<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/NCT03270020</url>
  </required_header>
  <id_info>
    <org_study_id>20159460</org_study_id>
    <nct_id>NCT03270020</nct_id>
  </id_info>
  <brief_title>Denosumab for the Treatment of Adult LCH</brief_title>
  <official_title>Evaluation of Efficacy of Denosumab in Adult Patients With Langerhans Cell Histiocytosis (LCH): a Multiple-site, Single Arm, Open Label Clinical Trial</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Hellenic Society for the Study of Bone Metabolism</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Hellenic Society for the Study of Bone Metabolism</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>
      This study is aiming to evaluate the efficacy of denosumab among adult patients suffering&#xD;
      from Langerhans Cell Histiocytosis (LCH).&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The majority and diversity of clinical manifestations in LCH are attributed to immunological&#xD;
      dysfunction resulting from langerhans cell (LC) derived cytokine secretion both at the&#xD;
      lesional and systemic level. In a recent study, Receptor Activator of Nuclear Factor Kappa-B&#xD;
      Ligand (RANKL) was found to be abundantly expressed in cells within diverse LCH lesions from&#xD;
      adult patients, especially in inflammatory infiltrates, a finding in line with a previously&#xD;
      reported high osteoprotegerin (OPG) and low RANKL levels in the serum of patients with or&#xD;
      without bone involvement. RANKL expression was associated with concomitant p65 Nuclear Factor&#xD;
      Kappa-B (NFκB) nuclear staining, the main downstream effector of RANKL signaling, suggesting&#xD;
      that lesional cell activation may be triggered locally by RANKL. Combining the serum and the&#xD;
      lesional results, it can be inferred that there is an ongoing process of countervailing OPG&#xD;
      production against lesional RANKL, which could be one of the self defense mechanisms among&#xD;
      LCH patients. Therefore, the use of denosumab seems a rational treatment option in LCH in&#xD;
      order to support and enhance the defensive OPG action and hopefully control or even interrupt&#xD;
      the lesional immunological process.&#xD;
&#xD;
      The primary study objective is to assess the therapeutic efficacy of denosumab 120 mg every 8&#xD;
      weeks (Q8W) sc in adult LCH patients.&#xD;
&#xD;
      Secondary Objectives:&#xD;
&#xD;
        1. To define an uniform treatment approach for LCH patients with mild symptoms and low risk&#xD;
           disease.&#xD;
&#xD;
        2. To explore the efficacy of denosumab 120 mg Q8W sc in reducing disease reactivations&#xD;
           after treatment completion.&#xD;
&#xD;
        3. To illustrate the safety profile of denosumab in LCH patients. The primary efficacy&#xD;
           endpoint is defined as the percentage of patients with progression of disease at Month&#xD;
           8.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">September 7, 2017</start_date>
  <completion_date type="Actual">September 30, 2022</completion_date>
  <primary_completion_date type="Actual">June 22, 2022</primary_completion_date>
  <phase>Phase 2</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>
    <intervention_model_description>The investigational arm will recruit patients who will receive denosumab 120mg sc every 2 months. The estimated duration of the recruitment period is 12 months.&#xD;
The treatment period would be 6 months (denosumab administration on months: 0, 2, 4, 6) and the follow-up period would be 12 months.</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Primary efficacy endpoint: effect of denosumab treatment on the activity status of the disease (Incidence of patients with active disease)</measure>
    <time_frame>8 months</time_frame>
    <description>The primary efficacy endpoint will be measured through the incidence of patients with active disease at Month 8. Given that all patients have active disease at baseline the incidence of patients with active disease at Month 8 will provide the efficacy of denosumab in controlling the disease within this time frame.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Secondary efficacy endpoint: development of disease-related permanent sequelae during the study period (Incidence of disease-related permanent sequelae)</measure>
    <time_frame>18 months</time_frame>
