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

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.

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.

Eligibility Criteria:
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)