<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/NCT03023111</url>
  </required_header>
  <id_info>
    <org_study_id>Mil GM CL-2017</org_study_id>
    <nct_id>NCT03023111</nct_id>
  </id_info>
  <brief_title>Miltefosine and GM-CSF in Cutaneous Leishmaniasis</brief_title>
  <official_title>Miltefosine and GM-CSF in Cutaneous Leishmaniasis: a Randomized and Controlled Trial</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Hospital Universitário Professor Edgard Santos</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Oswaldo Cruz Foundation</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Hospital Universitário Professor Edgard Santos</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>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      Cutaneous leishmaniasis (CL) standard treatment is done with parenteral pentavalent antimony&#xD;
      (Sbv) at the dose of 15-20mg / kg per day for 20 days. However, therapeutic failure has been&#xD;
      described in up to 50% of patients, and the long period of 60 to 90 days required for healing&#xD;
      of the ulcerated lesion indicate the need for alternative drugs. Currently the alternatives&#xD;
      include other parenteral drugs such as pentamidine and amphotericin B, whose use is limited&#xD;
      either by toxicity or because, as with Sbv, the parenteral route hinders adherence and&#xD;
      regularity of treatment in the rural area. Recent studies by our group indicate that oral&#xD;
      miltefosine is the most effective drug for the treatment of patients with CL caused by L.&#xD;
      (V.) guyanensis and L. (V.) braziliensis in Brazil, with a cure rate of 71.4% and 75%&#xD;
      respectively. CL pathogenesis is associated with intense inflammatory infiltrate and tissue&#xD;
      damage. Previous trials associating GM-CSF to Sbv improved the cure rate of CL caused by L.&#xD;
      (V.) braziliensis. The objective of this trial is to evaluate the therapeutic response to the&#xD;
      use of miltefosine associated to GM-CSF in the treatment of CL caused by L. (V.) braziliensis&#xD;
      in an endemic region in Bahia and Ceará, and by L. (V.) guyanensis in the Amazon region.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">June 30, 2017</start_date>
  <completion_date type="Actual">February 14, 2020</completion_date>
  <primary_completion_date type="Actual">August 9, 2019</primary_completion_date>
  <phase>Phase 3</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>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Final cure rate or complete cicatrization of the ulcer</measure>
    <time_frame>6 months after the end of treatment</time_frame>
    <description>All lesions will be categorized as either active or healed (cured) at follow-up visits. Only lesions with complete re-epithelialization, without raised borders, infiltrations or crusts will be considered healed. Evaluation of the lesions will be performed by 2 clinicians who will be unaware of the group assignment of all patients. Bidirectional measurements of ulcers will be taken of the patients' lesions at the initial visit, and at each follow-up visit with standardized caliper. The area involved will be calculated as the product of the two measurements.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Initial cure rate or initial cicatrization of the ulcer</measure>
    <time_frame>2 months after the end of treatment</time_frame>
    <description>All lesions will be categorized as either active or healed (cured) at follow-up visits. Only lesions with complete re-epithelialization, without raised borders, infiltrations or crusts will be considered healed. Evaluation of the lesions will be performed by 2 clinicians who will be unaware of the group assignment of all patients. Bidirectional measurements of ulcers will be taken of the patients' lesions at the initial visit, and at each follow-up visit with standardized caliper. The area involved will be calculated as the product of the two measurements.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Healing time</measure>
    <time_frame>Up to 2 months after the end of treatment</time_frame>
    <description>Time (in days) to achieve complete cicatrization will be recorded.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Clinical and laboratory adverse events</measure>
    <time_frame>During treatment and through study completion, an average of 1 year</time_frame>
    <description>Clinical and laboratory adverse events will be recorded and graded according to the Common Terminology Criteria for Adverse Event (CTCAE) of the National Cancer Institute</description>
  </secondary_outcome>
  <number_of_arms>3</number_of_arms>
  <enrollment type="Actual">300</enrollment>
  <condition>Cutaneous Leishmaniasis</condition>
  <arm_group>
    <arm_group_label>Sbv</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Meglumine antimoniate (Glucantime):&#xD;
Dosage: 20 mg / kg / day, intravenously, during 20 days.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Miltefosine plus placebo</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Miltefosine (28 days / 2.5mg / Kg / day at a maximum dose of 150mg / day orally) + Topical placebo (gel cream, 2 times a day for 28 days)</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Miltefosine plus GM-CSF</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Miltefosine (28 days / 2.5mg / kg / day at a maximum dose of 150mg / day orally) + Topical GM-CSF (0.01% gel cream, 2 times a day for 28 days)</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Sbv</intervention_name>
    <description>Standard treatment for CL, parenteral drug used during 20 days.</description>
    <arm_group_label>Sbv</arm_group_label>
