<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/NCT02201563</url>
  </required_header>
  <id_info>
    <org_study_id>PRO14020381</org_study_id>
    <nct_id>NCT02201563</nct_id>
  </id_info>
  <brief_title>Minocycline Therapy for Management of Adverse Radiation Effects</brief_title>
  <official_title>A Safety and Feasibility Study of Minocycline Therapy for Management of Adverse Radiation Effects After Brain Metastases Radiosurgery</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Pittsburgh</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>University of Pittsburgh</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Stereotactic radiosurgery (SRS) is a well-established treatment for patients with metastatic&#xD;
      brain tumors. Although SRS has a very high tumor growth control these interventions are&#xD;
      associated with adverse radiation effects (ARE) in approximately 15 % of patients. The&#xD;
      traditional approach, and still a mainstay, is the administration of a course of high dose&#xD;
      anti-inflammatory corticosteroids. Currently there are no other effective oral&#xD;
      neuroprotective agents in clinical practice which can improve outcomes of patients with ARE&#xD;
      after radiosurgery for brain metastases.&#xD;
&#xD;
      Minocycline, an antibiotic with a favorable adverse effect profile and pharmacokinetics, has&#xD;
      been shown to have neuroprotective properties in experimental models of a variety of&#xD;
      neurological diseases, as well as in human clinical trials. The investigators propose a&#xD;
      single arm clinical trial, to evaluate the safety and feasibility of minocycline in improving&#xD;
      ARE. This study will recruit 15 patients who will be treated with minocycline (100mg BID) for&#xD;
      3 months. This clinical trial has the potential to prove that minocycline therapy is safe in&#xD;
      this patient population. In addition, positive results will provide preliminary evidence for&#xD;
      its use in an array of radiosurgical indications.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Although stereotactic radiosurgery (SRS) has proven to be highly effective in the management&#xD;
      of brain metastases, it is not without risk. Despite selective targeting of lesions and the&#xD;
      sharp dose fall-off associated with radiosurgical treatments, adverse radiation effects&#xD;
      (AREs) can occur in 10-15% of patients. Adverse radiation effects (AREs) can be defined as&#xD;
      unexpected or undesirable post-radiosurgery imaging change regardless of whether it is&#xD;
      clinically symptomatic. Patients showing ARE have limited therapeutic options with&#xD;
      corticosteroids being the main treatment modality. This single arm clinical trial, will&#xD;
      evaluate the safety and feasibility of minocycline in improving AREs. Brain metastases&#xD;
      patients with documented AREs will be treated with minocycline (100 mg twice a day) for 3&#xD;
      months in addition to the standard treatment with oral corticosteroids. The investigators&#xD;
      anticipate recruiting a total of 15 patients over 12 months.&#xD;
&#xD;
      Primary aim:&#xD;
&#xD;
      The primary aim is of this study to evaluate safety and feasibility of minocycline therapy in&#xD;
      patients with ARE after radiosurgery. The investigators' hypothesis is that minocycline will&#xD;
      be safe in this patient population. Safety will be assessed by monitoring blood levels of&#xD;
      drug, liver enzymes, renal function tests, and monitoring for major and minor side-effects.&#xD;
&#xD;
      Research Strategy The investigators plan to conduct a single arm observational study to&#xD;
      evaluate safety and feasibility of minocycline in patients diagnosed with radiosurgery&#xD;
      associated adverse radiation effects. In addition to clinical and biochemical monitoring for&#xD;
      safety, the investigators will also employ neuroimaging techniques to investigate whether&#xD;
      minocycline reduces enhancement at lesion in post contrast T1 weighted MRI and reduces hyper&#xD;
      intensity surrounding the tumor as detected by T2 MRI radiosurgery.&#xD;
&#xD;
      Primary Outcomes: 1) The primary clinical outcome will be safety of minocycline use in this&#xD;
      patient population.&#xD;
&#xD;
      Secondary outcomes: 1) The investigators will also review brain images in detail to find any&#xD;
      evidence of benefit from Minocycline therapy such as reduction or resolution of volume of T2&#xD;
      hyper intensity and contrast enhancement at the lesion (radiation necrosis) at 4-6 weeks and&#xD;
      3 month follow-up. 2) Overall neurological status 3) Change in neurocognitive status, 4)&#xD;
      Reduction in the number of patients needing resection 5) Changes in plasma biomarkers, and&#xD;
      plasma drug levels.&#xD;
&#xD;
      Target Population: Recruitment will take place at Center of Image-guided Neurosurgery of&#xD;
      UPMC. All patients with AREs after brain metastases radiosurgery will be potentially eligible&#xD;
      for the study. The investigators anticipate enrolling 15 patients. Patients will be diagnosed&#xD;
      based on MRI findings. The investigators will evaluate T1 pre and post contrast, T2, FLAIR&#xD;
      and Perfusion MR in order to diagnose ARE. MR spectroscopy or CT Pet will be obtained when&#xD;
      clinically indicated. The investigators will use T1/T2 matching and proportion of edema&#xD;
      versus lesion volume as a guide for diagnosing ARE.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Terminated</overall_status>
  <why_stopped>
    Very slow recruitment (only one patient was recruited)&#xD;
  </why_stopped>
  <start_date>November 2015</start_date>
  <completion_date type="Actual">May 31, 2018</completion_date>
  <primary_completion_date type="Actual">May 31, 2018</primary_completion_date>
  <phase>Phase 1</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>Monitoring for adverse effects of Minocycline</measure>
    <time_frame>3 months</time_frame>
    <description>Safety will be assessed by monitoring blood levels of drug, liver enzymes, renal function tests, and monitoring for major and minor side-effects.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Monitoring for imaging improvement</measure>
    <time_frame>3 months</time_frame>
    <description>Brain MRIs will be performed to investigate whether minocycline reduces enhancement at lesion in post contrast T1 weighted MRI and reduces hyper intensity surrounding the tumor as detected by T2 MRI radiosurgery.</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">1</enrollment>
  <condition>Irradiation; Adverse Effect</condition>
  <arm_group>
    <arm_group_label>Minocycline</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>oral Minocycline 100 mg twice a day for 3 months.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Minocycline</intervention_name>
    <description>Oral minocycline (100mg twice a day) for 3 months</description>
    <arm_group_label>Minocycline</arm_group_label>
    <other_name>Dynacin, Minocin, Minocin PAC, Myrac, Solodyn, Vectrin</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Age range: 18 - 90 years&#xD;
&#xD;
          -  Males and females.&#xD;
&#xD;
          -  Patients must have undergone cranial radiosurgery.&#xD;
&#xD;
          -  MRI evidence supporting the diagnosis of ARE and/or surgical biopsy evidence of&#xD;
             necrosis without tumor at ≤2 months before study entry.&#xD;
&#xD;
          -  Karnofsky performance status of ≥60,&#xD;
&#xD;
          -  With or without evidence of progressive neurologic signs or symptoms appropriate to&#xD;
             the location of the ARE, and no previous bevacizumab therapy.&#xD;
&#xD;
          -  With or without previous chemotherapy for their tumor.&#xD;
&#xD;
          -  Routine laboratory study results with bilirubin ≤1.5 times the upper limit of normal,&#xD;
             aspartate aminotransferase and/or alanine aminotransferase &lt;2.5 times the upper limit&#xD;
             of normal, creatinine &lt;2.0 times the upper limit of normal.&#xD;
&#xD;
          -  Patients with a history of seizures will be required to be receiving anticonvulsant&#xD;
             therapy and to be seizure-free for ≥1 week before study.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Significant mass effect requiring resection (as assessed by a clinical neurosurgeon)&#xD;
&#xD;
          -  Known hypersensitivity to tetracyclines&#xD;
&#xD;
          -  Women of childbearing age must be non-lactating and have a negative urine pregnancy&#xD;
             test (adequate birth control includes use of intra uterine device, or a barrier&#xD;
             method, e.g. condom, diaphragm). The results of animal studies indicate that&#xD;
             tetracyclines cross the placenta and are found in fetal tissues, having potentially&#xD;
             toxic effects on the developing fetus (often related to retardation of skeletal&#xD;
             development). Evidence of embryo toxicity has been noted in animals treated early in&#xD;
             pregnancy. Therefore pregnant women will not be allowed to participate in this study&#xD;
&#xD;
          -  Female subjects on oral contraceptives&#xD;
&#xD;
          -  Contraindication to undergo MRI&#xD;
&#xD;
          -  Significant cardiopulmonary, renal or neurological co-morbidities&#xD;
&#xD;
          -  Current diagnosis of major depression, substance abuse, or other psychiatric&#xD;
             disorders;&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>90 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Ajay Niranjan, MD, MBA</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Pittsburgh</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>UPMC</name>
      <address>
        <city>Pittsburgh</city>
        <state>Pennsylvania</state>
        <zip>15213</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>June 2018</verification_date>
  <study_first_submitted>July 24, 2014</study_first_submitted>
  <study_first_submitted_qc>July 25, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">July 28, 2014</study_first_posted>
  <last_update_submitted>June 20, 2018</last_update_submitted>
  <last_update_submitted_qc>June 20, 2018</last_update_submitted_qc>
  <last_update_posted type="Actual">June 25, 2018</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>University of Pittsburgh</investigator_affiliation>
    <investigator_full_name>Ajay Niranjan</investigator_full_name>
    <investigator_title>Associate Professor</investigator_title>
  </responsible_party>
  <keyword>Adverse radiation effects (ARE)</keyword>
  <keyword>Radiosurgery</keyword>
  <keyword>Brain metastases</keyword>
  <keyword>Minocycline</keyword>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Minocycline</mesh_term>
  </intervention_browse>
  <!-- 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/NCT02201563
org study id: PRO14020381
nct id: NCT02201563
lead sponsor: 
has dmc: No
Stereotactic radiosurgery (SRS) is a well-established treatment for patients with metastatic
      brain tumors. Although SRS has a very high tumor growth control these interventions are
      associated with adverse radiation effects (ARE) in approximately 15 % of patients. The
      traditional approach, and still a mainstay, is the administration of a course of high dose
      anti-inflammatory corticosteroids. Currently there are no other effective oral
      neuroprotective agents in clinical practice which can improve outcomes of patients with ARE
      after radiosurgery for brain metastases.

      Minocycline, an antibiotic with a favorable adverse effect profile and pharmacokinetics, has
      been shown to have neuroprotective properties in experimental models of a variety of
      neurological diseases, as well as in human clinical trials. The investigators propose a
      single arm clinical trial, to evaluate the safety and feasibility of minocycline in improving
      ARE. This study will recruit 15 patients who will be treated with minocycline (100mg BID) for
      3 months. This clinical trial has the potential to prove that minocycline therapy is safe in
      this patient population. In addition, positive results will provide preliminary evidence for
      its use in an array of radiosurgical indications.
Although stereotactic radiosurgery (SRS) has proven to be highly effective in the management
      of brain metastases, it is not without risk. Despite selective targeting of lesions and the
      sharp dose fall-off associated with radiosurgical treatments, adverse radiation effects
      (AREs) can occur in 10-15% of patients. Adverse radiation effects (AREs) can be defined as
      unexpected or undesirable post-radiosurgery imaging change regardless of whether it is
      clinically symptomatic. Patients showing ARE have limited therapeutic options with
      corticosteroids being the main treatment modality. This single arm clinical trial, will
      evaluate the safety and feasibility of minocycline in improving AREs. Brain metastases
      patients with documented AREs will be treated with minocycline (100 mg twice a day) for 3
      months in addition to the standard treatment with oral corticosteroids. The investigators
      anticipate recruiting a total of 15 patients over 12 months.

