Combination, Miltefosine Monotherapy & Antimonial Therapy for Cutaneous Leishmaniasis in New World

• ClinicalTrials.gov Identifier: NCT04515186
• Recruitment Status: Recruiting
• First Posted: August 17, 2020
• Last Update Posted: October 28, 2021
• Sponsor: Drugs for Neglected Diseases
• Information provided by (Responsible Party): Drugs for Neglected Diseases

Study Description

Brief Summary:

This study evaluates if the combination of thermotherapy (one application, 50⁰C for 30") and 3 weeks of miltefosine is safe and have a comparable cure rate with the current recommended first line treatments comprising meglumine antimoniate for 3 weeks or miltefosine monotherapy for 4 weeks, for the treatment of uncomplicated cutaneous leishmaniasis cases in the New World.

Condition or disease	Intervention/treatment	Phase
Cutaneous Leishmaniases	Drug: Meglumine Antimoniate; Drug: Miltefosine; Device: Thermotherapy machine	Phase 3

Detailed Description:

This randomized, open label, multi-centre, non-inferiority study aims to compare that the combination of thermotherapy (one application, 50⁰C for 30") and 3 weeks of miltefosine (2.5 mg/kg/day for 21 days orally) (here after referred to as combination), is non-inferior to the current recommended first line treatments, meglumine antimoniate (20 mg/kg/day for 20 days parenterally) or miltefosine monotherapy (2.5 mg/kg/day for 28 days orally), for uncomplicated CL cases in the New World.

Primary Objective

• To determine the non-inferior efficacy of the combination in comparison to the standard first line treatment (meglumine antimoniate) and/or to miltefosine monotherapy as measured by the percentage of patients with initial clinical cure at Day 90.

Secondary objectives

• Assess the proportion of patients who show clinical improvement at D90 (have more or equal of 75% and less than 100% re-epithelization) and achieve 100% re-epithelization at D105 (late responders).
• Assess the proportion of relapses at D180.
• Assess the safety and tolerability profile for each regimen (percentage of treatment discontinuation, frequency and severity, causality with each study drug and seriousness of Adverse Events (AEs)).
• Assess the time to achieve 100% re-epithelialization/ flattening of ulcerated/ non ulcerated lesions by Leishmania species.

A computer-generated randomization code will be used for patient treatment allocation to one of the three arms indicated and utilizing a 1:1:1 allocation ratio.

Patients assigned to the combination treatment will start treatment at Day 1 and have a follow-up visit on 24 hours to assess safety of thermotherapy. Hereafter, these patients are required to return at Days 7, 14, 21, 45, 63, 90, 105 (late responders only) and 180 after the beginning of treatment to assess safety and efficacy.In Brazil, women of childbearing potential are required to also return on D120 and D150 to perform blood pregnancy tests. Women with irregular menstrual cycle, should return for blood pregnancy tests every two weeks until D150.

Patients assigned to the meglumine antimoniate treatment are required to come at Days 1, 7, 14, 21, 45, 63, 90, 105 (late responders only) and 180 after the beginning of treatment to assess safety and efficacy.

Patients assigned to the miltefosine monotherapy are required to come at Days 1, 7, 14, 21, 28, 45, 63, 90, 105 (late responders only) and 180 after the beginning of treatment to assess safety and efficacy. In Brazil, women of childbearing potential are required to also return on D120 and D150 to perform blood pregnancy tests. Women with irregular menstrual cycle, should return for blood pregnancy tests every two weeks until D150.

Patients who have 100% re-epithelization at D90 are declared cured and appointed to come to their D180 assessment. If at D90 re-epithelization of the ulcer(s) is more or equal to 75% but less than 100%, patients will be defined as having clinical improvement and will be asked to return to D105 for a late responder assessment.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 306 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Efficacy and Safety of Thermotherapy in Combination With Miltefosine Compared to Meglumine Antimoniate and Miltefosine Monotherapy for the Treatment of New World Cutaneous Leishmaniasis: A Phase III, Open Label, Multicenter Randomized Trial
• Actual Study Start Date: January 26, 2021
• Estimated Primary Completion Date: June 30, 2022
• Estimated Study Completion Date: March 30, 2023

Arms and Interventions

Arm	Intervention/treatment
Active Comparator: Meglumine Antimoniate; Meglumine Antimoniate, 20 mg/kg/day for 20 days parenterally	Drug: Meglumine Antimoniate; Vials of a 5mL solution. Each vial contains 405 mg of Sb5+ corresponding to 8.1% Sb5+ (81 mg/mL).; Other Name: Glucantime®
Active Comparator: Miltefosine monotherapy; Miltefosine monotherapy 2.5 mg/kg/day for 28 days orally	Drug: Miltefosine; 50 mg capsule; Other Name: Impavido®
Experimental: Thermotherapy + miltefosine; Thermotherapy (one session, 50⁰C for 30" applications*) + miltefosine 2.5 mg/kg/day for 21 days orally.	Drug: Miltefosine; 50 mg capsule; Other Name: Impavido®; Device: Thermotherapy machine; Localized Current Field radio-frequency generating device; Other Name: ThermoMed™

Outcome Measures

Primary Outcome Measures :

1. The proportion of initial clinical cure in each arm. [ Time Frame: Day 90 ]
   Defined for ulcerated lesions as 100% re-epithelialization of the ulcer(s) on D90 as compared to D1 and for non-ulcerated lesions as flattening and/or no signs of induration of the lesion(s) on D90 as compared to D1.

