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| Name | Class |
|---|---|
| London School of Hygiene and Tropical Medicine | OTHER |
| Uppsala University | OTHER |
| University of Stellenbosch | OTHER |
| Armauer Hansen Research Institute, Ethiopia |
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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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Control arm | Active Comparator | Standard of Care: Sodium Stibogluconate |
|
| Miltefosine Arm | Active Comparator | Miltefosine |
|
| Miltefosine + Paromomycin Arm | Active Comparator | Miltefosine + Paromomycin |
|
| LamB Arm | Active Comparator | Liposomal amphotericin B |
|
| Pentamidine Arm | Active Comparator | Pentamidine isethionate |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Sodium Stibogluconate (SSG) | Drug | Intramuscular Administration - once daily for 28 days |
| |
| 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 |
| 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). |
| 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 |
Inclusion Criteria:
Exclusion Criteria:
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Bart Smekens | Contact | +3233455672 | bsmekens@itg.be | |
| Katrien Clinckx | Contact | kclinckx@itg.be |
| Name | Affiliation | Role |
|---|---|---|
| Johan Van Griensven | Institute of Tropical Medicine, Antwerp, Belgium | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| ALERT Hospital | Addis Ababa | Ethiopia |
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| OTHER |
| Wollo University | OTHER |
| Arba Minch University | OTHER |
Multi-Arm Multi-stage
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| Miltefosine |
| Drug |
Miltefosine - Oral Administration, daily for 28 days |
|
| Miltefosine + Paromomycin | Drug | Miltefosine - Oral Administration, daily for 28 days + Paromomycine - Intramuscular Administration, once daily for 14 days |
|
| Liposomal Amphotericin B (LAmB) | Drug | Intravenous Administration, once daily on days 1, 3, 5, 7, 10, 12, 14, 17, 19, 21 |
|
| Pentamidine isethionate | Drug | Intravenous Administration - once daily on days 1, 3, 5, 7, 9, 11, 13 |
|
| 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.
| 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.
| 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:
| 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:
| Day 1, Day 42, Day 90, Day 180 |
| 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 |
| Arba Minch General Hospital | Arba Minch | Ethiopia |
|
| Boru Meda General Hospital | Boru | Ethiopia |
|
| ID | Term |
|---|---|
| D016773 | Leishmaniasis, Cutaneous |
| ID | Term |
|---|---|
| D007896 | Leishmaniasis |
| D056986 | Euglenozoa Infections |
| D011528 | Protozoan Infections |
| D010272 | Parasitic Diseases |
| D007239 | Infections |
| D012876 | Skin Diseases, Parasitic |
| D000079426 | Vector Borne Diseases |
| D012874 | Skin Diseases, Infectious |
| D012871 | Skin Diseases |
| D017437 | Skin and Connective Tissue Diseases |
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| ID | Term |
|---|---|
| D000967 | Antimony Sodium Gluconate |
| C039128 | miltefosine |
| D010303 | Paromomycin |
| C068538 | liposomal amphotericin B |
| D010419 | Pentamidine |
| ID | Term |
|---|---|
| D009930 | Organic Chemicals |
| D005942 | Gluconates |
| D013400 | Sugar Acids |
| D000144 | Acids, Acyclic |
| D002264 | Carboxylic Acids |
| D006880 | Hydroxy Acids |
| D002241 | Carbohydrates |
| D000617 | Aminoglycosides |
| D006027 | Glycosides |
| D001550 | Benzamidines |
| D000578 | Amidines |
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