OPTImizing MIltefosine Treatment for Cutaneous LEISHmaniasis Patients (OPTIMILEISH)

While there are indications that 28 days of miltefosine is not sufficient for treating CL by L. aethiopica, a better understanding of what happens in terms of parasite clearance and drug dosing is lacking. In this study, longitudinal measurements of parasite and drug concentrations during treatment are done to monitor parasite kinetics as well as pharmacokinetics. This data will be crucial to provide more information on duration and dosing of miltefosine in CL patients globally, and in Ethiopia and pediatric patients in particular.

Study Overview

• Status: Recruiting
• Conditions: Cutaneous Leishmaniases
• Intervention / Treatment: Drug: Miltefosine

Detailed Description

In this project, parasite dynamics and miltefosine pharmacokinetics in the skin and blood during routine durations of miltefosine treatment (4-8 weeks) are studied with the aim to provide evidence to optimize miltefosine dosing for treatment of CL. By also studying these factors in children who get allometric miltefosine dosing, data which can be used to adapt the current allometric dosing scheme specifically to children with CL will be produced. Exploratory objectives will look into searching for more objective outcome assessment measures, resistance, helminth infection and nutritional status as potential factors affecting treatment response.

• Study Type: Observational
• Enrollment (Estimated): 80

Contacts and Locations

• Study Contact: Name: Shimelis Nigusse, MD; Phone Number: 0911642060; Email: shimelis321@gmail.com

Study Locations

• Ethiopia
  • Addis Abeba, Ethiopia
    • Recruiting
    • Africa Leprosy, Tuberculosis, Rehabilitation and Training (ALERT) Hospital
    • Contact: Shimelis Negusse, MD; Phone Number: +251 09 11642060; Email: shimelis321@gmail.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: N/A

• Sampling Method: Non-Probability Sample

Study Population

A total of 40 children on allometric dosing and 40 other patients will be enrolled in the study

Description

Inclusion Criteria:

• Clinical or parasitological (microscopy or PCR) confirmation of leishmaniasis
• Age >2
• Clinical decision to start miltefosine treatment as systemic treatment
• In case of females of child-bearing age: willing to take contraceptive for 6 months (parenteral or IUD or implant)
• Willing and able to provide informed consent
• Willing to be hospitalized for the duration of treatment

Exclusion Criteria:

• Currently on treatment or having received modern treatment for leishmaniasis in the last 3 months
• Pregnant (pregnancy test at D0) or breastfeeding
• Unlikely to come for follow-up visits
• Abnormal lab values Hemoglobin <5.0g/100mL Platelets <50 x 10^9/L White blood count <1 x 10^9/L ASAT/ALAT >3x upper normal range Creatinine above the normal limit

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Non-allometric dosing; 40 patients who will not use allometric dosing will be included miltefosine will be given based on weight: 30-45 kg: 100mg miltefosine per day >45 kg: 150mg miltefosine per day	Drug: Miltefosine; Miltefosine will be prescribed by the treating physician for a minimum of 4 weeks. If treatment response is not sufficient, treatment extension could be decided by the treating physician up to 8 weeks
allometric dosing (weight below 30 kg); 40 patients who weigh less than 30kg and therefore get allometric dosing will be recruited. Dosing is given based on weight, height, and sex, according to Dorlo et al 2012	Drug: Miltefosine; Miltefosine will be prescribed by the treating physician for a minimum of 4 weeks. If treatment response is not sufficient, treatment extension could be decided by the treating physician up to 8 weeks

