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Pleconaril Enteroviral Sepsis Syndrome

Primary Purpose

Enteroviral Sepsis

Status
Completed
Phase
Phase 2
Locations
International
Study Type
Interventional
Intervention
Placebo
Pleconaril (VP63843)
Sponsored by
National Institute of Allergy and Infectious Diseases (NIAID)
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Enteroviral Sepsis focused on measuring enterovirus, enteroviral sepsis, Pleconaril, infants

Eligibility Criteria

undefined - 15 Days (Child)All SexesDoes not accept healthy volunteers

Inclusion Criteria: Signed informed consent statement by parent or legal guardian. Age less than or equal to 15 days at time of onset of disease symptoms. Symptoms of systemic illness include but are not limited to fever, irritability, poor feeding, emesis, or diarrhea. Signs of systemic illness include, but are not limited to, jaundice, seizures, or lethargy. Onset of disease symptoms less than or equal to 10 days (240 hours) prior to administration of first dose of study medication. Birth weight greater than or equal to 1500 grams. Gestational age of greater than or equal to 32 weeks. Suspected or proven enteroviral disease. One or more of the following three conditions: serum glutamic pyruvic transaminase (SGPT) greater than 3 times the upper limit of normal (ULN); platelet count less than 100,000 and prothrombin time greater than 1.5 times ULN and positive fibrin split products; cardiac shortening fraction less than 25% or cardiac ejection fraction less than 50% as measured by echocardiography. Exclusion Criteria: Diagnosis of bacterial or non-enterovirus viral pathogen that can produce the constellation of presenting symptoms, known at the time of study enrollment. Imminent demise (estimated life expectancy less than 24 hours). Cyanotic congenital heart lesion. Alimentary tract abnormalities which may interfere with the absorption of the study drug. These include mechanical obstruction of the gastrointestinal tract, necrotizing enterocolitis, and severe ileus (the definition of which is left to the clinical judgment of the participating investigator). Infants known to be born to women who are human immunodeficiency virus (HIV) positive (but HIV testing is not required for study entry). These infants are at known risk of acquiring HIV, which would alter their immune response to other infections, including enteroviral infections. Additionally, they may be receiving antiretroviral and/or antiviral drugs during the time in which the study of pleconaril is being conducted. As such, they will be excluded if the mother's positive HIV status is known at the time of evaluation for study inclusion. If at any point following enrollment it is learned that an infant is HIV positive, however, he/she will be continued on the study protocol.

Sites / Locations

  • University of Alabama - Children's of Alabama - Clinical Virology
  • University of Arkansas - Arkansas Children's Hospital Research Institute
  • Ronald Reagan University of California Los Angeles Medical Center
  • Rady Children's Hospital San Diego
  • Stanford University - Stanford Hospital and Clinics - Pediatrics - Infectious Diseases
  • Children's Hospital Colorado - Infectious Disease
  • University of Florida - Shands Children's Hospital
  • The University of Chicago - Comer Children's Hospital - Infectious Diseases
  • University of Louisville School of Medicine - Kosair Childrens Hospital - Infectious Diseases
  • Tulane University - Tulane Medical Center - Pediatrics
  • University of Mississippi - Children's Infectious Diseases
  • Washington University School of Medicine in St. Louis - Center for Clinical Studies
  • University of Nebraska Medical Center - Children's Hospital and Medical Center - Infectious Diseases
  • Children's Hospital and Medical Center - Infectious Disease Clinic
  • Childrens Hospital at Saint Peters University Hospital - Allergy, Immunology and Infectious Diseases
  • Steven and Alexandra Cohen Childrens Medical Center of New York - New Hyde Park - Infectious Disease
  • SUNY Upstate Medical University Hospital - Pediatrics
  • Nationwide Children's Hospital - Infectious Diseases
  • Children's Hospital of Pittsburgh of UPMC - Allergy, Immunology and Infectious Diseases
  • Rhode Island Hospital - Pediatrics
  • Vanderbilt University - Pediatric - Infectious Diseases
  • Parkland Memorial Hospital
  • University of Texas Southwestern Medical Center - Pediatrics
  • Cook Children's Infectious Disease Services
  • University of Texas Medical Branch - Pediatrics - Infectious Diseases and Immunology - Galveston
  • University of Texas Health Science Center San Antonio - Pediatrics - Immunology & Infectious Disease
  • University of Alberta Hospital - Pediatrics

