Trial to Determine Efficacy of Fexinidazole in Visceral Leihmaniasis Patients in Sudan

Phase II Proof of Concept Trial to Determine Efficacy of Fexinidazole in Visceral Leishmaniasis 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