lxe408 for treatment of visceral leishmaniasis in ethiopia, a proof of concept study

Conditions: Primary Visceral Leishmaniasis

Summary: 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