Arms of the Study

Arm 1

Arm 2

Arm Type

Placebo Comparator

Experimental

Arm Label

Placebo

Pleconaril (VP63843)

Arm Description

Placebo.

The first dosing cohort received 5 mg/kg/dose oral every 8 hours for 7 days (21 doses) of a 40 mg/mL oral liquid formulation. Subsequent dosing cohorts are receiving 8.5 mg/kg/dose oral every 8 hours for 7 days (21 doses) of a 40 mg/mL oral suspension formulation.

Outcomes

Primary Outcome Measures

Percentage of patients shedding virus (as detected by viral culture) from the oropharynx (i.e. throat).

Secondary Outcome Measures

Change in baseline laboratory abnormalities [aspartate aminotransferase (AST), alanine aminotransferase (ALT), bilirubin, platelets, creatinine), reflecting either resolution or progression of enteroviral disease.
Duration (in days) of total hospitalization.
Duration (in days) of shedding of virus (as detected by viral culture) from the rectum, oropharynx (i.e. throat), urine and serum.
Time (in days) to resolution of residual organ-related abnormalities following acute disease.
Safety.
Survival at two months of age.
Survival at one year of age.
Pleconaril pharmacokinetics.

Full Information

First Posted
March 6, 2002
Last Updated
February 28, 2013
Sponsor
National Institute of Allergy and Infectious Diseases (NIAID)
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1. Study Identification

Unique Protocol Identification Number
NCT00031512
Brief Title
Pleconaril Enteroviral Sepsis Syndrome
Official Title
A Double-Blind, Placebo-Controlled, Virologic Efficacy Trial of Pleconaril in the Treatment of Neonates With Enteroviral Sepsis Syndrome
Study Type
Interventional

2. Study Status

Record Verification Date
August 2012
Overall Recruitment Status
Completed
Study Start Date
June 2001 (undefined)
Primary Completion Date
September 2010 (Actual)
Study Completion Date
September 2012 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
National Institute of Allergy and Infectious Diseases (NIAID)

