A Study Evaluating Sitamaquine Compared With Amphotericin B In The Treatment Of Visceral Leishmaniasis.

Condition(s) targeted: Visceral Leishmaniasis

Intervention: sitamaquine (Drug)

Phase: Phase 2

Status: Completed

Sponsored by: GlaxoSmithKline

Official(s) and/or principal investigator(s):
GSK Clinical Trial, MD, Study Director, Affiliation: GlaxoSmithKline

Sitamaquine is an 8-aminoquinoline which is being developed as an oral treatment for visceral leishmaniasis (VL). Pre-clinical and subsequent clinical investigations have demonstrated oral efficacy against Leishmania donovani. The purposes of this study are to characterise the pharmacokinetic profile of sitamaquine, administered orally, and to determine if the pharmacokinetic profile is affected by administration with food. The study is also designed to further characterise the safety and tolerability of sitamaquine compared with amphotericin B, particularly in reference to renal, hepatic and cardiac adverse events, prior to initiation of phase III studies. Finally the study will investigate the efficacy of a 21 day treatment course. Previous studies have used 28 days dosing, but parasitological evidence from one study suggests that shorter courses may be effective.

Official title: A Phase II, Multi-Centre, Open-Label, Randomised Study to Evaluate the Safety, Tolerability and Pharmacokinetics of Oral Sitamaquine Compared With Amphotericin B in the Treatment of Visceral Leishmaniasis Caused by L. Donovani in Endemic Areas.

Study design: Treatment, Randomized, Open Label, Active Control, Parallel Assignment, Pharmacokinetics Study

Primary outcome: AUC(0-) Cmax time to maximum concentration (tmax)accumulation ratio for sitamaquine.

Secondary outcome: 1. Safety parameters; adverse events, 12-lead ECG, echocardiography, vital signs, safety laboratory parameters 2. Initial parasitological cure (28 days) 3. Final parasitological cure (6 months) 4. PK parameter terminal half-life (t1/2) for sitamaquine

Minimum age: 16 Years. Maximum age: 50 Years. Gender(s): Both.

Criteria:

Inclusion criteria:

- Clinical diagnosis of visceral leishmaniasis; symptoms and signs compatible with VL

and diagnosis confirmed by visualisation of amastigotes in splenic aspirate or bone marrow.

- Written informed consent or witnessed oral consent.

- Willing to comply with the study visits and procedures.

- For female subjects, a negative urine pregnancy test at screening and before dosing

and the subject agrees to use an established method of birth control (including abstinence).

Exclusion criteria:

- Past history of renal disease or impaired renal function at screening.

- History of any significant hepatic or biliary disease, or the following abnormal

laboratory values at screening; hepatic dysfunction (AST or ALT 2. 5 times upper limit of normal).

- Subjects with the following abnormal laboratory values; haemoglobin 6. 5 g/dl,

neutrophils <750/ mm3, platelets <50,000 / mm3, any clinically relevant abnormality identified on screening examination or clinical laboratories which would preclude the subject's safe participation in the study.

- History of cardiac disease, arrhythmias, conduction abnormalities or any clinically

relevant abnormality identified on 12-lead ECG at screening.

Subjects suffering from a concomitant infection, blood disorder or any other serious underlying disease which would preclude evaluation of the subject's response to the study medication.

Methaemoglobin levels >5% at screening. G6PD deficiency.

- Positive HIV antibody, hepatitis B surface antigen or hepatitis C antibody at

screening.

- Pregnant or nursing women; women of childbearing potential who are unwilling or unable

to use an appropriate form of contraception, from prior to study medication administration until 2 weeks following the last dose of investigational product.

- Any contraindication to splenic aspirate (or bone marrow aspirate), including but not

limited to PT prolonged >3 seconds longer than control or platelets <50,000 / mm3.

- Subjects with a known hypersensitivity reaction to 8-aminoquinolines (e. g. primaquine)

or any of the investigational product excipients.

- Treatment with an established antileishmanial chemotherapeutic agent within 30 days or

5 half-lives (whichever is longer) preceding the first dose of study medication.

- Treatment with an investigational drug within 30 days or 5 half-lives (whichever is

longer) preceding the first dose of study medication.

GSK Clinical Trials Call Center, Muzaffarpur, India

GSK Clinical Trials Call Center, Patna 800007, India

Starting date: July 2006
Last updated: March 12, 2008