      Primary aim:

      The primary aim is of this study to evaluate safety and feasibility of minocycline therapy in
      patients with ARE after radiosurgery. The investigators' hypothesis is that minocycline will
      be safe in this patient population. Safety will be assessed by monitoring blood levels of
      drug, liver enzymes, renal function tests, and monitoring for major and minor side-effects.

      Research Strategy The investigators plan to conduct a single arm observational study to
      evaluate safety and feasibility of minocycline in patients diagnosed with radiosurgery
      associated adverse radiation effects. In addition to clinical and biochemical monitoring for
      safety, the investigators will also employ neuroimaging techniques to investigate whether
      minocycline reduces enhancement at lesion in post contrast T1 weighted MRI and reduces hyper
      intensity surrounding the tumor as detected by T2 MRI radiosurgery.

      Primary Outcomes: 1) The primary clinical outcome will be safety of minocycline use in this
      patient population.

      Secondary outcomes: 1) The investigators will also review brain images in detail to find any
      evidence of benefit from Minocycline therapy such as reduction or resolution of volume of T2
      hyper intensity and contrast enhancement at the lesion (radiation necrosis) at 4-6 weeks and
      3 month follow-up. 2) Overall neurological status 3) Change in neurocognitive status, 4)
      Reduction in the number of patients needing resection 5) Changes in plasma biomarkers, and
      plasma drug levels.

      Target Population: Recruitment will take place at Center of Image-guided Neurosurgery of
      UPMC. All patients with AREs after brain metastases radiosurgery will be potentially eligible
      for the study. The investigators anticipate enrolling 15 patients. Patients will be diagnosed
      based on MRI findings. The investigators will evaluate T1 pre and post contrast, T2, FLAIR
      and Perfusion MR in order to diagnose ARE. MR spectroscopy or CT Pet will be obtained when
      clinically indicated. The investigators will use T1/T2 matching and proportion of edema
      versus lesion volume as a guide for diagnosing ARE.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Monitoring for adverse effects of Minocycline
time frame: 3 months
description: Safety will be assessed by monitoring blood levels of drug, liver enzymes, renal function tests, and monitoring for major and minor side-effects.
measure: Monitoring for imaging improvement
time frame: 3 months
description: Brain MRIs will be performed to investigate whether minocycline reduces enhancement at lesion in post contrast T1 weighted MRI and reduces hyper intensity surrounding the tumor as detected by T2 MRI radiosurgery.
arm group label: Minocycline
arm group type: Experimental
description: oral Minocycline 100 mg twice a day for 3 months.
intervention type: Drug
intervention name: Minocycline
description: Oral minocycline (100mg twice a day) for 3 months
arm group label: Minocycline
other name: Dynacin, Minocin, Minocin PAC, Myrac, Solodyn, Vectrin
criteria: 
gender: All
minimum age: 18 Years
maximum age: 90 Years
healthy volunteers: No
last name: Ajay Niranjan, MD, MBA
role: Principal Investigator
affiliation: University of Pittsburgh
facility: 
country: United States
responsible party type: Principal Investigator
investigator affiliation: University of Pittsburgh
investigator full name: Ajay Niranjan
investigator title: Associate Professor
mesh term: Minocycline