xml: <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/NCT05964569</url>
    </required_header>
    <id_info>
      <org_study_id>RadOnk-Indigo</org_study_id>
      <nct_id>NCT05964569</nct_id>
    </id_info>
    <brief_title>Feasibility of Individualized, Model-guided Optimization of Proton Beam Treatment Planning in Patients With Low Grade Glioma</brief_title>
    <acronym>INDIGO</acronym>
    <official_title>Prospective Phase II Trial to Assess Feasibility of Individualized, Model-guided Optimization of Proton Beam Treatment Planning in Patients With Low Grade Glioma Multicentric, Prospective Interventional, Randomized, Observer Blind Two Arm (Active Control), Parallel Group Investigator-initiated Phase II Trial</official_title>
    <sponsors>
      <lead_sponsor>
        <agency>University Hospital Heidelberg</agency>
        <agency_class>Other</agency_class>
      </lead_sponsor>
    </sponsors>
    <source>University Hospital Heidelberg</source>
    <oversight_info>
      <has_dmc>No</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>
        Low-grade glioma (LGG) represent typically slowly growing primary brain tumors with world&#xD;
        health organization (WHO) grade I or II who affect young adults around their fourth decade.&#xD;
        Radiological feature on MRI is a predominantly T2 hyperintense signal, LGG show typically no&#xD;
        contrast uptake. Radiotherapy plays an important role in the treatment of LGG. However, not&#xD;
        least because of the good prognosis with long term survivorship the timing of radiotherapy&#xD;
        has been discussed controversially. In order to avoid long term sequelae such as&#xD;
        neurocognitive impairment, malignant transformation or secondary neoplasms initiation was&#xD;
        often postponed as long as possible&#xD;
      </textblock>
    </brief_summary>
    <detailed_description>
      <textblock>
        Since patients with low grade glioma are expected to become long-term survivors, the&#xD;
        prevention of long-term sequelae is particularly important. In addition to disease&#xD;
        progression, also treatment related side effects such as decline of neurocognitive function,&#xD;
        endocrine impairment or sensorineural deficits can have a negative impact on patient's&#xD;
        quality of life.&#xD;
  &#xD;
        Owing to the biophysical properties of protons with an inverse depth dose profile compared to&#xD;
        photons and a steep dose fall of to the normal tissue, there is a strong rationale for the&#xD;
        use of PRT in the treatment of patients with low-grade glioma. Although data from large&#xD;
        randomized trials are still missing there is increasing evidence from smaller prospective&#xD;
        trials and retrospective analyses that the expected advantages indeed transform into clinical&#xD;
        advantages.&#xD;
  &#xD;
        However, in about 20 % of all patients, late contrast-enhancing brain lesions (CEBL) appear&#xD;
        on follow-up MR images 6 - 24 months after treatment. At HIT in Heidelberg and at OncoRay in&#xD;
        Dresden, CEBLs have been observed to occur at very distinct locations in the brain and&#xD;
        relative to the treatment field. Retrospective analysis has elucidated potential key factors&#xD;
        that lead to CEBL occurrence. However, avoidance of CEBLs is hardly feasible using&#xD;
        conventional treatment planning strategies. Model-aided risk avoidance denotes the use of&#xD;
        model-based CEBL risk calculations as an auxiliary tool for clinical treatment planning:&#xD;
        Model-based risk calculations and risk reduction via software-based optimization help the&#xD;
        clinician to minimize risk of CEBL occurrence during treatment planning.&#xD;
      </textblock>
    </detailed_description>
    <overall_status>Not yet recruiting</overall_status>
    <start_date type="Anticipated">September 1, 2023</start_date>
    <completion_date type="Anticipated">September 1, 2028</completion_date>
    <primary_completion_date type="Anticipated">September 1, 2026</primary_completion_date>
    <phase>Phase 2</phase>
    <study_type>Interventional</study_type>
    <has_expanded_access>No</has_expanded_access>
    <study_design_info>
      <allocation>Randomized</allocation>
      <intervention_model>Parallel Assignment</intervention_model>
      <intervention_model_description>randomized, observer blind two arm (active control), parallel group</intervention_model_description>