4. Oversight

5. Study Description

Brief Summary
A common group of viruses that infect humans are enteroviruses. Enteroviruses produce illnesses in children which may range from very mild (summer colds) to severe (infections of the brain, liver, and heart). The purpose of this study is to determine if a new drug called pleconaril helps treat babies with enteroviral sepsis. In addition, researchers are attempting to determine a safe and effective dose of pleconaril to help babies with this disease. Infants who are 15 days or younger when diagnosed with enteroviral disease are eligible for this study. Two out of 3 babies will be randomly assigned to receive Pleconaril and the other one out of three will receive a placebo (inactive substitute). Participants will be hospitalized while receiving study medication. Babies will receive standard treatment care for their symptoms and will be observed for their medical progress. Participants may be in the study for up to 2 years.
Detailed Description
Enteroviral infection is a serious health problem in the newborn infant. Approximately 60-70% of infants diagnosed with enteroviral disease within the first 10 days of life acquire their infection by transmission from the mother at the time of delivery. Congenital infection is rare but often fatal. Perinatal transmission of enteroviral infections in newborn nurseries has also been implicated as an important route of spread of the disease in newborn infants and postnatal transmission of enteroviral infections during seasonal peaks of enterovirus activity occurs commonly. Thus, during periods of high prevalence of enterovirus infection in the community, there are many potential sources of infection both during and after discharge from the nursery, including the mother, other family members, and hospital staff. Approximately 75% of cases of neonatal enteroviral disease carry a benign outcome, with diagnosis and symptomatic treatment in non-intensive care unit settings. For the remainder of patients, more serious consequences can result from systemic enteroviral infection, including meningoencephalitis, cardiovascular collapse, myocarditis, or hepatitis. These last two organ-specific complications carry high mortality rates. Historically, symptom management and supportive care have been the rule in the management of these patients. No specific therapeutic intervention is currently available for the management of these gravely ill neonates. The current study will evaluate the antiviral drug pleconaril as a treatment for enterovial sepsis syndrome. This trial is a multi-center, randomized, placebo-controlled study to evaluate the virologic efficacy, safety, and pharmacokinetics of pleconaril in the treatment of severe enteroviral sepsis syndrome. Patients will be randomized 2:1 to drug or placebo. For enrollment into this trial, infants must have evidence of severe hepatic involvement, myocardial involvement, and/or consumptive coagulopathy. Their age must be 15 days or less at the time of the onset of disease symptoms. Enrollment will continue until 45 subjects with confirmed enteroviral disease have been enrolled. The primary objective of this investigation is to determine if administration of pleconaril to critically ill neonates with enteroviral sepsis syndrome results in more rapid clearance of virus from various body sites. Other objectives of this study are to assess the safety and pharmacokinetics of this drug in this patient population. The effects of pleconaril on measures of clinical outcome also will be evaluated. These include the degree of inotropic and blood product support required during the acute illness; duration of hospitalization; the time to resolution of residual organ injury; and short-term (at 2 months of age) and long-term (at 1 year of age) survival. The primary endpoint will be the percentage of patients shedding virus (as detected by viral culture) from the oropharynx (i.e. throat) 5 days after beginning study drug. The secondary endpoints will include: duration (in days) of shedding of virus (as detected by viral culture) from the oropharynx, rectum, urine, and serum; change in baseline laboratory abnormalities [aspartate aminotransferase (AST), alanine aminotransferase (ALT), bilirubin, platelets, creatinine), reflecting either resolution or progression of enteroviral disease; pleconaril pharmacokinetics; safety; duration (in days) of total hospitalization; survival at 2 months of age; time (in days) to resolution of residual organ-related abnormalities following acute disease; and survival at 1 year of age.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Enteroviral Sepsis
Keywords
enterovirus, enteroviral sepsis, Pleconaril, infants

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigator
Allocation
Randomized
Enrollment
61 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
Placebo.
Arm Title
Pleconaril (VP63843)
Arm Type
Experimental
Arm Description
The first dosing cohort received 5 mg/kg/dose oral every 8 hours for 7 days (21 doses) of a 40 mg/mL oral liquid formulation. Subsequent dosing cohorts are receiving 8.5 mg/kg/dose oral every 8 hours for 7 days (21 doses) of a 40 mg/mL oral suspension formulation.
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
Placebo.
Intervention Type
Drug
Intervention Name(s)
Pleconaril (VP63843)
Intervention Description
5 mg/kg /dose oral every 8 hours for 7 days (21 doses) of a 40 mg/mL oral liquid formulation and 8.5 mg/kg/dose oral every 8 hours for 7 days (21 doses) of a 40 mg/mL oral suspension formulation.
Primary Outcome Measure Information:
Title
Percentage of patients shedding virus (as detected by viral culture) from the oropharynx (i.e. throat).
Time Frame
5 days after beginning study drug.
Secondary Outcome Measure Information:
Title
Change in baseline laboratory abnormalities [aspartate aminotransferase (AST), alanine aminotransferase (ALT), bilirubin, platelets, creatinine), reflecting either resolution or progression of enteroviral disease.
Time Frame
Day 1 (at study enrollment), 3, 5, 7, 10 and 14.
Title
Duration (in days) of total hospitalization.
Time Frame
At discharge from hospital.
Title
Duration (in days) of shedding of virus (as detected by viral culture) from the rectum, oropharynx (i.e. throat), urine and serum.
Time Frame
Day 1 (immediately prior to first dose of study drug), Days 2, 3, 4, 5, 7, 10 and 14.
Title
Time (in days) to resolution of residual organ-related abnormalities following acute disease.
Time Frame
Day(s) from onset of acute disease
Title
Safety.
Time Frame
After each clinical and safety evaluation during the treatment and follow-up period (through Day 180 +/- 14 days).
Title
Survival at two months of age.
Time Frame
2 months.
Title
Survival at one year of age.
Time Frame
1 year.
Title
Pleconaril pharmacokinetics.
Time Frame
Days 1, 3 and 7.

