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

Overview

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.

Full Title of Study: “Randomized, Double-Blind, Placebo-Controlled, Parallel Group, Single-Ascending Dose Study to Determine the Safety, Tolerability and Pharmacokinetics of UV-4B Solution Administered Orally in Healthy Subjects”

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: Randomized
    • Intervention Model: Parallel Assignment
    • Primary Purpose: Treatment
    • Masking: Double (Participant, Investigator)
  • Study Primary Completion Date: July 2015

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.

Interventions

  • Drug: UV-4B 3 mg
    • Oral solution, single dose
  • Drug: UV-4B 10 mg
    • Oral solution, single dose
  • Drug: UV-4B 30 mg
    • Oral solution, single dose
  • Drug: UV-4B 90 mg
    • Oral solution, single dose
  • Drug: UV-4B 180 mg
    • Oral solution, single dose
  • Drug: UV-4B 360 mg
    • Oral solution, single dose
  • Drug: UV-4B 720 mg
    • Oral solution, single dose
  • Drug: UV-4B 1000 mg
    • Oral solution, single dose
  • Drug: Placebo
    • Oral solution, single dose

Arms, Groups and Cohorts

  • Experimental: Cohort 1 – 3 mg UV-4B
    • Subjects receiving UV-4B 3 mg oral solution or placebo
  • Experimental: Cohort 2 – 10 mg UV-4B
    • Subjects receiving UV-4B 10 mg oral solution or placebo
  • Experimental: Cohort 3- 30 mg UV-4B
    • Subjects receiving UV-4B 30 mg oral solution or placebo
  • Experimental: Cohort 4 – 90 mg UV-4B
    • Subjects receiving UV-4B 90 mg oral solution or placebo
  • Experimental: Cohort 5 – 180 mg UV-4B
    • Subjects receiving UV-4B 180 mg oral solution or placebo
  • Experimental: Cohort 6 – 360 mg UV-4B
    • Subjects receiving UV-4B 360 mg oral solution or placebo
  • Experimental: Cohort 7 – 720 mg UV-4B
    • Subjects receiving UV-4B 720 mg oral solution or placebo
  • Experimental: Cohort 8 – 1000 mg UV-4B
    • Subjects receiving UV-4B 1000 mg oral solution or placebo

Clinical Trial Outcome Measures

Primary Measures

  • Subjects With Treatment-emergent Adverse Event (TEAEs) by Treatment Group
    • Time Frame: From time of the first dose administration through Day 9 ± 1
    • TEAEs are those AEs occurring only after administration of investigational product
  • Subjects With Serious Adverse Event (SAEs) by Treatment Group
    • Time Frame: From time of the first dose administration through Day 9 ± 1
    • Subjects with AEs considered serious by the investigator
  • Number of Subjects With Vital Sign Values of Toxicity Grade 1 or Higher Postdose by Treatment Group (Safety Population)
    • Time Frame: 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 Electrocardiogram Outlier Values Postdose by Treatment Group
    • Time Frame: 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
  • Number of Subjects With Clinical Laboratory Test Results of Toxicity Grade 1 or Higher at Day 9 by Treatment Group
    • Time Frame: 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.

Secondary Measures

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

Participating in This Clinical Trial

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)

Gender Eligibility: All

Minimum Age: 18 Years

Maximum Age: 45 Years

Are Healthy Volunteers Accepted: Accepts Healthy Volunteers

Investigator Details

  • Lead Sponsor
    • Emergent BioSolutions
  • Collaborator
    • Quintiles, Inc.
  • Provider of Information About this Clinical Study
    • Sponsor
  • Overall Official(s)
    • Thomas Murtaugh, Dr, Principal Investigator, Senior Medical Research Director, Quintiles

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