Short Course Regimens for Treatment of PKDL (Sudan)

Study Overview
=================
Brief Summary
-----------------
This is an open label, randomized non comparative phase II clinical trial conducted on parallel groups, to assess the safety and efficacy of the combination of Paromomycin (20 mg/kg/d) IM for 14 days and Miltefosine (allometric dosing) oral for 42 days, and a combination of AmBisome® (20 mg/kg total dose) IV over 7 days and Miltefosine oral for 28 days (allometric dosing) for the treatment of PKDL patients in Sudan.

Official Title
-----------------
An Open Label, Randomized, Parallel Arm Clinical Trial of Two Regimens to Assess the Safety and Efficacy for Treatment of Post Kala-azar Dermal Leishmaniasis (PKDL) Patients in Sudan

Conditions
-----------------
PKDL - Post-Kala-Azar Dermal Leishmanioid

Intervention / Treatment
-----------------
* Drug: Paromomycin
* Drug: Ambisome
* Drug: Miltefosine


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Confirmed PKDL case by clinical presentation and demonstration of parasites by microscopy in a skin smear or by PCR, with documented stable or progressive disease for at least 6 months or grade 3 PKDL Male or Female patients aged 6 to 60 years Written voluntarily informed consent is obtained from the patient, or his guardian if the patient is < 18 years old. In the case of minors aged >12 to <18, assent from the children is also needed in addition to the guardian's consent. Exclusion Criteria: Patients who had prior treatment of PKDL within the last 1 year Pregnant and lactating women and women of childbearing age (12 to 55 years) who do not accept to have a pregnancy test and who do not agree to use contraception during treatment period and for 5 months after the end of treatment. Patients with signs and symptoms of severe diseases: defined as suffering from a concomitant severe infection such as TB or any other serious known underlying disease (cardiac, renal, hepatic), Severe malnutrition defined by BMI for age WHO reference curves for gender, Z score < -3 for subjects 6 to < 19 years; BMI < 16 for subjects > 19 years old Patients with haemoglobin < 5g/dL Patients with known skin disease Patients with abnormal liver function (ALT and AST) tests of more than three times the normal range. Patients with total bilirubin levels >1.5 times the upper normal range Patients with serum creatinine above the upper limit of normal range Patients with serum potassium < 3.5 mmol/L Patients with pre-existing clinical hearing loss based on audiometry at baseline Patients with a positive HIV test as applicable Patients / guardian not willing to participate Patients with history of allergy or hypersensitivity to the relevant study drug Patients on immunomodulators therapy

Ages Eligible for Study
-----------------
Minimum Age: 6 Years
Maximum Age: 60 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm 1: Paromomycin + Miltefosine<br>Paromomycin 20 mg/kg/d IM for 14 days combined with Miltefosine allometric BID PO dosing for 42 days | Drug: Paromomycin<br>* Paromomycin (20 mg/kg/d) IM for 14 days<br>Drug: Miltefosine<br>* Miltefosine oral (allometric dosing) for 42 days (arm 1) or 28 days (arm 2)<br>* Other names: Impavido;|
| Experimental: Arm 2: Ambisome + Miltefosine<br>AmBisome® 5mg/kg/d IV infusion at D1, D3, D5 and D7 (20 mg/kg total dose) combined with Miltefosine allometric BID PO dosing for 28 days | Drug: Ambisome<br>* AmBisome® (20 mg/kg total dose) IV over 7 days<br>* Other names: Liposomal Amphotericin B;Drug: Miltefosine<br>* Miltefosine oral (allometric dosing) for 42 days (arm 1) or 28 days (arm 2)<br>* Other names: Impavido;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Definitive Cure | definitive cure at 12 months after treatment onset, defined as clinical cure (100% lesions resolution) and no additional PKDL treatment between end of therapy and 12 months follow-up assessment. | 12 months follow-up assessment | 
| Incidence of treatment-emergent adverse events | Frequency of SAE from start of treatment to 12 months follow-up Frequency and severity of all adverse events Frequency and severity of adverse events that lead to treatment discontinuation | from start of treatment to 12 month follow-up | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetics of Miltefosine | To assess the maximal accumulation (Cmax) of Miltefosine in the skin at the end of treatment and correlate it with achieved plasma concentrations. | Miltefosine concentration in the skin will be measured at day 14 and day 42 for MF+PM arm and at day 7 and day 28 for Ambisome+MF arm. Miltefosine concentration in the blood will be measured at day 1, day 7, day 14, day 28, day 42 and 3 month | 
| Pharmacokinetics of Amphotericin B (MF + Ambisome arm only) | To assess the maximal accumulation (Cmax) of Amphotericin B in the skin at the end of treatment and correlate it with achieved plasma concentrations. | Amphotericin B concentration will be measured in the skin at day 7 and day 28. Amphotericin B concentration in the blood will be measured at day 1 and day 7. | 
| Pharmacokinetics of Paromomycin (MF + Paromomycin arm only) | To assess the maximal accumulation (Cmax) of Paromomycin in the skin at the end of treatment and correlate it with achieved plasma concentrations. | Paromomycin concentration will be measured in the skin at day 14 and day 42. Paromomycin concentration in the blood will be measured at day 1 and day 14. | 
| Immune Response | To assess the change in immune response during and after end of treatment by measuring cytokines profiles level in the peripheral blood. | At screening, at day 42 (end of treatment) and at 6 month follow-up | 
| Parasite quantification in blood and skin | Parasites will be quantified in blood and skin, by microscopy and qPCR, to assess the clearance before and after treatment. | At screening, day 42 (end of treatment), 3 month follow-up, 6 month follow-up and 12 month follow-up. |