Study to Determine the Safety, Tolerability and Pharmacokinetics of UV-4B Solution Administered Orally in Healthy Subjects

Phase 1

Completed

Conditions: Viral Infection

Interventions: Drug: UV-4B 720 mg
Drug: UV-4B 1000 mg
Drug: UV-4B 3 mg
Drug: UV-4B 30 mg
Drug: UV-4B 90 mg
Drug: UV-4B 10 mg
Drug: UV-4B 180 mg
Drug: UV-4B 360 mg
Drug: Placebo

Registration Number: NCT02061358

Lead Sponsor: Emergent BioSolutions

Brief Summary: 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.

Detailed Description: 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 64

Inclusion Criteria

Healthy subjects
Women: non-pregnant, non-lactating; if of childbearing potential, on specified contraception measures during the study period
Men: using barrier contraception measures during the study period

Exclusion Criteria

Health conditions
Taking prescription and non-prescription drugs (exceptions: acetaminophen, vitamins, hormonal birth control)

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Cohort 7 - 720 mg UV-4B	UV-4B 720 mg	Subjects receiving UV-4B 720 mg oral solution or placebo
Cohort 8 - 1000 mg UV-4B	UV-4B 1000 mg	Subjects receiving UV-4B 1000 mg oral solution or placebo
Cohort 1 - 3 mg UV-4B	UV-4B 3 mg	Subjects receiving UV-4B 3 mg oral solution or placebo
Cohort 7 - 720 mg UV-4B	Placebo	Subjects receiving UV-4B 720 mg oral solution or placebo
Cohort 8 - 1000 mg UV-4B	Placebo	Subjects receiving UV-4B 1000 mg oral solution or placebo
Cohort 3- 30 mg UV-4B	UV-4B 30 mg	Subjects receiving UV-4B 30 mg oral solution or placebo
Cohort 1 - 3 mg UV-4B	Placebo	Subjects receiving UV-4B 3 mg oral solution or placebo
Cohort 2 - 10 mg UV-4B	Placebo	Subjects receiving UV-4B 10 mg oral solution or placebo
Cohort 3- 30 mg UV-4B	Placebo	Subjects receiving UV-4B 30 mg oral solution or placebo
Cohort 4 - 90 mg UV-4B	UV-4B 90 mg	Subjects receiving UV-4B 90 mg oral solution or placebo
Cohort 2 - 10 mg UV-4B	UV-4B 10 mg	Subjects receiving UV-4B 10 mg oral solution or placebo
Cohort 4 - 90 mg UV-4B	Placebo	Subjects receiving UV-4B 90 mg oral solution or placebo
Cohort 5 - 180 mg UV-4B	UV-4B 180 mg	Subjects receiving UV-4B 180 mg oral solution or placebo
Cohort 5 - 180 mg UV-4B	Placebo	Subjects receiving UV-4B 180 mg oral solution or placebo
Cohort 6 - 360 mg UV-4B	UV-4B 360 mg	Subjects receiving UV-4B 360 mg oral solution or placebo
Cohort 6 - 360 mg UV-4B	Placebo	Subjects receiving UV-4B 360 mg oral solution or placebo

Primary Outcome Measures

Name	Time	Method
Number of Subjects With Vital Sign Values of Toxicity Grade 1 or Higher Postdose by Treatment Group (Safety Population)	From time of the first dose administration through Day 9 ± 1	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
Number of Subjects With Clinical Laboratory Test Results of Toxicity Grade 1 or Higher at Day 9 by Treatment Group	Day 9 ± 1	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.
Subjects With Serious Adverse Event (SAEs) by Treatment Group	From time of the first dose administration through Day 9 ± 1	Subjects with AEs considered serious by the investigator
Number of Subjects With Electrocardiogram Outlier Values Postdose by Treatment Group	From time of the first dose administration through Day 9 ± 1	Number of subjects in a treatment group with outlier ECG findings: QTcF (Fridericia's), PR, and QRS intervals
Subjects With Treatment-emergent Adverse Event (TEAEs) by Treatment Group	From time of the first dose administration through Day 9 ± 1	TEAEs are those AEs occurring only after administration of investigational product

Secondary Outcome Measures

Name	Time	Method
Interval and Cumulative Amount (mg) of UV-4 Excreted in Urine, Ae, by Treatment Group	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	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.
Cmax by Treatment Group: UV-4	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)	Cmax is the maximum plasma concentration, obtained directly from the observed concentration versus time data.
Tmax by Treatment Group: UV-4	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 is the time of maximum concentration observed directly from the observed concentration versus time data.
Vz/F by Treatment Group: UV-4	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 is the apparent volume of distribution of UV-4 based on the terminal phase, calculated as dose (free-base equivalent) divided by \[λ(z) × AUC(0-inf)\].
CLr by Treatment Group: UV-4	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)	CLr is the renal clearance, calculated at Ae(0-last) divided by AUC(0-last).
AUC(0-last) by Treatment Group: UV-4	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) 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.
AUC(0-inf) by Treatment Group: UV-4	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) 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).
CL/F by Treatment Group: UV-4	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 is the apparent systematic clearance, calculated as dose (free-base equivalent) divided by AUC(0-inf).
Interval and Cumulative Percent of UV-4 Excreted in Urine, fe, by Treatment Group	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	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.
t(1/2) by Treatment Group: UV-4	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) is the apparent terminal half-life, determined as ln(2)/λ(z).