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

AUC is defined as the area under the concentration-time curve from 0 to last quantifiable concentration (AUC 0-tau). AUC is a measure of exposure. Blood samples for determination of plasma concentrations of sitamaquine was obtained at the following time points on days 1, 10 and 21: immediately pre-dose, and at 1, 2, 3, 4, 6, 10, 16 hours post dose. An additional sample was taken on Day 23 and Day 24 to approximate 48 hours and 72 hours post last dose on Day 21. Only those participants with data available at the specified time points were analyzed.

Cmax was defined as the maximum concentration of sitamaquine. Blood samples for determination of plasma concentrations of sitamaquine was obtained at the following time points on days 1, 10 and 21: immediately pre-dose, and at 1, 2, 3, 4, 6, 10, 16 hours. An additional sample was taken on Day 23 and Day 24 to approximate 48 hours and 72 hours post last dose on Day 21.

Tmax is defined as the time to peak concentration from initiation of sitamaquine dosing. Blood samples for determination of plasma concentrations of sitamaquine was obtained at the following time points on days 1, 10 and 21: immediately pre-dose, and at 1, 2, 3, 4, 6, 10, 16 hours post dose. An additional sample was taken on Day 23 and Day 24 to approximate 48 hours and 72 hours post last dose on Day 21.

Point estimate was the ratio of adjusted geometric means between repeat dosing days (Day 21 or Day 10) and single dose day (Day 1). An evaluation on the accumulation rate was based upon the comparison of AUC(0-24) values after repeated dosing to the values from the first dose on day 1. Blood samples for determination of plasma concentrations of sitamaquine was obtained at the following time points on days 1, 10 and 21: immediately pre-dose, and at 1, 2, 3, 4, 6, 10, 16 hours post dose. An additional sample was taken on Day 23 and Day 24 to approximate 48 hours and 72 hours post last dose on Day 21. Individual observed accumulation ratios on Day 10 were calculated by dividing AUC (0-tau) on Day 10 by AUC (0-tau) on Day 1. A similar formula was applied to the accumulation ratio on Day 21.

An AE is any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An SAE is defined as any untoward medical occurrence that, at any dose, results in death, is life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, is a congenital anomaly/birth defect, or is an event of possible drug-induced liver injury. Data for on-treatment AEs have been reported,

Data for abnormal findings have been reported at Day 22 for Sitamaquine and Day 31 for Amphotericin B. All ECGs were collected in the supine position with the electrodes placed in the standard positions, 4 hours after dosing on drug administration days, and prior to blood collection or pulse rate measurement.

2-D echocardiograms were performed at screening (all participants), Days 22 and 49 (sitamaquine only) and days 31 and 58 (amphotericin B only). All echocardiograms were obtained after the participant has rested in a semi-supine position for at least 10 minutes. All echocardiograms were stored electronically (e.g video home system [VHS] tape, optical drive, etc.). Ejection fraction was estimated using the modified Simpson's rule method. Data for number of participants with abnormal echocardiography results have been reported.

Blood pressure (SBP and DBP) was recorded after the participant had rested in a semi-supine position for at least 10 minutes. Change from Baseline was calculated as any post-Baseline value minus the Baseline value. Baseline visit was Day 1 pre-dose.

Heart rate was recorded after the participant had rested in a semi-supine position for at least 10 minutes. Change from Baseline was calculated as any post-Baseline value minus the Baseline value. Baseline visit was Day 1 pre-dose.

Body temperature was recorded after the participant had rested in a semi-supine position for at least 10 minutes. Change from Baseline was calculated as any post-Baseline value minus the Baseline value. Baseline visit was Day 1 pre-dose.

Body weight was recorded after the participant had rested in a semi-supine position for at least 10 minutes. Change from Baseline was calculated as any post-Baseline value minus the Baseline value. Baseline visit was Day 1 pre-dose.

Data for number of participants with hematology abnormalities for the end of study (Day 180) is presented. Hematology abnormalities were classified using Common Terminology Criteria for Adverse Events (CTCAE) v3.0 Grades and grade 3 ranges are as follows (selected): Hemoglobin (grams per liter [G/L])- <80 - 65; Total Neutrophils (gram international units per liter[GI/L])- <1.0 - 0.5 x 10^9/L; Platelet count(GI/L) <50.0- 25.0 x 10^9 /L; White Blood Cell (WBC) (GI/L)- <2.0 - 1.0 x 10^9 /L. Data only for categories with values have been presented.

Aspartate Amino Transferase (AST) ([international units per liter [IU/L])- >5.0 - 20.0 x upper limit of normal (ULN); Albumin(G/L)- <20 g/dL; Alkaline Phosphatase(IU/L)- >5.0 - 20.0 x ULN; Alanine Amino Transferase(IU/L)- >5.0 - 20.0 x ULN; Total Bilirubin( micromoles per liter [µMOL/L])- >3.0 - 10.0 x ULN; Urea(millimoles per liter [MMOL/L])- 5.1 - 10 x ULN; Cholesterol (MMOL/L) - >10.34 - 12.92; Creatine Kinase MB (microgram per liter[µ/L])->5 x ULN - 10 x ULN; Creatinine Clearance(milliliter per minute [mL/min])- <25% lower limit of normal (LLN); Creatinine(µMOL/L)- >3.0 - 6.0 x ULN; Gamma Glutamyl Transferase(IU/L)- >5.0 - 20.0 x ULN; Potassium(MMOL/L)- >6.0 - 7.0(high) and <3.0 - 2.5 (low); Sodium(MMOL/L)- >155 - 160; Sodium(MMOL/L)- <130 - 120; Triglycerides(MMOL/L)- >5.0 - 10.0 x ULN. Data only for categories with values have been presented.

Initial parasitological cure was defined as a parasite-negative splenic aspirate at completion of treatment or, if the leishmania index (a quantitative assessment of parasites in the splenic aspirate) was +1, a parasite-negative result at the repeat splenic aspirate 28 days later.

Final clinical cure was defined as initial parasitological cure (initial parasitological cure was defined as a parasite-negative splenic aspirate at completion of treatment or, if the leishmania index [a quantitative assessment of parasites in the splenic aspirate] was +1, a parasite-negative result at the repeat splenic aspirate 28 days later) and no evidence of relapse at 6 months.

Half life is defined as the period of time required for the amount of drug in the body to be reduced by half. Blood samples for determination of plasma concentrations of sitamaquine was obtained at the following time points on days 1, 10 and 21: immediately pre-dose, and at 1, 2, 3, 4, 6, 10, 16 hours post dose. An additional sample was taken on Day 23 and Day 24 to approximate 48 hours and 72 hours post last dose on Day 21.