Acyclovir for Herpes Infections Involving the Central Nervous System in Neonates
A Placebo-Controlled Phase III Evaluation of Suppressive Therapy With Oral Acyclovir Suspension Following Neonatal Herpes Simplex Virus Infections Involving the Central Nervous System
4 other identifiers
interventional
46
2 countries
29
Brief Summary
The purpose of this study is to test whether long term treatment with acyclovir given orally (by mouth) improves the outcome for infants with herpes simplex virus infection of the brain or spinal cord (known as the central nervous system \[CNS\]). Infants with herpes viral infection of the CNS that has or has not spread to other parts of the body will be enrolled in this study. All participants will receive treatment in a hospital for 21 days with acyclovir, given intravenously (by a needle inserted into a vein). Participants will then be divided into two groups: those with CNS disease that has or has not spread to the skin, and those whose viral infection has spread and involves the CNS. Both groups will be randomly assigned to receive either oral acyclovir or placebo (inactive substance) for 6 months. Infants in the US and Canada will participate for 5 years. A physical exam, hearing exam, eye exam, and an evaluation of the nervous system will be performed throughout the study.
Trial Health
Trial Health Score
Automated assessment based on enrollment pace, timeline, and geographic reach
participants targeted
Target at below P25 for phase_3
Started Dec 1997
Longer than P75 for phase_3
29 active sites
Health score is calculated from publicly available data and should be used for screening purposes only.
Trial Relationships
Click on a node to explore related trials.
Study Timeline
Key milestones and dates
Study Start
First participant enrolled
December 1, 1997
CompletedFirst Submitted
Initial submission to the registry
March 6, 2002
CompletedFirst Posted
Study publicly available on registry
March 7, 2002
CompletedPrimary Completion
Last participant's last visit for primary outcome
February 1, 2008
CompletedStudy Completion
Last participant's last visit for all outcomes
April 1, 2008
CompletedResults Posted
Study results publicly available
April 9, 2010
CompletedMay 16, 2012
October 1, 2009
10.2 years
March 6, 2002
April 2, 2009
May 10, 2012
Conditions
Keywords
Outcome Measures
Primary Outcomes (2)
Participants With Neurologic Impairment at 12 Months as Measured by a Bayley's Neuro-developmental Assessment (Motor Scores).
Motor scores of all participants completing 6 months of blinded therapy as measured by the Bayleys neuro-developmental assessment at 12 months. Scores are classified as the following: greater than or equal to 115 suggests accelerated performance; 85 - 114 suggests development within normal limits; 70 - 84 suggests mildly delayed development; and less than or equal to 69 suggests significant delayed development.
At 12 months of life.
Participants With Neurologic Impairment at 12 Months as Measured by Bayley's Neuro-developmental Assessment.(Mental Scores)
Mental scores of all subjects completing 6 months of blinded therapy as measured by the Bayleys neuro-developmental assessment at 12 months. Scores are classified as the following: greater than or equal to 115 suggests accelerated performance; 85 - 114 suggests development within normal limits; 70 - 84 suggests mildly delayed development; and less than or equal to 69 suggests significant delayed development.
At 12 months of life.
Secondary Outcomes (2)
Number of Participants With Two or Fewer Episodes of Cutaneous Recurrence of Herpes Simplex Virus (HSV) Disease Post-randomization During the Initial 12 Months of Life.
post randomization - 12 months
Detection of Herpes Simplex Virus (HSV) DNA in the Cerebrospinal Fluid (CSF) by PCR at Anytime During the Initial 12 Months of Life.
post randomization - 12 months
Study Arms (2)
Acyclovir
EXPERIMENTALPlacebo
PLACEBO COMPARATORInterventions
Oral banana flavored acyclovir suspension: 300 mg/m\^2/dose three times a day (TID), to be given at least 6 to 8 hours apart for 6 months. Dosage adjustments will be made monthly to compensate for increases in body surface area.
Oral banana flavored placebo suspension: to be given at least 6 to 8 hours apart for 6 months. Dosage adjustments will be made monthly to compensate for increases in body surface area.
Eligibility Criteria
You may qualify if:
- Viral Culture:
- If cutaneous lesions are present, then isolation of Herpes Simplex Virus (HSV)-1 or HSV-2 by viral culture from any site (skin, oropharynx, cerebral spinal fluid \[CSF\], urine, etc.) will be required for study entry.
