#xD;
      In the present study, it was originally planned to investigate the therapeutic efficiency and&#xD;
      safety of valproic acid and the autophagy inhibitor chloroquine, both in addition to&#xD;
      temozolomide therapy. Since distribution of Resochin junior (chloroquine phosphate) was&#xD;
      terminated, recruitment of new patients was stopped on August 8, 2019. For continuation of&#xD;
      the trial, the chloroquine arm was closed but the patients already recruited in this arm will&#xD;
      be followed up.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Indication:&#xD;
&#xD;
      First-line treatment of high grade gliomas, diffuse intrinsic pontine glioma, and gliomatosis&#xD;
      cerebri in paediatric patients &lt; 18 years of age.&#xD;
&#xD;
      Background:&#xD;
&#xD;
      Based on published preclinical and clinical results regarding the potential therapeutic&#xD;
      benefit of adult and pediatric high grade glioma patients receiving the histone deacetylase&#xD;
      (HDAC) inhibitor valproic acid (VPA; Barker et al. 2013; Wolff et al. 2008, 2011; Felix et&#xD;
      al. 2011; Su et al. 2011; Rokes et al. 2010; Masoudi et al. 2008; Guthrie et al. 2013; Weller&#xD;
      et al. 2011) in addition to radiochemotherapy, the present trial is aimed to investigate if&#xD;
      the addition of VPA to radiochemo- and maintenance therapy with temozolomide (Stupp et al.&#xD;
      2005; Cohen et al. 2011a, b) provides a survival advantage in comparison to radiochemo- and&#xD;
      maintenance therapy with temozolomide alone. Therapeutic efficiency of VPA will be evaluated&#xD;
      by comparison with a historical patient control from the previous trial HIT-HGG-2007 with&#xD;
      temozolomide radiochemo- and maintenance therapy alone. Besides therapeutic efficiencies as&#xD;
      indicated by event-free survival (EFS) and overall survival (OS) treatment-related toxicities&#xD;
      will also be analysed.&#xD;
&#xD;
      Therapy:&#xD;
&#xD;
      TMZ and VPA will be studied as investigational medicinal products in the present trial.&#xD;
&#xD;
        -  Trial treatment will be performed as follows: Surgery with best possible extent of&#xD;
           tumour resection&#xD;
&#xD;
        -  Start as soon as diagnosis is confirmed with VPA 10 mg/kg/d in two daily doses&#xD;
           preferencially as NONRETARDED FORMULA (e.g. Valproat-neuraxpharm®, Valproat-neuraxpharm®&#xD;
           Lösung, Ergenyl®, Ergenyl®-Lösung or Orfiril® Saft; however, any VPA preparation&#xD;
           including generic drugs is allowed; the use of a retarded formula might be helpful in&#xD;
           some case as indicated below), increase by 10 mg/kg/d once per week up until recommended&#xD;
           target Serum level of 75-100 μg/ml (520-694 μmol/L) is reached. If target serum levels&#xD;
           cannot be reached with non-retarded formula and/or side effects occur which might be&#xD;
           connected to VPA, change to a retarded formula may be helpful to obtain sufficient VPA&#xD;
           serum levels and/or reduce side effects. If VPA target serum levels are still not&#xD;
           reached and/or side effects occur even with a retarded VPA formula, please contact the&#xD;
           HIT-HGG study office.&#xD;
&#xD;
      After start of VPA induction with simultaneous radiochemotherapy:&#xD;
&#xD;
        -  Fractionated, locoregional radiotherapy, total dose 54-60 Gy&#xD;
&#xD;
        -  Simultaneous chemotherapy with oral temozolomide, 7 days per week at 75 mg/m2/d,&#xD;
           starting at day 1 for the entire period of radiotherapy (at maximum 49 days; oral&#xD;
           temozolomide treatment may be started in single cases at maximum 7 days before&#xD;
           radiotherapy if the 49 days treatment period still fully covers radiotherapy).&#xD;
&#xD;
        -  Please, use temozolomide capsules (for oral application) and temozolomide powder (for&#xD;
           preparation of an intravenously applicable solution). Any temozolomide preparation&#xD;
           including generic drugs is allowed except for patients who are not able to swallow&#xD;
           capsules and in whom the use of an intravenous solution is no Option only Temodal®&#xD;
           capsules must be used to generate a temozolomide suspension as described in the Appendix&#xD;
           A.11. Parents have to be advised how to prepare the Temodal® suspension at the trial&#xD;
           site. PLEASE NOTE: Capsules of generic temozolomide drugs other than Temodal® MUST NOT&#xD;
           be opened and used for generating temozolomide suspension.&#xD;
&#xD;
        -  Maintenance therapy with daily VPA and temozolomide four weeks after simultaneous&#xD;
           radiochemotherapy initiation of a 5 day-course of oral temozolomide [150-200 mg/m2/d],&#xD;
           repeated every 28 days for in total 12 courses VPA treatment is performed until day 28&#xD;
           of the 12th course of temozolomide.&#xD;
&#xD;
        -  Treatment doses may vary according to available medication formulations and sizes. Thus,&#xD;
