Add-on Study of Pentoxifylline in Cutaneous Leishmaniasis (GT)

This study is currently recruiting participants.
Verified March 2014 by Centro Internacional de Entrenamiento e Investigaciones Médicas
Sponsor:
Information provided by (Responsible Party):
Centro Internacional de Entrenamiento e Investigaciones Médicas
ClinicalTrials.gov Identifier:
NCT01464242
First received: October 24, 2011
Last updated: March 11, 2014
Last verified: March 2014
  Purpose

The purpose of this study is to determine whether adding pentoxifylline to treatment of American cutaneous leishmaniasis with meglumine antimoniate increases the rate and speed of clinical response without diminishing safety, and to identify immune correlates of the healing response.


Condition Intervention Phase
Cutaneous Leishmaniasis
Drug: Meglumine antimonate
Drug: Placebo
Drug: Pentoxifylline
Phase 2
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator)
Primary Purpose: Treatment
Official Title: Therapeutic Gain of Adding the Immunomodulator Pentoxifylline to the Treatment of Cutaneous Leishmaniasis

Resource links provided by NLM:


Further study details as provided by Centro Internacional de Entrenamiento e Investigaciones Médicas:

Primary Outcome Measures:
  • Primary efficacy outcome: Definitive Cure [ Time Frame: Participants will be followed up to 26 weeks ] [ Designated as safety issue: No ]
    Definitive cure, defined as complete re-epithelialization and absence of inflammatory signs in all cutaneous leishmaniasis lesions, and absence of new leishmaniasis lesions

  • Primary safety outcome: Adverse Events [ Time Frame: Participants will be followed up to 26 weeks ] [ Designated as safety issue: Yes ]
    Clinical and laboratory adverse events will be qualified according to the Common Toxicity Criteria for Adverse Effects (CTCAE). All unexpected non serious adverse events will be notified and expected adverse events of moderate or higher category will be reported. All serious adverse events will be reported.


Secondary Outcome Measures:
  • In vitro lymphoproliferation [ Time Frame: Participants will be followed for an average of 20 days ] [ Designated as safety issue: No ]
    Proliferation of peripheral blood mononuclear cells (PBMCs) after stimulation invitro with L. panamensis antigens will be measured by tritiated thymidine uptake

  • Cytokine secretion by PBMCs [ Time Frame: Participants will be followed for an average of 20 days ] [ Designated as safety issue: No ]
    Secretion of a panel of cytokines relevant to the inflammatory and immune responses will be measured in supernatants from PBMCs cultured with L. panamensis antigens using Luminex technology

  • Macrophage leishmanicidal capacity [ Time Frame: Participants will be followed for an average of 20 days ] [ Designated as safety issue: No ]
    Macrophages will be differentiated from peripheral blood monocytes and their leishmanicidal capacity will be measured by luminometry after infecton with luciferase-transfected promastigotes.

  • Macrophage inducible nitric oxide synthase (iNOS) expression [ Time Frame: Participants will be followed for an average of 20 days ] [ Designated as safety issue: No ]
    Macrophage expression of iNOS after infection will be measured by quantitative real-time Polymerase Chain Reaction (RT-PCR).


Estimated Enrollment: 100
Study Start Date: November 2011
Estimated Study Completion Date: December 2014
Estimated Primary Completion Date: December 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Glucantime® + pentoxifylline
Glucantime® 20mg/kg/day intramuscular injection (IM) daily for 20 days + pentoxifylline 400mg orally 3 times a day for 20 days.
Drug: Meglumine antimonate
Glucantime® 20mg/kg/day IM daily for 20 days
Other Name: Glucantime ®
Drug: Pentoxifylline
Pentoxifylline 400mg orally 3 times a day for 20 days
Placebo Comparator: Glucantime® + placebo
Glucantime® 20mg/kg/day IM each day for 20 days + placebo 400mg orally 3 times a day for 20 days.
Drug: Meglumine antimonate
Glucantime® 20mg/kg/day IM daily for 20 days
Other Name: Glucantime ®
Drug: Placebo
Placebo 400mg orally 3 times a day for 20 days

Detailed Description:

Failure of first line therapies for cutaneous leishmaniasis is a public health issue. Since pathogenesis of dermal leishmaniasis is mediated by the immune and inflammatory responses, resolution of disease and control of infection are intimately linked to the host response. Several investigations have substantiated "proof of principal" for the therapeutic gain of co-adjuvant immunotherapy. This study will evaluate the efficacy and safety of using pentoxifylline (PTX) as a co-adjuvant in the treatment of cutaneous leishmaniasis with meglumine antimoniate in a randomized, double-blind, controlled trial. One arm will receive meglumine antimoniate and PTX and the other arm will receive meglumine antimoniate plus placebo. Efficacy will be assessed at the end of the treatment, and 5, 7, 13 and 26 weeks after initiation of treatment. Efficacy will be measured as the proportion of patients with definitive cure at 26 weeks after initiation of treatment, and time to healing. Safety will be assessed at the end of treatment with respect to the frequency and severity of adverse events.