Secondary Outcome Measures :

1. The number of patients who fulfil the criteria for clinical improvement at D90 and late responders at D105. [ Time Frame: Days 90 and 105 ]

   Clinical improvement is defined for ulcerated lesions as more than or equal to 75% but less than 100% re-epithelization of the ulcer(s) as compared to D1, and for non-ulcerated lesions as more than or equal to 75% but less than 100% of flattening and/ or signs of induration of the lesion(s) as compared to D1.

   Late responders isdefined for ulcerated lesions as 100% re-epithelialization of the ulcer(s) on D105 compared to D1, and for non-ulcerated lesions as 100% of flattening and/or no signs of induration of the lesion(s) on D105 as compared to D1.

2. The number of patients who fulfil the criteria of initial cure at D90 or late responders at D105 and have no relapse by D180 (final cure). [ Time Frame: Day 180 ]
3. Percentage of treatment discontinuation, frequency, severity, causality with each study drug and seriousness of AEs by treatment group. [ Time Frame: Through study completion, i.e up to 6 months ]
4. Proportion of lesions with 100% re-epithelialization/flattening at each measurement time point by Leishmania sp. [ Time Frame: Days 7, 14 and 21. At end of treatment (days 21 or 28), and at days 45, 63, 90, 105 and 180. ]

Eligibility Criteria

• Ages Eligible for Study: 12 Years to 60 Years (Child, Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Males and females, aged ≥12 and ≤60 years old (upper age limit according to local regulations), and weighing ≥ 30Kg.
• 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 Polymerase Chain Reaction (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, or on a location that in the opinion of the Principal Investigator (PI) is difficult to apply the TT.
  • Patient with ≤ 4 CL lesions.
  • Duration of lesion less than 4 months by patient history.
• Patient able to give written informed consent/ assent form.
• In the opinion of the investigator, the patient is capable of understanding and complying with the protocol.

Exclusion Criteria:

• Female with a positive urine or blood pregnancy test at screening or who is breast feeding or female at fertile age who does not agree to take appropriate effective contraception during treatment period and up to D180 visit. In Brazil: female at fertile age who does not agree to use two effective methods of contraception: one barrier method and one highly effective method (defined in section 8.2.4) 30 days prior to the treatment onset and up to D180 visit.
• History of clinically significant medical problems / treatment that might interact, either negatively or positively, with treatment of cutaneous leishmaniasis including any immunocompromising condition.
• Within 8 weeks (56 days) of Day 1, received treatment for the entry lesion 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.
• Electrocardiogram (ECG) at screening: QTc above 400msec for men and 450msec for women.

• Has laboratory values at screening as follows:

  • Serum amylase and lipase: 2 times above upper normal level*,
  • Serum creatinine: above upper normal level*.

  • Alanine aminotransferase (ALT) or Aspartate aminotransferase (AST): 3 times above upper normal level*.

    • Normal ranges obtained from local laboratory.
• Patient who is not willing to attend the study visits or is not able to comply with follow-up visits up to 6 months.
• Known history of addiction/ alcohol abuse.
• Hypersensitivity to miltefosine or antimonial drugs or any study medication excipients.
• Patients with Sjogren-Larson Syndrome.

Contacts and Locations

Contacts

Contact: Byron Arana; +41229069258; barana@dndi.org

Contact: Joelle Rode; +552125290402; jrode@dndi.org

Locations

Bolivia

Fundación Nacional de Dermatología; Not yet recruiting

Santa Cruz de la Sierra, Bolivia

Contact: Jaime Soto

Brazil

Julio Muller University Hospital Federal University of Mato Grosso; Recruiting

Cuiaba, Brazil

Contact: Marcia Hueb

Federal University of Bahia Immunology Department; Recruiting

Salvador, Brazil

Contact: Paulo Machado

Panama

Instituto Conmemorativo Gorgas de Estudios de la Salud; Recruiting

Panama, Panama

Contact: Juan Miguel Pascale

Peru

Universidad Peruana Cayetano Heredia; Recruiting

Lima, Peru

Contact: Alejandro Llanos-Cuentas

Sponsors and Collaborators

Drugs for Neglected Diseases

Investigators

• Principal Investigator: Paulo Machado; Federal University of Bahia
• Principal Investigator: Marcia Hueb; Julio Muller University Hospital Federal University of Mato Grosso
• Principal Investigator: Alejandro Llanos-Cuentas; Universidad Peruana Cayetano Heredia
• Principal Investigator: Juan Miguel Pascale; Instituto Conmemorativo Gorgas de Estudios de la Salud
• Principal Investigator: Jaime Soto; Fundación Nacional de Dermatología

More Information

• Responsible Party: Drugs for Neglected Diseases
• ClinicalTrials.gov Identifier: NCT04515186
• Other Study ID Numbers: DNDi-MILT-08-CL
• First Posted: August 17, 2020
• Last Update Posted: October 28, 2021
• Last Verified: October 2021

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: Yes
• Product Manufactured in and Exported from the U.S.: Yes

Additional relevant MeSH terms:

Leishmaniasis; Leishmaniasis, Cutaneous; Euglenozoa Infections; Protozoan Infections; Parasitic Diseases; Infections; Skin Diseases, Parasitic; Vector Borne Diseases; Skin Diseases, Infectious; Skin Diseases; Miltefosine; Meglumine Antimoniate; Antifungal Agents; Anti-Infective Agents; Antineoplastic Agents; Antiprotozoal Agents; Antiparasitic Agents