Efficacy and Safety of Miltefosine or Thermotherapy for Cutaneous Leishmaniasis in Colombia.
Condition: Cutaneous Leishmaniasis
MeSH terms: Leishmaniasis; Leishmaniasis, Cutaneous
Study type: Interventional
Phase: Phase 3

Summary: 
      Cutaneous leishmaniasis (CL) is a worldwide disease, endemic in 88 countries, that has shown
      an increasing incidence the last two decades. It is estimated that in 2005, about of 20,000
      new cases of CL were diagnosed in Colombia.

      So far, pentavalent antimony compounds have been considered the treatment of choice with a
      percentage of cure of about 85%. However, the high efficacy of these drugs is counteracted by
      their adverse events and disadvantages. Previous studies have shown that miltefosine could be
      a potential alternative of treatment for CL.

      The main objective of this study is to evaluate the efficacy and safety of miltefosine or
      thermotherapy for the treatment for CL. In this study the efficacy of oral treatment of
      miltefosine 150 mg/day for 28 days or a thermotherapy device used for one session at 50
      celsius degrees during 30 seconds will be compared with the standard treatment of
      intramuscular injections of 20 mg/Kg/day of pentavalent antimonials (GlucantimeÒ) for 20 days
      in CL parasitologically proven patients.

      This trial will be conducted according to the International approved GCP (Good Clinical
      Practice) guidelines.
    

Detailed description: 
      Evaluation of Efficacy and Safety of Miltefosine for Cutaneous Leishmaniasis in Colombia
      Leishmaniasis is taking dramatic dimensions in Colombia, due to its rapid expansion,
      reemergence (which has made Colombia became in the second South American country in levels of
      annual incidence) the appearance of new infection sources, the entrance of the vector to the
      homes, the urbanization of the disease, the higher population in risk of infection, the
      absence of adequate medications ( safe, non-expensive, easily available, with oral or topic
      route of administration) and the higher resistance to the only available medication for its
      treatment. It is estimated that in 2005 more than 20,000 new cases were diagnosed; 10,265 of
      them among the Colombian military forces personnel, but it is well known that in most of the
      rural areas the major proportion of cases are not diagnosed and the people cannot reach to an
      adequate treatment and they have to use empiric options.

      On the other hand, the Program for Research and Control in tropical diseases (PECET) is
      working among Tropical Diseases Research/World Health Organization(TDR/WHO) in the evaluation
      of drugs and vaccines against Leishmaniasis; besides, PECET belongs to the TDR/WHO Clinical
      Monitors groups, TDR/WHO Data Management and participates in the Initiative for Public Health
      Products Development Doctorate among five Asiatic universities. The Ministry of Social
      Protection is aware of the need of new therapeutic alternatives for Leishmaniasis and has
      requested to PECET to conduct a controlled clinical trial to determinate the efficacy and
      safety of Miltefosine compared with Glucantime for the treatment of Cutaneous Leishmaniasis
      (CL) in Colombia, even though previous, no conclusive trials, conducted in Guatemala and
      Colombia, have demonstrated efficacy this could be an alternative of treatment for this
      country.

      Thermomed is a battery-operated medical device that delivers precisely controlled localized
      current field radio frequency heat to selectively destroy certain diseased tissue. Radio
      frequency energy is directed through the handset to the applicator that is placed in direct
      contact with the lesion. (the applicator contains a thermocouple to continuously monitor and
      control temperature to within 50º Celsius. The thermomed has been used for research on
      treatment for cutaneous leishmaniasis, and recent clinical studies have shown not only
      clinical improvement, but also that therapy elicits an immune response to the disease.
      Through this trial we will try to perform a conclusive clinical evaluation about this drug.

      In summary, with this project to conduct a clinical trial to determine the efficacy and
      safety of Miltefosine or thermotherapy compared with Glucantime for treatment of CL in
      Colombian patients.

      Population CL in is a remerging disease in Colombia affecting civilian and military
      population as well, sharing the same epidemiologic characteristics.

      The selected population will be composed from National Army of Colombia soldiers from CL
      endemic areas (Caquetá, Meta, Guaviare, Putumayo, Córdoba, Antioquia and Chocó).

