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

A Multi-Arm, Multi-Stage Randomized Controlled Clinical Trial Evaluating Systemic Therapeutic Regimens for the Treatment of Cutaneous Leishmaniasis in Ethiopia

MAMS4CL comprises a clinical trial with three embedded sub-studies designed to comprehensively evaluate the administered treatments and assess the impact of CL treatment on patients and the healthcare system.

The multi-centre multi-arm multi-stage phase 3 clinical trial is designed to rigorously evaluate a total of 4 alternative treatment options for systemic CL against Sodium Stibugluconate (SSG) as the standard of care. The trial comprises two seamlessly linked stages. In stage 1, all four investigational arms will be evaluated against the control arm for efficacy to inform the selection of the arms, based on a pre-defined efficacy threshold that will advance to stage 2, in addition to the control arm. After stage 2, the experimental interventions will be compared with SSG similar to a standard superiority trial for efficacy. The general study design in stage 1 and stage 2 will be identical; only the number of investigational arms may differ.

Patients will be randomized into the respective treatment arms at the recruitment sites of Arba Minch hospital, Boru Meda hospital and ALERT hospital in Ethiopia. Individuals will be hospitalized during the entire course of their treatment. As different arms have different treatment duration, patient hospitalization period and visit schedules will differ between arms. In total, the study will last 180 days for each participant.

Study Overview

• Status: Not yet recruiting
• Conditions: Cutaneous Leihmaniasis
• Intervention / Treatment: Drug: Sodium Stibogluconate (SSG); Drug: Miltefosine; Drug: Miltefosine + Paromomycin; Drug: Liposomal Amphotericin B (LAmB); Drug: Pentamidine isethionate

• Study Type: Interventional
• Enrollment (Estimated): 900
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Bart Smekens; Phone Number: +3233455672; Email: bsmekens@itg.be
• Study Contact Backup: Name: Katrien Clinckx; Email: kclinckx@itg.be

Study Locations

• Ethiopia
  • Addis Ababa, Ethiopia
    • ALERT Hospital
    • Contact: Shimelis Doni Nigusse; Email: shimelis321@gmail.com
    • Principal Investigator: Shimelis Doni
  • Arba Minch, Ethiopia
    • Arba Minch General Hospital
    • Contact: Mehret Techane; Email: mehrettechane@gmail.com
    • Principal Investigator: Mehret Techane
  • Boru, Ethiopia
    • Boru Meda General Hospital
    • Contact: Wosen Ketema; Email: markwesaketema@gmail.com
    • Principal Investigator: Wosen Ketema

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Parasitological (microscopy, culture or PCR) confirmation of leishmaniasis
• Age ≥4 and ≤65 years old
• Need systemic treatment based on meeting at least one of the following criteria: >4 lesions/ At least one with lesion size >4cm/ Mucosal involvement, or at risk for mucosal involvement (<1 cm from the nose, eyes or vermillion border of the lips)/ Previous failure of lesion-directed treatment /Lesions on areas not suitable for lesion-directed therapy (e.g. joints, eyelids, fingers)/ Deep or extensive lesion(s) with risk of functional impairment
• Informed consent provided, as follows: For patients ≥18 years of age: Patient is willing and able to provide informed consent. / For patients aged 8 to 17 years (inclusive): Parent or caregiver is willing and able to provide informed consent, and patient is willing and able to provide assent / For patients aged 4 to 7 years (inclusive): Parent or caregiver is willing and able to provide informed consent.
• Willing and able to be hospitalized for the duration of treatment
• Willing and able to attend all follow-up visits
• If female and of child-bearing age: willing to take contraceptives during treatment and for 5 months after EoT (parenteral, intrauterine device (IUD) or implant). Note that actually taking the contraceptives is only required when randomized in an investigational arm containing miltefosine.

Exclusion Criteria:

• Pregnant (positive pregnancy test at screening) or breastfeeding
• Any known severe medical comorbidities, or signs and symptoms of severe disease, that in the opinion of the investigator disqualifies the patient of being enrolled in the trial or precludes evaluation of the patient's response to the study medication. Examples are: Severe known active infections such as tuberculosis, schistosomiasis, malaria, hepatitis B virus, active hepatitis C virus/ Serious underlying disease (e.g. cardiac, renal, hepatic (including diabetes mellitus) or chronic disease/ Immunocompromising conditions: transplant patients, or patients receiving immunosuppressant medication/ Pre-existing ocular conditions evaluated at baseline: e.g. keratitis, uveitis, scleritis/ Pre-existing sensorineural hearing loss evaluated at baseline, or previously diagnosed with ototoxicity
• HIV Infection
• Severe malnutrition: ≤5 years old: Mean upper arm circumference (MUAC) <115mm/ 6-10 years old: MUAC <135mm/ 11-17 years old: MUAC <160mm/ ≥ 18 years old: Body mass index (BMI) <16kg/m²
• (History of) ECG abnormalities: Clinically significant cardiac arrythmias: e.g. 2nd degree or 3rd degree AV block without pacemaker, sustained ventricular tachycardia/ Prolonged QTc interval >450ms
• Lab abnormalities: Haemoglobin <5.0g/dL/ Platelets <50 x 10^9/L/ White blood count <1 x 10^9/L / Alanine aminotransferase (AST) / aspartate aminotransferase (ALT) >3x upper limit of normal (ULN)/ Serum creatinine >1.5 x ULN/ Bilirubin >1.5 x ULN/ Fasting blood glucose (preferred) >7mmol/L (126mg/dl) or blood glucose >11.1 mmol/L (200mg/dl) at any time/ Potassium <3.5mmol/L
• Having received any allopathic treatment for CL lesion(s) in the past 6 months: cryotherapy, thermotherapy, SSG, meglumine antimoniate, paromomycin, pentamidine, liposomal amphotericin B, non-liposomal amphotericin B, miltefosine
• Diffuse cutaneous leishmaniasis (DCL)
• Patients on treatment with any of the prohibited medications, which are any treatments with the potential to influence lesion healing, skin condition, or participant safety. This includes any form of chemotherapy, antituberculosis medication, systemic antibiotics or antifungals, antivirals, corticosteroids and immunosuppressants. Topical antibiotics or antifungals are allowed as long as they are not applied on any of the CL lesions.
• Onset of lesions >24 months ago
• Known allergies or serious adverse reactions to one of the study components/medications
• Any other condition for which participation in the trial, as judged by the investigator, could compromise the well-being of the patient or prevent, limit or confound protocol-specified assessments

