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/NCT06016452</url>
    </required_header>
    <id_info>
      <org_study_id>900970</org_study_id>
      <nct_id>NCT06016452</nct_id>
    </id_info>
    <brief_title>A Study of Chlorophyllin for the Management of Brain Radio-necrosis in Patients With Diffuse Glioma</brief_title>
    <acronym>CHROME</acronym>
    <official_title>A Prospective Phase 2 Study of Chlorophyllin for the Management of Brain Radionecrosis in Patients With Diffuse Glioma</official_title>
    <sponsors>
      <lead_sponsor>
        <agency>Tata Memorial Centre</agency>
        <agency_class>Other</agency_class>
      </lead_sponsor>
      <collaborator>
        <agency>Bhabha Atomic Research Centre (BARC)</agency>
        <agency_class>Other</agency_class>
      </collaborator>
    </sponsors>
    <source>Tata Memorial Centre</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>
        Diffuse gliomas are common tumors involving the brain. They are usually treated by surgery&#xD;
        followed by radiation and chemotherapy. Radiotherapy is used for the treatment of brain&#xD;
        tumors which causes damage to the tumor cells. However, radiotherapy can also affect the&#xD;
        surrounding healthy cells in the brain, causing inflammation and swelling in the region,&#xD;
        which is known as radio necrosis (RN). This is considered a late side effect of radiation and&#xD;
        is seen in 10-25% of patients treated with radiation for brain tumors. Sometimes,&#xD;
        radionecrosis can be detected on routine imaging during follow-up without new symptoms&#xD;
        (asymptomaticRN).&#xD;
  &#xD;
        At the same time, in some patients, it can give rise to new symptoms like headaches,&#xD;
        weakness, seizures,etc (symptomatic RN). The standard treatment of RN includes steroid&#xD;
        medicines called dexamethasone, which is helpful in a proportion of patients.&#xD;
  &#xD;
        This is a prospective phase 2 study. This study is being conducted to investigate the ability&#xD;
        of the drug Chlorophyllin in the treatment of radionecrosis.&#xD;
  &#xD;
        Chlorophyllin is a water-soluble compound obtained from the green plant pigment called&#xD;
        chlorophyll. It has been shown to have anti-cancer, anti-bacterial, anti-viral,&#xD;
        anti-inflammatory, and antioxidant properties. It is also used as an oral formulation and is&#xD;
        an over-the-counter drug in various countries, and also as a food colouring agent.&#xD;
  &#xD;
        This is the first time chlorophyllin will be used in the setting of brain radionecrosis. Our&#xD;
        primary aim of the study is to assess whether CHL will improve the clinical-radiological&#xD;
        response rates. This study will be conducted on a population of 118 patients for a duration&#xD;
        of 3 months. The total study duration is 2 years.&#xD;
  &#xD;
        The study is funded by Bhabha Atomic Research Centre (BARC).&#xD;
      </textblock>
    </brief_summary>
    <detailed_description>
      <textblock>
        Radiotherapy (RT) forms an integral role in the multi modality management of diffuse gliomas.&#xD;
        Radiation is indicated in low-grade gliomas with high-risk features or high-grade gliomas&#xD;
        following maximal safe resection. Higher doses of RT can lead to symptomatic radio-necrosis&#xD;
        (RN) in approximately 5-15% of patients, typically within the first 2-3 years of RT&#xD;
        completion. Development of RN can lead to significant morbidity with new-onset or worsening&#xD;
        of pre-existing neurodeficit with substantial implications on quality of life, and in extreme&#xD;
        situations, can lead to mortality as well. The pathogenesis of RN is multi factorial, with a&#xD;
        complex interplay of vascular-mediated damage and injury to glial cells primarily postulated&#xD;
        through the activation of several inflammatory markers like tumor necrosis factor,&#xD;
        interleukins, and vascular endothelial growth factor. Corticosteroids, preferably&#xD;
        dexamethasone, form the first line of management of RN, with variable response rates ranging&#xD;
        from 25-60%, impacted by several factors like a dose of RT and response evaluation methods&#xD;
        (neurological/ radiographic). The response rate in our practice concurs with the reported&#xD;
        literature with combined clinical and radiological responses seen in approximately 50% of&#xD;
        patients from institutional experience and audit. It is important to note the long-standing&#xD;
        use of corticosteroids comes at the cost of complications like hyperglycemia, myopathy, and&#xD;
        increased risk of infections precluding prolonged use. Also, a proportion of patients remain&#xD;
        refractory to steroids or turn out to be dependent on steroids, where bevacizumab&#xD;
        (anti-angiogenic agent) can be used as second-line therapy in appropriately selected&#xD;
        patients. However, the major disadvantages of bevacizumab remain intravenous administration&#xD;
        requiring regular hospital visits, treatment costs, and concerns for related toxicities like&#xD;
        hypertension, and intracranial or extracranial haemorrhage. Other agents like hyperbaric&#xD;
