LXE408 for Treatment of Visceral Leishmaniasis in Ethiopia, a Proof of Concept Study

This is a randomized, open-label, phase II, single-centre study, with one LXE408 regimen and one calibrator arm with the standard of care SSG combined with PM, to be conducted in male and female adult (≥18 years and \<45 years) patients with confirmed primary visceral leishmaniasis in Ethiopia.

The study will enrol and randomize approximately 52 patients aged ≥18 years and \<45 years in a ratio of 3:1 (arm 1 to arm 2):

* Arm 1: LXE408 orally once daily for 14 days (39 patients)
* Arm 2: Standard of care sodium stibogluconate 20 mg/kg/day intravenous/intramuscular (IV/IM) q.d. and paromomycin 15 mg/kg/day IM q.d. for 17 days (13 patients)

In both arms, the study will consist of a screening period of up to 7 days, a treatment duration of 14 or 17 days, and a follow-up period from end of treatment to Day 180. All patients will be hospitalized for approximately 21-24 days, from the first day of the screening period to the Day 14 or Day 17 visit (LXE408 or SSG/PM arms, respectively), after which they are expected to be discharged. They will return to the study sites at the scheduled Day 28 visit (±1 day) for the initial test of cure (primary endpoint), at Day 56 visit (± 7 days) and for the EOS visit at Day 180 (± 14 days) for the final assessment of cure (secondary endpoint). In addition, during follow-up between Day 56 and Day 180, the study team will contact the study patients by phone on a monthly basis to check on their well-being and any reappearance of VL symptoms.

This study is run by DNDi with Novartis as co-development partner.

Eligibility Criteria:
Inclusion Criteria:

* Male and female patients ≥18 and \<45 years (at the time of the screening visit) who are able to comply with the study protocol
* Written informed consent must be obtained before any study protocol specific assessment is performed, other than procedures performed as part of standard of care
* Primary symptomatic VL (defined as typical parameters including, but not limited to, fever for \>2 weeks, weight loss and splenomegaly)
* Visualization of Leishmania amastigotes by microscopy in tissue samples (spleen or bone marrow)

Exclusion Criteria:

* Clinical signs of severe VL (including for example jaundice, spontaneous bleeding, oedema, ascites, coma, organ failure)
* Laboratory abnormalities including ALT/SGPT \>3 times ULN, total bilirubin \>1.5 times ULN, creatinine \>1.5 times ULN, serum amylase or lipase \>1.5 times ULN, haemoglobin \<6 g/dL or other clinically significant abnormal laboratory parameters which, in the opinion of the investigator, may indicate severe VL
* Patients with history of visceral leishmaniasis and confirmed relapse
* Patients with para-kala-azar dermal leishmaniasis
* Patients with severe malnutrition (Mid-Upper Arm Circumference (MUAC) \<170 mm)
* History of congenital or acquired immunodeficiency, including positive HIV (test at screening), as these patients present lower efficacy rates, higher toxicity and higher lethality compared to non-HIV patients, requiring different case management and care
* ECG abnormalities, either historic (no longer present) or current which, in the view of the investigator, indicate a significant risk to study participation. These include, but are not limited to, the following:

  1. Clinically significant cardiac arrhythmias (e.g., sustained ventricular tachycardia and clinically significant second- or third-degree AV block without a pacemaker)
  2. QTcF ≥ 450 ms
  3. History of familial long QT syndrome or known family history of Torsades de Pointes
  4. Resting heart rate (physical exam or 12 lead ECG) \<60 bpm
* Concomitant known infections, including tuberculosis, severe malaria and any other serious underlying disease that may interfere with disease assessment (e.g., cardiac, renal, hepatic, haematologic and pancreatic)
* Infection with hepatitis B (HBV) or hepatitis C virus (HCV). Patients with a positive HBV surface antigen (HBsAg) test, or if standard local practice, a positive HBV core antigen test, and patients with a positive HCV antibody test must be excluded and will be followed up as per local practice.
* Known history of hearing impairment and/or clinical signs and symptoms of hearing impairment identified during routine physical examination
* Patients with previous history of hypersensitivity reaction or known drug class allergy to any of the study treatments or excipients
* Pregnant or nursing (lactating) women
* Women of childbearing potential who do not agree to have a pregnancy test done at screening and who do not agree to use highly effective contraception while taking the investigational drug and for 5 days after stopping the investigational drug
* Sexually active males unwilling to use a condom during intercourse while taking the investigational drug and for 5 days after stopping the investigational drug
* Patients who cannot comply with the planned scheduled visits and procedures of the study protocol