Short Course Regimens for Treatment of PKDL (Sudan)

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

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.

Study Overview

• Status: Unknown
• Conditions: PKDL - Post-Kala-Azar Dermal Leishmanioid
• Intervention / Treatment: Drug: Paromomycin; Drug: Miltefosine; Drug: Ambisome

• Study Type: Interventional
• Enrollment (Anticipated): 110
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Gina M Ouattara, manager; Phone Number: +254 20 3995000; Email: gmouattara@dndi.org
• Study Contact Backup: Name: Severine Monnerat, coordinator; Phone Number: +41 22 907 7891; Email: smonnerat@dndi.org

Study Locations

• Sudan
  • Gedaref
    • Doka, Gedaref, Sudan
      • Recruiting
      • Prof. Elhassan Centre for tropical Medicine
      • Contact: Brima Musa, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 6 years to 60 years (ADULT, CHILD)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Arm 1: Paromomycin + Miltefosine; Paromomycin 20 mg/kg/d IM for 14 days combined with Miltefosine allometric BID PO dosing for 42 days	Drug: Paromomycin; Paromomycin (20 mg/kg/d) IM for 14 days; Drug: Miltefosine; Miltefosine oral (allometric dosing) for 42 days (arm 1) or 28 days (arm 2); Other Names: Impavido
EXPERIMENTAL: Arm 2: Ambisome + Miltefosine; 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: Miltefosine; Miltefosine oral (allometric dosing) for 42 days (arm 1) or 28 days (arm 2); Other Names: Impavido; Drug: Ambisome; AmBisome® (20 mg/kg total dose) IV over 7 days; Other Names: Liposomal Amphotericin B

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.

Collaborators and Investigators

• Sponsor: Drugs for Neglected Diseases

Study record dates

Study Major Dates

• Study Start (ACTUAL): May 9, 2018
• Primary Completion (ANTICIPATED): May 9, 2021
• Study Completion (ANTICIPATED): May 1, 2022

Study Registration Dates

• First Submitted: December 7, 2017
• First Submitted That Met QC Criteria: January 8, 2018
• First Posted (ACTUAL): January 17, 2018

Study Record Updates

• Last Update Posted (ACTUAL): January 18, 2020
• Last Update Submitted That Met QC Criteria: January 15, 2020
• Last Verified: January 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Skin Diseases; Infections; Vector Borne Diseases; Parasitic Diseases; Protozoan Infections; Skin Diseases, Parasitic; Skin Diseases, Infectious; Euglenozoa Infections; Leishmaniasis; Leishmaniasis, Visceral; Anti-Infective Agents; Antineoplastic Agents; Anti-Bacterial Agents; Antifungal Agents; Antiprotozoal Agents; Antiparasitic Agents; Amebicides; Miltefosine; Paromomycin; Amphotericin B; Liposomal amphotericin B
• Other Study ID Numbers: DNDi-MILT COMB-02-PKDL

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No