    <description>Incidence of disease-related permanent sequelae, developed during the study, at month 18. In specific, permanent sequelae such as diabetes insipidus, anterior pituitary deficiencies, and pulmonary failure will be assessed at the end of the study in order to evaluate the efficacy of denosumab in preventing those conditions.</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Safety endpoints: Incidence of all Adverse Events during the trial</measure>
    <time_frame>18 months</time_frame>
    <description>Incidence of Adverse Events during the trial. In specific, all adverse events will be assessed at the end of the study period in order to evaluate the safety issues of denosumab treatment in LCH.</description>
  </other_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">10</enrollment>
  <condition>Langerhans Cell Histiocytosis</condition>
  <arm_group>
    <arm_group_label>Treatment arm</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>This is a single arm study; the study arm include all patients participating in the study who will all receive Denosumab 70 MG/ML [Xgeva]</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Denosumab 70 MG/ML [Xgeva]</intervention_name>
    <description>As already described in arm description</description>
    <arm_group_label>Treatment arm</arm_group_label>
    <other_name>Xgeva</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Adults (&gt;18 years of age)&#xD;
&#xD;
          -  Definitive diagnosis of LCH [Based on clinic-pathological evidence with microscopic&#xD;
             examination and at least one of the following immunological staining: Langerin (CD&#xD;
             207) positivity, Cluster of Differentiation 1a (CD1a) positivity, Presence of Birbeck&#xD;
             granules on electronic microscopy]&#xD;
&#xD;
          -  Mild symptoms (symptoms of low intensity; no need for hospitalization) and low risk&#xD;
             disease needing first line systemic therapy for LCH because of:&#xD;
&#xD;
               -  single system disease with multifocal lesions, or&#xD;
&#xD;
               -  single system disease with &quot;special site&quot; lesions (vertebral lesions with&#xD;
                  intraspinal extension, craniofacial bone lesions with soft tissue extension), or&#xD;
&#xD;
               -  multi-system disease without involvement of risk organs [hematopoietic system,&#xD;
                  spleen, liver, tumorous central nervous system (CNS)].&#xD;
&#xD;
          -  Have signed the informed consent form (consent should be taken before any&#xD;
             study-specific procedure is performed).&#xD;
&#xD;
          -  A patient should undergo a PET-CT imaging test, in order for him to be deemed suitable&#xD;
             for the study. The initial PET-CT either may have been carried out, within 3 months&#xD;
             prior to visit 1, regardless of the diagnostic center or the type of the device, which&#xD;
             has been used for, or may take place in the context of visit 2, at the diagnostic&#xD;
             center(s) specialized on Nuclear Medicine, which have been partnered with the Sponsor.&#xD;
             Whichever is the case, the initial PET-CT report should be legible and accurate, so&#xD;
             that to be assessed by the qualified physician, responsible for the PET-CT test at the&#xD;
             partnered diagnostic center(s).&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Symptomatic multi system LCH - no risk organs involved.&#xD;
&#xD;
          -  Multi-system LCH (with or without symptoms) - risk organs involved.&#xD;
&#xD;
          -  Isolated pulmonary LCH disease&#xD;
&#xD;
          -  Previous administration of denosumab from clinical trials or other use (e.g.&#xD;
             commercial use).&#xD;
&#xD;
          -  Current participation in another clinical trial or having received any investigational&#xD;
             product within the last 3 months.&#xD;
&#xD;
          -  Impaired renal function as determined by an estimated glomerular filtration rate&#xD;
             (eGFR) of ≤ 30 mL/min/1,73m2 [using the Chronic Kidney Disease-Epidemiology, (CKD-EPI)&#xD;
             formula].&#xD;
&#xD;
          -  Patients that have received oral bisphosphonates within 6 months of study enrollment&#xD;
             or intravenous bisphosphonates, fluoride and strontium ranelate within 1 year of study&#xD;
             enrollment.&#xD;