    <other_name>Glucantime</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Miltefosine plus placebo</intervention_name>
    <description>Oral treatment for CL, capsules with 50mg used 3 times a day, during 28 days. Placebo gel cream will be used topically.</description>
    <arm_group_label>Miltefosine plus placebo</arm_group_label>
    <other_name>Impavido plus placebo</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Miltefosine plus GM-CSF</intervention_name>
    <description>Oral treatment for CL, capsules with 50mg used 3 times a day, during 28 days. GM-CSF gel cream will be used topically.</description>
    <arm_group_label>Miltefosine plus GM-CSF</arm_group_label>
    <other_name>Impavido plus GM-CSF</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Untreated ulcerative cutaneous leishmaniasis, with laboratory diagnosis obtained&#xD;
             through at least one of the following tests: direct examination of the lesion,&#xD;
             positive culture or PCR for Leishmania.&#xD;
&#xD;
          2. Age: 18 to 65 years;&#xD;
&#xD;
          3. Sex: male and female patients;&#xD;
&#xD;
          4. Presence of at least 1 ulcerated lesion at any location;&#xD;
&#xD;
          5. Presence of a maximum of 3 ulcerated lesions;&#xD;
&#xD;
          6. Diameter of lesions varying between 1 and 5 cm;&#xD;
&#xD;
          7. Clinical evolution of the disease of not less than 1 month and not more than 3 months.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Evidence of severe underlying disease (cardiac, renal, hepatic, pulmonary) or&#xD;
             malignant disease;&#xD;
&#xD;
          2. Patients with immunodeficiency or HIV carriers;&#xD;
&#xD;
          3. Serious protein and / or caloric malnutrition;&#xD;
&#xD;
          4. Active and uncontrolled infectious-contagious disease such as tuberculosis, leprosy,&#xD;
             systemic fungal disease (histoplasmosis, paracoccidioidomycosis) or any other similar&#xD;
             condition;&#xD;
&#xD;
          5. Women who are pregnant or breastfeeding;&#xD;
&#xD;
          6. Allergy to Sbv or miltefosine;&#xD;
&#xD;
          7. Previous treatment for leishmaniasis;&#xD;
&#xD;
          8. Lack of capacity or willingness to provide informed consent (patient and / or parent /&#xD;
             legal representative); Absence of availability for the visits or to comply with the&#xD;
             study procedures.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>65 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Paulo RL Machado, MD, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Federal University of Bahia</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Edgar M Carvalho, MD, PhD</last_name>
    <role>Study Director</role>
    <affiliation>Instituto Fernandes Figueira</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Manoel Barral Neto, MD, PhD</last_name>
    <role>Study Chair</role>
    <affiliation>Instituto Fernandes Figueira</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Gerson Penna, MD, PhD</last_name>
    <role>Study Chair</role>
    <affiliation>Instituto Fernandes Figueira</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Fundação de Medicina Tropical do Amazonas</name>
      <address>
        <city>Manaus</city>
        <state>Amazonas</state>
        <zip>69.040-000</zip>
        <country>Brazil</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Corte de Pedra Health Post</name>
      <address>
        <city>Presidente Tancredo Neves</city>
        <state>Bahia</state>
        <zip>40000</zip>
        <country>Brazil</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Brazil</country>
  </location_countries>
  <verification_date>April 2020</verification_date>
  <study_first_submitted>December 27, 2016</study_first_submitted>
  <study_first_submitted_qc>January 17, 2017</study_first_submitted_qc>
  <study_first_posted type="Estimate">January 18, 2017</study_first_posted>
  <last_update_submitted>April 3, 2020</last_update_submitted>
  <last_update_submitted_qc>April 3, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">April 7, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Hospital Universitário Professor Edgard Santos</investigator_affiliation>
    <investigator_full_name>Paulo Roberto Lima Machado</investigator_full_name>
    <investigator_title>MD, PhD</investigator_title>
  </responsible_party>
  <keyword>Cutaneous leishmaniasis</keyword>
  <keyword>miltefosine</keyword>
  <keyword>cytokines</keyword>
  <keyword>treatment</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Leishmaniasis</mesh_term>
    <mesh_term>Leishmaniasis, Cutaneous</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Miltefosine</mesh_term>
    <mesh_term>Meglumine Antimoniate</mesh_term>
    <mesh_term>Molgramostim</mesh_term>
    <mesh_term>Sargramostim</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/NCT03023111
org study id: Mil GM CL-2017
nct id: NCT03023111
lead sponsor: 
collaborator: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
is us export: No
Cutaneous leishmaniasis (CL) standard treatment is done with parenteral pentavalent antimony
      (Sbv) at the dose of 15-20mg / kg per day for 20 days. However, therapeutic failure has been
      described in up to 50% of patients, and the long period of 60 to 90 days required for healing
      of the ulcerated lesion indicate the need for alternative drugs. Currently the alternatives
      include other parenteral drugs such as pentamidine and amphotericin B, whose use is limited
      either by toxicity or because, as with Sbv, the parenteral route hinders adherence and
      regularity of treatment in the rural area. Recent studies by our group indicate that oral
      miltefosine is the most effective drug for the treatment of patients with CL caused by L.
