Safety and Pharmacokinetics of UV-4B Solution Administered Orally as Multiple Ascending Doses to Healthy Subjects

• Sponsor: Emergent BioSolutions (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT02696291
• Collaborator: National Institute of Allergy and Infectious Diseases (NIAID) (NIH)
• Enrollment: 7
• Locations: 2
• Arms: 5
• Actual Duration (Months): 9.2
• Patients Per Site: 3.5
• Patients Per Site Per Month: 0.4

Study Details

Study Description

Brief Summary

The purpose of this study is to evaluate the safety and pharmacokinetics of UV-4B oral solution when administered to healthy subjects three times a day (TID) for 7 days.

Condition or Disease	Intervention/Treatment	Phase
Viral Infection	Drug: UV-4B 30 mg oral solution; Drug: UV-4B 75 mg oral solution; Drug: UV-4B 150 mg oral solution; Drug: UV-4B X mg (dose to be determined) oral solution; Drug: UV-4B Y mg (dose to be determined) oral solution; Drug: Placebo	Phase 1

Detailed Description

This is a phase 1, randomized, double-blind, placebo-controlled multiple-ascending dose study to evaluate the safety and pharmacokinetics of UV-4B oral solution when administered to healthy subjects TID for 7 days. Three cohorts of 8 subjects each (6 active, 2 placebo) are planned and up to 2 additional cohorts may be added pending safety review of the initial cohorts. Safety review will occur after each cohort. Safety is evaluated through Day 15 on the basis of adverse event (AE) monitoring, clinical laboratory testing (hematology, serum chemistry, coagulation, urinalysis), vital signs, physical examinations (PE), electrocardiograms (ECG), and fecal occult blood testing. Blood samples are collected at specified intervals up to Day 10 for pharmacokinetic assessment.

Study Design

• Study Type: Interventional
• Actual Enrollment: 7 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Randomized, Double-blind, Placebo-controlled, Multiple Ascending Dose Study to Determine the Safety, Tolerability and Pharmacokinetics of UV-4B Solution Administered Orally in Healthy Subjects
• Actual Study Start Date: May 27, 2016
• Actual Primary Completion Date: Mar 2, 2017
• Actual Study Completion Date: Mar 2, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Cohort 1 - 30 mg Subjects receiving UV-4B 30 mg oral solution or placebo	Drug: UV-4B 30 mg oral solution; UV-4B 30 mg oral solution administered TID (every 8 ± 0.5 hours) for 7 days; Drug: Placebo; Placebo oral solution administered TID (every 8 ± 0.5 hours) for 7 days
Experimental: Cohort 2 - 75 mg Subjects receiving UV-4B 75 mg oral solution or placebo	Drug: UV-4B 75 mg oral solution; UV-4B 75 mg oral solution administered TID (every 8 ± 0.5 hours) for 7 days; Drug: Placebo; Placebo oral solution administered TID (every 8 ± 0.5 hours) for 7 days
Experimental: Cohort 3 - 150 mg Subjects receiving UV-4B 150 mg oral solution or placebo	Drug: UV-4B 150 mg oral solution; UV-4B 150 mg oral solution administered TID (every 8 ± 0.5 hours) for 7 days; Drug: Placebo; Placebo oral solution administered TID (every 8 ± 0.5 hours) for 7 days
Experimental: Cohort 4 - X mg (dose to be determined) Subjects receiving UV-4B X mg (dose to be determined) oral solution or placebo	Drug: UV-4B X mg (dose to be determined) oral solution; UV-4B X mg (dose to be determined) oral solution administered TID (every 8 ± 0.5 hours) for 7 days; Drug: Placebo; Placebo oral solution administered TID (every 8 ± 0.5 hours) for 7 days
Experimental: Cohort 5 - Y mg (dose to be determined) Subjects receiving UV-4B Y mg (dose to be determined) oral solution or placebo	Drug: UV-4B Y mg (dose to be determined) oral solution; UV-4B Y mg (dose to be determined) oral solution administered TID (every 8 ± 0.5 hours) for 7 days; Drug: Placebo; Placebo oral solution administered TID (every 8 ± 0.5 hours) for 7 days

Outcome Measures

Primary Outcome Measures

1. Number of Subjects Reporting Treatment-emergent Adverse Events (TEAEs) by Group [From the time of first dosing on Day 1 through the Day 15 final follow-up visit]

   The incidence of TEAEs spontaneously reported by subjects or elicited during examination is reported by dose group. Subjects having multiple TEAEs are counted only once.

