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

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ClinicalTrials.gov Identifier: NCT02696291
Recruitment Status : Terminated (Product development halted for business reasons.)
First Posted : March 2, 2016
Results First Posted : March 16, 2018
Last Update Posted : April 18, 2018
Sponsor:
Collaborator:
National Institute of Allergy and Infectious Diseases (NIAID)
Information provided by (Responsible Party):
Emergent BioSolutions

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 Type : Interventional  (Clinical Trial)
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 : March 2, 2017
Actual Study Completion Date : March 2, 2017


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



Primary Outcome Measures :
  1. Number of Subjects Reporting Treatment-emergent Adverse Events (TEAEs) by Group [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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)] [ Time Frame: 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)] [ Time Frame: 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)] [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: Day 7 ]
    Plasma concentrations of UV-4 are determined by means of high performance liquid chromatography/tandem mass spectrometric assay. AR is derived from individual subject plasma concentration-time data, calculated as AUC(0-8) after the last dose divided by AUC(0-8) after the first dose. 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.



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Ages Eligible for Study:   18 Years to 45 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02696291


Locations
United States, Texas
Clinical Research Unit
Dallas, Texas, United States, 75247
United States, Wisconsin
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)

Documents provided by Emergent BioSolutions:
Statistical Analysis Plan  [PDF] May 31, 2017
Study Protocol  [PDF] January 10, 2017


Additional Information:
Responsible Party: Emergent BioSolutions
ClinicalTrials.gov Identifier: NCT02696291     History of Changes
Other Study ID Numbers: DMID 15-0062
HHSN272201100030C ( Other Grant/Funding Number: NIAID )
8311-270 ( Other Identifier: Covance )
First Posted: March 2, 2016    Key Record Dates
Results First Posted: March 16, 2018
Last Update Posted: April 18, 2018
Last Verified: March 2018
Individual Participant Data (IPD) Sharing Statement:
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:
Infection
Virus Diseases
Pharmaceutical Solutions