        oxygen therapy, pentoxifylline, and tocopherol have been suggested in refractory&#xD;
        radionecrosis, with questionable benefits. Sodium-copper-Chlorophyllin is a&#xD;
        phytopharmaceutical drug obtained from the green plant pigment chlorophyll. It is a&#xD;
        semi-synthetic mixture of sodium copper salts derived from chlorophyll. Chlorophyllin&#xD;
        scavenges RT-induced free radicals and reactive oxygen species. It is used as a food colorant&#xD;
        and over-the-counter in the USA, Japan, Australia, and China for many years for a variety of&#xD;
        health benefits, including prevention of body odor in geriatric patients, enhanced wound&#xD;
        healing, antibacterial action, prevention of cancer in the high-risk population exposed to&#xD;
        hepatocarcinogen aflatoxin B1, treatment of fecal incontinence, etc. Studies have shown that&#xD;
        Chlorophyllin has immunostimulatory, anti-inflammatory, and antiviral effects in addition to&#xD;
        antioxidant and radioprotective properties. It increases the expression of a transcription&#xD;
        factor (protein) Nrf2, improving lymphocyte survival and enabling efficient detoxification&#xD;
        after RT exposure. Chlorophyllin also delays microtubule polymerization and slows cell&#xD;
        division in normal cells.&#xD;
      </textblock>
    </detailed_description>
    <overall_status>Not yet recruiting</overall_status>
    <start_date type="Anticipated">September 2023</start_date>
    <completion_date type="Anticipated">September 2025</completion_date>
    <primary_completion_date type="Anticipated">September 2025</primary_completion_date>
    <phase>Phase 2</phase>
    <study_type>Interventional</study_type>
    <has_expanded_access>No</has_expanded_access>
    <study_design_info>
      <allocation>Non-Randomized</allocation>
      <intervention_model>Parallel Assignment</intervention_model>
      <intervention_model_description>The proposed phase II prospective study will be split into two strata: Stratum A (symptomatic RN) and Stratum B (asymptomatic RN).</intervention_model_description>
      <primary_purpose>Treatment</primary_purpose>
      <masking>None (Open Label)</masking>
    </study_design_info>
    <primary_outcome>
      <measure>Response rates</measure>
      <time_frame>1 month post treatment with chlorophyllin</time_frame>
      <description>Clinical-radiological</description>
    </primary_outcome>
    <secondary_outcome>
      <measure>Survival Analysis</measure>
      <time_frame>3 months</time_frame>
      <description>Progression-Free Survival and Overall Survival using Kaplan-Meier survival plot.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Health Questionnaire</measure>
      <time_frame>3 months</time_frame>
      <description>EORTC QOL C -30 and (Brain module) BN-20 questionnaire. The global score and scores of subdomains will be calculated and compared with baseline.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Response rates</measure>
      <time_frame>3 months</time_frame>
      <description>Radiological response rates at 3 months using Response Assessment in Neuro-Oncology (RANO) criteria.</description>
    </secondary_outcome>
    <other_outcome>
      <measure>Biological response rate</measure>
      <time_frame>3 months</time_frame>
      <description>Using functional imaging (PET &amp; MRI) to describe the difference of SUV maximum (Maximum Standardized Uptake Value)or T/W ratio for PET scan and perfusion values e.g., rCBV ( relative Cerebral Blood Volume) for MRI.</description>
    </other_outcome>
    <number_of_arms>2</number_of_arms>
    <enrollment type="Anticipated">118</enrollment>
    <condition>Diffuse Glioma</condition>
    <condition>Radionecrosis of Brain</condition>
    <condition>High Grade Glioma</condition>
    <condition>Glioblastoma Multiforme</condition>
    <arm_group>
      <arm_group_label>Stratum A (Symptomatic)</arm_group_label>
      <arm_group_type>Experimental</arm_group_type>
      <description>Response rates at 1 month with a combination of steroids and CHL in this study is expected to be 65% as compared to the standard 50% response with the use of dexamethasone alone. For the study with an α of 0.1 and power of 80%,50 pts will be needed to achieve the desired output. In the first stage, 22 patients will be needed for assessment and continued to stage 2 if &gt;10 responses are seen.The stage 2 of the study will be considered successful if &gt;29 responses are achieved using the pre-specified response assessment criteria.Considering an attrition rate of 10% from lack of follow-up and another 10% for disease progression, an estimated 60 patients will be accrued in stratum A with the purpose of achieving 50 patients with endpoints available for analysis.</description>
    </arm_group>
    <arm_group>
      <arm_group_label>Stratum B (Asymptomatic)</arm_group_label>
      <arm_group_type>Experimental</arm_group_type>
      <description>This stratum includes pts without neurological worsening during imaging diagnosis of RN (asymptomatic RN).Approx 30% of patients continue to be neurologically/ radiologically stable or regression of imaging findings without need for further interventions (including corticosteroids).In the proposed study with the use of CHL, 45% patients are assumed to remain clinically and neurologically stable. With an α of 0.1 and power of 80%, 48 patients will be needed to achieve the desired outcome. In the first stage, 23 patients will be needed for assessment and continue to stage 2 if &gt;6 responses are seen.&#xD;