2. Number of Subjects Reporting Serious Adverse Events (SAEs) by Group [From the time of first dosing on Day 1 through the Day 15 final follow-up visit]

   The incidence of SAEs spontaneously reported by subjects or elicited during examination is reported by dose group. Subjects having multiple SAEs are counted only once.

3. Number of Subjects With Clinical Laboratory Abnormalities of Toxicity Grade 1 or Higher by Group [From the time of first dosing on Day 1 through the Day 15 final follow-up visit]

   Clinical laboratory abnormalities are presented as the total of Grade 1 (mild) through Grade 4 (potentially life-threatening) abnormalities according to criteria adapted from the Food and Drug Administration (FDA) Guidance for Industry, Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials (September 2007) and the Division of Microbiology and Infectious Diseases (DMID) Adult Toxicity Table (November 2007). Within each parameter, subjects having multiple abnormalities are counted only once.

Secondary Outcome Measures

1. Number of Subjects With Outlying Vital Sign Results by Group [From the time of first dosing on Day 1 through the Day 15 final follow-up visit]

   Vital signs of blood pressure (BP), pulse, respiratory rate, and oral temperature were taken after being supine for 10 minutes. Orthostatic vital signs (BP, pulse) were taken after 2 minutes standing. Vital sign results are presented as the number of subjects having Grade 1 (mild) through Grade 4 (potentially life-threatening) abnormalities according to criteria adapted from the FDA Guidance for Industry, Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials (September 2007), or having abnormal orthostatic change (standing minus supine result). Within each parameter, subjects having multiple abnormalities are counted only once.

2. Number of Subjects With 12-lead Electrocardiogram (ECG) Abnormalities Postdose by Group [From the time of first dosing on Day 1 through the Day 15 final follow-up visit]

   ECGs (ventricular heart rate, wave intervals - PR, QRS, QT, QTcF) were recorded in a supine position (for at least 10 minutes). Baseline was calculated from the average of the triplicate ECGs on Day 1 predose. Within each parameter, subjects having multiple abnormalities are counted only once.

3. Maximum Plasma Concentration (Cmax) [Day 1, Day 7]

   Plasma concentrations of UV-4 are determined by means of high performance liquid chromatography/tandem mass spectrometric assay. Values of Cmax are derived from individual subject plasma concentration-time data. Blood collected at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 5, 6, and 8 hrs after the first dose on Day 1; and at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 5, 6, 8, 10, 12, and 14 hrs after the final dose on Day 7.

4. Time of Maximum Plasma Concentration (Tmax) [Day 1, Day 7]

   Plasma concentrations of UV-4 are determined by means of high performance liquid chromatography/tandem mass spectrometric assay. Values of tmax are derived from individual subject plasma concentration-time data. Blood collected at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 5, 6, and 8 hrs after the first dose on Day 1; and at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 5, 6, 8, 10, 12, and 14 hrs after the final dose on Day 7.

5. Area Under the Concentration-time Curve From Time Zero (Predose) to Time of the Last Quantifiable Concentration After the Last Dose [AUC(0-last)] [Day 7]

   Plasma concentrations of UV-4 are determined by means of high performance liquid chromatography/tandem mass spectrometric assay. Values of AUC(0-last) are derived from individual subject plasma concentration-time data, calculated using the linear trapezoidal rule for increasing concentrations and the logarithmic rule for decreasing concentrations. Blood collected at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 5, 6, 8, 10, 12, and 14 hrs after the final dose on Day 7.

6. Total Daily Exposure at Steady State: Area Under the Concentration-time Curve From Time Zero (Predose) Until 24 Hours After the Last Dose [AUC(0-24)] [Day 7]

   Plasma concentrations of UV-4 are determined by means of high performance liquid chromatography/tandem mass spectrometric assay. Values of AUC(0-24) are derived from individual subject plasma concentration-time data, calculated as AUC(0-8) x 3 (Day 7 last dose only). Blood collected at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 5, 6, 8, 10, 12, and 14 hrs after the final dose on Day 7.

7. Area Under the Concentration-time Curve From Time Zero (Predose) Until 8 Hours After the Final Dose [AUC(0-8)] [Day 1, Day 7]

   Plasma concentrations of UV-4 are determined by means of high performance liquid chromatography/tandem mass spectrometric assay. Values of AUC(0-8) are derived from individual subject plasma concentration-time data, calculated using the linear trapezoidal rule for increasing concentrations and the logarithmic rule for decreasing concentrations. Blood collected at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 5, 6, and 8 hrs after the first dose on Day 1; and at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 5, 6, 8, 10, 12, and 14 hrs after the final dose on Day 7.