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Control arm; Standard of Care: Sodium Stibogluconate	Drug: Sodium Stibogluconate (SSG); Intramuscular Administration - once daily for 28 days
Active Comparator: Miltefosine Arm; Miltefosine	Drug: Miltefosine; Miltefosine - Oral Administration, daily for 28 days
Active Comparator: Miltefosine + Paromomycin Arm; Miltefosine + Paromomycin	Drug: Miltefosine + Paromomycin; Miltefosine - Oral Administration, daily for 28 days + Paromomycine - Intramuscular Administration, once daily for 14 days
Active Comparator: LamB Arm; Liposomal amphotericin B	Drug: Liposomal Amphotericin B (LAmB); Intravenous Administration, once daily on days 1, 3, 5, 7, 10, 12, 14, 17, 19, 21
Active Comparator: Pentamidine Arm; Pentamidine isethionate	Drug: Pentamidine isethionate; Intravenous Administration - once daily on days 1, 3, 5, 7, 9, 11, 13

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
For each of the investigational arms (miltefosine/miltefosine + paromomycin / liposomal amphotericin B/pentamidine isethionate), to determine whether it has superior efficacy to the control arm in terms of achieving cure of all lesions at Day 90	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)).	Day 90

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
For each investigational arm, to determine whether it has superior efficacy to the control arm, in terms of achieving cure of all lesions at Day 180.	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).	Day 180
To compare between the control arm and each of the investigational arms: proportion of participants with all lesions cured, cure for all lesions considered individually, the proportion of participants whose index lesion is cured.	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.	End of Treatment, Day 42, Day 90 and Day 180
To compare between the control arm and each of the investigational arms: proportion of participants that reach at least substantial improvement of all lesions and the index lesion + at least substantial improvement for all lesions individually,	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.	End of Treatment, Day 42, Day 90, Day 180
To compare between the control arm and each of the investigational arms, the proportion of participants with treatment failure at Day 42, Day 90, and Day 180.	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.	Day 42, Day 90, Day 180
To assess safety by describing safety & tolerability of each arm by listing number, proportion & severity of AEs/Comparing number, proportion & reason of withdrawals and number & proportion of patients with SAEs between control and investigational arm	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.	Day 180
To compare between control arm and each investigational arm, the change in patient-reported outcomes over time between treatment arms	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.	Day 1, Day 42, Day 90, Day 180

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
PK/PD outcome: To assess plasma and skin concentrations of SSG, miltefosine, paromomycin, LAmB, and pentamidine	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.	Day 14, Day 21 or Day 28 depending on treatment arm
PK/PD outcome: To characterize the PK profiles of SSG, miltefosine, paromomycin, LAmB, and pentamidine	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-∞).	from 24 hours post dose until Day 14, Day 21 or Day 28 depending treatment arm
PK/PD outcome: To evaluate the correlation between PK parameters and clinical outcome within the control arm and each investigational arm.	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	Day 90, Day 180
PK/PD Outcome: To evaluate Leishmania parasite clearance in the control arm and each investigational arm, as assessed by direct microscopy and/or quantitative PCR (qPCR).	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.	During treatment and at Day 14, Day 21 or Day 28 depending on treatment arm

Collaborators and Investigators

• Sponsor: Institute of Tropical Medicine, Belgium
• Collaborators: London School of Hygiene and Tropical Medicine; Uppsala University; University of Stellenbosch; Arba Minch University; Wollo University; Armauer Hansen Research Institute (AHRI), Ethiopia
• Investigators: Study Director: Johan Van Griensven, Institute of Tropical Medicine, Antwerp, Belgium

Study record dates

Study Major Dates

• Study Start (Estimated): January 1, 2027
• Primary Completion (Estimated): March 1, 2029
• Study Completion (Estimated): August 31, 2029

Study Registration Dates

• First Submitted: February 9, 2026
• First Submitted That Met QC Criteria: March 6, 2026
• First Posted (Actual): March 10, 2026

Study Record Updates

• Last Update Posted (Actual): March 10, 2026
• Last Update Submitted That Met QC Criteria: March 6, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Keywords: Paromomycin; Standard of care; Ethiopia; Pentamidine; Liposomal amphotericin B; Miltefosine; Sodium stibogluconate; Multi-Arm Multi-Stage; cutaneous Leishmaniasis
• Additional Relevant MeSH Terms: Vector Borne Diseases; Infections; Protozoan Infections; Parasitic Diseases; Skin Diseases; Skin Diseases, Infectious; Skin Diseases, Parasitic; Euglenozoa Infections; Skin and Connective Tissue Diseases; Leishmaniasis; Leishmaniasis, Cutaneous; Organic Chemicals; Carbohydrates; Sugar Acids; Acids, Acyclic; Carboxylic Acids; Hydroxy Acids; Glycosides; Aminoglycosides; Amidines; Gluconates; Benzamidines; Paromomycin; Antimony Sodium Gluconate; Pentamidine; miltefosine; liposomal amphotericin B
• Other Study ID Numbers: MAMS4CL

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No