           deviances of +/- 15% of the recommended doses may be acceptable if not stated&#xD;
           otherwise.The starting points of treatment may also vary in single cases. Thus,&#xD;
           deviances of +/- 7 days of the recommended time periods to start treatment may be&#xD;
           acceptable if not stated otherwise.&#xD;
&#xD;
      Primary end point : Event-free survival&#xD;
&#xD;
      Biometry (regarding the primary objectives):&#xD;
&#xD;
        1. Confirmatory statistical design:&#xD;
&#xD;
           1. Difference between the treatment with additional VPA and the historic sample from the&#xD;
           HIT-HGG-2007 study with respect to EFS. Rejection of H0 will be interpreted as a&#xD;
           significant difference between VPA treatment and the historic sample. A directional&#xD;
           interpretation will detect either a superiority of the VPA-treatment compared to the&#xD;
           historic sample, or a superiority of the historic sample compared to the VPA Treatment&#xD;
           sample.&#xD;
&#xD;
           Statistical tests: adaptive Log-rank test / (conventional) Log-rank test&#xD;
&#xD;
           Multiple Significance level α(overall) = 5% Power = 80% Assumed 6 months EFS-rates = 55%&#xD;
           vs. 70%&#xD;
&#xD;
           Multiple Testing: No Multiplicity Problem in this trial.&#xD;
&#xD;
        2. Estimated sample sizes:&#xD;
&#xD;
      About 167 recruitments at final analysis&#xD;
&#xD;
      Patient recruitment will be performed for 5,4 years. Individual follow-up (including study&#xD;
      treatment) is required for this protocol for at least 1 year and 30 days after study entry.&#xD;
      Long-term follow-up is strongly recommended and will be organised according to national&#xD;
      guidelines and recommendations.&#xD;
&#xD;
      Financial support:&#xD;
&#xD;
      Deutsche Kinderkrebsstiftung, Bonn, Germany&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">July 17, 2018</start_date>
  <completion_date type="Anticipated">December 31, 2023</completion_date>
  <primary_completion_date type="Anticipated">December 31, 2023</primary_completion_date>
  <phase>Phase 3</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Comparison of effects of valproine acid with respect to historical control group.</measure>
    <time_frame>5.4 years</time_frame>
    <description>To confirm that the Event-Free Survival (EFS) in patients ≥ 3 years of age with paed HGG WHO grade IV, anaplastic astrocytoma WHO grade III (AAIII), DIPG, and gliomatosis cerebri differs for children treated with additional VPA compared to children in the historical HIT-HGG-2007 study sample.</description>
  </primary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Anticipated">167</enrollment>
  <condition>Glioblastoma WHO Grade IV</condition>
  <condition>Diffuse Midline Glioma Histone 3 K27M WHO Grade IV</condition>
  <condition>Anaplastic Astrocytoma WHO Grade III</condition>
  <condition>Diffuse Intrinsic Pontine Glioma</condition>
  <condition>Gliomatosis Cerebri</condition>
  <arm_group>
    <arm_group_label>Temozolomide + Valproic acid</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>E.g. Valproat-neuraxpharm®, Valproat-neuraxpharm® Lösung, Ergenyl®, Ergenyl®-Lösung oder Orfiril® Saft (Valproic acid), [10 mg/kg/d] tablet oder juice, p.o., every day in parallel to simultaneous radiochemotherapy with cytostatic drug Temodal (Temozolomid): [75 mg/m2/d] during simultaneous radiochemotherapy (7 days a week, max. 49 days); [150-200 mg/m2/d] during consolidation therapy (for 5 days every 28 days, 12 cycles), tablets, p.o. (or powder for preparation of an intravenously applicable solution).</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Temozolomide + Valproic Acid</intervention_name>
    <description>Valproic acid additionally to simultaneous radiochemotherapy with temozolomide</description>
    <arm_group_label>Temozolomide + Valproic acid</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Newly diagnosed, previously untreated diffuse paediatric high grade glioma with&#xD;
             central neuropathological review including paedHGG (WHO grade IV) and anaplastic&#xD;
             astrocytoma (WHO grade III).&#xD;
&#xD;
          -  Newly diagnosed, previously untreated diffuse intrinsic pontine glioma with central&#xD;
             neuroradiological review&#xD;
&#xD;
          -  Newly diagnosed, previously untreated gliomatosis cerebri of all tumour grades with&#xD;
             central neuroradiological review&#xD;
&#xD;
          -  Patient ≥ 3 years and &lt; 18 years of age at time of diagnosis&#xD;
&#xD;
          -  Written informed consent of the patient and/or the patient's parents or legal guardian&#xD;
             according to national laws&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Pre-treatment of paedHGG (WHO grade IV), anaplastic astrocytoma (WHO grade III),&#xD;
             diffuse intrinsic pontine glioma (as confirmed by neuroradiological review), and&#xD;