8. Apparent Systemic Clearance (CL/F) at Steady State [Day 7]

   Plasma concentrations of UV-4 are determined by means of high performance liquid chromatography/tandem mass spectrometric assay. Values of CL/F are derived from individual subject plasma concentration-time data, calculated as dose (free-base equivalent) divided by AUC(0-8). Blood collected at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 5, 6, 8, 10, 12, and 14 hrs after the final dose on Day 7.

9. Apparent Volume of Distribution of UV-4 During the Terminal Phase (Vz/F) After Multiple Doses [Day 7]

   Plasma concentrations of UV-4 are determined by means of high performance liquid chromatography/tandem mass spectrometric assay. Values of Vz/F are derived from individual subject plasma concentration-time data, calculated as CL/F divided by λz. Blood collected at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 5, 6, 8, 10, 12, and 14 hrs after the final dose on Day 7.

10. Apparent Terminal Half Life (t1/2) [Day 7]

    Plasma concentrations of UV-4 are determined by means of high performance liquid chromatography/tandem mass spectrometric assay. Values of t1/2 are derived from individual subject plasma concentration-time data, calculated as ln2/λz. Blood collected at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 5, 6, 8, 10, 12, and 14 hrs after the final dose on Day 7.

11. Accumulation Ratio (AR) [Day 7]

    Accumulation Ratio (AR) Day 1/Day 7

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 45 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

• Nonsmoking, healthy male or female subject aged 18 to 45 years, inclusive.

• Female subject is not pregnant and not lactating.

• (Female subjects only who are not postmenopausal or sterile) agreement to use hormonal contraception OR intrauterine device PLUS barrier contraception (condom or occlusive cap such as a diaphragm or surgical vault cap) AND spermicidal foam/gel/cream/suppository starting at least 14 days before the first dose and continuing for at least 3 months after the last dose.

• (Male subjects only) agreement to use barrier contraception during sexual intercourse and to also refrain from sperm donation from the first day of dosing until 3 months after the last dose of the study product.

• Body weight within 60 to 90 kg, inclusive, and body mass index between 18 to 32 kg/m², inclusive.

• Agreement to avoid strenuous exercise starting 4 days before the start of dosing through the period of confinement in the clinical unit and for at least 96 hours before the follow-up visits.

Exclusion Criteria:

• History of allergy to drugs in the iminosugar class.

• Treatment with any investigational products or therapies within 30 days (or 5 half-lives, whichever is greater) before the first day of dosing.

• Current or past history of disease/dysfunction of the pulmonary, cardiovascular, endocrine, hematologic, neurological, immune, gastrointestinal genitourinary, or other body system.

• Abnormalities on physical examination suggestive of conditions that may pose an increased risk to the subject; abnormal electrocardiogram results (excluding benign conditions); and Grade 1 or higher abnormalities in vital signs at screening and Grade 2 or higher abnormalities in vital signs at check-in based on a modified version of the FDA Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials.

• Clinical laboratory tests outside the normal range at screening and Grade 2 or higher at check-in to the clinical unit.

• Creatinine clearance < 90 mL/min (based on Cockcroft-Gault equation).

• Proteinuria greater than or equal to 1+.

• Any known or expected risk of bleeding.

• Scheduled surgical procedure during study participation.

• History of alcohol and/or drug abuse within 1 year prior to dosing and/or a positive urine drug screen for substances of abuse at screening or check-in. Urine alcohol above 50 mg/dL.

• Plasma or blood donation within 30 days before the first day of dosing or intention to donate within 30 days after the final day of dosing.

• Treatment with any medication, either prescription or nonprescription, including dietary supplements or herbal medications, within 14 days before dosing (within 30 days before dosing for hepatic or renal clearance-altering agents) and is unable to refrain from any medication during the study period. Exceptions are acetaminophen (not more than 2 g/day), vitamin products at recommended daily doses or hormonal birth control.

• Positive serology test for HIV antibodies, hepatitis B surface antigen, or hepatitis C virus antibody at screening.

• History of relevant food allergies (ie, eggs or other components of standard clinic meals) or unwilling to comply with diet restrictions.

