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

Phase 3Not Yet RecruitingNCT07463040

Institute of Tropical Medicine, Belgium900 enrolled

Overview

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 Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

SINGLE

Enrollment

900

Conditions

Cutaneous Leihmaniasis

Eligibility

Sex: ALLMin age: 4 YearsMax age: 65 Years

Medical Language ↔ Plain English

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

Outcomes

Primary Outcomes

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)).

Time frame: Day 90

Secondary Outcomes

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).

Time frame: 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. 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.

Time frame: 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. 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.

Time frame: 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.

Time frame: 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: 1. 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,. 2. 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; 3. 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.

Time frame: 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: 1. 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. 2. 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. 3. 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.

Time frame: Day 1, Day 42, Day 90, Day 180