Miltefosine/Paromomycin Phase III Trial for Treatment of Primary Visceral Leishmaniasis (VL) Patients in Eastern Africa

Study Overview
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Brief Summary
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This is an open label, Phase III, randomized, controlled, parallel arm multicentre non-inferiority clinical trial to compare the efficacy and safety of two combination regimens of Miltefosine and Paromomycin with the standard SSG-PM for the treatment of primary adult and children VL patients in Eastern Africa.

Detailed Description
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The 2 treatment regimens to be tested are: Arm 1: Paromomycin 20 mg/kg/d IM for 14 days combined with oral miltefosine allometric dosing for 14 days Arm 2: Paromomycin 20 mg/kg/d IM for 14 days combined with oral miltefosine allometric dosing for 28 days (recruitment in this arm was discontinued under protocol v4.0 dated 22 Jul 2019) The reference arm is the current standard treatment for VL: • Arm 3: Sodium Stibogluconate 20 mg/kg/day IM/IV combined with Paromomycin 15 mg/kg/day IM for 17 days The target population will be VL patients from 4 to 50 years old in order to cover both paediatric and adult population. Patients will be hospitalized for 14 days of PM and MF treatment for both arm 1 and arm 2. MF treatment will start at the same time as PM treatment and for arm 2 it will continue on an out-patient basis until completion of the 28 days treatment. SSG&PM combination therapy will be administered for 17 days according to routine VL treatment guidelines and patients will remain hospitalized for the entire duration of the treatment. All patients will be asked to return to the hospital for a full assessment on day 28, and for followup visits on day 56 and at six months. To respond to the objectives, study assessments will be carried out at screening and on days 1, 3, 7, 14, 21, 28, 56 (one-month post-treatment) and 210 (six-month post-treatment). These assessments will include clinical, parasitological, haematological, biochemistry, safety, pharmacokinetic and pharmacodynamics assessments.

Official Title
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An Open Label, Phase III, Randomized Controlled, Multicentre Non-Inferiority Trial to Compare Efficacy and Safety of Miltefosine and Paromomycin With SSG and PM Combination for Treatment of Primary Visceral Leishmaniasis (VL) Patients in Eastern Africa

Conditions
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Visceral Leishmaniasis

Intervention / Treatment
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* Drug: Miltefosine
* Drug: Paromomycin
* Drug: Sodium stibogluconate


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with clinical signs and symptoms of VL and confirmatory parasitological microscopic diagnosis Patients aged 4 to < 50 years who are able to comply with the study protocol. Patients for whom written informed consent has been obtained (if aged 18 years and over) or signed by parents(s) or legal guardian for patients under 18 years of age. In the case of minors, assent from the children also needs to be obtained as per each country regulatory requirements Exclusion Criteria: Patients who are relapse cases Patients with Para-Kala azar dermal leishmaniasis grade 3 Patients who have received any anti-leishmanial drugs in the last 6 months Patients with severe malnutrition (for children aged <5 years: weight-for-height WHO reference curves by sex, z score <-3; for children patients 5-18 years: BMI-for-age WHO reference curves by sex, z score < -3; for adults >18 years: BMI < 16)* Patients with positive HIV diagnosis Patients with previous history of hypersensitivity reaction or known drug class allergy to any of the study treatments Patients with previous history of cardiac arrhythmia or with a clinically significant abnormal ECG Patients suffering from a concomitant severe infection such as TB, schistosomiasis or any other serious underlying disease (e.g. cardiac, renal, hepatic) or chronic condition which would preclude evaluation of the patient's response to study medication Pregnant or lactating women Female patients of child bearing age who do not accept to have a pregnancy test done at screening and/or who do not agree to use contraception from treatment period until 5 months after the end of treatment (see section 15.2) Patients with haemoglobin < 5g/dl Patients with signs of severe VL according to Investigator's judgement, requiring an indication for AmBisome therapy based on the clinical manifestations (such as jaundice, bleeding, edema) and clinically significant abnormalities in the following laboratory parameters: haemoglobin, WBC, platelets, liver enzymes (ALT and AST), total bilirubin and creatinine Patients with pre-existing hearing loss based on audiometry at baseline Patients who cannot comply with the planned scheduled visits and procedures of the study protocol Note: for Ethiopia only: Patients with severe malnutrition (for patients 4-18 years: MUAC cut-off based on MUAC-for-height reference table; for patients > 18 years: MUAC < 170 mm)

Ages Eligible for Study
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Minimum Age: 4 Years
Maximum Age: 50 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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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 - MF/PM 14d<br>Paromomycin 20 mg/kg/d IM for 14 days combined with oral miltefosine allometric dosing for 14 days | Drug: Miltefosine<br>* Miltefosine 10mg and 50mg capsules<br>* Other names: Impavido;Drug: Paromomycin<br>* Paromomycin sulfate equiv to 750mg paromomycin / 2ml amp<br>* Other names: Paromomycin sulfate;|
| Experimental: Arm 2 - MF 28d/PM 14d<br>Paromomycin 20 mg/kg/d IM for 14 days combined with oral miltefosine allometric dosing for 28 days | Drug: Miltefosine<br>* Miltefosine 10mg and 50mg capsules<br>* Other names: Impavido;Drug: Paromomycin<br>* Paromomycin sulfate equiv to 750mg paromomycin / 2ml amp<br>* Other names: Paromomycin sulfate;|
| Active Comparator: Arm 3 - SSG/PM 17d<br>Sodium Stibogluconate 20 mg/kg/day IM/IV combined with Paromomycin 15 mg/kg/day IM for 17 days | Drug: Paromomycin<br>* Paromomycin sulfate equiv to 750mg paromomycin / 2ml amp<br>* Other names: Paromomycin sulfate;Drug: Sodium stibogluconate<br>* Sodium stibogluconate 33% 30 ml inj.<br>* Other names: SSG;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Definitive Cure | Cure at 6 months follow up defined as absence of clinical signs and symptoms of VL at D210 and no requirement for rescue treatment during the trial (e.g. no relapse or initial treatment failure). | 6 months follow-up (Day 210) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Treatment-Emergent Adverse Events | Frequency of SAEs and AEs requiring treatment discontinuation Frequency and severity of adverse events from the start of treatment through the last visit, at day 210. | From Screening to day 210 | 
| Initial cure at day 28 | Initial cure: cure at the end of treatment (Day 28), defined as recovery of clinical signs and symptoms; absence of parasites (microscopy) and no rescue treatment administered up to and including Day 28. Probable cure: absence of clinical signs and symptoms of VL at D56 and no prior requirement for rescue medication. | Initial cure: day 28; Probable cure: day 56 | 
| Pharmacokinetics of paromomycin and miltefosine | Total and partial blood plasma exposure to paromomycin and miltefosine defined as the area under the concentration-time curve | During treatment, at 1 month (day 56) and 6 months (day 210) follow-up | 
| Pharmacodynamics | Blood parasite clearance over time (qualitative and quantitative), as measured by qPCR from blood samples | From baseline until day 210, and at any suspicion of relapse during the trial. | 
| Compliance to miltefosine treatment in an outpatient setting | Compliance to MF treatment in an outpatient setting will be assessed through patients' hospital records history, drug accountability and PK measurements. | Day 15 to day 28 miltefosine treatment |