• Psychological and/or emotional problems which would render the informed consent invalid, or limit the ability of the subject to comply with the study requirements;

• Concurrent enrollment in any other clinical trial within 30 days.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Clinical Research Unit	Dallas	Texas	United States	75247
2	Clinical Research Unit	Madison	Wisconsin	United States	53704

Sponsors and Collaborators

• Emergent BioSolutions
• National Institute of Allergy and Infectious Diseases (NIAID)

Investigators

• Study Director: Timothy Babinchak, MD, Emergent BioSolutions

Study Documents (Full-Text)

• Statistical Analysis Plan - May 31, 2017
• Study Protocol - Jan 10, 2017

More Information

Additional Information:

• For information on dengue fever

Publications

None provided.

• Responsible Party: Emergent BioSolutions
• ClinicalTrials.gov Identifier: NCT02696291
• Other Study ID Numbers: DMID 15-0062; HHSN272201100030C; 8311-270
• First Posted: Mar 2, 2016
• Last Update Posted: Mar 11, 2020
• Last Verified: Mar 1, 2020

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Keywords provided by Emergent BioSolutions: Dengue; Arbovirus Infections; Flaviviridae Infections; Flavivirus Infections; Hemorrhagic Fevers, Viral; RNA Virus Infections; Virus Diseases; Pharmaceutical Solutions; Pharmacologic Actions; Therapeutic Uses
• Additional relevant MeSH terms: Infections; Virus Diseases; Pharmaceutical Solutions

Study Results

Participant Flow

Recruitment Details	Healthy subjects were recruited from a phase 1 clinical research unit. Recruitment was initiated on 27 May 2016 and the last subject completed the final study visit for Cohort 1 on 02 March 2017.

Arm/Group Title	Cohort 1 - 30 mg UV-4B	Cohort 1 - Placebo
Arm/Group Description	Subjects receiving UV-4B 30 mg oral solution TID (every 8 ± 0.5 hours) for 7 days	Subjects receiving placebo TID (every 8 ± 0.5 hours) for 7 days
Period Title: Overall Study
STARTED	5	2
COMPLETED	5	2
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Cohort 1 - 30 mg UV-4B	Cohort 1 - Placebo	Total
Arm/Group Description	Subjects receiving UV-4B 30 mg oral solution TID (every 8 ± 0.5 hours) for 7 days	Subjects receiving placebo TID (every 8 ± 0.5 hours) for 7 days	Total of all reporting groups
Overall Participants	5	2	7
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	31.2 (8.3)	41.5 (4.9)	34.1 (8.7)
Sex: Female, Male (Count of Participants)
Female	3 60%	2 100%	5 71.4%
Male	2 40%	0 0%	2 28.6%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	2 40%	1 50%	3 42.9%
Not Hispanic or Latino	3 60%	1 50%	4 57.1%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	1 20%	0 0%	1 14.3%
White	4 80%	2 100%	6 85.7%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%
Body Mass Index (kg/m^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg/m^2]	26.0 (1.0)	28.4 (2.3)	26.7 (1.7)

Outcome Measures

1. Primary Outcome

Title	Number of Subjects Reporting Treatment-emergent Adverse Events (TEAEs) by Group
Description	The incidence of TEAEs spontaneously reported by subjects or elicited during examination is reported by dose group. Subjects having multiple TEAEs are counted only once.
Time Frame	From the time of first dosing on Day 1 through the Day 15 final follow-up visit

Outcome Measure Data

Analysis Population Description

Safety Population: all subjects who received at least one dose of study product or placebo.

Arm/Group Title	Cohort 1 - 30 mg UV-4B	Cohort 1 - Placebo
Arm/Group Description	Subjects receiving UV-4B 30 mg oral solution TID (every 8 ± 0.5 hours) for 7 days	Subjects receiving placebo TID (every 8 ± 0.5 hours) for 7 days
Measure Participants	5	2
Count of Participants [Participants]	5 100%	2 100%

2. Primary Outcome

Title	Number of Subjects Reporting Serious Adverse Events (SAEs) by Group
Description	The incidence of SAEs spontaneously reported by subjects or elicited during examination is reported by dose group. Subjects having multiple SAEs are counted only once.
Time Frame	From the time of first dosing on Day 1 through the Day 15 final follow-up visit

Outcome Measure Data

Analysis Population Description

Safety Population: all subjects who received at least one dose of study product or placebo.

