Clinical trial NCT02687971: Thermotherapy + a Short Course of Miltefosine for the Treatment of Uncomplicated Cutaneous Leishmaniasis in the New World¨
Official title: A Randomized, Open Label, Multicenter Study to Determine the Efficacy and Safety of Combining Thermotherapy and a Short Course of Miltefosine for the Treatment of Uncomplicated Cutaneous Leishmaniasis in the New World¨
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Cutaneous Leishmaniasis
Lead sponsor: Drugs for Neglected Diseases
Sponsor class: OTHER
First posted: 2016-02-23
Enrollment: 130
Sex: ALL
Minimum age (years): 18
Maximum age (years): 60
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The purpose of this trial is to determine the efficacy and safety of a combined therapy using thermotherapy (TT) (one session, 50 degrees Celsius for 30") + miltefosine at a standard dose of 2.5 mg/kg/day for 21 days for the treatment of uncomplicated CL in Peru and Colombia

Detailed description: The use of topical treatments for Cutaneous leishmaniasis (CL) is an option that has been widely explored and it is currently listed as an options by WHO in those situations where the patient has few lesions (≤ 4) of less than ≤ 4 cm in diameter and located in areas of the body which may be treated topically.

Local heat, especially the one produced by radio frequency waves (Themo-Med®) has been widely tested for CL in both Old and New World. The advantages of using thermotherapy include: 1) high security profile; 2) only one session is required which ensures compliance with treatment; 3) easy to use in the field since the machine operates with batteries; 4) its effectiveness does not depend on the species of Leishmania causing the lesion as it is a physical measure; and 5) it can be used in patients in whom systemic treatment with antimonials are contraindicated, including women who are pregnant or breastfeeding. In the New World, Thermo-Med® has been evaluated in Mexico, Guatemala, Colombia and Brazil (all but one were randomized clinical trials), reporting cure rates of 90%, 73%, 64% and 75% respectively

There are no clinical trials evaluating the efficacy of miltefosine for CL when given for less than 20 days. The 21-day course was chosen to give the best chances to the combination approach and based on a) the results of a Phase II trial conducted in Colombia showing that a mean dose of miltefosine of 133 mg/day/20 days resulted in a cure rate of 82%20 and; b) a report showing that the a daily administration of 100 mg/day (2.5 mg/kg of body weight/day for 28 days) resulted in a mean maximum concentration of drug in serum at day 23 of treatment of 70,000 ng/ml21.

The theoretical advantages offered by this combination are that a) we are using two approaches that are currently recommended for use individually and for which there is good information regarding their efficacy and safety when used alone; b) the use of a topical plus a systemic treatment would hypothetically have an additive effect, since systemic treatment would eliminate those circulating or remaining parasites located in the periphery of the lesion that topical treatment fails to remove and which might be the cause of relapses22,23; c) it offers the opportunity to increase the current cure rate reported with any other treatment approach available when used alone; d) it will reduce the length of treatment with miltefosine and hopefully the cost and rates of adverse events associated with 28 days of treatment with miltefosine.

Eligibility criteria: Inclusion Criteria:

Patient with a confirmed diagnosis of CL in at least one lesion by at least one of the following methods: 1) microscopic identification of amastigotes in stained lesion tissue, or 2) demonstration of Leishmania by PCR, or 3) positive culture for promastigotes,

Patient has a lesion that satisfies the following criteria:

* Lesion size ≥ 0.5 cm and \</= 4 cm (Longest diameter),
* Not located on the ear, face, close to mucosal membranes, joints or on a location that in the opinion of the PI is difficult to apply TT,
* Patient with \</= 4 CL lesions,
* Duration of lesion less than 4 months by patient history, Patient able to give written informed consent, In the opinion of the investigator, the patient is capable of understanding and complying with the protocol

Exclusion Criteria:

* Female with a positive urine pregnancy test at screening or who is breast feeding, lactating or female at fertile age who does not agree to take appropriate contraception during treatment period and up to D90,
* History of clinically significant medical problems / treatment that might interact, either negatively or positively, with topical treatment of leishmaniasis including any immunocompromising condition,
* Within 8 weeks (56 days) of trial Day 1, received treatment for leishmaniasis with any medication including antimonials likely, in the opinion of the PI, to modify the course of the Leishmania infection,
* Has diagnosis or suspected diagnosis of mucocutaneous leishmaniasis based on physical exam,
* History of known or suspected hypersensitivity or idiosyncratic reactions to trial medication or exipients,
* Patient who is not willing to attend the trial visits, or is not able to comply with follow-up visits up to 6 months,
* Known history of drug addiction and/or alcohol abuse

Primary outcomes:
measure: Initial cure rate
timeFrame: Day 90, after start of treatment
Secondary outcomes:
measure: Final cure rate
timeFrame: Day 180, after star of treatment
measure: Frequency and severity of AEs
timeFrame: Day 45
Other outcomes:
Locations:
city: Medellin
country: Colombia
facility: Programa de Estudios y Control de Enfermedades Tropicales (PECET), Universidad de Antioquia
city: Lima
country: Peru
facility: IMT Alexander Von Humboldt
Study officials:
affiliation: PECET, Universidad de Antioquia, Medellin, Colombia
name: Ivan Dario Velez, Prof
role: PRINCIPAL_INVESTIGATOR
affiliation: Universidad Peruana Cayetano Heredia, Lima, Peru
name: Alejandro Llanos-Cuentas, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Lopez L, Valencia B, Alvarez F, Ramos AP, Llanos-Cuentas A, Echevarria J, Velez I, Boni M, Rode J, Quintero J, Jimenez A, Tabares Y, Mendez C, Arana B. A phase II multicenter randomized study to evaluate the safety and efficacy of combining thermotherapy and a short course of miltefosine for the treatment of uncomplicated cutaneous leishmaniasis in the New World. PLoS Negl Trop Dis. 2022 Mar 7;16(3):e0010238. doi: 10.1371/journal.pntd.0010238. eCollection 2022 Mar.