Short Course Regimens for Treatment of PKDL (Sudan)

• ClinicalTrials.gov Identifier: NCT03399955
• Recruitment Status: Recruiting
• First Posted: January 17, 2018
• Last Update Posted: July 19, 2018
• Sponsor: Drugs for Neglected Diseases
• Information provided by (Responsible Party): Drugs for Neglected Diseases

Study Description

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.

Condition or disease	Intervention/treatment	Phase
PKDL - Post-Kala-Azar Dermal Leishmanioid	Drug: Paromomycin; Drug: Ambisome; Drug: Miltefosine	Phase 2

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 110 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• 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
• Actual Study Start Date: May 9, 2018
• Estimated Primary Completion Date: May 9, 2021
• Estimated Study Completion Date: May 1, 2022

Arms and Interventions

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 Name: 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: Ambisome; AmBisome® (20 mg/kg total dose) IV over 7 days; Other Name: Liposomal Amphotericin B; Drug: Miltefosine; Miltefosine oral (allometric dosing) for 42 days (arm 1) or 28 days (arm 2); Other Name: Impavido

Outcome Measures

Primary Outcome Measures :

1. Definitive Cure [ Time Frame: 12 months follow-up assessment ]
   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.
2. Incidence of treatment-emergent adverse events [ Time Frame: from start of treatment to 12 month follow-up ]
   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

Secondary Outcome Measures :

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

Eligibility Criteria

• Ages Eligible for Study: 6 Years to 60 Years (Child, Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Contacts

Contact: Gina M Ouattara, manager; +254 20 3995000; gmouattara@dndi.org

Contact: Severine Monnerat, coordinator; +41 22 907 7891; smonnerat@dndi.org

Locations

Sudan

Prof. Elhassan Centre for tropical Medicine; Recruiting

Doka, Gedaref, Sudan

Contact: Brima Musa, MD

Sponsors and Collaborators

Drugs for Neglected Diseases

More Information

• Responsible Party: Drugs for Neglected Diseases
• ClinicalTrials.gov Identifier: NCT03399955 History of Changes
• Other Study ID Numbers: DNDi-MILT COMB-02-PKDL
• First Posted: January 17, 2018
• Last Update Posted: July 19, 2018
• Last Verified: July 2018

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Leishmaniasis, Visceral; Leishmaniasis; Euglenozoa Infections; Protozoan Infections; Parasitic Diseases; Skin Diseases, Parasitic; Skin Diseases, Infectious; Skin Diseases; Amphotericin B; Paromomycin; Miltefosine; Liposomal amphotericin B; Amebicides; Antiprotozoal Agents; Antiparasitic Agents; Anti-Infective Agents; Anti-Bacterial Agents; Antifungal Agents; Antineoplastic Agents