      <primary_purpose>Treatment</primary_purpose>
      <masking>None (Open Label)</masking>
    </study_design_info>
    <primary_outcome>
      <measure>incidence of contrast enhancing brain leasions</measure>
      <time_frame>observed within 24 months after PRT measured by quarterly contrast enhanced MRI of the brain</time_frame>
      <description>the cumulative incidence of contrast enhancing brain lesions</description>
    </primary_outcome>
    <secondary_outcome>
      <measure>radiation-induced brain injuries</measure>
      <time_frame>observed within 24 months after PRT measured by quarterly contrast enhanced MRI of the brain</time_frame>
      <description>incidence of radiation-induced brain injuries &gt; CTC°II</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>progression-free survival</measure>
      <time_frame>observed within 24 months after PRT measured by quarterly contrast enhanced MRI of the brain</time_frame>
      <description>number of surviving patients without tumor progression</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>overall survival</measure>
      <time_frame>observed within 24 months after Proton Beam Therapy (PRT) measured by quarterly contrast enhanced MRI of the brain</time_frame>
      <description>number of surviving patients</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>patient reported outcome</measure>
      <time_frame>up to 24 months after completion of radiotherapy</time_frame>
      <description>patient reported outcome according to points on the PRO-CTCAE questionaire, scored 0/1 for absent/present)</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>quality of life QLQ-C30</measure>
      <time_frame>up to 24 months after completion of PRT</time_frame>
      <description>scores on the QLQ-C30 questionare, scored 0 (absence) to 5 (fully present)</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>quality of life QLQ-BN20</measure>
      <time_frame>up to 24 months after completion of PRT</time_frame>
      <description>scores on the QLQ-BN20 questionare, scored 0 (absence) to 5 (fully present)</description>
    </secondary_outcome>
    <number_of_arms>2</number_of_arms>
    <enrollment type="Anticipated">120</enrollment>
    <condition>Low Grade Glioma</condition>
    <arm_group>
      <arm_group_label>Standard treatment plan</arm_group_label>
      <arm_group_type>Active Comparator</arm_group_type>
      <description>Model-based NTCP is calculated after plan approval, however, no further adjustments are to be made to the approved treatment plan</description>
    </arm_group>
    <arm_group>
      <arm_group_label>Optimized treatment plan</arm_group_label>
      <arm_group_type>Experimental</arm_group_type>
      <description>Allocated to Control Calculation of normal tissue complication probability (NTCP) Model-guided replanning. Replanning is performed with Raysearch Raystation. Optimizations objectives are:&#xD;
  the optimization objectives that control the maximum dose in the target volume employ a variable, LETd-dependent model for RBE that allows us to include the RBE-variations predicted by the NTCP model&#xD;
  the periventricular volume, defined as the volume closer than 4 mm to the ventricular wall, is included into the optimization with a constraint on its Equivalent Uniform Dose (EUD) and with the variable RBE model described above. Thereby, the combined effect of the RBE variation and increased sensitivity of the periventricular volume, as predicted by the NTCP model, is included.&#xD;
  The effectiveness of the re-planning is verified by a second NTCP computation.</description>
    </arm_group>
    <intervention>
      <intervention_type>Other</intervention_type>
      <intervention_name>model-guided optimization of treatment plan</intervention_name>
      <description>original treatmant plans are optimized based on model-based NTCP</description>
      <arm_group_label>Optimized treatment plan</arm_group_label>
    </intervention>
    <intervention>
      <intervention_type>Other</intervention_type>
      <intervention_name>standard treatment plan, no optimization</intervention_name>
      <description>original treatment plans are not optimized</description>
      <arm_group_label>Standard treatment plan</arm_group_label>
    </intervention>
    <eligibility>
      <criteria>
        <textblock>
          Inclusion Criteria:&#xD;
  &#xD;
            -  Age &gt; 18 years&#xD;
  &#xD;
            -  histologically proven low-grade glioma&#xD;
  &#xD;
            -  indication for definitive or adjuvant radiotherapy&#xD;
