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

This study has been terminated.
(Study termination was precipitated by a decision from NIAID who will complete the study (Cohorts 2 through 5) under NIAID sponsorship.)
Sponsor:
ClinicalTrials.gov Identifier:
NCT02696291
First Posted: March 2, 2016
Last Update Posted: June 22, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
Collaborator:
National Institute of Allergy and Infectious Diseases (NIAID)
Information provided by (Responsible Party):
Emergent BioSolutions
  Purpose
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 Intervention 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

Study Type: Interventional
Study Design: 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

Resource links provided by NLM:


Further study details as provided by Emergent BioSolutions:

Primary Outcome Measures:
  • Number of subjects reporting AEs by group [ Time Frame: From the time of first dosing on Day 1 through the Day 15 final follow-up visit ]
    The incidence of AEs spontaneously reported by subjects or elicited during examination is reported by dose group. Subjects having multiple AEs are counted only once.

  • 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.

  • 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 tests are performed at screening, Day -1, Days 1-8, Day 10, and Day 15. Clinical laboratory abnormalities are presented as the total of Grade 1 (mild), Grade 2 (moderate), Grade 3 (severe), and 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). Within each parameter, subjects having multiple abnormalities are counted only once for their highest severity grade level.


Secondary Outcome Measures:
  • Number of subjects with clinically significant abnormalities during PE by group [ Time Frame: From the time of first dosing on Day 1 through the Day 15 final follow-up visit ]
    Evaluations are conducted at screening and Day 15 (complete PE); Day -1, Day 8, and Day 10 (abbreviated PE and neurological exam); Day -1, Days 1-8, and Day 10 (brief PE); and as needed at other time points (targeted PE). A complete PE includes evaluation of the skin, head/eyes/ears/nose/throat, lymph nodes, heart, lungs, abdomen, extremities, joints, and other. An abbreviated PE includes evaluation of general appearance, heart, lungs, skin, abdomen, and other. A neurological exam includes evaluation of mental status, motor system, sensory system, and other. A brief PE includes evaluation of skin, oropharyngeal mucosa, and other. Targeted PEs are conducted if an AE is reported or if otherwise warranted. Findings are specified by site/system and reported as normal, abnormal not clinically significant, abnormal clinically significant, and not performed. The number of subjects with clinically significant abnormalities is reported. Subjects having multiple abnormalities are counted once.

  • Number of subjects with vital sign 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 ]
    Vital signs taken after being supine for 10 minutes are blood pressure, pulse rate, respiratory rate, and oral temperature (performed at screening; Day -1; Days 1-7 at predose and hourly up until 2 hours after the third dose of the study drug; Day 8; Day 10; and Day 15). Orthostatic vital signs taken after 2 minutes standing are blood pressure and pulse rate (performed at screening; Day -1; and Days 1-8 at predose and hourly up until 2 hours after the third dose of the study drug). Vital signs abnormalities are presented as the total of 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). Within each parameter, subjects having multiple abnormalities are counted only once for their highest severity grade level.

  • Number of subjects with 12-lead ECG abnormalities postdose by group [ Time Frame: Evaluations conducted at screening, Day -1, Days 1-8, Day 10, and Day 15. ]
    Results are recorded in a supine position (for at least 10 minutes) as ventricular heart rate, wave intervals (PR, QRS, QT, QTcF), interpretation (normal; abnormal, not clinically significant; abnormal, clinically significant), and specification of any abnormal result. Triplicate ECGs are collected on Day 1 predose and single ECGs at other time points. Baseline is calculated from the average of the triplicate ECGs on Day 1 predose. If a subject experiences more than one episode of abnormality for the same parameter, the subject is counted only once for the parameter.

  • Maximum plasma concentration (Cmax) [ Time Frame: Blood collected pre-first dose on Days 1-6; at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 5, 6, and 8 hrs after the first dose on Day 1; Days 7-8 before the final dose 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; and Day 10. ]
    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.

  • Time of maximum plasma concentration (tmax) [ Time Frame: Blood collected pre-first dose on Days 1-6; at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 5, 6, and 8 hrs after the first dose on Day 1; Days 7-8 before the final dose 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; and Day 10. ]
    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.

  • Area under the concentration-time curve from time zero (predose) to time of the last quantifiable concentration [AUC(0-last)] [ Time Frame: Blood collected pre-first dose on Days 1-6; at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 5, 6, and 8 hrs after the first dose on Day 1; Days 7-8 before the final dose 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; and Day 10. ]
    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 by linear up/log down trapezoidal summation.

  • Area under the concentration-time curve from time zero (predose) until 24 hours after the last dose [AUC(0-24)] [ Time Frame: Blood collected pre-first dose on Days 1-6; at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 5, 6, and 8 hrs after the first dose on Day 1; Days 7-8 before the final dose 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; and Day 10. ]
    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 by linear up/log down trapezoidal summation.

  • Area under the concentration-time curve from time zero (predose) extrapolated to infinite time [AUC(0-inf)] [ Time Frame: Blood collected pre-first dose on Days 1-6; at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 5, 6, and 8 hrs after the first dose on Day 1; Days 7-8 before the final dose 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; and Day 10. ]
    Plasma concentrations of UV-4 are determined by means of high performance liquid chromatography/tandem mass spectrometric assay. Values of AUC(0-inf) are derived from individual subject plasma concentration-time data, 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)/λz.

  • Apparent systemic clearance (CL/F) [ Time Frame: Blood collected pre-first dose on Days 1-6; at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 5, 6, and 8 hrs after the first dose on Day 1; Days 7-8 before the final dose 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; and Day 10. ]
    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-inf).

  • Apparent volume of distribution of UV-4 based on the terminal phase (Vz/F) [ Time Frame: Blood collected pre-first dose on Days 1-6; at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 5, 6, and 8 hrs after the first dose on Day 1; Days 7-8 before the final dose 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; and Day 10. ]
    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 dose (free-base equivalent) divided by [λz x AUC(0-inf)].

  • Apparent terminal half life (t1/2) [ Time Frame: Blood collected pre-first dose on Days 1-6; at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 5, 6, and 8 hrs after the first dose on Day 1; Days 7-8 before the final dose 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; and Day 10. ]
    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.


Enrollment: 7
Actual Study Start Date: May 27, 2016
Study Completion Date: March 2, 2017
Primary Completion Date: February 15, 2017 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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

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.
  Eligibility

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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.
  Contacts and Locations
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
Covance Clinical Research Unit
Dallas, Texas, United States, 75247
United States, Wisconsin
Covance 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
  More Information

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 Submitted: February 22, 2016
First Posted: March 2, 2016
Last Update Posted: June 22, 2017
Last Verified: June 2017
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