      Treatment:

      In this phase III, randomized open trial, subjects meeting inclusion criteria of the trial
      will be randomly allocated into two groups according to a randomization list. One group will
      be treated with 150 mg/day of oral miltefosine for 28 days a second group will be treated
      with thermotherapy device used for one session at 50 celsius degrees during 30 seconds and a
      third group will be treated with intramuscular injections of 20 mg/kg/day Glucantime® for 20
      days. A written instruction sheet will be given to each included patient, and the patient
      will be instructed to contact the research team on appearance of symptoms suggesting severe
      side effects (intractable diarrhea and/or vomiting, symptoms of liver, kidney or
      hematopoietic system dysfunction. Until six weeks after the termination of the treatment, any
      patient who received oral miltefosine or was treated with thermotherapy and has active lesion
      will be treated with intramuscular Glucantime® injections (20mg/kg/day for 20 days).

      Study development Schedule of activities Screening (-2 or day 0): Protocol explanation,
      invitation to participate, inform consent signature, parasitological diagnosis (Direct test),
      laboratory tests (Complete hemogram, Ureic Nitrogen (BUN), creatinine, amylase,
      Glutamic-pyruvic transaminase(GTP or ALT), glutamic-oxaloacetic transaminase(GOT or AST)).

      Inclusion (Visit 1): Randomization, sampling of Cultures, physical examination, vital signs
      measure, oral treatment initiation (Miltefosine for 28 days) or Glucantime® intramuscular
      application initiation (for the 20 subsequent days) or thermotherapy ( Local heat), patient's
      clinical record, CRF (Case Report Format) fulfilling, lesions picture taking.

      Visit 2 (Middle of treatment): Laboratory tests (Complete hemogram, BUN, creatinine, amylase,
      GOT, GPT), physical examination, vital signs measure, CRF (Case Report Format) fulfilling,
      Lesions picture taking.

      Visit 3 (End of treatment, +10 days): Laboratory tests (Complete hemogram, BUN, creatinine,
      amylase, GTP, GOT), physical examination, vital signs measure, CRF (Case Report Format)
      fulfilling, lesions picture taking, Evaluation of treatment efficacy.

      Visit 4 (Six weeks after treatment, ± 15 days): Physical examination, Vital signs measure,
      CRF (Case Report Format) fulfilling, lesions picture taking, evaluation of treatment
      efficacy.

      Visit 5 (Three months after treatment, ± 30 days): Physical examination, Vital signs measure,
      CRF (Case Report Format) fulfilling, lesions picture taking, evaluation of treatment
      efficacy.

      Visit 6 (Six months after treatment, ± 40 days): Physical examination, Vital signs measure,
      CRF (Case Report Format) fulfilling, lesions picture taking, evaluation of treatment
      efficacy.

      Procedures:

      Physical examination A complete physical examination will be realized and vital signs will be
      measured.

      Blood samples withdrawn

      Blood samples will be withdrawn from the antecubital vein to perform the following analyses:

        -  Creatinine and Blood Urea Nitrogen.

        -  Alanine transaminase (ALT)

        -  Aspartate transaminase (AST)

        -  Pancreatic amylase.

        -  Complete hemogram.

      Technique for the sampling of cultures The sample for the culture may be obtained by
      suctioning the ulcer active edge in a phosphate-buffered saline solution (PBS) with
      antibiotics (1000 IU of crystalline Penicillin per cc), before it is put in the culture
      medium.

      A tuberculin syringe 0.5 cc of PBS solution with antibiotics is used in the suction
      technique. Previous asepsis of the ulcer with alcohol at 70%, a needle is introduced into the
      dermis and through rotating movements a small amount of tissue is macerated by the needle
      bevel during about a minute, after which it is suctioned into the syringe. The sample is
      deposited in aseptic conditions into a NNN (Novy-MacNeal-Nicole ) culture medium and
      incubated at 26°C during 4 weeks. The strains are identified by species using the monoclonal
      antibodies.

      Toxicity

      The grade of toxicity will be evaluated according the following parameters:

        -  Systemic: Fever, Headache.

        -  Gastrointestinal: Nausea, vomiting, oral discomfort.

        -  Cardiovascular: cardiac rhythm, hypertension, hypotension.

