Cutaneous Leishmaniases
Conditions
Brief summary
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.
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.
Interventions
DRUGMiltefosine
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
Sponsors
Alert Hospital, Ethiopia
Armauer Hansen Research Institute, Ethiopia
Uppsala University
The Netherlands Cancer Institute
Institute of Tropical Medicine, Belgium
Study design
Observational model
COHORT
Time perspective
PROSPECTIVE
Eligibility
Sex/Gender
ALL
Age
2 Years to No maximum
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Miltefosine plasma concentrations - Area under the plasma concentration versus time curve (AUC) | Day 0, Day 3, Day 7, Day 14, Day 21, Day 28, Day 42/Day 56, Day 90, Day 180 | 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. |
| MIltefosine plasma concentrations - Time of maximum concentration (Tmax) | Day 0, Day 3, Day 7, Day 14, Day 21, Day 28, Day 42/Day 56, Day 90, Day 180 | Determined by LC-MS/MS, stratified by whether patients received allometric dosing or not. |
| Miltefosine plasma concentrations - Maximum plasma concentration (Cmax) | Day 0, Day 3, Day 7, Day 14, Day 21, Day 28, Day 42/Day 56, Day 90, Day 180 | Determined by LC-MS/MS, stratified by whether patients received allometric dosing or not. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Adapted allometric dosing scheme specifically for children with CL | Day 0, Day 3, Day 7, Day 14, Day 21, Day 28, Day 42/Day 56, Day 90, Day 180 | 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. |
| Parasite kinetics in blood and skin | Day 0, Day 3, Day 7, Day 14, Day 21, Day 28, Day 42/Day 56, Day 90, Day 180 | To determine parasite kinetics in terms of Ct-values in blood and skin (microbiopsy sample) measured by quantitative PCR |
| Treatment outcomes of patients on miltefosine treatment | Day 28, day 90 and day 180 | Clinical cure rate determined by complete flattening, complete reepithelization and absence of erythema, crustation, and swelling |
| Assess safety of miltefosine | Day 28 | Side-effects: number and proportion of patients with adverse events |
Other
| Measure | Time frame | Description |
|---|---|---|
| To explore whether helminth infection in CL patients is related to treatment outcomes | Helminth infection at Day 0, outcome at Day 90/Day 180 | 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. |
| To explore whether nutritional status in CL patients is related to treatment outcomes | Nutritional status at Day 0, outcome at Day 90/Day 180 | Logistic regression models will be made with clinical cure/no cure as outcome, and nutritional status measured through Z-scores as predictor. |
| To explore skin tissue miltefosine concentrations | Day 28/Day 42/Day 56 | Measured by LC-MS/MS |
| To explore sequencing to detect intrinsic and acquired resistance markers for miltefosine | Day 0, Day 28/Day 42/Day 56, unscheduled visit | Whole genome sequencing will be done at AHRI to check for intrinsic (before treatment samples) and acquired resistance (relapse and end of treatment samples). |
| To explore optimization of outcome assessment using a 3D scanner | Day 28, Day 90, Day 180 | Machine learning models will be built to explore accuracy (% correctly predicted) of 3D scanning models to predict clinical outcomes. |
Countries
Ethiopia
Contacts
Primary ContactShimelis Nigusse, MD
Outcome results
None listed