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

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

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.

Study Overview

• Status: Completed
• Conditions: Viral Infection
• Intervention / Treatment: Drug: UV-4B 3 mg; Drug: Placebo; Drug: UV-4B 10 mg; Drug: UV-4B 30 mg; Drug: UV-4B 90 mg; Drug: UV-4B 180 mg; Drug: UV-4B 360 mg; Drug: UV-4B 720 mg; Drug: UV-4B 1000 mg

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.

• Study Type: Interventional
• Enrollment (Actual): 64
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Kansas
    • Overland Park, Kansas, United States, 66211
      • Quintiles, Inc

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 45 years (Adult)
• Accepts Healthy Volunteers: Yes

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

8

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Cohort 1 - 3 mg UV-4B; Subjects receiving UV-4B 3 mg oral solution or placebo	Drug: UV-4B 3 mg; Oral solution, single dose; Drug: Placebo; Oral solution, single dose
Experimental: Cohort 2 - 10 mg UV-4B; Subjects receiving UV-4B 10 mg oral solution or placebo	Drug: Placebo; Oral solution, single dose; Drug: UV-4B 10 mg; Oral solution, single dose
Experimental: Cohort 3- 30 mg UV-4B; Subjects receiving UV-4B 30 mg oral solution or placebo	Drug: Placebo; Oral solution, single dose; Drug: UV-4B 30 mg; Oral solution, single dose
Experimental: Cohort 4 - 90 mg UV-4B; Subjects receiving UV-4B 90 mg oral solution or placebo	Drug: Placebo; Oral solution, single dose; Drug: UV-4B 90 mg; Oral solution, single dose
Experimental: Cohort 5 - 180 mg UV-4B; Subjects receiving UV-4B 180 mg oral solution or placebo	Drug: Placebo; Oral solution, single dose; Drug: UV-4B 180 mg; Oral solution, single dose
Experimental: Cohort 6 - 360 mg UV-4B; Subjects receiving UV-4B 360 mg oral solution or placebo	Drug: Placebo; Oral solution, single dose; Drug: UV-4B 360 mg; Oral solution, single dose
Experimental: Cohort 7 - 720 mg UV-4B; Subjects receiving UV-4B 720 mg oral solution or placebo	Drug: Placebo; Oral solution, single dose; Drug: UV-4B 720 mg; Oral solution, single dose
Experimental: Cohort 8 - 1000 mg UV-4B; Subjects receiving UV-4B 1000 mg oral solution or placebo	Drug: Placebo; Oral solution, single dose; Drug: UV-4B 1000 mg; Oral solution, single dose

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Subjects With Treatment-emergent Adverse Event (TEAEs) by Treatment Group	TEAEs are those AEs occurring only after administration of investigational product	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	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	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	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.	Day 9 ± 1

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cmax by Treatment Group: UV-4	Cmax is the maximum plasma concentration, obtained directly from the observed concentration versus time data.	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.	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.	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).	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).	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)].	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).	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.	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.	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).	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)

Collaborators and Investigators

• Sponsor: Emergent BioSolutions
• Collaborators: Quintiles, Inc.; Unither Virology
• Investigators: Principal Investigator: Thomas Murtaugh, Dr, Senior Medical Research Director, Quintiles

Publications and helpful links

General Publications

• Callahan M, Treston AM, Lin G, Smith M, Kaufman B, Khaliq M, Evans DeWald L, Spurgers K, Warfield KL, Lowe P, Duchars M, Sampath A, Ramstedt U. Randomized single oral dose phase 1 study of safety, tolerability, and pharmacokinetics of Iminosugar UV-4 Hydrochloride (UV-4B) in healthy subjects. PLoS Negl Trop Dis. 2022 Aug 8;16(8):e0010636. doi: 10.1371/journal.pntd.0010636. eCollection 2022 Aug.

Helpful Links

• Information on dengue fever

Study record dates

Study Major Dates

• Study Start: July 1, 2014
• Primary Completion (Actual): July 1, 2015
• Study Completion (Actual): September 1, 2015

Study Registration Dates

• First Submitted: February 6, 2014
• First Submitted That Met QC Criteria: February 11, 2014
• First Posted (Estimated): February 12, 2014

Study Record Updates

• Last Update Posted (Actual): March 18, 2024
• Last Update Submitted That Met QC Criteria: March 14, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Keywords: Virus Diseases; Dengue; Pharmacologic Actions; Therapeutic Uses; Arbovirus Infections; Flaviviridae Infections; Flavivirus Infections; Hemorrhagic Fevers, Viral; RNA Virus Infections; Pharmaceutical Solutions
• Additional Relevant MeSH Terms: Infections; Virus Diseases
• Other Study ID Numbers: DMID 13-0001; KQA71264; UV-DEN-0001

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO