Antimicrobial Adjuvants to Revert the Imbalance of Skin Microbiota for Improved Outcomes of Complicated Cutaneous Leishmaniasis Treatment in Ethiopia

Phase 3Not Yet RecruitingNCT06695143

Institute of Tropical Medicine, Belgium180 enrolled

Overview

This clinical trial aims to evaluate the effectiveness of combining the standard treatment for complicated cutaneous leishmaniasis (CL), sodium stibogluconate (SSG), with either topical fusidic acid 2% cream or a vehicle cream without active ingredient. The goal is to assess whether this combination improves treatment outcomes by restoring the balance of the skin microbiome (dysbiosis) in patients with severe CL, a condition common in Ethiopia. The study will compare three treatment groups: * Fusidic Acid Group: SSG plus topical fusidic acid for 2 weeks. * Vehicle Cream Group: SSG plus topical vehicle cream for 2 weeks. * Control Group: SSG only, with no topical treatment. The primary objective is to determine if the addition of fusidic acid improves treatment outcomes compared to SSG alone, as measured by substantial improvement in the index lesion at the end of treatment (EoT). A total of 180 patients will be enrolled at two hospitals in Ethiopia. The trial will run for 24 months, with a focus on understanding how restoring the skin microbiome can improve CL treatment outcomes and potentially provide a low-cost, accessible treatment strategy for CL patients.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

180

Conditions

Leishmaniasis, Cutaneous

Interventions

Eligibility

Sex: ALLMin age: 4 Years

Medical Language ↔ Plain English

Clinically suspected complicated CL patients visiting the study site meeting the following inclusion criteria and none of the exclusion criteria: Inclusion: * Clinical diagnosis of CL * Need for systemic treatment (1 or more of these criteria) * Mucosal involvement of lesion or at risk for mucosal involvement (\< 1 cm from the nose, eyes and vermillion border of the lips) * Lesion size \>4 cm * \>4 lesions * Lesions on joints or fingers * Lesions previously not responding to local treatment * Lesions unsuitable for local treatment (e.g., eyelids) * Lesions with signs of dissemination (satellite lesions, nodular lymphangitis, sporotrichoid pattern) * Age \> 4 (minimum age to receive systemic treatment with SSG) * At least one lesion eligible for treatment\* (meeting all criteria below) * lesion with surface change, including ulcerated, crusted and scaly lesions * distinguishable from other lesions (minimum 0.5 cm apart) * no mucosal involvement against which a topical agent would likely not be effective (e.g., lesions that are located too deep within the nasal passages or on the inner lip, where proper application is challenging and the ointment may be easily removed or not adequately absorbed) * Willing and able to provide informed consent. For participants under the age of 18, parental or caregiver consent is required. Additionally, assent must be obtained from adolescents aged 12 to 17 * Willing to be hospitalized for 4 weeks Exclusion: * DCL patients * Only lesions not eligible for treatment\* * Currently on treatment or having received non-traditional antileishmanial treatment (cryotherapy, thermotherapy, sodium stibogluconate, meglumine antimoniate, paromomycin, pentamidine, AmBisome, miltefosine, non-liposomal amphotericin B) in the past 1 month * Currently on or having received topical antibiotic treatment for CL lesion(s) in the past 1 month * Currently on or having received systemic antibiotic treatment in general in the past 1 month * Currently in need for systemic antibiotics * Pregnant (positive pregnancy test at D0) or breastfeeding * Abnormal lab values * Hemoglobin \< 5.0g/100mL * Platelets \< 50 x 10\^9/L * White blood count \< 1 x 10\^9/L * ASAT/ALAT \> 3x upper normal range * Creatinine above the normal limit * Prolonged QTc interval or arrythmia on ECG or history of arrythmias * Known serious kidney or liver disease * Known allergies to one of the study components/medications * Serious adverse reaction to a previous SSG dose \*If a patient has multiple lesions, of which some are eligible for treatment and others are not, the patient can still be involved in the study. Only the eligible lesions will be subjected to treatment and outcome assessment.

