Study Comparing Several Drugs to Understand Which Work Against Cutaneous Leishmaniasis (CL)

Cure of all lesions at Day 90, pairwise compared between the control arm and each of the investigational arms.

Cure at the lesion level is defined as 100% improvement of the area of erythema, induration, and ulceration of a lesion compared to the baseline assessment. Cure at the patient level is defined as cure of all lesions present at baseline, and no new lesions appearing. Cure is assessed at multiple timepoints, including Day 90.

Cure at Day 90 is defined as cure assessed at Day 90, or cure assessed at the latest available time point before Day 90, without relapse (known as last observation carried forward (LOCF)).

Cure of all lesions at Day 180, pairwise compared between the control arm and each of the investigational arms .

Cure at Day 180 is defined as cure assessed at Day 180, or cure assessed at the latest available timepoint before Day 180, without relapse (LOCF).

Cure at End of Treatment, Day 42, Day 90, and Day 180 at the patient and lesion level.

• Cure of all lesions (patient level) at EoT and D42, pairwise compared between each of the investigational arms and the control arm.
• Cure at End of Treatment, Day 42, Day 90, and Day 180, at the lesion level, adjusted for patient level, pairwise compared between each of the investigational arms and the control arm.
• Cure of the index lesion at End of Treatment, Day 42, Day 90, and Day 180, pairwise compared between each of the investigational arms and the control arm.

Substantial improvement at participants and lesion level at End of Treatment, Day 42, Day 90, and Day 180 is defined as ≥50%-99% improvement of the area of erythema, induration, and ulceration, compared to the baseline assessment.

Substantial improvement at a specific timepoint is defined as substantial improvement assessed at that timepoint, or at the latest available earlier timepoint.

At least substantial improvement is defined as substantial improvement or cure.

• At least substantial improvement of all lesions (patient level) at EoT, D42, D90, and D180, pairwise compared between each of the investigational arms and the control arm.
• At least substantial improvement at EoT, D42, D90, and D180 at the lesion level, adjusted for patient level, pairwise compared between each of the investigational arms and the control arm.
• At least substantial improvement of the index lesion at EoT, D42, D90, and D180, pairwise compared between each of the investigational arms and control arm.

Treatment failure at Day 42, Day 90, and Day 180. Treatment failure is defined as having the study treatment suspended for any reason as described in section 4.7.2, as having no improvement compared to baseline at Day 42, as having <50% improvement compared to baseline at Day 90, as having anything but all lesions cured at Day 180, or as having worsening of lesions or new lesions compared to the previous visit.

Assessment of safety by:

• Number and proportion, type, and severity of adverse events (both all and possibly, probably or definitely related to the study intervention) reported per study arm during the course of the study,.
• Permanent withdrawal from study intervention due to an adverse event that is possibly, probably or definitely related to the study intervention, including reason for withdrawal;
• Having at least one SAE that is possibly, probably or definitely related to the study intervention, between administration of the first dose of study medication and Day 180.

Assessment of patient-reported outcomes by:

• Dermatology Life Quality Index (DLQI) and Children's DLQI (cDLQI): measured at Day 1, Day 42, Day 90, and Day 180 as a discrete number that can be categorized. Change in patient reported outcome will be measured as the difference in score between the subsequent visits (Day 42, Day 90, and Day 180) and Day 1, and compared between arms.
• Cutaneous Leishmaniasis Impact Questionnaire : measured at Day 1, Day 42, Day 90, and Day 180 as a discrete number. Change in patient reported outcome will be measured as the difference in score between the subsequent visits (Day 90, Day 180) and Day 1, and compared between arms.
• Patient and Observer Scar Assessment Score measured at Day 42, Day 90, and Day 180 as a discrete number. Scores for each time point will be compared between arms.

Assessment of drug concentrations: Median (interquartile range) concentrations of sodium stibogluconate, miltefosine, paromomycin, liposomal amphotericin B, and pentamidine will be measured in plasma and skin at EoT, along with the corresponding skin-to-plasma concentration ratios.

Characterization of plasma exposure: Total and partial plasma exposure to sodium stibogluconate, miltefosine, paromomycin, liposomal amphotericin B, and pentamidine will be characterized by calculating the area under the concentration-time curve (AUC) over relevant intervals (e.g., AUC0-24h, AUC0-EOT, AUC0-∞).

Correlation between plasma drug exposure and clinical outcomes. Plasma exposure to will be measured using the area under the plasma concentration-time curve (AUC₀-24h, AUC₀-EOT, AUC₀-∞) derived from pharmacokinetic plasma concentration measurements. Clinical outcomes will be assessed by investigator evaluation of lesion healing and categorized as cure of all lesions, substantial improvement of all lesions, or treatment failure at Day 90 and/or Day 180. Correlation between AUC values and clinical outcome categories will be evaluated within each treatment arm

Parasite reduction: Percentage reduction in parasite load from baseline will be assessed in skin lesion samples collected during treatment and at EoT, by direct microscopy and/or qPCR. Pairwise comparisons will be made between each investigational arm and the control arm.