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.
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.
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
Parallel
Sodium Stibogluconate (SSG)
DrugIntramuscular Administration - once daily for 28 days
Miltefosine
DrugMiltefosine - Oral Administration, daily for 28 days
Miltefosine + Paromomycin
DrugMiltefosine - Oral Administration, daily for 28 days + Paromomycine - Intramuscular Administration, once daily for 14 days
Liposomal Amphotericin B (LAmB)
DrugIntravenous Administration, once daily on days 1, 3, 5, 7, 10, 12, 14, 17, 19, 21
Pentamidine isethionate
DrugIntravenous Administration - once daily on days 1, 3, 5, 7, 9, 11, 13
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)).
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).
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. 1. Cure of all lesions (patient level) at EoT and D42, pairwise compared between each of the investigational arms and the control arm. 2. 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. 3. 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.
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. 1. 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. 2. 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. 3. 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.
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.
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.
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-∞).
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
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.
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Institute of Tropical Medicine, Belgium
Lead sponsor
London School of Hygiene and Tropical Medicine
Collaborator
Uppsala University
Collaborator
University of Stellenbosch
Collaborator
Armauer Hansen Research Institute, Ethiopia
Collaborator
Wollo University
Collaborator
Arba Minch University
Collaborator
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