Arm/Group Title	Cohort 1 - 30 mg UV-4B	Cohort 1 - Placebo
Arm/Group Description	Subjects receiving UV-4B 30 mg oral solution TID (every 8 ± 0.5 hours) for 7 days	Subjects receiving placebo TID (every 8 ± 0.5 hours) for 7 days
Measure Participants	5	2
Count of Participants [Participants]	1 20%	0 0%

3. Primary Outcome

Title	Number of Subjects With Clinical Laboratory Abnormalities of Toxicity Grade 1 or Higher by Group
Description	Clinical laboratory abnormalities are presented as the total of Grade 1 (mild) through Grade 4 (potentially life-threatening) abnormalities according to criteria adapted from the Food and Drug Administration (FDA) Guidance for Industry, Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials (September 2007) and the Division of Microbiology and Infectious Diseases (DMID) Adult Toxicity Table (November 2007). Within each parameter, subjects having multiple abnormalities are counted only once.
Time Frame	From the time of first dosing on Day 1 through the Day 15 final follow-up visit

Outcome Measure Data

Analysis Population Description

Safety Population: all subjects who received at least one dose of study product or placebo.

Arm/Group Title	Cohort 1 - 30 mg UV-4B	Cohort 1 - Placebo
Arm/Group Description	Subjects receiving UV-4B 30 mg oral solution TID (every 8 ± 0.5 hours) for 7 days	Subjects receiving placebo TID (every 8 ± 0.5 hours) for 7 days
Measure Participants	5	2
Any ≥ Grade 1 result	5 100%	2 100%
≥ Grade 1 activated partial thromboplastin time	1 20%	0 0%
≥ Grade 1 hemoglobin decreased	5 100%	2 100%
≥ Grade 1 leukocytes decreased	1 20%	0 0%
≥ Grade 1 magnesium decreased	0 0%	1 50%
≥ Grade 1 prothrombin time increased	4 80%	1 50%
≥ Grade 1 sodium decreased	1 20%	0 0%
≥ Grade 1 urine erythrocytes (present)	4 80%	2 100%

4. Secondary Outcome

Title	Number of Subjects With Outlying Vital Sign Results by Group
Description	Vital signs of blood pressure (BP), pulse, respiratory rate, and oral temperature were taken after being supine for 10 minutes. Orthostatic vital signs (BP, pulse) were taken after 2 minutes standing. Vital sign results are presented as the number of subjects having Grade 1 (mild) through Grade 4 (potentially life-threatening) abnormalities according to criteria adapted from the FDA Guidance for Industry, Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials (September 2007), or having abnormal orthostatic change (standing minus supine result). Within each parameter, subjects having multiple abnormalities are counted only once.
Time Frame	From the time of first dosing on Day 1 through the Day 15 final follow-up visit

Outcome Measure Data

Analysis Population Description

Safety Population: all subjects who received at least one dose of study product or placebo.

Arm/Group Title	Cohort 1 - 30 mg UV-4B	Cohort 1 - Placebo
Arm/Group Description	Subjects receiving UV-4B 30 mg oral solution TID (every 8 ± 0.5 hours) for 7 days	Subjects receiving placebo TID (every 8 ± 0.5 hours) for 7 days
Measure Participants	5	2
Any ≥ Grade 1 result	5 100%	2 100%
≥ Grade 1 supine systolic BP ≤ 89 mmHg	1 20%	0 0%
≥ Grade 1 supine pulse ≤ 50 bpm (if baseline ≤ 60)	1 20%	0 0%
≥ Grade 1 supine pulse ≤ 54 bpm (if baseline > 60)	1 20%	0 0%
≥ Grade 1 supine pulse ≥ 101 bpm	0 0%	1 50%
≥ Grade 1 respiratory rate ≥ 17 breaths/min	2 40%	1 50%
Any orthostatic change	5 100%	2 100%
Orthostatic change in diastolic BP ≤ -10 mmHg	1 20%	1 50%
Orthostatic change in pulse > 30 bpm	5 100%	1 50%

5. Secondary Outcome

Title	Number of Subjects With 12-lead Electrocardiogram (ECG) Abnormalities Postdose by Group
Description	ECGs (ventricular heart rate, wave intervals - PR, QRS, QT, QTcF) were recorded in a supine position (for at least 10 minutes). Baseline was calculated from the average of the triplicate ECGs on Day 1 predose. Within each parameter, subjects having multiple abnormalities are counted only once.
Time Frame	From the time of first dosing on Day 1 through the Day 15 final follow-up visit

Outcome Measure Data

Analysis Population Description

Safety Population: all subjects who received at least one dose of study product or placebo.