  The phase 2 study will be considered successful if &gt;18 responses are achieved using the pre-specified response assessment criteria. Further considering an attrition rate of 10% from lack of follow-up and another 10% for disease progression, an estimated 58 patients will be accrued in stratum B with the purpose of achieving 48 patients with endpoints available for analysis.</description>
    </arm_group>
    <intervention>
      <intervention_type>Drug</intervention_type>
      <intervention_name>Chlorophyllin</intervention_name>
      <description>Chlorophyllin is a water-soluble compound obtained from the green plant pigment called chlorophyll. It has been shown to have anti-cancer, anti-bacterial, anti-viral, anti-inflammatory, and antioxidant properties. It is also used as an oral formulation and is an over-the-counter drug in various countries, and also as a food coloring agent.</description>
      <arm_group_label>Stratum A (Symptomatic)</arm_group_label>
      <arm_group_label>Stratum B (Asymptomatic)</arm_group_label>
      <other_name>Stratum A (Symptomatic)</other_name>
      <other_name>Stratum A (Asymptomatic)</other_name>
    </intervention>
    <eligibility>
      <criteria>
        <textblock>
          Inclusion Criteria:&#xD;
  &#xD;
            -  Histological diagnosis of diffuse glioma.&#xD;
  &#xD;
            -  Radionecrosis on imaging with new neurological symptoms/ worsening of prior deficits&#xD;
               (Stratum A) or&#xD;
  &#xD;
            -  without new symptoms (Stratum B).&#xD;
  &#xD;
            -  Karnofsky Performance Scale (KPS) ≥ 50.&#xD;
  &#xD;
          Exclusion Criteria:&#xD;
  &#xD;
            -  No tissue diagnosis.&#xD;
  &#xD;
            -  KPS&lt; 50.&#xD;
  &#xD;
            -  Disease progression&#xD;
  &#xD;
            -  Contraindications to corticosteroids.&#xD;
  &#xD;
            -  Altered mental status with deficits in understanding or inability to consent to the&#xD;
               study.&#xD;
  &#xD;
            -  Brainstem glioma&#xD;
  &#xD;
            -  Indeterminate for radionecrosis vs disease progression&#xD;
  &#xD;
            -  Prior treatment with bevacizumab (either for disease progression or radionecrosis)&#xD;
        </textblock>
      </criteria>
      <gender>All</gender>
      <minimum_age>18 Years</minimum_age>
      <maximum_age>70 Years</maximum_age>
      <healthy_volunteers>No</healthy_volunteers>
    </eligibility>
    <overall_official>
      <last_name>Archya Dasgupta, MD</last_name>
      <role>Principal Investigator</role>
      <affiliation>Tata Memorial Hospital</affiliation>
    </overall_official>
    <overall_contact>
      <last_name>Archya Dasgupta, MD, DNB</last_name>
      <phone>02224177000</phone>
      <email>archya1010@gmail.com</email>
    </overall_contact>
    <overall_contact_backup>
      <last_name>Tejpal Gupta, MD, DNB</last_name>
      <email>drtejpalgupta@gmail.com</email>
    </overall_contact_backup>
    <verification_date>September 2023</verification_date>
    <study_first_submitted>August 10, 2023</study_first_submitted>
    <study_first_submitted_qc>August 24, 2023</study_first_submitted_qc>
    <study_first_posted type="Actual">August 29, 2023</study_first_posted>
    <last_update_submitted>September 4, 2023</last_update_submitted>
    <last_update_submitted_qc>September 4, 2023</last_update_submitted_qc>
    <last_update_posted type="Actual">September 6, 2023</last_update_posted>
    <responsible_party>
      <responsible_party_type>Principal Investigator</responsible_party_type>
      <investigator_affiliation>Tata Memorial Centre</investigator_affiliation>
      <investigator_full_name>Dr Archya Dasgupta</investigator_full_name>
      <investigator_title>Assistant Professor, Radiation Oncology</investigator_title>
    </responsible_party>
    <condition_browse>
      <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
      <mesh_term>Glioblastoma</mesh_term>
      <mesh_term>Glioma</mesh_term>
    </condition_browse>
    <intervention_browse>
      <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
      <mesh_term>Chlorophyllin</mesh_term>
    </intervention_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/NCT06016452
  org study id: 900970
  nct id: NCT06016452
  lead sponsor: 
  collaborator: 
  has dmc: Yes
  is fda regulated drug: No
  is fda regulated device: No
  Diffuse gliomas are common tumors involving the brain. They are usually treated by surgery
        followed by radiation and chemotherapy. Radiotherapy is used for the treatment of brain
        tumors which causes damage to the tumor cells. However, radiotherapy can also affect the
        surrounding healthy cells in the brain, causing inflammation and swelling in the region,
        which is known as radio necrosis (RN). This is considered a late side effect of radiation and
        is seen in 10-25% of patients treated with radiation for brain tumors. Sometimes,
        radionecrosis can be detected on routine imaging during follow-up without new symptoms
        (asymptomaticRN).
  
        At the same time, in some patients, it can give rise to new symptoms like headaches,
        weakness, seizures,etc (symptomatic RN). The standard treatment of RN includes steroid
        medicines called dexamethasone, which is helpful in a proportion of patients.
  
        This is a prospective phase 2 study. This study is being conducted to investigate the ability
        of the drug Chlorophyllin in the treatment of radionecrosis.
  
        Chlorophyllin is a water-soluble compound obtained from the green plant pigment called
        chlorophyll. It has been shown to have anti-cancer, anti-bacterial, anti-viral,
        anti-inflammatory, and antioxidant properties. It is also used as an oral formulation and is
        an over-the-counter drug in various countries, and also as a food colouring agent.
  
        This is the first time chlorophyllin will be used in the setting of brain radionecrosis. Our
        primary aim of the study is to assess whether CHL will improve the clinical-radiological
        response rates. This study will be conducted on a population of 118 patients for a duration
        of 3 months. The total study duration is 2 years.
  
        The study is funded by Bhabha Atomic Research Centre (BARC).
  Radiotherapy (RT) forms an integral role in the multi modality management of diffuse gliomas.
        Radiation is indicated in low-grade gliomas with high-risk features or high-grade gliomas
        following maximal safe resection. Higher doses of RT can lead to symptomatic radio-necrosis
        (RN) in approximately 5-15% of patients, typically within the first 2-3 years of RT
        completion. Development of RN can lead to significant morbidity with new-onset or worsening
        of pre-existing neurodeficit with substantial implications on quality of life, and in extreme
        situations, can lead to mortality as well. The pathogenesis of RN is multi factorial, with a
        complex interplay of vascular-mediated damage and injury to glial cells primarily postulated
        through the activation of several inflammatory markers like tumor necrosis factor,
        interleukins, and vascular endothelial growth factor. Corticosteroids, preferably
        dexamethasone, form the first line of management of RN, with variable response rates ranging
        from 25-60%, impacted by several factors like a dose of RT and response evaluation methods
        (neurological/ radiographic). The response rate in our practice concurs with the reported
        literature with combined clinical and radiological responses seen in approximately 50% of
        patients from institutional experience and audit. It is important to note the long-standing
        use of corticosteroids comes at the cost of complications like hyperglycemia, myopathy, and
        increased risk of infections precluding prolonged use. Also, a proportion of patients remain
        refractory to steroids or turn out to be dependent on steroids, where bevacizumab
        (anti-angiogenic agent) can be used as second-line therapy in appropriately selected
        patients. However, the major disadvantages of bevacizumab remain intravenous administration
        requiring regular hospital visits, treatment costs, and concerns for related toxicities like
        hypertension, and intracranial or extracranial haemorrhage. Other agents like hyperbaric
        oxygen therapy, pentoxifylline, and tocopherol have been suggested in refractory
        radionecrosis, with questionable benefits. Sodium-copper-Chlorophyllin is a
        phytopharmaceutical drug obtained from the green plant pigment chlorophyll. It is a
        semi-synthetic mixture of sodium copper salts derived from chlorophyll. Chlorophyllin
        scavenges RT-induced free radicals and reactive oxygen species. It is used as a food colorant
        and over-the-counter in the USA, Japan, Australia, and China for many years for a variety of
        health benefits, including prevention of body odor in geriatric patients, enhanced wound
        healing, antibacterial action, prevention of cancer in the high-risk population exposed to
        hepatocarcinogen aflatoxin B1, treatment of fecal incontinence, etc. Studies have shown that
        Chlorophyllin has immunostimulatory, anti-inflammatory, and antiviral effects in addition to
        antioxidant and radioprotective properties. It increases the expression of a transcription
        factor (protein) Nrf2, improving lymphocyte survival and enabling efficient detoxification
        after RT exposure. Chlorophyllin also delays microtubule polymerization and slows cell
        division in normal cells.
  allocation: Non-Randomized
  intervention model: Parallel Assignment
  intervention model description: The proposed phase II prospective study will be split into two strata: Stratum A (symptomatic RN) and Stratum B (asymptomatic RN).
  primary purpose: Treatment
  masking: None (Open Label)
  measure: Response rates
  time frame: 1 month post treatment with chlorophyllin
  description: Clinical-radiological
  measure: Survival Analysis
  time frame: 3 months
  description: Progression-Free Survival and Overall Survival using Kaplan-Meier survival plot.
  measure: Health Questionnaire
  time frame: 3 months
  description: EORTC QOL C -30 and (Brain module) BN-20 questionnaire. The global score and scores of subdomains will be calculated and compared with baseline.
  measure: Response rates
  time frame: 3 months
  description: Radiological response rates at 3 months using Response Assessment in Neuro-Oncology (RANO) criteria.
  measure: Biological response rate
  time frame: 3 months
  description: Using functional imaging (PET & MRI) to describe the difference of SUV maximum (Maximum Standardized Uptake Value)or T/W ratio for PET scan and perfusion values e.g., rCBV ( relative Cerebral Blood Volume) for MRI.
  arm group label: Stratum A (Symptomatic)
  arm group type: Experimental
  description: Response rates at 1 month with a combination of steroids and CHL in this study is expected to be 65% as compared to the standard 50% response with the use of dexamethasone alone. For the study with an α of 0.1 and power of 80%,50 pts will be needed to achieve the desired output. In the first stage, 22 patients will be needed for assessment and continued to stage 2 if >10 responses are seen.The stage 2 of the study will be considered successful if >29 responses are achieved using the pre-specified response assessment criteria.Considering an attrition rate of 10% from lack of follow-up and another 10% for disease progression, an estimated 60 patients will be accrued in stratum A with the purpose of achieving 50 patients with endpoints available for analysis.
  arm group label: Stratum B (Asymptomatic)
  arm group type: Experimental
  description: This stratum includes pts without neurological worsening during imaging diagnosis of RN (asymptomatic RN).Approx 30% of patients continue to be neurologically/ radiologically stable or regression of imaging findings without need for further interventions (including corticosteroids).In the proposed study with the use of CHL, 45% patients are assumed to remain clinically and neurologically stable. With an α of 0.1 and power of 80%, 48 patients will be needed to achieve the desired outcome. In the first stage, 23 patients will be needed for assessment and continue to stage 2 if >6 responses are seen.
  The phase 2 study will be considered successful if >18 responses are achieved using the pre-specified response assessment criteria. Further considering an attrition rate of 10% from lack of follow-up and another 10% for disease progression, an estimated 58 patients will be accrued in stratum B with the purpose of achieving 48 patients with endpoints available for analysis.
  intervention type: Drug
  intervention name: Chlorophyllin
  description: Chlorophyllin is a water-soluble compound obtained from the green plant pigment called chlorophyll. It has been shown to have anti-cancer, anti-bacterial, anti-viral, anti-inflammatory, and antioxidant properties. It is also used as an oral formulation and is an over-the-counter drug in various countries, and also as a food coloring agent.
  arm group label: Stratum A (Symptomatic)
  arm group label: Stratum B (Asymptomatic)
  other name: Stratum A (Symptomatic)
  other name: Stratum A (Asymptomatic)
  criteria: 
  gender: All
  minimum age: 18 Years
  maximum age: 70 Years
  healthy volunteers: No
  last name: Archya Dasgupta, MD
  role: Principal Investigator
  affiliation: Tata Memorial Hospital
  last name: Archya Dasgupta, MD, DNB
  phone: 02224177000
  email: archya1010@gmail.com
  last name: Tejpal Gupta, MD, DNB
  email: drtejpalgupta@gmail.com
  responsible party type: Principal Investigator
  investigator affiliation: Tata Memorial Centre
  investigator full name: Dr Archya Dasgupta
  investigator title: Assistant Professor, Radiation Oncology
  mesh term: Glioblastoma
  mesh term: Glioma
  mesh term: Chlorophyllin
  sharing ipd: No