Miltefosine and GM-CSF in Cutaneous Leishmaniasis
Primary Purpose
Cutaneous Leishmaniasis
Status
Completed
Phase
Phase 3
Locations
Brazil
Study Type
Interventional
Intervention
Sbv
Miltefosine plus placebo
Miltefosine plus GM-CSF
Sponsored by
About this trial
This is an interventional treatment trial for Cutaneous Leishmaniasis focused on measuring Cutaneous leishmaniasis, miltefosine, cytokines, treatment
Eligibility Criteria
Inclusion Criteria:
- Untreated ulcerative cutaneous leishmaniasis, with laboratory diagnosis obtained through at least one of the following tests: direct examination of the lesion, positive culture or PCR for Leishmania.
- Age: 18 to 65 years;
- Sex: male and female patients;
- Presence of at least 1 ulcerated lesion at any location;
- Presence of a maximum of 3 ulcerated lesions;
- Diameter of lesions varying between 1 and 5 cm;
- Clinical evolution of the disease of not less than 1 month and not more than 3 months.
Exclusion Criteria:
- Evidence of severe underlying disease (cardiac, renal, hepatic, pulmonary) or malignant disease;
- Patients with immunodeficiency or HIV carriers;
- Serious protein and / or caloric malnutrition;
- Active and uncontrolled infectious-contagious disease such as tuberculosis, leprosy, systemic fungal disease (histoplasmosis, paracoccidioidomycosis) or any other similar condition;
- Women who are pregnant or breastfeeding;
- Allergy to Sbv or miltefosine;
- Previous treatment for leishmaniasis;
- Lack of capacity or willingness to provide informed consent (patient and / or parent / legal representative); Absence of availability for the visits or to comply with the study procedures.
Sites / Locations
- Fundação de Medicina Tropical do Amazonas
- Corte de Pedra Health Post
Arms of the Study
Arm 1
Arm 2
Arm 3
Arm Type
Active Comparator
Experimental
Experimental
Arm Label
Sbv
Miltefosine plus placebo
Miltefosine plus GM-CSF
Arm Description
Meglumine antimoniate (Glucantime): Dosage: 20 mg / kg / day, intravenously, during 20 days.
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)
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)
Outcomes
Primary Outcome Measures
Final cure rate or complete cicatrization of the ulcer
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.
Secondary Outcome Measures
Initial cure rate or initial cicatrization of the ulcer
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.
Healing time
Time (in days) to achieve complete cicatrization will be recorded.
Clinical and laboratory adverse events
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
Full Information
NCT ID
NCT03023111
First Posted
December 27, 2016
Last Updated
April 3, 2020
Sponsor
Hospital Universitário Professor Edgard Santos
Collaborators
Oswaldo Cruz Foundation
1. Study Identification
Unique Protocol Identification Number
NCT03023111
Brief Title
Miltefosine and GM-CSF in Cutaneous Leishmaniasis
Official Title
Miltefosine and GM-CSF in Cutaneous Leishmaniasis: a Randomized and Controlled Trial
Study Type
Interventional
2. Study Status
Record Verification Date
April 2020
Overall Recruitment Status
Completed
Study Start Date
June 30, 2017 (Actual)
Primary Completion Date
August 9, 2019 (Actual)
Study Completion Date
February 14, 2020 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Hospital Universitário Professor Edgard Santos
Collaborators
Oswaldo Cruz Foundation
4. Oversight
Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Product Manufactured in and Exported from the U.S.
No
Data Monitoring Committee
Yes
5. Study Description
Brief Summary
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Cutaneous Leishmaniasis
Keywords
Cutaneous leishmaniasis, miltefosine, cytokines, treatment
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
300 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Sbv
Arm Type
Active Comparator
Arm Description
Meglumine antimoniate (Glucantime):
Dosage: 20 mg / kg / day, intravenously, during 20 days.
Arm Title
Miltefosine plus placebo
Arm Type
Experimental
Arm 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 Title
Miltefosine plus GM-CSF
Arm Type
Experimental
Arm 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(s)
Sbv
Other Intervention Name(s)
Glucantime
Intervention Description
Standard treatment for CL, parenteral drug used during 20 days.
Intervention Type
Drug
Intervention Name(s)
Miltefosine plus placebo
Other Intervention Name(s)
Impavido plus placebo
Intervention Description
Oral treatment for CL, capsules with 50mg used 3 times a day, during 28 days. Placebo gel cream will be used topically.