&#xD;
          -  Treatment with immune suppressive agents within 4 weeks from baseline evaluation.&#xD;
&#xD;
          -  Patients with severe impairment of clinical condition including: severely impaired&#xD;
             pulmonary function [for example total lung capacity (TLC)&lt;60%, forced expiratory&#xD;
             volume 1 (FEV1)&lt;30%, diffusing capacity of the lungs for carbon monoxide (DLCO)&lt;30%,&#xD;
             partial pressure of oxygen (PaO2)&lt;55 mmHg), long term oxygen therapy or cor pulmonale.&#xD;
&#xD;
          -  Known to have a liver failure or chronic hepatic disease e.g. cirrhosis, chronic&#xD;
             hepatitis; or elevated transaminases defined as alanine aminotransferase (ALT) and/or&#xD;
             aspartate aminotransferase (AST) &gt; 2 fold the upper limit of normal laboratory range.&#xD;
&#xD;
          -  Heart failure [New York Heart Association (NYHA) Functional Classification above 2].&#xD;
&#xD;
          -  Patients with life expectancy of less than one year.&#xD;
&#xD;
          -  Female subjects of childbearing potential who refuse to use a reliable contraceptive&#xD;
             method throughout the study, defined as use of 2 highly effective forms of&#xD;
             contraception and continuation of use for 7 months after last administration of study&#xD;
             drug. Birth control methods that can achieve a failure rate of less than 1% per year,&#xD;
             when used consistently and correctly, are considered as highly effective.&#xD;
&#xD;
          -  Pregnancy, planning a pregnancy or currently lactating&#xD;
&#xD;
          -  Severe concurrent illness which in the investigator's opinion may confound patient&#xD;
             evaluation, e.g. malignancy (except basal cell carcinoma, cervical or breast ductal&#xD;
             carcinoma in situ) within the last 5 years.&#xD;
&#xD;
          -  Known alcohol or drug abuse.&#xD;
&#xD;
          -  Parathyroid hormone (PTH), PTH derivatives, teriparatide, odanacatib, anabolic&#xD;
             steroids, testosterone, glucocorticosteroids (&gt; 5 mg/day of prednisone equivalent for&#xD;
             &gt; 10 days), systemic hormone-replacement therapy, selective estrogen receptor&#xD;
             modulators (SERMs), raloxifene, tibolone, calcitonin use within the last 6 weeks.&#xD;
&#xD;
          -  Evidence of hyper- or hypothyroidism; patients with an abnormal thyroid stimulate&#xD;
             hormone (TSH) level on thyroid treatment (patients on stable thyroid treatment with a&#xD;
             normal TSH allowed); current hyper- or hypoparathyroidism; current hyper or&#xD;
             hypocalcemia (hypercalcemia based on albumin adjusted serum calcium &gt; 10.40 mg/dL;&#xD;
             hypocalcemia based on albumin adjusted serum calcium &lt; 8.5 mg/dL); vitamin D&#xD;
             deficiency (25-hydroxy vitamin D level &lt; 20 ng/mL; if the resulted value of the retest&#xD;
             is 20 ≥ ng/Ml, after repletion with 50,000 - 100,000 IU of cholecalciferol, subject&#xD;
             will be allowed. The retest should be carried out within 30 days post to visit&#xD;
             1(screening)); rheumatoid arthritis; Paget's disease; any known bone disease with&#xD;
             osteolytic and/or osteoblastic lesions that would interfere with interpretation of&#xD;
             findings.&#xD;
&#xD;
          -  Known sensitivity to mammalian cells, denosumab or any components of denosumab 120mg,&#xD;
             or any of the products to be administered during the study (e.g., calcium or vitamin&#xD;
             D).&#xD;
&#xD;
          -  History of any Solid Organ or Bone Marrow Transplant.&#xD;
&#xD;
          -  History of osteonecrosis of the jaw, and/or recent tooth extraction or other dental&#xD;
             surgery; or planned invasive dental work during the study.&#xD;
&#xD;
          -  Intolerance to calcium supplements.&#xD;
&#xD;
          -  Malabsorption syndrome; severe malabsorption including Celiac disease, Short Bowel&#xD;
             Syndrome, Crohn's disease, Previous Gastric Bypass.&#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_official>
    <last_name>Polyzois Makras, MD, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Dpt of Endocrinology &amp; Diabetes, 251 Hellenic AirForce &amp; VA General Hospital, Athens, Greece</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>251 Hellenic AirForce &amp; VA General Hospital, Dpt of Endocrinology</name>