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Miltefosine plasma concentrations - Area under the plasma concentration versus time curve (AUC)	Determined by LC-MS/MS, miltefosine pharmacokinetics are assessed through calculation of the area under the plasma concentration-time curve from start of treatment until end of treatment (AUC0-EoT), stratified by whether patients received allometric dosing or not.	Day 0, Day 3, Day 7, Day 14, Day 21, Day 28, Day 42/Day 56, Day 90, Day 180
Miltefosine plasma concentrations - Maximum plasma concentration (Cmax)	Determined by LC-MS/MS, stratified by whether patients received allometric dosing or not.	Day 0, Day 3, Day 7, Day 14, Day 21, Day 28, Day 42/Day 56, Day 90, Day 180
MIltefosine plasma concentrations - Time of maximum concentration (Tmax)	Determined by LC-MS/MS, stratified by whether patients received allometric dosing or not.	Day 0, Day 3, Day 7, Day 14, Day 21, Day 28, Day 42/Day 56, Day 90, Day 180

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Parasite kinetics in blood and skin	To determine parasite kinetics in terms of Ct-values in blood and skin (microbiopsy sample) measured by quantitative PCR	Day 0, Day 3, Day 7, Day 14, Day 21, Day 28, Day 42/Day 56, Day 90, Day 180
Adapted allometric dosing scheme specifically for children with CL	Population PK and PK-PD analysis of the relationship between miltefosine exposure and parasite kinetics will be done at UU, based on results from miltefosine plasma concentrations. Structural pharmacokinetic modelling will be used to develop and simulate alternative dosing schemes for children with CL, using Monte Carlo simulations.	Day 0, Day 3, Day 7, Day 14, Day 21, Day 28, Day 42/Day 56, Day 90, Day 180
Treatment outcomes of patients on miltefosine treatment	Clinical cure rate determined by complete flattening, complete reepithelization and absence of erythema, crustation, and swelling	Day 28, day 90 and day 180
Assess safety of miltefosine	Side-effects: number and proportion of patients with adverse events	Day 28

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
To explore optimization of outcome assessment using a 3D scanner	Machine learning models will be built to explore accuracy (% correctly predicted) of 3D scanning models to predict clinical outcomes.	Day 28, Day 90, Day 180
To explore whether nutritional status in CL patients is related to treatment outcomes	Logistic regression models will be made with clinical cure/no cure as outcome, and nutritional status measured through Z-scores as predictor.	Nutritional status at Day 0, outcome at Day 90/Day 180
To explore whether helminth infection in CL patients is related to treatment outcomes	Logistic regression models will be made with clinical cure/no cure as outcome, and helminth infection (determined as present/not present by wet mount stool exam) as predictor.	Helminth infection at Day 0, outcome at Day 90/Day 180
To explore sequencing to detect intrinsic and acquired resistance markers for miltefosine	Whole genome sequencing will be done at AHRI to check for intrinsic (before treatment samples) and acquired resistance (relapse and end of treatment samples).	Day 0, Day 28/Day 42/Day 56, unscheduled visit
To explore skin tissue miltefosine concentrations	Measured by LC-MS/MS	Day 28/Day 42/Day 56

Collaborators and Investigators

• Sponsor: Institute of Tropical Medicine, Belgium
• Collaborators: Uppsala University; The Netherlands Cancer Institute; Armauer Hansen Research Institute, Ethiopia; Alert Hospital, Ethiopia
• Investigators: Principal Investigator: Saskia Van Henten, Institute of Tropical Medicine

Study record dates

Study Major Dates

• Study Start (Actual): June 18, 2024
• Primary Completion (Estimated): December 30, 2025
• Study Completion (Estimated): December 30, 2026

Study Registration Dates

• First Submitted: June 20, 2024
• First Submitted That Met QC Criteria: July 16, 2024
• First Posted (Actual): July 23, 2024

Study Record Updates

• Last Update Posted (Actual): July 23, 2024
• Last Update Submitted That Met QC Criteria: July 16, 2024
• Last Verified: July 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Skin Diseases; Infections; Vector Borne Diseases; Parasitic Diseases; Protozoan Infections; Skin Diseases, Parasitic; Skin Diseases, Infectious; Euglenozoa Infections; Leishmaniasis; Leishmaniasis, Cutaneous; Anti-Infective Agents; Antineoplastic Agents; Antifungal Agents; Antiprotozoal Agents; Antiparasitic Agents; Miltefosine
• Other Study ID Numbers: 1708/23

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No