             gliomatosis cerebri (as confirmed by neuroradiological review).&#xD;
&#xD;
          -  Known hypersensitivity or contraindication to study drugs and/or dacarbazine&#xD;
&#xD;
          -  Prior chemotherapy within the last 30 days before HIT-HGG-2013 treatment or&#xD;
             radiotherapy which prevents adequate Performance of radiotherapy as outlined by the&#xD;
             present protocol. This may mainly apply to patients with secondary high grade glioma&#xD;
             after previous malignant brain tumour, e.g. medulloblastoma, ependymoma,&#xD;
             craniopharyngeoma. If previous treatment does not prevent the adequate performance of&#xD;
             the outlined Treatment protocol patients with secondary high grade glioma will be&#xD;
             eligible for the present trial.&#xD;
&#xD;
          -  Other (simultaneous) malignancies&#xD;
&#xD;
          -  Pregnancy and / or lactation&#xD;
&#xD;
          -  Patients who are sexually active refusing to use effective contraception (oral&#xD;
             contraception, intrauterine devices, barrier method of contraception in conjunction&#xD;
             with spermicidal jelly)&#xD;
&#xD;
          -  Current or recent (within 30 days prior to start of trial treatment) treatment with&#xD;
             another investigational drug or participation in another investigational trial.&#xD;
&#xD;
          -  Clinical (e.g. a constitutional mismatch repair deficiency score ≥ 3; Wimmer et al.&#xD;
             2014) and/or other hints (e.g. absent intratumoral immunohistochemical expression of&#xD;
             at least one of the MLH1, MSH2, MSH6, or PMS2 mismatch repair proteins and/or high&#xD;
             microsatellite instability) for an underlying biallelic (constitutional) mismatch&#xD;
             repair deficiency (bMMRD/CMMRD) or a heterozygous mismatch repair deficiency&#xD;
             (hereditary non-polyposis colon cancer syndrome/HNPCC syndrome/Lynch syndrome): These&#xD;
             patients and their relatives should be offered human genetic counseling and rapid&#xD;
             genetic diagnostics to confirm or rule out These conditions. These patients might not&#xD;
             benefit from the present study treatment but maybe from other therapeutic strategies&#xD;
             (Bouffet et al. 2016). Since patients with clinically suspected neurofibromatosis type&#xD;
             1 may display similar symptoms as in CMMRD, patients with clinically suspected&#xD;
             neurofibromatosis type 1 should be also checked for CMMRD as suggested above.&#xD;
&#xD;
          -  Very poor clinical condition as defined by demand of mechanical ventilation and/or&#xD;
             demand for intravenous catecholamines and/or very severe neurological damage&#xD;
             equivalent to a coma and/or tetraplegia with complete incapability for communication&#xD;
             (deafness, blindness, mutism)&#xD;
&#xD;
          -  Severe concomitant diseases (e.g. immune deficiency syndrome; known tumour&#xD;
             predisposition syndromes which do not affect adequate performance of the trial&#xD;
             represent no exclusion criterion a priori&#xD;
&#xD;
          -  Known HIV positivity&#xD;
&#xD;
          -  Known severe manifest hepatic disease including hepatic porphyria as well as personal&#xD;
             or family history of severe hepatic dysfunction, especially drug-related&#xD;
&#xD;
          -  Known severe pancreatic disease&#xD;
&#xD;
          -  Known lethal hepatic dysfunction in a sibling during valproic acid treatment&#xD;
&#xD;
          -  Known urea cycle defect&#xD;
&#xD;
          -  Known mitochondrial diseases caused by genetic mutations within the gene coding for&#xD;
             the enzyme polymerase gamma (POLG), e.g. Alpers-Huttenlocher syndrome, as well as&#xD;
             suspected POLGrelated disorders in children under the age of two years&#xD;
&#xD;
          -  Known severe coagulation disorders (in regards to thrombopenia see prerequisite for&#xD;
             blood cell count before starting treatment)&#xD;
&#xD;
          -  Valproic acid as antiepileptc drug for any pre-existing epilepsy (Exception: Valproic&#xD;
             acid treatment due to tumour-related epilepsy will be tolerated, if the time interval&#xD;
             between start of valproic acid treatment and trial enrolment is ≤ 8 weeks.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>3 Years</minimum_age>
    <maximum_age>17 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Christof Kramm, Prof., MD</last_name>
    <role>Study Chair</role>
    <affiliation>University of Göttingen</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Christof Kramm, Prof., MD</last_name>
    <phone>49(0)551 39 63081</phone>
    <email>christof.kramm@med.uni-goettingen.de</email>
  </overall_contact>
  <location>
    <facility>
      <name>Universitätsklinik RWTH Aachen</name>
      <address>
        <city>Aachen</city>
        <country>Germany</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Udo Kontny, Prof. Dr.</last_name>