Arm/Group Title	Cohort 1 - 30 mg UV-4B	Cohort 1 - Placebo
Arm/Group Description	Subjects receiving UV-4B 30 mg oral solution TID (every 8 ± 0.5 hours) for 7 days	Subjects receiving placebo TID (every 8 ± 0.5 hours) for 7 days
Measure Participants	5	2
Any ECG abnormality	2 40%	0 0%
PR > 220 ms	2 40%	0 0%

6. Secondary Outcome

Title	Maximum Plasma Concentration (Cmax)
Description	Plasma concentrations of UV-4 are determined by means of high performance liquid chromatography/tandem mass spectrometric assay. Values of Cmax are derived from individual subject plasma concentration-time data. Blood collected at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 5, 6, and 8 hrs after the first dose on Day 1; and at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 5, 6, 8, 10, 12, and 14 hrs after the final dose on Day 7.
Time Frame	Day 1, Day 7

Outcome Measure Data

Analysis Population Description

Pharmacokinetic Population: all subjects who received study product, had measurable values, and completed scheduled postdose pharmacokinetic measurements without protocol deviations or events thought to significantly affect the pharmacokinetics of the drug.

Arm/Group Title	Cohort 1 - 30 mg UV-4B
Arm/Group Description	Subjects receiving UV-4B 30 mg oral solution TID (every 8 ± 0.5 hours) for 7 days
Measure Participants	5
Day 1 Cmax	291 (15.8)
Day 7 Cmax	285 (5.1)

7. Secondary Outcome

Title	Time of Maximum Plasma Concentration (Tmax)
Description	Plasma concentrations of UV-4 are determined by means of high performance liquid chromatography/tandem mass spectrometric assay. Values of tmax are derived from individual subject plasma concentration-time data. Blood collected at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 5, 6, and 8 hrs after the first dose on Day 1; and at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 5, 6, 8, 10, 12, and 14 hrs after the final dose on Day 7.
Time Frame	Day 1, Day 7

Outcome Measure Data

Analysis Population Description

Pharmacokinetic Population: all subjects who received study product, had measurable values, and completed scheduled postdose pharmacokinetic measurements without protocol deviations or events thought to significantly affect the pharmacokinetics of the drug.

Arm/Group Title	Cohort 1 - 30 mg UV-4B
Arm/Group Description	Subjects receiving UV-4B 30 mg oral solution TID (every 8 ± 0.5 hours) for 7 days
Measure Participants	5
Day 1 tmax	0.7 (0.2)
Day 7 tmax	1.0 (0.4)

8. Secondary Outcome

Title	Area Under the Concentration-time Curve From Time Zero (Predose) to Time of the Last Quantifiable Concentration After the Last Dose [AUC(0-last)]
Description	Plasma concentrations of UV-4 are determined by means of high performance liquid chromatography/tandem mass spectrometric assay. Values of AUC(0-last) are derived from individual subject plasma concentration-time data, calculated using the linear trapezoidal rule for increasing concentrations and the logarithmic rule for decreasing concentrations. Blood collected at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 5, 6, 8, 10, 12, and 14 hrs after the final dose on Day 7.
Time Frame	Day 7

Outcome Measure Data

Analysis Population Description

Pharmacokinetic Population: all subjects who received study product, had measurable values, and completed scheduled postdose pharmacokinetic measurements without protocol deviations or events thought to significantly affect the pharmacokinetics of the drug.

Arm/Group Title	Cohort 1 - 30 mg UV-4B
Arm/Group Description	Subjects receiving UV-4B 30 mg oral solution TID (every 8 ± 0.5 hours) for 7 days
Measure Participants	5
Geometric Mean (Geometric Coefficient of Variation) [ng*hr/mL]	1800 (14.2)

9. Secondary Outcome

Title	Total Daily Exposure at Steady State: Area Under the Concentration-time Curve From Time Zero (Predose) Until 24 Hours After the Last Dose [AUC(0-24)]
Description	Plasma concentrations of UV-4 are determined by means of high performance liquid chromatography/tandem mass spectrometric assay. Values of AUC(0-24) are derived from individual subject plasma concentration-time data, calculated as AUC(0-8) x 3 (Day 7 last dose only). Blood collected at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 5, 6, 8, 10, 12, and 14 hrs after the final dose on Day 7.
Time Frame	Day 7

Outcome Measure Data

Analysis Population Description

Pharmacokinetic Population: all subjects who received study product, had measurable values, and completed scheduled postdose pharmacokinetic measurements without protocol deviations or events thought to significantly affect the pharmacokinetics of the drug.