        -  Musculoskeletal: Arthralgia (joint pain) , myalgia,

      During the treatment and the follow-up visits, the patients will be asked about adverse
      events. Each adverse event will be classified by the physician as serious or non-serious A
      serious adverse event should meet one or more of the following criteria:

        -  Death

        -  Life-threatening (i.e., immediate risk of death)

        -  In-patient hospitalization or prolongation of existing hospitalization

        -  Persistent or significant disability/incapacity The presence of a serious adverse event
           that puts the patient's life at risk and/or requires immediate medical or surgical
           procedure will call for the discontinuation of the treatment and the initiation of the
           pertinent medical management of the patients. The study staff will notify the Adverse
           IEC/IRB of the University of Antioquia of any serious adverse event within 24 hours of
           having knowledge of it.

      A non-serious adverse event will be classified as follows:

      Mild: The patients are aware of their symptoms and/or signs, but those are tolerable. They do
      not require medical intervention or specific treatment.

      Moderate: Patients present troubles that interfere with their daily activities. They require
      medical intervention or specific treatment.

      Severe: The patients are unable to work or to attend their daily activities. They require
      medical intervention or specific treatment.

      The possible relationship between the adverse events and the tested medication will be
      classified by the investigator on the basis of his/her clinical judgment and the following
      definitions:

      Definitely related: Event can be fully explained by the administration of the tested
      medication.

      Probably related: Event is most likely to be explained by the administration of the tested
      medication rather than other medications or by the patient's clinical state.

      Possibly related: Event may be explained by the administration of the tested medication or
      other medications or by the patient's clinical state.

      Not related: Event is most likely to be explained by the patient's clinical state or other
      medications, rather than the tested one.

      Data analysis phase. The healing rate will be calculated according to each group (treatment
      and control) by intention to treat and by protocol. Subgroups will be established depending
      on the clinical response, adverse events and according to Leishmania specie. Besides, the
      characteristics of the lesion (size, localization, type of lesion), demographic
      characteristics and how long the healing takes after the treatment is settled.

      In all cases significance test will be performed to compare both treatments.

      Endpoints Primary Clinical response: Complete re-epithelization of all lesions with
      disappearance of induration (with or without scar). No parasitological evaluation will be
      done on clinically cured lesions determined until 45 days posttreatment.

      Clinical improvement: Reduction of a ≥50% area of induration and ulcer compared with
      immediately previous evaluation.

      Secondary:

      Treatment failure: No change or increase in the size of induration and ulcer. Absence of
      clinical response: Induration and ulcer area ≤50% compared with the immediately previous
      evaluation.

      Final reports At the end of the study the results will be evaluated and discussed and a final
      report presented to Colombian army and Ministry of Social Protection, entities sponsoring the
      project. The relevant results will be published in both, national and international journals,
      and presented in congresses and scientific meetings.

      Ethical aspects This study will be conduced according with the Declaration of Helsinki , the
      Colombian legislation as per the resolution 008430/93 from the Ministry of Health, Canadian
      Council of Animal Care, National Institute for drugs and foods vigilance and control -
      (INVIMA)(Colombia), International Conference on Harmonisation-Good Clinical Practice
      (ICH-GCP) guidelines, and TDR/WHO guidelines for clinical research.

      Prior to the admission of the patients in the study, the objectives and the methodology will
      be explained and informed consent obtained.

      The study was approved for the Sede de Investigación Universitaria (SIU) bioethics committee
      (CBEIH-SIU) and the Leishmaniasis Committee of the Colombian Military Forces.

      The right to confidentiality of the patients will be maintained in all the phases of the
      study.

      Competing of interests:

      The authors declare that they have no competing of interests.
    

Intervention name(s): Miltefosine; Thermotherapy; Glucantime®
Intervention type(s): Drug; Device; Drug
Intervention description(s): Miltefosine 2.5 mg/Kg/day with a maximum dose of 150 mg PO day.; One session of local heat using a thermotherapy device at 50 celsius degrees during 30 seconds.; Glucantime® 20 mg /Kg /day for 20 days (intramuscular)
Other intervention name(s): Impavido®; Thermomed; Glucantime® (meglumine antimoniate)
Intervention MeSH terms: Miltefosine; Meglumine Antimoniate
Allocation: Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Miltefosine; Leishmaniasis; Glucantime; Thermotherapy; Colombia