10. Eligibility

Sex
All
Maximum Age & Unit of Time
15 Days
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Signed informed consent statement by parent or legal guardian. Age less than or equal to 15 days at time of onset of disease symptoms. Symptoms of systemic illness include but are not limited to fever, irritability, poor feeding, emesis, or diarrhea. Signs of systemic illness include, but are not limited to, jaundice, seizures, or lethargy. Onset of disease symptoms less than or equal to 10 days (240 hours) prior to administration of first dose of study medication. Birth weight greater than or equal to 1500 grams. Gestational age of greater than or equal to 32 weeks. Suspected or proven enteroviral disease. One or more of the following three conditions: serum glutamic pyruvic transaminase (SGPT) greater than 3 times the upper limit of normal (ULN); platelet count less than 100,000 and prothrombin time greater than 1.5 times ULN and positive fibrin split products; cardiac shortening fraction less than 25% or cardiac ejection fraction less than 50% as measured by echocardiography. Exclusion Criteria: Diagnosis of bacterial or non-enterovirus viral pathogen that can produce the constellation of presenting symptoms, known at the time of study enrollment. Imminent demise (estimated life expectancy less than 24 hours). Cyanotic congenital heart lesion. Alimentary tract abnormalities which may interfere with the absorption of the study drug. These include mechanical obstruction of the gastrointestinal tract, necrotizing enterocolitis, and severe ileus (the definition of which is left to the clinical judgment of the participating investigator). Infants known to be born to women who are human immunodeficiency virus (HIV) positive (but HIV testing is not required for study entry). These infants are at known risk of acquiring HIV, which would alter their immune response to other infections, including enteroviral infections. Additionally, they may be receiving antiretroviral and/or antiviral drugs during the time in which the study of pleconaril is being conducted. As such, they will be excluded if the mother's positive HIV status is known at the time of evaluation for study inclusion. If at any point following enrollment it is learned that an infant is HIV positive, however, he/she will be continued on the study protocol.
Facility Information:
Facility Name
University of Alabama - Children's of Alabama - Clinical Virology
City
Birmingham
State/Province
Alabama
ZIP/Postal Code
35233-1711
Country
United States
Facility Name
University of Arkansas - Arkansas Children's Hospital Research Institute
City
Little Rock
State/Province
Arkansas
ZIP/Postal Code
72202-3500
Country
United States
Facility Name
Ronald Reagan University of California Los Angeles Medical Center
City
Los Angeles
State/Province
California
ZIP/Postal Code
90095-1752
Country
United States
Facility Name
Rady Children's Hospital San Diego
City
San Diego
State/Province
California
ZIP/Postal Code
92123-4223
Country
United States
Facility Name
Stanford University - Stanford Hospital and Clinics - Pediatrics - Infectious Diseases
City
Stanford
State/Province
California
ZIP/Postal Code
94305-2200
Country
United States
Facility Name
Children's Hospital Colorado - Infectious Disease
City
Aurora
State/Province
Colorado
ZIP/Postal Code
80045-7106
Country
United States
Facility Name
University of Florida - Shands Children's Hospital
City
Gainesville
State/Province
Florida
ZIP/Postal Code
32610-0296
Country
United States
Facility Name
