Efficacy and Safety of Miltefosine or Thermotherapy for Cutaneous Leishmaniasis in Colombia.

Phase 3 Open-label Study of Efficacy and Safety of Miltefosine or Thermotherapy vs Glucantime for Cutaneous Leishmaniasis in Colombia.

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.

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.

Inclusion Criteria:

• Parasitologically proven cases of CL based on positive smear and/or culture.
• Patients belonging to the National Colombian Army.
• Otherwise healthy subjects on the basis of medical history, physical examination and results of blood test (if seemed necessary by the physician)
• Age 18-40 years.
• Willing to participate in the study, sign the informed consent , to go to the scheduled visits and to the follow-up visits.
• Abstain to receive any other treatment for CL during the trial and follow-up periods.
• Non purulent lesions.
• Mentally sane volunteers.
• No Leishmaniasis treatment in the six months prior to the recruitment.
• Number of lesions no more than 5

Exclusion criteria:

• None of the lesions must be close to the anal, oral and nasal mucosa, or next to the urogenital and anal canal.
• Serious systemic illnesses (as judged by the physician)
• Patients with mucosal compromise.
• Patients with diffuse Leishmaniasis ( defined as 10 or more cutaneous lesions and negative Montenegro's test)