Clinical trial NCT00381394: A Study Evaluating Sitamaquine Compared With Amphotericin B In The Treatment Of Visceral Leishmaniasis.
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 type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Leishmaniasis, Visceral
Keywords: amphotericin B
safety
tolerability and pharmacokinetics of oral sitamaquine
Visceral leishmaniasis
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
First posted: 2006-09-27
Enrollment: 61
Sex: ALL
Minimum age (years): 16
Maximum age (years): 50
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.


Eligibility 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.

Primary outcomes:
measure: Area under the concentration-time curve over the dosing interval AUC(0-tau) for sitamaquine
timeFrame: At Day 1, 10 and 21: immediately pre-dose, and at 1, 2, 3, 4, 6, 10, 16 hours post dose
measure: Maximum plasma concentration (Cmax) for sitamaquine
timeFrame: At Day 1, 10 and 21: immediately pre-dose, and at 1, 2, 3, 4, 6, 10, 16 hours post dose.
measure: Time to maximum observed plasma concentration (tmax) for sitamaquine
timeFrame: At Day 1, 10 and 21: immediately pre-dose, and at 1, 2, 3, 4, 6, 10, 16 hours post dose.
measure: Accumulation ratio for sitamaquine
timeFrame: At Day 1, 10 and 21: immediately pre-dose, and at 1, 2, 3, 4, 6, 10, 16 hours post dose
Secondary outcomes:
measure: Number of participants with adverse events(AEs) and serious adverse events(SAEs)
timeFrame: Up to 180 days
measure: Number of participants with abnormal 12-lead Electrocardiogram (ECG) values
timeFrame: At Day 22 for Sitamaquine and Day 31 for Amphotericin B
measure: Number of participants with abnormal echocardiography results
timeFrame: Up to Day 22 and 49 (sitamaquine only) and Day 31 and 58 (amphotericin B only)
measure: Change from Baseline in systolic blood pressure (SBP) and diastolic blood pressure (DBP) at Day 180
timeFrame: Baseline (Day 1 pre-dose) and Day 180
measure: Change from Baseline in heart rate
timeFrame: Baseline (Day 1 pre-dose) and Day 180
measure: Change from Baseline in body temperature
timeFrame: Baseline (Day 1 pre-dose) and Day 180
measure: Change from Baseline in body weight
timeFrame: Baseline (Day 1 pre-dose) and Day 49 for Sitamaquine and Day 58 for Amphotericin B
measure: Number of participants with abnormal hematology values at the end of study (Day 180)
timeFrame: Day 180
measure: Number of participants with abnormal clinical chemistry values at the end of study (Day 180)
timeFrame: Day 180
measure: Number of participants with Initial parasitological cure (28 days)
timeFrame: Up to 28 days
measure: Number of participants with Final parasitological cure (6 months)
timeFrame: Up to 180 days
measure: Terminal elimination half-life (t1/2) for sitamaquine
timeFrame: At Day 1, 10 and 21: immediately pre-dose, and at 1, 2, 3, 4, 6, 10, 16 hours post dose
Other outcomes:
Locations:
city: Muzaffarpur
country: India
facility: GSK Investigational Site
city: Muzaffarpur
country: India
facility: GSK Investigational Site
city: Patna
country: India
facility: GSK Investigational Site
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References:
citation: Sundar S, Sinha PK, Dixon SA, Buckley R, Miller AK, Mohamed K, Al-Banna M. Pharmacokinetics of oral sitamaquine taken with or without food and safety and efficacy for treatment of visceral leishmaniais: a randomized study in Bihar, India. Am J Trop Med Hyg. 2011 Jun;84(6):892-900. doi: 10.4269/ajtmh.2011.10-0409.