Arm/Group Title	Cohort 1 - 30 mg UV-4B
Arm/Group Description	Subjects receiving UV-4B 30 mg oral solution TID (every 8 ± 0.5 hours) for 7 days
Measure Participants	5
Geometric Mean (Geometric Coefficient of Variation) [ng*hr/mL]	3810 (3.7)

10. Secondary Outcome

Title	Area Under the Concentration-time Curve From Time Zero (Predose) Until 8 Hours After the Final Dose [AUC(0-8)]
Description	Plasma concentrations of UV-4 are determined by means of high performance liquid chromatography/tandem mass spectrometric assay. Values of AUC(0-8) are derived from individual subject plasma concentration-time data, calculated using the linear trapezoidal rule for increasing concentrations and the logarithmic rule for decreasing concentrations. Blood collected at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 5, 6, and 8 hrs after the first dose on Day 1; and at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 5, 6, 8, 10, 12, and 14 hrs after the final dose on Day 7.
Time Frame	Day 1, Day 7

Outcome Measure Data

Analysis Population Description

Pharmacokinetic Population: all subjects who received study product, had measurable values, and completed scheduled postdose pharmacokinetic measurements without protocol deviations or events thought to significantly affect the pharmacokinetics of the drug.

Arm/Group Title	Cohort 1 - 30 mg UV-4B
Arm/Group Description	Subjects receiving UV-4B 30 mg oral solution TID (every 8 ± 0.5 hours) for 7 days
Measure Participants	5
Day 1 AUC(0-8)	965 (8.7)
Day 7 AUC(0-8)	1270 (3.7)

11. Secondary Outcome

Title	Apparent Systemic Clearance (CL/F) at Steady State
Description	Plasma concentrations of UV-4 are determined by means of high performance liquid chromatography/tandem mass spectrometric assay. Values of CL/F are derived from individual subject plasma concentration-time data, calculated as dose (free-base equivalent) divided by AUC(0-8). Blood collected at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 5, 6, 8, 10, 12, and 14 hrs after the final dose on Day 7.
Time Frame	Day 7

Outcome Measure Data

Analysis Population Description

Pharmacokinetic Population: all subjects who received study product, had measurable values, and completed scheduled postdose pharmacokinetic measurements without protocol deviations or events thought to significantly affect the pharmacokinetics of the drug.

Arm/Group Title	Cohort 1 - 30 mg UV-4B
Arm/Group Description	Subjects receiving UV-4B 30 mg oral solution TID (every 8 ± 0.5 hours) for 7 days
Measure Participants	5
Geometric Mean (Geometric Coefficient of Variation) [L/h]	23.6 (3.7)

12. Secondary Outcome

Title	Apparent Volume of Distribution of UV-4 During the Terminal Phase (Vz/F) After Multiple Doses
Description	Plasma concentrations of UV-4 are determined by means of high performance liquid chromatography/tandem mass spectrometric assay. Values of Vz/F are derived from individual subject plasma concentration-time data, calculated as CL/F divided by λz. Blood collected at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 5, 6, 8, 10, 12, and 14 hrs after the final dose on Day 7.
Time Frame	Day 7

Outcome Measure Data

Analysis Population Description

Pharmacokinetic Population: all subjects who received study product, had measurable values, and completed scheduled postdose pharmacokinetic measurements without protocol deviations or events thought to significantly affect the pharmacokinetics of the drug.

Arm/Group Title	Cohort 1 - 30 mg UV-4B
Arm/Group Description	Subjects receiving UV-4B 30 mg oral solution TID (every 8 ± 0.5 hours) for 7 days
Measure Participants	5
Geometric Mean (Geometric Coefficient of Variation) [L]	246 (30.6)

13. Secondary Outcome

Title	Apparent Terminal Half Life (t1/2)
Description	Plasma concentrations of UV-4 are determined by means of high performance liquid chromatography/tandem mass spectrometric assay. Values of t1/2 are derived from individual subject plasma concentration-time data, calculated as ln2/λz. Blood collected at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 5, 6, 8, 10, 12, and 14 hrs after the final dose on Day 7.
Time Frame	Day 7

Outcome Measure Data

Analysis Population Description

Pharmacokinetic Population: all subjects who received study product, had measurable values, and completed scheduled postdose pharmacokinetic measurements without protocol deviations or events thought to significantly affect the pharmacokinetics of the drug.