  &#xD;
            -  ability to understand character and personal consequences of the clinical trial&#xD;
  &#xD;
            -  written informed consent&#xD;
  &#xD;
          Exclusion Criteria:&#xD;
  &#xD;
            -  previous cerebral irradiation&#xD;
  &#xD;
            -  contraindication for contrast-enhanced MRI&#xD;
  &#xD;
            -  neurofibromatosis&#xD;
  &#xD;
            -  participation in another clinical trial with competing objectives&#xD;
        </textblock>
      </criteria>
      <gender>All</gender>
      <minimum_age>18 Years</minimum_age>
      <maximum_age>N/A</maximum_age>
      <healthy_volunteers>No</healthy_volunteers>
    </eligibility>
    <overall_contact>
      <last_name>Semi Harrabi, MD</last_name>
      <phone>+496221 56</phone>
      <phone_ext>8201</phone_ext>
      <email>semi.harrabi@med.uni-heidelberg.de</email>
    </overall_contact>
    <overall_contact_backup>
      <last_name>Adriane Lentz-Hommertgen, Phd</last_name>
      <phone>+496221 56</phone>
      <phone_ext>8201</phone_ext>
      <email>adriane.lentz-hommertgen@med.uni-heidelberg.de</email>
    </overall_contact_backup>
    <location>
      <facility>
        <name>Department of Radiotherapy, University of Heidelberg</name>
        <address>
          <city>Heidelberg</city>
          <zip>69120</zip>
          <country>Germany</country>
        </address>
      </facility>
    </location>
    <location_countries>
      <country>Germany</country>
    </location_countries>
    <verification_date>August 2023</verification_date>
    <study_first_submitted>July 19, 2023</study_first_submitted>
    <study_first_submitted_qc>July 19, 2023</study_first_submitted_qc>
    <study_first_posted type="Actual">July 28, 2023</study_first_posted>
    <last_update_submitted>August 4, 2023</last_update_submitted>
    <last_update_submitted_qc>August 4, 2023</last_update_submitted_qc>
    <last_update_posted type="Actual">August 8, 2023</last_update_posted>
    <responsible_party>
      <responsible_party_type>Principal Investigator</responsible_party_type>
      <investigator_affiliation>University Hospital Heidelberg</investigator_affiliation>
      <investigator_full_name>Juergen Debus</investigator_full_name>
      <investigator_title>Department Head</investigator_title>
    </responsible_party>
    <condition_browse>
      <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
      <mesh_term>Glioma</mesh_term>
    </condition_browse>
    <patient_data>
      <sharing_ipd>No</sharing_ipd>
    </patient_data>
    <!-- Results have not yet been posted for this study                                          -->
  </clinical_study>
  
  
text: 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/NCT05964569
  org study id: RadOnk-Indigo
  nct id: NCT05964569
  lead sponsor: 
  has dmc: No
  is fda regulated drug: No
  is fda regulated device: No
  Low-grade glioma (LGG) represent typically slowly growing primary brain tumors with world
        health organization (WHO) grade I or II who affect young adults around their fourth decade.
        Radiological feature on MRI is a predominantly T2 hyperintense signal, LGG show typically no
        contrast uptake. Radiotherapy plays an important role in the treatment of LGG. However, not
        least because of the good prognosis with long term survivorship the timing of radiotherapy
        has been discussed controversially. In order to avoid long term sequelae such as
        neurocognitive impairment, malignant transformation or secondary neoplasms initiation was
        often postponed as long as possible
  Since patients with low grade glioma are expected to become long-term survivors, the
        prevention of long-term sequelae is particularly important. In addition to disease
        progression, also treatment related side effects such as decline of neurocognitive function,
        endocrine impairment or sensorineural deficits can have a negative impact on patient's
        quality of life.
  
        Owing to the biophysical properties of protons with an inverse depth dose profile compared to
        photons and a steep dose fall of to the normal tissue, there is a strong rationale for the
        use of PRT in the treatment of patients with low-grade glioma. Although data from large
        randomized trials are still missing there is increasing evidence from smaller prospective
        trials and retrospective analyses that the expected advantages indeed transform into clinical
        advantages.