The University of Chicago - Comer Children's Hospital - Infectious Diseases
City
Chicago
State/Province
Illinois
ZIP/Postal Code
60637-1425
Country
United States
Facility Name
University of Louisville School of Medicine - Kosair Childrens Hospital - Infectious Diseases
City
Louisville
State/Province
Kentucky
ZIP/Postal Code
40202-1821
Country
United States
Facility Name
Tulane University - Tulane Medical Center - Pediatrics
City
New Orleans
State/Province
Louisiana
ZIP/Postal Code
70112-2600
Country
United States
Facility Name
University of Mississippi - Children's Infectious Diseases
City
Jackson
State/Province
Mississippi
ZIP/Postal Code
39216-4505
Country
United States
Facility Name
Washington University School of Medicine in St. Louis - Center for Clinical Studies
City
Saint Louis
State/Province
Missouri
ZIP/Postal Code
63110-1010
Country
United States
Facility Name
University of Nebraska Medical Center - Children's Hospital and Medical Center - Infectious Diseases
City
Omaha
State/Province
Nebraska
ZIP/Postal Code
68114-4108
Country
United States
Facility Name
Children's Hospital and Medical Center - Infectious Disease Clinic
City
Omaha
State/Province
Nebraska
ZIP/Postal Code
68114-4113
Country
United States
Facility Name
Childrens Hospital at Saint Peters University Hospital - Allergy, Immunology and Infectious Diseases
City
New Brunswick
State/Province
New Jersey
ZIP/Postal Code
08901-1766
Country
United States
Facility Name
Steven and Alexandra Cohen Childrens Medical Center of New York - New Hyde Park - Infectious Disease
City
New Hyde Park
State/Province
New York
ZIP/Postal Code
11040-1433
Country
United States
Facility Name
SUNY Upstate Medical University Hospital - Pediatrics
City
Syracuse
State/Province
New York
ZIP/Postal Code
13210-2342
Country
United States
Facility Name
Nationwide Children's Hospital - Infectious Diseases
City
Columbus
State/Province
Ohio
ZIP/Postal Code
43205-2664
Country
United States
Facility Name
Children's Hospital of Pittsburgh of UPMC - Allergy, Immunology and Infectious Diseases
City
Pittsburgh
State/Province
Pennsylvania
ZIP/Postal Code
15213-3320
Country
United States
Facility Name
Rhode Island Hospital - Pediatrics
City
Providence
State/Province
Rhode Island
ZIP/Postal Code
02903-4923
Country
United States
Facility Name
Vanderbilt University - Pediatric - Infectious Diseases
City
Nashville
State/Province
Tennessee
ZIP/Postal Code
37232-0011
Country
United States
Facility Name
Parkland Memorial Hospital
City
Dallas
State/Province
Texas
ZIP/Postal Code
75235-7708
Country
United States
Facility Name
University of Texas Southwestern Medical Center - Pediatrics
City
Dallas
State/Province
Texas
ZIP/Postal Code
75390-9063
Country
United States
Facility Name
Cook Children's Infectious Disease Services
City
Fort Worth
State/Province
Texas
ZIP/Postal Code
76104-2710
Country
United States
Facility Name
University of Texas Medical Branch - Pediatrics - Infectious Diseases and Immunology - Galveston
City
Galveston
State/Province
Texas
ZIP/Postal Code
77555-5302
Country
United States
Facility Name
University of Texas Health Science Center San Antonio - Pediatrics - Immunology & Infectious Disease
City
San Antonio
State/Province
Texas
ZIP/Postal Code
78229-3901
Country
United States
Facility Name
University of Alberta Hospital - Pediatrics
City
Edmonton
State/Province
Alberta
ZIP/Postal Code
T6G 2B7
Country
Canada

12. IPD Sharing Statement

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Pleconaril Enteroviral Sepsis Syndrome

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