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| Name | Class |
|---|---|
| Alert Hospital, Ethiopia | OTHER |
| Armauer Hansen Research Institute, Ethiopia | OTHER |
| Uppsala University | OTHER |
| The Netherlands Cancer Institute |
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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| 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 |
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| 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 |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Miltefosine | Drug | 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 |
| 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 |
| 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 |
| 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 |
Inclusion Criteria:
Exclusion Criteria:
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A total of 40 children on allometric dosing and 40 other patients will be enrolled in the study
| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Shimelis Nigusse, MD | Contact | 0911642060 | shimelis321@gmail.com |
| Name | Affiliation | Role |
|---|---|---|
| Saskia Van Henten | Institute of Tropical Medicine | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Africa Leprosy, Tuberculosis, Rehabilitation and Training (ALERT) Hospital | Recruiting | Addis Ababa | Ethiopia |
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| ID | Term |
|---|---|
| D016773 | Leishmaniasis, Cutaneous |
| ID | Term |
|---|---|
| D007896 | Leishmaniasis |
| D056986 | Euglenozoa Infections |
| D011528 | Protozoan Infections |
| D010272 | Parasitic Diseases |
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| ID | Term |
|---|---|
| C039128 | miltefosine |
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| OTHER |
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Dried blood spots for PK analysis Microbiopsy from skin for PCR analysis Routine Skin slit smear for genomic sequencing optional 2mm punch biopsy for PK analysis optional microbiopsy for PK analysis Serum sample for biobanking WB sample for biobanking
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 |
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 |
| D007239 |
| Infections |
| D012876 | Skin Diseases, Parasitic |
| D000079426 | Vector Borne Diseases |
| D012874 | Skin Diseases, Infectious |
| D012871 | Skin Diseases |
| D017437 | Skin and Connective Tissue Diseases |