    </contact>
  </location>
  <location>
    <facility>
      <name>Klinikum Augsburg</name>
      <address>
        <city>Augsburg</city>
        <country>Germany</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Michael Frühwald, Prof.</last_name>
    </contact>
  </location>
  <location>
    <facility>
      <name>Charité Universitätsmedizin Berlin</name>
      <address>
        <city>Berlin</city>
        <country>Germany</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Pablo Hernaiz-Driever, PD Dr.</last_name>
    </contact>
  </location>
  <location>
    <facility>
      <name>HELIOS Klinikum Berlin Buch</name>
      <address>
        <city>Berlin</city>
        <country>Germany</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Patrick Hundsdörfer, PD Dr.</last_name>
    </contact>
  </location>
  <location>
    <facility>
      <name>Evangelisches Krankenhaus Bielefeld</name>
      <address>
        <city>Bielefeld</city>
        <country>Germany</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Norbert Jorch, Dr.</last_name>
    </contact>
  </location>
  <location>
    <facility>
      <name>Universitätsklinikum Bonn</name>
      <address>
        <city>Bonn</city>
        <country>Germany</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Gabriele Calaminus, Dr.</last_name>
    </contact>
  </location>
  <location>
    <facility>
      <name>Städtisches Klinikum Braunschweig gGmbH</name>
      <address>
        <city>Braunschweig</city>
        <country>Germany</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Torsten Ebeling, Dr.</last_name>
    </contact>
  </location>
  <location>
    <facility>
      <name>Klinikum Bremen-Mitte gGmbH</name>
      <address>
        <city>Bremen</city>
        <country>Germany</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Arnulf Pekrun, Prof.</last_name>
    </contact>
  </location>
  <location>
    <facility>
      <name>Carl-Thiem-Klinikum Cottbus gGmbH</name>
      <address>
        <city>Cottbus</city>
        <country>Germany</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Georg Schwabe, PD Dr.</last_name>
    </contact>
  </location>
  <location>
    <facility>
      <name>Klinikum Dortmund gGmbH</name>
      <address>
        <city>Dortmund</city>
        <country>Germany</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Dominik Schneider, Prof. Dr.</last_name>
    </contact>
  </location>
  <location>
    <facility>
      <name>Universitätsklinikum Carl Gustav Carus Dresden</name>
      <address>
        <city>Dresden</city>
        <country>Germany</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Ralf Knöfler, Prof. Dr.</last_name>
    </contact>
  </location>
  <location>
    <facility>
      <name>Sana Kliniken Duisburg GmbH - Wedau Kliniken</name>
      <address>
        <city>Duisburg</city>
        <country>Germany</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Tanja Höll, Dr.</last_name>
    </contact>
  </location>
  <location>
    <facility>
      <name>HELIOS Klinikum Erfurt GmbH</name>
      <address>
        <city>Erfurt</city>
        <country>Germany</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Axel Sauerbrey, Prof. Dr.</last_name>
    </contact>
  </location>
  <location>
    <facility>
      <name>Universitätsklinikum Erlangen</name>
      <address>
        <city>Erlangen</city>
        <country>Germany</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Markus Metzler, Prof.</last_name>
    </contact>
  </location>
  <location>
    <facility>
      <name>Universitätsklinikum Essen</name>
      <address>
        <city>Essen</city>
        <country>Germany</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Regina Wieland, Dr.</last_name>
    </contact>
  </location>
  <location>
    <facility>
      <name>Universitätsklinikum Frankfurt</name>
      <address>
        <city>Frankfurt</city>
        <country>Germany</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Martina Becker, Dr.</last_name>
    </contact>
  </location>
  <location>
    <facility>
      <name>Universitätsklinikum Freiburg</name>
      <address>
        <city>Freiburg</city>
        <country>Germany</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Charlotte Niemeyer, Prof.</last_name>
    </contact>
  </location>
  <location>
    <facility>
      <name>Universitätsklinikum Gießen und Marburg GmbH</name>
      <address>
        <city>Gießen</city>
        <country>Germany</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Christine Mauz-Körholz, Prof. Dr.</last_name>
    </contact>
  </location>
  <location>
    <facility>
      <name>Universitätsmedizin Greifswald</name>
      <address>
        <city>Greifswald</city>
        <country>Germany</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Holger Lode, Prof.</last_name>
    </contact>
  </location>
  <location>
    <facility>
      <name>Universitätsmedizin Göttingen</name>
      <address>
        <city>Göttingen</city>
        <country>Germany</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Christof Kramm, Prof.</last_name>