      <address>
        <city>Athens</city>
        <state>Attiki</state>
        <zip>11525</zip>
        <country>Greece</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Greece</country>
  </location_countries>
  <reference>
    <citation>Makras P, Tsoli M, Anastasilakis AD, Thanou M, Kaltsas G. Denosumab for the treatment of adult multisystem Langerhans cell histiocytosis. Metabolism. 2017 Apr;69:107-111. doi: 10.1016/j.metabol.2017.01.004. Epub 2017 Jan 12.</citation>
    <PMID>28285639</PMID>
  </reference>
  <reference>
    <citation>Makras P, Salagianni M, Revelos K, Anastasilakis AD, Schini M, Tsoli M, Kaltsas G, Andreakos E. Rationale for the application of RANKL inhibition in the treatment of Langerhans cell histiocytosis. J Clin Endocrinol Metab. 2015 Feb;100(2):E282-6. doi: 10.1210/jc.2014-2654. Epub 2014 Nov 6.</citation>
    <PMID>25375981</PMID>
  </reference>
  <reference>
    <citation>Makras P, Polyzos SA, Anastasilakis AD, Terpos E, Kanakis G, Schini M, Papatheodorou A, Kaltsas GA. Serum osteoprotegerin, RANKL, and Dkk-1 levels in adults with Langerhans cell histiocytosis. J Clin Endocrinol Metab. 2012 Apr;97(4):E618-21. doi: 10.1210/jc.2011-2962. Epub 2012 Jan 25.</citation>
    <PMID>22278426</PMID>
  </reference>
  <reference>
    <citation>Girschikofsky M, Arico M, Castillo D, Chu A, Doberauer C, Fichter J, Haroche J, Kaltsas GA, Makras P, Marzano AV, de Menthon M, Micke O, Passoni E, Seegenschmiedt HM, Tazi A, McClain KL. Management of adult patients with Langerhans cell histiocytosis: recommendations from an expert panel on behalf of Euro-Histio-Net. Orphanet J Rare Dis. 2013 May 14;8:72. doi: 10.1186/1750-1172-8-72.</citation>
    <PMID>23672541</PMID>
  </reference>
  <verification_date>October 2022</verification_date>
  <study_first_submitted>August 26, 2017</study_first_submitted>
  <study_first_submitted_qc>August 31, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">September 1, 2017</study_first_posted>
  <last_update_submitted>October 1, 2022</last_update_submitted>
  <last_update_submitted_qc>October 1, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">October 4, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>treatment</keyword>
  <keyword>denosumab</keyword>
  <keyword>Positron Emission Tomography (PET) CT scan</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Histiocytosis, Langerhans-Cell</mesh_term>
    <mesh_term>Histiocytosis</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Denosumab</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/NCT03270020
org study id: 20159460
nct id: NCT03270020
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
This study is aiming to evaluate the efficacy of denosumab among adult patients suffering
      from Langerhans Cell Histiocytosis (LCH).
The majority and diversity of clinical manifestations in LCH are attributed to immunological
      dysfunction resulting from langerhans cell (LC) derived cytokine secretion both at the
      lesional and systemic level. In a recent study, Receptor Activator of Nuclear Factor Kappa-B
      Ligand (RANKL) was found to be abundantly expressed in cells within diverse LCH lesions from
      adult patients, especially in inflammatory infiltrates, a finding in line with a previously
      reported high osteoprotegerin (OPG) and low RANKL levels in the serum of patients with or
      without bone involvement. RANKL expression was associated with concomitant p65 Nuclear Factor
      Kappa-B (NFκB) nuclear staining, the main downstream effector of RANKL signaling, suggesting
      that lesional cell activation may be triggered locally by RANKL. Combining the serum and the
      lesional results, it can be inferred that there is an ongoing process of countervailing OPG
      production against lesional RANKL, which could be one of the self defense mechanisms among
      LCH patients. Therefore, the use of denosumab seems a rational treatment option in LCH in
      order to support and enhance the defensive OPG action and hopefully control or even interrupt
      the lesional immunological process.

      The primary study objective is to assess the therapeutic efficacy of denosumab 120 mg every 8
      weeks (Q8W) sc in adult LCH patients.

      Secondary Objectives:

        1. To define an uniform treatment approach for LCH patients with mild symptoms and low risk
           disease.

