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

Study Overview
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Brief Summary
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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
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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.

Official Title
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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

Conditions
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Viral Infection

Intervention / Treatment
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* Drug: UV-4B 3 mg
* 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
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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)

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 45 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

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

What is the study measuring?
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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) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Dengue, Arbovirus Infections, Flaviviridae Infections, Flavivirus Infections, Hemorrhagic Fevers, Viral, RNA Virus Infections, Virus Diseases, Pharmaceutical Solutions, Pharmacologic Actions, Therapeutic Uses