    </contact>
  </location>
  <location>
    <facility>
      <name>Universitätsklinikum Halle</name>
      <address>
        <city>Halle</city>
        <country>Germany</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Toralf Bernig, Dr.</last_name>
    </contact>
  </location>
  <location>
    <facility>
      <name>Universitätsklinikum Hamburg</name>
      <address>
        <city>Hamburg</city>
        <country>Germany</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Uwe Kordes, Dr.</last_name>
    </contact>
  </location>
  <location>
    <facility>
      <name>Medizinische Hochschule Hannover</name>
      <address>
        <city>Hannover</city>
        <country>Germany</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Annette Sander, Dr.</last_name>
    </contact>
  </location>
  <location>
    <facility>
      <name>Angelika-Lautenschläger-Klinik</name>
      <address>
        <city>Heidelberg</city>
        <country>Germany</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Olaf Witt, Prof. Dr.</last_name>
    </contact>
  </location>
  <location>
    <facility>
      <name>SLK-Kliniken Heilbronn GmbH</name>
      <address>
        <city>Heilbronn</city>
        <country>Germany</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Monika Streiter</last_name>
    </contact>
  </location>
  <location>
    <facility>
      <name>Gemeinschaftskrankenhaus Herdecke</name>
      <address>
        <city>Herdecke</city>
        <country>Germany</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Alfred Längler, Prof. Dr.</last_name>
    </contact>
  </location>
  <location>
    <facility>
      <name>Universitätsklinikum des Saarlandes</name>
      <address>
        <city>Homburg</city>
        <country>Germany</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Norbert Graf, Prof.</last_name>
    </contact>
  </location>
  <location>
    <facility>
      <name>Universitätsklinikum Jena</name>
      <address>
        <city>Jena</city>
        <country>Germany</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Bernd Gruhn, Prof. Dr.</last_name>
    </contact>
  </location>
  <location>
    <facility>
      <name>Städtisches Klinikum Karlsruhe</name>
      <address>
        <city>Karlsruhe</city>
        <country>Germany</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Alfred Leipold, Dr.</last_name>
    </contact>
  </location>
  <location>
    <facility>
      <name>Gesundheit Nordhessen - Klinikum Kassel</name>
      <address>
        <city>Kassel</city>
        <country>Germany</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Michaela Nathrath, Prof.</last_name>
    </contact>
  </location>
  <location>
    <facility>
      <name>UKSH Kiel</name>
      <address>
        <city>Kiel</city>
        <country>Germany</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Alexander Claviez, PD Dr.</last_name>
    </contact>
  </location>
  <location>
    <facility>
      <name>Gemeinschaftsklinikum Mittelrhein gGmbH</name>
      <address>
        <city>Koblenz</city>
        <country>Germany</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Ümmügül Behr, Dr.</last_name>
    </contact>
  </location>
  <location>
    <facility>
      <name>HELIOS Klinikum Krefeld</name>
      <address>
        <city>Krefeld</city>
        <country>Germany</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Thomas Imschweiler</last_name>
    </contact>
  </location>
  <location>
    <facility>
      <name>Kliniken der Stadt Köln gGmbH</name>
      <address>
        <city>Köln</city>
        <country>Germany</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Stefan Balzer, Dr.</last_name>
    </contact>
  </location>
  <location>
    <facility>
      <name>Universitätsklinikum Leipzig</name>
      <address>
        <city>Leipzig</city>
        <country>Germany</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Lars Fischer, Dr.</last_name>
    </contact>
  </location>
  <location>
    <facility>
      <name>UKSH Campus Lübeck</name>
      <address>
        <city>Lübeck</city>
        <country>Germany</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Thorsten Langer, Prof. Dr.</last_name>
    </contact>
  </location>
  <location>
    <facility>
      <name>Universitätsklinikum Magdeburg A. ö. R.</name>
      <address>
        <city>Magdeburg</city>
        <country>Germany</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Antje Redlich, Dr.</last_name>
    </contact>
  </location>
  <location>
    <facility>
      <name>Universitätsmedizin der Johannes Gutenberg-Universität Mainz</name>
      <address>
        <city>Mainz</city>
        <country>Germany</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Jörg Faber, Prof. Dr.</last_name>
    </contact>
  </location>
  <location>
    <facility>
      <name>UMM Universitätsmedizin Mannheim</name>
      <address>
        <city>Mannheim</city>
        <country>Germany</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Matthias Dürken, PD Dr.</last_name>
    </contact>
  </location>
  <location>
    <facility>
      <name>Johannes Wesling Klinikum Minden</name>
      <address>
        <city>Minden</city>
        <country>Germany</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Bernhard Erdlenbruch, Prof.</last_name>
    </contact>
  </location>
  <location>
    <facility>
      <name>Technische Universität München / Klinikum Schwabing</name>
      <address>
        <city>München</city>
        <country>Germany</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Irene Teichert-von-Lüttichau, PD Dr.</last_name>
    </contact>
  </location>
  <location>
    <facility>
      <name>Universitätsklinikum Münster</name>
      <address>
        <city>Münster</city>
        <country>Germany</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Ronald Sträter, PD Dr.</last_name>
    </contact>
  </location>
  <location>
    <facility>
      <name>Klinikum Oldenburg gGmbH</name>
      <address>
        <city>Oldenburg</city>
        <country>Germany</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Hermann Müller, Prof.</last_name>
    </contact>
  </location>
  <location>
    <facility>
      <name>Universitätsklinikum Regensburg</name>
      <address>
        <city>Regensburg</city>
        <country>Germany</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Marcus Jakob, Dr.</last_name>
    </contact>
  </location>
  <location>
    <facility>
      <name>Universitäts-Kinder- und Jugendklinik Rostock</name>
      <address>
        <city>Rostock</city>
        <country>Germany</country>
      </address>
    </facility>
    <status>Active, not recruiting</status>
  </location>
  <location>
    <facility>
      <name>ASKLEPIOS Klinik St. Augustin</name>
      <address>
        <city>Sankt Augustin</city>
        <country>Germany</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Harald Reinhard, PD Dr.</last_name>
    </contact>
  </location>
  <location>
    <facility>
      <name>HELIOS Kliniken Schwerin GmbH</name>
      <address>
        <city>Schwerin</city>
        <country>Germany</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Aram Prokop, Dr. Dr.</last_name>
    </contact>
  </location>
  <location>
    <facility>
      <name>Klinikum Stuttgart - Olgahospital</name>
      <address>
        <city>Stuttgart</city>
        <country>Germany</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Claudia Blattmann, PD Dr.</last_name>
    </contact>
  </location>
  <location>
    <facility>
      <name>Universitätsklinikum Tübingen</name>
      <address>
        <city>Tübingen</city>
        <country>Germany</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Martin Ebinger, PD Dr.</last_name>
    </contact>
  </location>
  <location>
    <facility>
      <name>Universitätsklinikum Ulm</name>
      <address>
        <city>Ulm</city>
        <country>Germany</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Klaus-Michael Debatin, Prof. Dr.</last_name>
    </contact>
  </location>
  <location>
    <facility>
      <name>Universitätsklinik Würzburg</name>
      <address>
        <city>Würzburg</city>
        <country>Germany</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Matthias Eyrich, Prof. Dr.</last_name>
    </contact>
  </location>
  <location_countries>
    <country>Germany</country>
  </location_countries>
  <verification_date>June 2022</verification_date>
  <study_first_submitted>August 4, 2017</study_first_submitted>
  <study_first_submitted_qc>August 4, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">August 9, 2017</study_first_posted>
  <last_update_submitted>June 2, 2022</last_update_submitted>
  <last_update_submitted_qc>June 2, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">June 6, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>University of Göttingen</investigator_affiliation>
    <investigator_full_name>Prof. Dr. Christof Kramm</investigator_full_name>
    <investigator_title>Coordinating investigator</investigator_title>
  </responsible_party>
  <keyword>Glioblastoma</keyword>
  <keyword>high grade glioma</keyword>
  <keyword>brain tumor</keyword>
  <keyword>Anaplastic astrocytoma</keyword>
  <keyword>DIPG</keyword>
  <keyword>Gliomatosis cerebri</keyword>
  <keyword>Diffuse midline glioma</keyword>
  <keyword>Valproic acid</keyword>
  <keyword>Temozolomide</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Glioblastoma</mesh_term>
    <mesh_term>Glioma</mesh_term>
    <mesh_term>Astrocytoma</mesh_term>
    <mesh_term>Diffuse Intrinsic Pontine Glioma</mesh_term>
    <mesh_term>Neoplasms, Neuroepithelial</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Temozolomide</mesh_term>
    <mesh_term>Valproic Acid</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03243461
org study id: 01153
secondary id: 2013-004187-56
nct id: NCT03243461
lead sponsor: 
collaborator: 
collaborator: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
The HIT-HGG-2013 trial offers an innovative high-quality diagnostics and science program for
      children and adolescents >3 years, suffering from one of the following types of high grade
      gliomas:

        1. glioblastoma WHO grade IV (GBM)

        2. diffuse midlineglioma histone 3 K27M mutated WHO grade IV (DMG)

        3. anaplastic astrocytoma WHO grade III (AA)

        4. diffuse intrinsic pontine glioma (DIPG)

        5. gliomatosis cerebri (GC) For 1.-3. diagnosis has to be confirmed by neuropathological
           survey, for 4. and 5. diagnosis has to be confirmed by neuroradiological survey.

      In addition to standard treatment (radiotherapy and temozolomide chemotherapy) the effect of
      valproic acid which is traditionally used for treatment of seizure disorder, will be
      investigated. The aim of the trial will be to investigate whether this drug may increase the
      effects of radio- and chemotherapy, resulting in a better survival of the treated patients.
      Scientific studies provided evidence for anti-tumoral effects of valproic acid: the drug
      seems to be a so-called histondeacetylase inhibitor (HDAC inhibitor), controlling important
      genetic processes of tumor growth.

      Studies in cell culture, animals and first clinical trials in adults as well provided
      evidence for efficacy of valproic acid in the treatment of glioblastoma. Due to this we hope
      children and adolescents suffering from GBM, DMG, AA, DIPG und GC will benefit from the
      treatment, too.

      The aim of the HIT-HGG-2013 trial will be to compare the effects of Valproic acid with data
      of the HIT-HGG-2007 trial (children and adolescents with same diseases, only treated with
      simultaneous temozolomide radiochemotherapy).

      In the present study, it was originally planned to investigate the therapeutic efficiency and
      safety of valproic acid and the autophagy inhibitor chloroquine, both in addition to
      temozolomide therapy. Since distribution of Resochin junior (chloroquine phosphate) was
      terminated, recruitment of new patients was stopped on August 8, 2019. For continuation of
      the trial, the chloroquine arm was closed but the patients already recruited in this arm will
      be followed up.
Indication:

      First-line treatment of high grade gliomas, diffuse intrinsic pontine glioma, and gliomatosis
      cerebri in paediatric patients < 18 years of age.

      Background:

      Based on published preclinical and clinical results regarding the potential therapeutic
      benefit of adult and pediatric high grade glioma patients receiving the histone deacetylase
      (HDAC) inhibitor valproic acid (VPA; Barker et al. 2013; Wolff et al. 2008, 2011; Felix et
      al. 2011; Su et al. 2011; Rokes et al. 2010; Masoudi et al. 2008; Guthrie et al. 2013; Weller
      et al. 2011) in addition to radiochemotherapy, the present trial is aimed to investigate if
      the addition of VPA to radiochemo- and maintenance therapy with temozolomide (Stupp et al.
      2005; Cohen et al. 2011a, b) provides a survival advantage in comparison to radiochemo- and
      maintenance therapy with temozolomide alone. Therapeutic efficiency of VPA will be evaluated
      by comparison with a historical patient control from the previous trial HIT-HGG-2007 with
      temozolomide radiochemo- and maintenance therapy alone. Besides therapeutic efficiencies as
      indicated by event-free survival (EFS) and overall survival (OS) treatment-related toxicities
      will also be analysed.

      Therapy:

      TMZ and VPA will be studied as investigational medicinal products in the present trial.

        -  Trial treatment will be performed as follows: Surgery with best possible extent of
           tumour resection

        -  Start as soon as diagnosis is confirmed with VPA 10 mg/kg/d in two daily doses
           preferencially as NONRETARDED FORMULA (e.g. Valproat-neuraxpharm®, Valproat-neuraxpharm®
           Lösung, Ergenyl®, Ergenyl®-Lösung or Orfiril® Saft; however, any VPA preparation
           including generic drugs is allowed; the use of a retarded formula might be helpful in
           some case as indicated below), increase by 10 mg/kg/d once per week up until recommended
           target Serum level of 75-100 μg/ml (520-694 μmol/L) is reached. If target serum levels
           cannot be reached with non-retarded formula and/or side effects occur which might be
           connected to VPA, change to a retarded formula may be helpful to obtain sufficient VPA
           serum levels and/or reduce side effects. If VPA target serum levels are still not
           reached and/or side effects occur even with a retarded VPA formula, please contact the
           HIT-HGG study office.

      After start of VPA induction with simultaneous radiochemotherapy:

        -  Fractionated, locoregional radiotherapy, total dose 54-60 Gy

        -  Simultaneous chemotherapy with oral temozolomide, 7 days per week at 75 mg/m2/d,
           starting at day 1 for the entire period of radiotherapy (at maximum 49 days; oral
           temozolomide treatment may be started in single cases at maximum 7 days before
           radiotherapy if the 49 days treatment period still fully covers radiotherapy).