Arm/Group Title	Cohort 1 - 30 mg UV-4B
Arm/Group Description	Subjects receiving UV-4B 30 mg oral solution TID (every 8 ± 0.5 hours) for 7 days
Measure Participants	5
Median (Full Range) [h]	8.1

14. Secondary Outcome

Title	Accumulation Ratio (AR)
Description	Accumulation Ratio (AR) Day 1/Day 7
Time Frame	Day 7

Outcome Measure Data

Analysis Population Description

Pharmacokinetic Population: all subjects who received study product, had measurable values, and completed scheduled postdose pharmacokinetic measurements without protocol deviations or events thought to significantly affect the pharmacokinetics of the drug.

Arm/Group Title	Cohort 1 - 30 mg UV-4B
Arm/Group Description	Subjects receiving UV-4B 30 mg oral solution TID (every 8 ± 0.5 hours) for 7 days
Measure Participants	5
Geometric Mean (Geometric Coefficient of Variation) [Ratio]	1.3 (5.8)

Adverse Events

Time Frame	Up to Day 15.
Adverse Event Reporting Description	On-treatment SAEs and non-serious AEs were collected from the start of investigational product until Day 15.
Arm/Group Title	Cohort 1 - 30 mg UV-4B		Cohort 1 - Placebo
Arm/Group Description	Subjects receiving UV-4B 30 mg oral solution TID (every 8 ± 0.5 hours) for 7 days		Subjects receiving placebo TID (every 8 ± 0.5 hours) for 7 days
All Cause Mortality
	Cohort 1 - 30 mg UV-4B		Cohort 1 - Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/5 (0%)		0/2 (0%)
Serious Adverse Events
	Cohort 1 - 30 mg UV-4B		Cohort 1 - Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/5 (20%)		0/2 (0%)
Gastrointestinal disorders
Haemorrhoids	1/5 (20%)	1	0/2 (0%)	0
Other (Not Including Serious) Adverse Events
	Cohort 1 - 30 mg UV-4B		Cohort 1 - Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	5/5 (100%)		2/2 (100%)
Cardiac disorders
Atrioventricular block first degree	1/5 (20%)	1	0/2 (0%)	0
Bradycardia	1/5 (20%)	1	0/2 (0%)	0
Gastrointestinal disorders
Flatulence	2/5 (40%)	2	0/2 (0%)	0
Abdominal pain	1/5 (20%)	1	0/2 (0%)	0
Constipation	1/5 (20%)	1	0/2 (0%)	0
Diarrhoea	1/5 (20%)	1	0/2 (0%)	0
Epigastric discomfort	1/5 (20%)	1	0/2 (0%)	0
Gingival bleeding	1/5 (20%)	1	0/2 (0%)	0
General disorders
Vessel puncture site haematoma	1/5 (20%)	1	1/2 (50%)	1
Vessel puncture site pain	1/5 (20%)	1	1/2 (50%)	1
Vessel puncture site haemorrhage	0/5 (0%)	0	1/2 (50%)	1
Investigations
Haemoglobin decreased	5/5 (100%)	5	2/2 (100%)	2
Prothrombin time prolonged	4/5 (80%)	4	1/2 (50%)	1
Activated partial thromboplastin time	1/5 (20%)	1	0/2 (0%)	0
White blood cell count decreased	1/5 (20%)	1	0/2 (0%)	0
Metabolism and nutrition disorders
Hypomagnesaemia	0/5 (0%)	0	1/2 (50%)	1
Hyponatraemia	1/5 (20%)	1	0/2 (0%)	0
Nervous system disorders
Dizziness	1/5 (20%)	1	0/2 (0%)	0
Headache	1/5 (20%)	1	0/2 (0%)	0
Renal and urinary disorders
Haematuria	3/5 (60%)	3	2/2 (100%)	2
Reproductive system and breast disorders
Testis discomfort	1/2 (50%)	1	0/2 (0%)	0

Limitations/Caveats

Study was terminated after Cohort 1. While no analysis was performed for change from baseline for physical exam (PE, a secondary endpoint), any change from baseline PE was reported/analyzed as an AE. AUC0-inf (secondary endpoint) was not calculated.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.