Clinical Trial: Add-on Study of Pentoxifylline in Cutaneous Leishmaniasis

Study Status: Completed
Recruit Status: Completed
Study Type: Interventional

Official Title: Therapeutic Gain of Adding the Immunomodulator Pentoxifylline to the Treatment of Cutaneous Leishmaniasis

Brief Summary: 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.

Detailed Summary:

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 mechan
Sponsor: Centro Internacional de Entrenamiento e Investigaciones Médicas

Current Primary Outcome:

• Primary efficacy outcome: Definitive Cure [ Time Frame: Participants will be followed up to 26 weeks ]
  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 ]
  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.

Original Primary Outcome:

• Primary efficacy outcome: Definitive Cure [ Time Frame: Participants will be followed for 26 weeks after the end of treatment, an expected average of 7 months ]
  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 for the duration of treatment, an expected average of 20 days ]
  Clinical and laboratory adverse events will be qualified according to the 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.

Current Secondary Outcome:

• In vitro lymphoproliferation [ Time Frame: Participants will be followed for an average of 20 days ]
  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 ]
  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 ]
  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 ]
  Macrophage expression of iNOS after infection will be measured by quantitative real-time Polymerase Chain Reaction (RT-PCR).

Original Secondary Outcome:

• In vitro lymphoproliferation [ Time Frame: Participants will be followed for the duration of treatment, an expected average of 20 days ]
  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 the duration of treatment, an expected average of 20 days ]
  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 the duration of treatment, an expected average of 20 days ]
  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 the duration of treatment, an expected average of 20 days ]
  Macrophages will be differentiated from peripheral blood monocytes and their expression of iNOS after infection will be measured by quantitative RT-PCR.

Information By: Centro Internacional de Entrenamiento e Investigaciones Médicas

Dates:
Date Received: October 24, 2011
Date Started: November 2011
Date Completion:
Last Updated: August 22, 2016
Last Verified: August 2016