        2. To explore the efficacy of denosumab 120 mg Q8W sc in reducing disease reactivations
           after treatment completion.

        3. To illustrate the safety profile of denosumab in LCH patients. The primary efficacy
           endpoint is defined as the percentage of patients with progression of disease at Month
           8.
allocation: N/A
intervention model: Single Group Assignment
intervention model description: The investigational arm will recruit patients who will receive denosumab 120mg sc every 2 months. The estimated duration of the recruitment period is 12 months.
The treatment period would be 6 months (denosumab administration on months: 0, 2, 4, 6) and the follow-up period would be 12 months.
primary purpose: Treatment
masking: None (Open Label)
measure: Primary efficacy endpoint: effect of denosumab treatment on the activity status of the disease (Incidence of patients with active disease)
time frame: 8 months
description: The primary efficacy endpoint will be measured through the incidence of patients with active disease at Month 8. Given that all patients have active disease at baseline the incidence of patients with active disease at Month 8 will provide the efficacy of denosumab in controlling the disease within this time frame.
measure: Secondary efficacy endpoint: development of disease-related permanent sequelae during the study period (Incidence of disease-related permanent sequelae)
time frame: 18 months
description: Incidence of disease-related permanent sequelae, developed during the study, at month 18. In specific, permanent sequelae such as diabetes insipidus, anterior pituitary deficiencies, and pulmonary failure will be assessed at the end of the study in order to evaluate the efficacy of denosumab in preventing those conditions.
measure: Safety endpoints: Incidence of all Adverse Events during the trial
time frame: 18 months
description: Incidence of Adverse Events during the trial. In specific, all adverse events will be assessed at the end of the study period in order to evaluate the safety issues of denosumab treatment in LCH.
arm group label: Treatment arm
arm group type: Experimental
description: This is a single arm study; the study arm include all patients participating in the study who will all receive Denosumab 70 MG/ML [Xgeva]
intervention type: Drug
intervention name: Denosumab 70 MG/ML [Xgeva]
description: As already described in arm description
arm group label: Treatment arm
other name: Xgeva
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Polyzois Makras, MD, PhD
role: Principal Investigator
affiliation: Dpt of Endocrinology & Diabetes, 251 Hellenic AirForce & VA General Hospital, Athens, Greece
facility: 
country: Greece
citation: Makras P, Tsoli M, Anastasilakis AD, Thanou M, Kaltsas G. Denosumab for the treatment of adult multisystem Langerhans cell histiocytosis. Metabolism. 2017 Apr;69:107-111. doi: 10.1016/j.metabol.2017.01.004. Epub 2017 Jan 12.
PMID: 28285639
citation: Makras P, Salagianni M, Revelos K, Anastasilakis AD, Schini M, Tsoli M, Kaltsas G, Andreakos E. Rationale for the application of RANKL inhibition in the treatment of Langerhans cell histiocytosis. J Clin Endocrinol Metab. 2015 Feb;100(2):E282-6. doi: 10.1210/jc.2014-2654. Epub 2014 Nov 6.
PMID: 25375981
citation: Makras P, Polyzos SA, Anastasilakis AD, Terpos E, Kanakis G, Schini M, Papatheodorou A, Kaltsas GA. Serum osteoprotegerin, RANKL, and Dkk-1 levels in adults with Langerhans cell histiocytosis. J Clin Endocrinol Metab. 2012 Apr;97(4):E618-21. doi: 10.1210/jc.2011-2962. Epub 2012 Jan 25.
PMID: 22278426
citation: Girschikofsky M, Arico M, Castillo D, Chu A, Doberauer C, Fichter J, Haroche J, Kaltsas GA, Makras P, Marzano AV, de Menthon M, Micke O, Passoni E, Seegenschmiedt HM, Tazi A, McClain KL. Management of adult patients with Langerhans cell histiocytosis: recommendations from an expert panel on behalf of Euro-Histio-Net. Orphanet J Rare Dis. 2013 May 14;8:72. doi: 10.1186/1750-1172-8-72.
PMID: 23672541
responsible party type: Sponsor
mesh term: Histiocytosis, Langerhans-Cell
mesh term: Histiocytosis
mesh term: Denosumab
sharing ipd: No