      (V.) guyanensis and L. (V.) braziliensis in Brazil, with a cure rate of 71.4% and 75%
      respectively. CL pathogenesis is associated with intense inflammatory infiltrate and tissue
      damage. Previous trials associating GM-CSF to Sbv improved the cure rate of CL caused by L.
      (V.) braziliensis. The objective of this trial is to evaluate the therapeutic response to the
      use of miltefosine associated to GM-CSF in the treatment of CL caused by L. (V.) braziliensis
      in an endemic region in Bahia and Ceará, and by L. (V.) guyanensis in the Amazon region.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
measure: Final cure rate or complete cicatrization of the ulcer
time frame: 6 months after the end of treatment
description: All lesions will be categorized as either active or healed (cured) at follow-up visits. Only lesions with complete re-epithelialization, without raised borders, infiltrations or crusts will be considered healed. Evaluation of the lesions will be performed by 2 clinicians who will be unaware of the group assignment of all patients. Bidirectional measurements of ulcers will be taken of the patients' lesions at the initial visit, and at each follow-up visit with standardized caliper. The area involved will be calculated as the product of the two measurements.
measure: Initial cure rate or initial cicatrization of the ulcer
time frame: 2 months after the end of treatment
description: All lesions will be categorized as either active or healed (cured) at follow-up visits. Only lesions with complete re-epithelialization, without raised borders, infiltrations or crusts will be considered healed. Evaluation of the lesions will be performed by 2 clinicians who will be unaware of the group assignment of all patients. Bidirectional measurements of ulcers will be taken of the patients' lesions at the initial visit, and at each follow-up visit with standardized caliper. The area involved will be calculated as the product of the two measurements.
measure: Healing time
time frame: Up to 2 months after the end of treatment
description: Time (in days) to achieve complete cicatrization will be recorded.
measure: Clinical and laboratory adverse events
time frame: During treatment and through study completion, an average of 1 year
description: Clinical and laboratory adverse events will be recorded and graded according to the Common Terminology Criteria for Adverse Event (CTCAE) of the National Cancer Institute
arm group label: Sbv
arm group type: Active Comparator
description: Meglumine antimoniate (Glucantime):
Dosage: 20 mg / kg / day, intravenously, during 20 days.
arm group label: Miltefosine plus placebo
arm group type: Experimental
description: Miltefosine (28 days / 2.5mg / Kg / day at a maximum dose of 150mg / day orally) + Topical placebo (gel cream, 2 times a day for 28 days)
arm group label: Miltefosine plus GM-CSF
arm group type: Experimental
description: Miltefosine (28 days / 2.5mg / kg / day at a maximum dose of 150mg / day orally) + Topical GM-CSF (0.01% gel cream, 2 times a day for 28 days)
intervention type: Drug
intervention name: Sbv
description: Standard treatment for CL, parenteral drug used during 20 days.
arm group label: Sbv
other name: Glucantime
intervention type: Drug
intervention name: Miltefosine plus placebo
description: Oral treatment for CL, capsules with 50mg used 3 times a day, during 28 days. Placebo gel cream will be used topically.
arm group label: Miltefosine plus placebo
other name: Impavido plus placebo
intervention type: Drug
intervention name: Miltefosine plus GM-CSF
description: Oral treatment for CL, capsules with 50mg used 3 times a day, during 28 days. GM-CSF gel cream will be used topically.
arm group label: Miltefosine plus GM-CSF
other name: Impavido plus GM-CSF
criteria: 
gender: All
minimum age: 18 Years
maximum age: 65 Years
healthy volunteers: No
last name: Paulo RL Machado, MD, PhD
role: Principal Investigator
affiliation: Federal University of Bahia
last name: Edgar M Carvalho, MD, PhD
role: Study Director
affiliation: Instituto Fernandes Figueira
last name: Manoel Barral Neto, MD, PhD
role: Study Chair
affiliation: Instituto Fernandes Figueira
last name: Gerson Penna, MD, PhD
role: Study Chair
affiliation: Instituto Fernandes Figueira
facility: 
facility: 
country: Brazil
responsible party type: Principal Investigator
investigator affiliation: Hospital Universitário Professor Edgard Santos
investigator full name: Paulo Roberto Lima Machado
investigator title: MD, PhD
mesh term: Leishmaniasis
mesh term: Leishmaniasis, Cutaneous
mesh term: Miltefosine
mesh term: Meglumine Antimoniate
mesh term: Molgramostim
mesh term: Sargramostim
sharing ipd: No