        -  Please, use temozolomide capsules (for oral application) and temozolomide powder (for
           preparation of an intravenously applicable solution). Any temozolomide preparation
           including generic drugs is allowed except for patients who are not able to swallow
           capsules and in whom the use of an intravenous solution is no Option only Temodal®
           capsules must be used to generate a temozolomide suspension as described in the Appendix
           A.11. Parents have to be advised how to prepare the Temodal® suspension at the trial
           site. PLEASE NOTE: Capsules of generic temozolomide drugs other than Temodal® MUST NOT
           be opened and used for generating temozolomide suspension.

        -  Maintenance therapy with daily VPA and temozolomide four weeks after simultaneous
           radiochemotherapy initiation of a 5 day-course of oral temozolomide [150-200 mg/m2/d],
           repeated every 28 days for in total 12 courses VPA treatment is performed until day 28
           of the 12th course of temozolomide.

        -  Treatment doses may vary according to available medication formulations and sizes. Thus,
           deviances of +/- 15% of the recommended doses may be acceptable if not stated
           otherwise.The starting points of treatment may also vary in single cases. Thus,
           deviances of +/- 7 days of the recommended time periods to start treatment may be
           acceptable if not stated otherwise.

      Primary end point : Event-free survival

      Biometry (regarding the primary objectives):

        1. Confirmatory statistical design:

           1. Difference between the treatment with additional VPA and the historic sample from the
           HIT-HGG-2007 study with respect to EFS. Rejection of H0 will be interpreted as a
           significant difference between VPA treatment and the historic sample. A directional
           interpretation will detect either a superiority of the VPA-treatment compared to the
           historic sample, or a superiority of the historic sample compared to the VPA Treatment
           sample.

           Statistical tests: adaptive Log-rank test / (conventional) Log-rank test

           Multiple Significance level α(overall) = 5% Power = 80% Assumed 6 months EFS-rates = 55%
           vs. 70%

           Multiple Testing: No Multiplicity Problem in this trial.

        2. Estimated sample sizes:

      About 167 recruitments at final analysis

      Patient recruitment will be performed for 5,4 years. Individual follow-up (including study
      treatment) is required for this protocol for at least 1 year and 30 days after study entry.
      Long-term follow-up is strongly recommended and will be organised according to national
      guidelines and recommendations.

      Financial support:

      Deutsche Kinderkrebsstiftung, Bonn, Germany
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Comparison of effects of valproine acid with respect to historical control group.
time frame: 5.4 years
description: To confirm that the Event-Free Survival (EFS) in patients ≥ 3 years of age with paed HGG WHO grade IV, anaplastic astrocytoma WHO grade III (AAIII), DIPG, and gliomatosis cerebri differs for children treated with additional VPA compared to children in the historical HIT-HGG-2007 study sample.
arm group label: Temozolomide + Valproic acid
arm group type: Experimental
description: E.g. Valproat-neuraxpharm®, Valproat-neuraxpharm® Lösung, Ergenyl®, Ergenyl®-Lösung oder Orfiril® Saft (Valproic acid), [10 mg/kg/d] tablet oder juice, p.o., every day in parallel to simultaneous radiochemotherapy with cytostatic drug Temodal (Temozolomid): [75 mg/m2/d] during simultaneous radiochemotherapy (7 days a week, max. 49 days); [150-200 mg/m2/d] during consolidation therapy (for 5 days every 28 days, 12 cycles), tablets, p.o. (or powder for preparation of an intravenously applicable solution).
intervention type: Drug
intervention name: Temozolomide + Valproic Acid
description: Valproic acid additionally to simultaneous radiochemotherapy with temozolomide
arm group label: Temozolomide + Valproic acid
criteria: 
gender: All
minimum age: 3 Years
maximum age: 17 Years
healthy volunteers: No
last name: Christof Kramm, Prof., MD
role: Study Chair
affiliation: University of Göttingen
last name: Christof Kramm, Prof., MD
phone: 49(0)551 39 63081
email: christof.kramm@med.uni-goettingen.de
facility: 
status: Recruiting
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status: Recruiting
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status: Recruiting
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status: Active, not recruiting
facility: 
status: Recruiting
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status: Recruiting
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status: Recruiting
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status: Recruiting
contact: 
country: Germany
responsible party type: Principal Investigator
investigator affiliation: University of Göttingen
investigator full name: Prof. Dr. Christof Kramm
investigator title: Coordinating investigator
mesh term: Glioblastoma
mesh term: Glioma
mesh term: Astrocytoma
mesh term: Diffuse Intrinsic Pontine Glioma
mesh term: Neoplasms, Neuroepithelial
mesh term: Temozolomide
mesh term: Valproic Acid
sharing ipd: No