Miltefosine and GM-CSF in Cutaneous Leishmaniasis

NCT03023111 | Completed Phase 3 DMC

• 1 other identifier: Mil GM CL-2017
• Study Type: interventional
• Target: 300
• Locations: 1 country
• Sites: 2

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.

Conditions

Cutaneous Leishmaniasis

Keywords

Cutaneous leishmaniasis; miltefosine; cytokines; treatment

Outcome Measures

Primary Outcomes (1)

• 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.

  6 months after the end of treatment

Secondary Outcomes (3)

• Initial cure rate or initial cicatrization of the ulcer

  2 months after the end of treatment

• Healing time

  Up to 2 months after the end of treatment

• Clinical and laboratory adverse events

  During treatment and through study completion, an average of 1 year

Study Arms (3)

Sbv

ACTIVE COMPARATOR

Meglumine antimoniate (Glucantime): Dosage: 20 mg / kg / day, intravenously, during 20 days.

Drug: Sbv

Miltefosine plus placebo

EXPERIMENTAL

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)

Drug: Miltefosine plus placebo

Miltefosine plus GM-CSF

EXPERIMENTAL

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)

Drug: Miltefosine plus GM-CSF

Interventions

Sbv DRUG

Standard treatment for CL, parenteral drug used during 20 days.

Also known as: Glucantime

Sbv

Miltefosine plus placebo DRUG

Oral treatment for CL, capsules with 50mg used 3 times a day, during 28 days. Placebo gel cream will be used topically.

Also known as: Impavido plus placebo

Miltefosine plus placebo

Miltefosine plus GM-CSF DRUG

Oral treatment for CL, capsules with 50mg used 3 times a day, during 28 days. GM-CSF gel cream will be used topically.

Also known as: Impavido plus GM-CSF

Miltefosine plus GM-CSF

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Hospital Universitário Professor Edgard Santos: lead
• Oswaldo Cruz Foundation: collaborator

Study Sites (2)

Fundação de Medicina Tropical do Amazonas

Manaus, Amazonas, 69.040-000, Brazil

Location

Corte de Pedra Health Post

Presidente Tancredo Neves, Estado de Bahia, 40000, Brazil

Location

Related Publications (2)

• 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.

  PMID: 33253864 DERIVED

• 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.

  PMID: 32894278 DERIVED

MeSH Terms

Conditions

Leishmaniasis, Cutaneous

Interventions

Meglumine Antimoniate; miltefosine; Granulocyte-Macrophage Colony-Stimulating Factor

Condition Hierarchy (Ancestors)

Leishmaniasis; Euglenozoa Infections; Protozoan Infections; Parasitic Diseases; Infections; Skin Diseases, Parasitic; Vector Borne Diseases; Skin Diseases, Infectious; Skin Diseases; Skin and Connective Tissue Diseases

Intervention Hierarchy (Ancestors)

Meglumine; Sorbitol; Sugar Alcohols; Alcohols; Organic Chemicals; Hexosamines; Amino Sugars; Carbohydrates; Colony-Stimulating Factors; Glycoproteins; Glycoconjugates; Hematopoietic Cell Growth Factors; Cytokines; Intercellular Signaling Peptides and Proteins; Peptides; Amino Acids, Peptides, and Proteins; Proteins; Biological Factors

Study Officials

• Paulo RL Machado, MD, PhD

  Federal University of Bahia

  PRINCIPAL INVESTIGATOR

• Edgar M Carvalho, MD, PhD

  Instituto Fernandes Figueira

  STUDY DIRECTOR

• Manoel Barral Neto, MD, PhD

  Instituto Fernandes Figueira

  STUDY CHAIR

• Gerson Penna, MD, PhD

  Instituto Fernandes Figueira

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: MD, PhD

Study Record Dates

• First Submitted: December 27, 2016
• First Posted: January 18, 2017
• Study Start: June 30, 2017
• Primary Completion: August 9, 2019
• Study Completion: February 14, 2020
• Last Updated: April 7, 2020

Record last verified: 2020-04

Data Sharing

• IPD Sharing: Will not share

Locations

BR (2)