Add-on Study of Pentoxifylline in Cutaneous Leishmaniasis (GT)
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.
Drug: meglumine antimonate
|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|
- 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 ] [ 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 for the duration of treatment, an expected average of 20 days ] [ Designated as safety issue: Yes ]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.
- In vitro lymphoproliferation [ Time Frame: Participants will be followed for the duration of treatment, an expected 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 the duration of treatment, an expected 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 the duration of treatment, an expected 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 the duration of treatment, an expected average of 20 days ] [ Designated as safety issue: No ]Macrophages will be differentiated from peripheral blood monocytes and their expression of iNOS after infection will be measured by quantitative RT-PCR.
|Study Start Date:||November 2011|
|Estimated Study Completion Date:||January 2013|
|Estimated Primary Completion Date:||December 2012 (Final data collection date for primary outcome measure)|
Experimental: Glucantime® + pentoxifylline
Glucantime® 20mgSb/kg/day IM daily for 20 days + pentoxifylline 400mg orally 3 times a day for 20 days.
Drug: meglumine antimonate
Glucantime® 20mgSb/kg/day IM daily for 20 daysDrug: Pentoxifylline
Pentoxifylline 400mg orally 3 times a day for 20 days
Placebo Comparator: Glucantime® + placebo
Glucantime® 20mgSb/kg/day IM each day for 20 days + placebo 400mg orally 3 times a day for 20 days.
Drug: meglumine antimonate
Glucantime® 20mgSb/kg/day IM daily for 20 daysDrug: Placebo
Placebo 400mg orally 3 times a day for 20 days
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.
|Contact: Alexandra Cossio, RN, MSc||+57 +2 5552164 ext email@example.com|
|Contact: Daniel Rodriguez, PhD. MD.||+57 +2 5552164 ext firstname.lastname@example.org|
|Corporación Centro Internacional de entrenamiento e Investigaciónes Médicas||Not yet recruiting|
|Cali, Valle, Colombia, 5930|
|Principal Investigator:||Nancy C Saravia, PhD||Centro Internacional de Entrenamiento e Investigación Médica|