Blood samples will be taken to evaluate the effects of PTX invitro and ex vivo on cells of the immune system. Proliferation and secretion of cytokines relevant to the immune and inflammatory responses by peripheral blood mononuclear cells will be measured before and after treatment. Likewise, macrophages will be differentiated from peripheral blood monocytes and infected with a strain of L. panamensis transfected with the luciferase (luc) gene. The investigators will measure the capacity of patient macrophages to kill parasites before and after treatment using a luminometric assay of viable parasite burden. Additionally, the investigators will measure the expression of inducible nitric oxide synthase, an enzyme that is necessary for nitric oxide production, one of the main leishmanicidal mechanisms used by macrophages. The investigators postulate that the use of the co-adjuvant with antimonials will increase the therapeutic response and that indicators predictive of a healing response can be identified by this prospective analysis of the immune response and therapeutic outcome.

  Eligibility

Ages Eligible for Study:   18 Years to 65 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Patients with clinical diagnosis of cutaneous leishmaniasis (parasitologic confirmation or presumptive biopsy plus a positive Montenegro skin test).
  • Age between 18 and 65 years.
  • Lesions of a duration equal to or greater than one month
  • More than one lesion or single lesion greater than 3 cm in diameter.
  • Willingness to participate in the study after being informed through a consent process approved by the institutional ethical review committee

Exclusion Criteria:

  • Pregnant or lactating women, and women who are planning to conceive during the study or that reject the use of birth control methods.
  • Medical conditions that compromise the immune system (HIV infection, neoplasias, diabetes mellitus, autoimmune diseases, or use of corticosteroids, immunomodulators or antineoplastic drugs).
  • Medical conditions that preclude the use of antimonials or pentoxifylline (cardiac, renal, hepatic or pancreatic disease or abnormalities).
  • Alcohol abuse or use of recreational drugs that interfere with adherence to treatment
  • Use of drugs with antileishmanial potential during the previous 13 weeks, including pentavalent antimonials, amphotericin B, miltefosine, and pentamidine
  • Use of Theophylline , anticoagulants or antiarrhythmics.
  • Diffuse or disseminated leishmaniasis.
  • Mucosal involvement secondary to Leishmania infection.
  • Incapacity to attend the study visits or any other condition that according to the investigator could interfere with adherence to study procedures.
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT01464242

Contacts
Contact: Alexandra Cossio, RN, MSc +57 +2 5552164 ext 114 acossio@cideim.org.co
Contact: Adriana Navas, Bs, Msc +57 +2 5552164 ext 114 amanazu@cideim.org.co

Locations
Colombia
Corporación Centro Internacional de entrenamiento e Investigaciónes Médicas Recruiting
Cali, Valle, Colombia, 5930
Sponsors and Collaborators
Centro Internacional de Entrenamiento e Investigaciones Médicas
Investigators
Principal Investigator: Nancy C Saravia, PhD Centro Internacional de Entrenamiento e Investigación Médica
  More Information

No publications provided

Responsible Party: Centro Internacional de Entrenamiento e Investigaciones Médicas
ClinicalTrials.gov Identifier: NCT01464242     History of Changes
Other Study ID Numbers: 222951928964
Study First Received: October 24, 2011
Last Updated: March 11, 2014
Health Authority: Colombia: INVIMA Instituto Nacional de Vigilancia de Medicamentos y Alimentos

Keywords provided by Centro Internacional de Entrenamiento e Investigaciones Médicas:
Cutaneous Leishmaniasis
pentoxifylline
immunomodulation

Additional relevant MeSH terms:
Leishmaniasis
Leishmaniasis, Cutaneous
Euglenozoa Infections
Protozoan Infections
Parasitic Diseases
Skin Diseases, Parasitic
Skin Diseases, Infectious
Skin Diseases
Pentoxifylline
Meglumine antimoniate
Phosphodiesterase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Platelet Aggregation Inhibitors
Hematologic Agents
Therapeutic Uses
Radiation-Protective Agents
Protective Agents
Physiological Effects of Drugs
Vasodilator Agents
Cardiovascular Agents
Free Radical Scavengers
Antioxidants
Antiprotozoal Agents
Antiparasitic Agents
Anti-Infective Agents

ClinicalTrials.gov processed this record on April 17, 2014