The objective is to evaluate the safety and tolerability of a single-ascending oral dose of UV-4B in healthy subjects and to determine pharmacokinetic parameters describing absorption and elimination following a single dose of UV-4B in healthy subjects.
The causative agent of dengue fever is Dengue Virus (DENV), a member of the flavivirus genus. There are four DENV serotypes. Infection with one serotype results in lifelong immunity against that serotype, but only limited short-term cross-protection from infection with the other serotypes. Immunity to one serotype has a downside as subsequent infections by other serotypes increase the risk of developing more severe forms of dengue, which includes the most lethal form of the disease, dengue hemorrhagic fever. Traditional epidemiologic and serologic-based estimates suggest a range of 50 to 100 million DENV infections per year distributed over 100 countries. Recent cartographic-based modeling studies suggest that up to 390 million of dengue infections per year, of which 96 million are associated with clinical symptoms.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
DOUBLE
Enrollment
64
Oral solution, single dose
Oral solution, single dose
Oral solution, single dose
Quintiles, Inc
Overland Park, Kansas, United States
Subjects With Treatment-emergent Adverse Event (TEAEs) by Treatment Group
TEAEs are those AEs occurring only after administration of investigational product
Time frame: From time of the first dose administration through Day 9 ± 1
Subjects With Serious Adverse Event (SAEs) by Treatment Group
Subjects with AEs considered serious by the investigator
Time frame: From time of the first dose administration through Day 9 ± 1
Number of Subjects With Vital Sign Values of Toxicity Grade 1 or Higher Postdose by Treatment Group (Safety Population)
Number of subjects in a treatment group, who had a vital sign value of toxicity Grade 1 or higher: supine and standing systolic blood pressure (BP), supine and standing diastolic BP, supine and standing pulse rate, respiratory rate, and temperature
Time frame: From time of the first dose administration through Day 9 ± 1
Number of Subjects With Electrocardiogram Outlier Values Postdose by Treatment Group
Number of subjects in a treatment group with outlier ECG findings: QTcF (Fridericia's), PR, and QRS intervals
Time frame: From time of the first dose administration through Day 9 ± 1
Number of Subjects With Clinical Laboratory Test Results of Toxicity Grade 1 or Higher at Day 9 by Treatment Group
Number of subjects with Grade 1 toxicity or higher for hematology, coagulation, chemistry and urinalysis analytes. ULN=upper limit of normal; WBC=white blood cell count.
Time frame: Day 9 ± 1
Cmax by Treatment Group: UV-4
Cmax is the maximum plasma concentration, obtained directly from the observed concentration versus time data.
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Oral solution, single dose
Oral solution, single dose
Oral solution, single dose
Oral solution, single dose
Oral solution, single dose
Oral solution, single dose
Time frame: Blood samples were collected at predose (0 hour) and at 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 9, 12, 18, 24, 36, and 48 hours postdose (1 hour window for predose)
Tmax by Treatment Group: UV-4
Tmax is the time of maximum concentration observed directly from the observed concentration versus time data.
Time frame: Blood samples were collected at predose (0 hour) and at 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 9, 12, 18, 24, 36, and 48 hours postdose (1 hour window for predose)
AUC(0-last) by Treatment Group: UV-4
AUC(0-last) is the area under the concentration-time curve from time zero (pre-dose) to time of last quantifiable concentration, calculated by linear up/log down trapezoidal summation.
Time frame: Blood samples were collected at predose (0 hour) and at 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 9, 12, 18, 24, 36, and 48 hours postdose (1 hour window for predose)
AUC(0-inf) by Treatment Group: UV-4
AUC(0-inf) is the area under the concentration-time curve in the sample from pre-dose extrapolated to infinite time, calculated by linear up/log down trapezoidal summation and extrapolated to infinity by addition of the last quantifiable concentration divided by the apparent terminal rate constant: AUC(0-last) - C(last)/λ(z).
Time frame: Blood samples were collected at predose (0 hour) and at 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 9, 12, 18, 24, 36, and 48 hours postdose (1 hour window for predose)
CL/F by Treatment Group: UV-4
CL/F is the apparent systematic clearance, calculated as dose (free-base equivalent) divided by AUC(0-inf).
Time frame: Blood samples were collected at predose (0 hour) and at 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 9, 12, 18, 24, 36, and 48 hours postdose (1 hour window for predose)
Vz/F by Treatment Group: UV-4
Vz/F is the apparent volume of distribution of UV-4 based on the terminal phase, calculated as dose (free-base equivalent) divided by \[λ(z) × AUC(0-inf)\].
Time frame: Blood samples were collected at predose (0 hour) and at 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 9, 12, 18, 24, 36, and 48 hours postdose (1 hour window for predose)
t(1/2) by Treatment Group: UV-4
t(1/2) is the apparent terminal half-life, determined as ln(2)/λ(z).
Time frame: Blood samples were collected at predose (0 hour) and at 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 9, 12, 18, 24, 36, and 48 hours postdose (1 hour window for predose)
Interval and Cumulative Amount (mg) of UV-4 Excreted in Urine, Ae, by Treatment Group
Ae is the by-interval and cumulative amounts of UV-4 drug excreted in urine. Intervals were 0 to 6, 6 to 12, 12 to 24, and 24 to 48 hours postdose. Ae by-interval amounts were calculated as the product of urine volume and urine concentration. Ae(0-last) is the cumulative amount of UV-4 drug excreted in urine over the entire collection period, 48 hours. Cumulative amounts were calculated as the summation of the amounts excreted in collection intervals.
Time frame: Pooled urine samples were collected at predose (-12 to 0 hour), and from 0 to 6, 6 to 12, 12 to 24, and 24 to 48 hours postdose
Interval and Cumulative Percent of UV-4 Excreted in Urine, fe, by Treatment Group
fe is the by-interval percentage of UV-4 drug excreted in urine. Intervals were 0 to 6, 6 to 12, 12 to 24, and 24 to 48 hours postdose. fe = Ae/(UV-4B dose x 100). fe(0-12), fe(0-24) and fe(0-last) are the cumulative percentages of UV-4 drug excreted in urine over 24 hours and the entire collection period, respectively.
Time frame: Pooled urine samples were collected at predose (-12 to 0 hour), and from 0 to 6, 6 to 12, 12 to 24, and 24 to 48 hours postdose
CLr by Treatment Group: UV-4
CLr is the renal clearance, calculated at Ae(0-last) divided by AUC(0-last).
Time frame: Blood samples were collected at predose (0 hour) and at 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 9, 12, 18, 24, 36, and 48 hours postdose (1 hour window for predose)