Intervention Type
Drug
Intervention Name(s)
Miltefosine plus GM-CSF
Other Intervention Name(s)
Impavido plus GM-CSF
Intervention Description
Oral treatment for CL, capsules with 50mg used 3 times a day, during 28 days. GM-CSF gel cream will be used topically.
Primary Outcome Measure Information:
Title
Final cure rate or complete cicatrization of the ulcer
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.
Time Frame
6 months after the end of treatment
Secondary Outcome Measure Information:
Title
Initial cure rate or initial cicatrization of the ulcer
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.
Time Frame
2 months after the end of treatment
Title
Healing time
Description
Time (in days) to achieve complete cicatrization will be recorded.
Time Frame
Up to 2 months after the end of treatment
Title
Clinical and laboratory adverse events
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
Time Frame
During treatment and through study completion, an average of 1 year
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
65 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
Untreated ulcerative cutaneous leishmaniasis, with laboratory diagnosis obtained through at least one of the following tests: direct examination of the lesion, positive culture or PCR for Leishmania.
Age: 18 to 65 years;
Sex: male and female patients;
Presence of at least 1 ulcerated lesion at any location;
Presence of a maximum of 3 ulcerated lesions;
Diameter of lesions varying between 1 and 5 cm;
Clinical evolution of the disease of not less than 1 month and not more than 3 months.
Exclusion Criteria:
Evidence of severe underlying disease (cardiac, renal, hepatic, pulmonary) or malignant disease;
Patients with immunodeficiency or HIV carriers;
Serious protein and / or caloric malnutrition;
Active and uncontrolled infectious-contagious disease such as tuberculosis, leprosy, systemic fungal disease (histoplasmosis, paracoccidioidomycosis) or any other similar condition;
Women who are pregnant or breastfeeding;
Allergy to Sbv or miltefosine;
Previous treatment for leishmaniasis;
Lack of capacity or willingness to provide informed consent (patient and / or parent / legal representative); Absence of availability for the visits or to comply with the study procedures.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Paulo RL Machado, MD, PhD
Organizational Affiliation
Federal University of Bahia
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Edgar M Carvalho, MD, PhD
Organizational Affiliation
Instituto Fernandes Figueira
Official's Role
Study Director
First Name & Middle Initial & Last Name & Degree
Manoel Barral Neto, MD, PhD
Organizational Affiliation
Instituto Fernandes Figueira
Official's Role
Study Chair
First Name & Middle Initial & Last Name & Degree
Gerson Penna, MD, PhD
Organizational Affiliation
Instituto Fernandes Figueira
Official's Role
Study Chair
Facility Information:
Facility Name
Fundação de Medicina Tropical do Amazonas
City
Manaus
State/Province
Amazonas
ZIP/Postal Code
69.040-000
Country
Brazil
Facility Name
Corte de Pedra Health Post
City
Presidente Tancredo Neves
State/Province
Bahia
ZIP/Postal Code
40000
Country
Brazil
12. IPD Sharing Statement
Plan to Share IPD
No
Citations:
PubMed Identifier
33253864
Citation
Mendes L, Guerra JO, Costa B, Silva ASD, Guerra MDGB, Ortiz J, Doria SS, Silva GVD, de Jesus DV, Barral-Netto M, Penna G, Carvalho EM, Machado PRL. Association of miltefosine with granulocyte and macrophage colony-stimulating factor (GM-CSF) in the treatment of cutaneous leishmaniasis in the Amazon region: A randomized and controlled trial. Int J Infect Dis. 2021 Feb;103:358-363. doi: 10.1016/j.ijid.2020.11.183. Epub 2020 Nov 27.
Results Reference
derived
PubMed Identifier
32894278
Citation
Machado PRL, Prates FVO, Boaventura V, Lago T, Guimaraes LH, Schriefer A, Corte TWF, Penna G, Barral A, Barral-Netto M, Carvalho EM. A Double-blind, Randomized Trial to Evaluate Miltefosine and Topical Granulocyte Macrophage Colony-stimulating Factor in the Treatment of Cutaneous Leishmaniasis Caused by Leishmania braziliensis in Brazil. Clin Infect Dis. 2021 Oct 5;73(7):e2465-e2469. doi: 10.1093/cid/ciaa1337.
Results Reference
derived
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Miltefosine and GM-CSF in Cutaneous Leishmaniasis
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