Trial to Determine Efficacy of Fexinidazole in Visceral Leihmaniasis Patients in Sudan
Trial to Determine Efficacy of Fexinidazole in Visceral Leihmaniasis Patients in Sudan
This study is designed to determine the efficacy of Fexinidazole as an oral treatment in
 Visceral Leishmanisasis sudanese adults patients.

 The results of this proof of concept study will allow to make a decision on whether to
 proceed with clinical development of Fexinidazole for visceral leishmaniasis.
Visceral Leishmaniasis (VL) is a neglected disease and it is fatal if left untreated.

 Until recently the first line treatment in East Africa was 30 days of Sodium Stibogluconate
 which can be cardiotoxic. Since 2010 WHO recommended Sodium Stibogluconate and Paromomycin
 for 17 days which is a shorter treatment but there remains the toxicity associated with these
 drugs. The second line treatment is Ambisome given as 6-10 intravenous infusions, whilst this
 has a better safety profile than other VL regimens it is expensive.

 So there is an urgent need for short course oral treatment for VL particularly in the East
 African region.

 Fexinidazole is a 2 substituted 5-nitroimidazole formulated for oral administration.
 Fexinidazole through its metabolites has demonstrated potent activity againts L. donovani
 intracellular amastigotes in vitro and in vivo in a visceral leishmaniasis mouse model.

 The dose selected for this study (1800 mg/1200 mg for 4/6 days) has been based on the dose
 selected for a phase II trial on Human African Trypasonomiasis. It is albeit well tolerated
 and is one dose level below the maximum tolerated dose level established in phase I.

 The trial is designed and will be analysed according to a sequential method known as the
 triangular test, using day 28 data. This sequential design allows for repeated interim
 analysis (every 10 patients). The null hypothesis is that the proportion cured is less than
 or equal to 75%. The primary endpoint is initial cure at day 28. The primary population for
 interim analyses and interim decision making will be the per protocol population.In the final
 analysis of cumulative patient data, Intention to Treat and Per Protocol Population analyses
 will be conducted.

 The conventional 6 months (day 210) follow up outcome is still an important secondary
 endpointfor the final decision on whether to proceed with clinical development of
 Fexinidazole for VL.
Inclusion Criteria:

 -  Patients with clinical signs and symptoms of primary VL (fever for at least 2 weeks,
 splenomegaly) and diagnosis confirmed by visualization of parasites in tissue samples
 (lymph node, bone marrow) on microscopy.

 -  Patients aged between 15 and 60 years (inclusive) who are able to comply with the
 protocol.

 -  Patients for whom written informed consent has been signed by the patients themselves
 (if aged 18 years and over) or by parents(s) or legal guardian for patients under 18
 years of age together with the patients assent.

 -  HIV negative status

 Exclusion Criteria:

 -  Patients who have previously been diagnosed with VL and received anti-leishmanial
 treatment (ie relapse)

 -  Patients with BMI <16 kg/m2

 -  Patients with contra-indication (known hypersensitivity) to other imidazoles (e.g.
 ketaconazole)

 -  Patients suffering from a concomitant severe underlying disease (cardiac, renal,
 hepatic) including hepatitis B, para kala-azar dermal leishmaniasis and tuberculosis

 -  Patient with clinically significant ECG findings or QTcF≥ 450 msec in 2 successive
 ECGs

 -  Major surgical intervention 4 weeks prior to enrollment.

 -  Patients who are pregnant or lactating.

 -  Female patients of child bearing age who do not agree to use an acceptable method of
 contraception

 -  Patients with haemoglobin < 5g/dl.

 -  Patients with platelets < 40,000/mm³.

 -  Patients with liver function (ALT and AST) tests of more than 2 times the upper limit
 of the normal range.

 -  Patients with serum creatinine above the normal range for age and gender.

 -  Patients with serum potassium (K+) above the normal range

 -  Patients with Bilirubin more than 1.5 times the upper limit of the normal range