Outcomes

Primary Outcomes

Improvement of index lesion at EoT

To assess if 4 weeks SoC with 2 weeks application of 2% fusidic acid twice per day (Arm 1, Treatment) is superior to 4 weeks SoC only (Arm 3, Control) for complicated CL patients, in terms of reaching at least substantial improvement\* of the index lesion\*\* at the end of treatment (EoT). \*Substantial improvement is defined as \>50% flattening and \>50% re-epithelization compared to the baseline assessment. Improvement will be measured for each lesion. At least the index lesion needs to be improved or cured for a patient to be considered substantially improved. \*\*Index lesion is defined as the largest lesion eligible for treatment.

Time frame: 28 days

Secondary Outcomes

Arm 1 superiority to arm 3 - index lesion

To assess if Arm 1 is superior to Arm 3, using an ordinal (no improvement, minor improvement, substantial improvement, cure, relapse) and continuous (% re-epithelization/flattening) outcome measures for the index lesion at EoT and D42

Time frame: 42 days

Arm 1 superiority to arm 3 - lesions eligible for treatment

To assess if Arm 1 is superior to Arm 3, using binary (at least substantial improvement), ordinal (no improvement, minor improvement, substantial improvement, cure, relapse) and continuous (% re-epithelization/flattening) outcome measures for all lesions eligible for treatment individually and combined at EoT and D42

Time frame: 42 days

Proportion of participants that reach substiantial improvement - arm 1 vs arm 2

To compare the proportion of patients that reach at least substantial improvement of the index lesion, all lesions combined and individually at EoT and D42 between patients who received SoC with topical 2% fusidic acid (Arm 1, Treatment), and those who received SoC combined with topical vehicle cream (Arm 2, Vehicle)

Time frame: 42 days

Proportion of participants that reach substiantial improvement - arm 2 vs arm 3

To compare the proportion of patients that reach at least substantial improvement of the index lesion, all lesions combined and individually at EoT and D42 between patients who received SoC combined with topical vehicle cream (Arm 2, Vehicle), and those who received SoC only (Arm 3, Control)

Time frame: 42 days

Cycles needed for final cure

To compare the number of cycles needed to reach final cure per treatment arm

Time frame: 180 days

Proportion of cured patients at day 180

To determine the proportion with 95% CI of patients that reach cure without relapsed or worsening at day 180 for the three treatment arms

Time frame: 180 days

Quality of life - patient reported outcome

To compare change over time of patient-reported outcomes - the dermatological life quality index (DLQI) scores and global assessment - per treatment arm

Time frame: 180 days

Safety and acceptability

To assess safety and acceptability of treatment arms a) Withdrawal from study intervention: proportion and 95% CI of patients withdrawn from intervention, per arm b) Adverse events: number and proportion of patients with adverse events, per arm c) Cumulative incidence of adverse events (AEs) related to the study drug d) Recommendability: acceptability and recommendability score (0-10) given by patients after treatment completion, per arm

Time frame: 180 days

Stability microbial diversity

To determine the stability of microbial diversity in the healthy skin over time

Time frame: 180 days

Increase microbial diversity

To assess the increase in microbial diversity indices within each trial arm at D14, EoT, D42 and M6 compared to D0.

Time frame: 180 days

Correlation microbial diversity and substantial improvement

To determine whether increase in microbial diversity at EoT compared to D0 is correlated with substantial improvement of the index lesion and all lesions combined at EoT for the three trial arms

Time frame: 180 days

Correlation microbial diversity and cure without relapse

To determine whether increase in microbial diversity at M6 compared to D0 is correlated with cure without relapse at M6, for the three trial arms

Time frame: 180 days

Antimicrobial Adjuvants to Revert the Imbalance of Skin Microbiota for Improved Outcomes of Complicated Cutaneous Leishmaniasis Treatment in Ethiopia

Overview

Conditions

Interventions

Eligibility

Locations (2)

Outcomes

Primary Outcomes

Secondary Outcomes

Central Contacts