  
        However, in about 20 % of all patients, late contrast-enhancing brain lesions (CEBL) appear
        on follow-up MR images 6 - 24 months after treatment. At HIT in Heidelberg and at OncoRay in
        Dresden, CEBLs have been observed to occur at very distinct locations in the brain and
        relative to the treatment field. Retrospective analysis has elucidated potential key factors
        that lead to CEBL occurrence. However, avoidance of CEBLs is hardly feasible using
        conventional treatment planning strategies. Model-aided risk avoidance denotes the use of
        model-based CEBL risk calculations as an auxiliary tool for clinical treatment planning:
        Model-based risk calculations and risk reduction via software-based optimization help the
        clinician to minimize risk of CEBL occurrence during treatment planning.
  allocation: Randomized
  intervention model: Parallel Assignment
  intervention model description: randomized, observer blind two arm (active control), parallel group
  primary purpose: Treatment
  masking: None (Open Label)
  measure: incidence of contrast enhancing brain leasions
  time frame: observed within 24 months after PRT measured by quarterly contrast enhanced MRI of the brain
  description: the cumulative incidence of contrast enhancing brain lesions
  measure: radiation-induced brain injuries
  time frame: observed within 24 months after PRT measured by quarterly contrast enhanced MRI of the brain
  description: incidence of radiation-induced brain injuries > CTC°II
  measure: progression-free survival
  time frame: observed within 24 months after PRT measured by quarterly contrast enhanced MRI of the brain
  description: number of surviving patients without tumor progression
  measure: overall survival
  time frame: observed within 24 months after Proton Beam Therapy (PRT) measured by quarterly contrast enhanced MRI of the brain
  description: number of surviving patients
  measure: patient reported outcome
  time frame: up to 24 months after completion of radiotherapy
  description: patient reported outcome according to points on the PRO-CTCAE questionaire, scored 0/1 for absent/present)
  measure: quality of life QLQ-C30
  time frame: up to 24 months after completion of PRT
  description: scores on the QLQ-C30 questionare, scored 0 (absence) to 5 (fully present)
  measure: quality of life QLQ-BN20
  time frame: up to 24 months after completion of PRT
  description: scores on the QLQ-BN20 questionare, scored 0 (absence) to 5 (fully present)
  arm group label: Standard treatment plan
  arm group type: Active Comparator
  description: Model-based NTCP is calculated after plan approval, however, no further adjustments are to be made to the approved treatment plan
  arm group label: Optimized treatment plan
  arm group type: Experimental
  description: Allocated to Control Calculation of normal tissue complication probability (NTCP) Model-guided replanning. Replanning is performed with Raysearch Raystation. Optimizations objectives are:
  the optimization objectives that control the maximum dose in the target volume employ a variable, LETd-dependent model for RBE that allows us to include the RBE-variations predicted by the NTCP model
  the periventricular volume, defined as the volume closer than 4 mm to the ventricular wall, is included into the optimization with a constraint on its Equivalent Uniform Dose (EUD) and with the variable RBE model described above. Thereby, the combined effect of the RBE variation and increased sensitivity of the periventricular volume, as predicted by the NTCP model, is included.
  The effectiveness of the re-planning is verified by a second NTCP computation.
  intervention type: Other
  intervention name: model-guided optimization of treatment plan
  description: original treatmant plans are optimized based on model-based NTCP
  arm group label: Optimized treatment plan
  intervention type: Other
  intervention name: standard treatment plan, no optimization
  description: original treatment plans are not optimized
  arm group label: Standard treatment plan
  criteria: 
  gender: All
  minimum age: 18 Years
  maximum age: N/A
  healthy volunteers: No
  last name: Semi Harrabi, MD
  phone: +496221 56
  phone ext: 8201
  email: semi.harrabi@med.uni-heidelberg.de
  last name: Adriane Lentz-Hommertgen, Phd
  phone: +496221 56
  phone ext: 8201
  email: adriane.lentz-hommertgen@med.uni-heidelberg.de
  facility: 
  country: Germany
  responsible party type: Principal Investigator
  investigator affiliation: University Hospital Heidelberg
  investigator full name: Juergen Debus
  investigator title: Department Head
  mesh term: Glioma
  sharing ipd: No