- If cutaneous lesions are not present, then viral isolation by culture is adequate for study entry but is not required. In the case of no cutaneous lesions and negative viral cultures, however, the CSF polymerase chain reaction (PCR) must be positive.
- Additional sites from which HSV culture will be attempted include conjunctivae, oropharynx, blood buffy coat, urine, and CSF.
- Evidence for central nervous system (CNS) HSV disease during the acute illness, including one or more of the following:
- Abnormal CSF indices for term infants: greater than 22 white blood cells (WBCs)/mm\^3 and protein greater than 115mg/dl.
- Abnormal CSF indices for preterm infants: greater than 25 WBCs/mm\^3 and protein greater than 220 mg/dl.
- Abnormal neuroimaging study (computed tomography \[CT\] with contrast, magnetic resonance imaging \[MRI\] with gadolinium, or head ultrasound) \[NOTE: CT with contrast is the preferred imaging study\].
- Abnormal electroencephalography (EEG), if performed (NOTE: EEG is suggested for the evaluation of infants with HSV disease but is not required for this study\].
- Positive CSF PCR for HSV deoxyribonucleic acid (DNA) \[NOTE: If no cutaneous lesions are present and all viral cultures are negative, the CSF PCR must be positive. If lesions are present and are culture-positive, abnormal CNS neurodiagnostic studies or abnormal CSF indices are sufficient for study entry\].
- Negative CSF PCR result within 48 hours prior to completion of intravenous acyclovir therapy.
- Less than or equal to 28 days of age at the time of initial presentation with CNS disease.
- Birth weight greater than or equal to 800 grams.
You may not qualify if:
- Infants with either a grade 3 or grade 4 intraventricular hemorrhage (IHV) prior to study enrollment.
- Breast feeding infants whose mothers are taking acyclovir, valacyclovir, or famciclovir for greater than 120 hours (greater than 5 days). If at any point following enrollment the mother takes these antiviral drugs for greater than 120 hours (greater than 5 days), she will be asked to refrain from breast feeding while taking the drug.
- Infants with HSV infection limited to the skin, eyes, or mouth (SEM). Patients with SEM HSV infection will be considered for enrollment and randomization in the ongoing Collaborative Antiviral Study Group (CASG) evaluation of oral suppressive acyclovir therapy following neonatal HSV infections limited to the SEM.
- Infants with creatinine greater than 1.5 mg/dl at time of study enrollment.
Contact the study team to confirm eligibility.
Sponsors & Collaborators
Study Sites (29)
University of Alabama at Birmingham
Birmingham, Alabama, 35233, United States
Arkansas Children's Hospital, Department of Infectious Diseases
Little Rock, Arkansas, 72202, United States
Children's Hospital Los Angeles - Pediatrics Infectious Diseases
Los Angeles, California, 90027, United States
Rady Children's Hospital San Diego
San Diego, California, 92123, United States
Stanford University School of Medicine
Stanford, California, 94305-5208, United States
University of Florida - College of Medicine - Jacksonville
Jacksonville, Florida, 32209, United States
The University of Chicago - Comer Children's Hospital - Infectious Diseases
Chicago, Illinois, 60637, United States
Kosair Children's Hospital
Louisville, Kentucky, 40202, United States
Tulane University - Tulane Medical Center - Department of Pediatrics
New Orleans, Louisiana, 70112, United States
Maine Medical Center - Department of Pediatric Specialty Care - Infectious Disease
Portland, Maine, 04101, United States
Johns Hopkins Hospital
Baltimore, Maryland, 21287, United States
Children's Hospital of Michigan - Pediatric Infectious Diseases
Detroit, Michigan, 48201, United States
University of Mississippi
Jackson, Mississippi, 39216-4505, United States
St. Louis Children's Hospital - Infectious Disease
St Louis, Missouri, 63110, United States
Mount Sinai Hospital
New York, New York, 10029, United States
UNY Upstate Medical University Hospital - Pediatrics
Syracuse, New York, 13210, United States
Carolinas Medical Center
Charlotte, North Carolina, 28203, United States
Cincinnati Children's Hospital Medical Center
Cincinnati, Ohio, 45231, United States
MetroHealth Medical Center - Pediatric Infectious Disease
Cleveland, Ohio, 44109-1998, United States
Nationwide Children's Hospital - Infectious Diseases
Columbus, Ohio, 43205, United States
Oregon Health and Science University
Portland, Oregon, 97201-3098, United States
Rhode Island Hospital
Providence, Rhode Island, 02903, United States
Medical University of South Carolina
Charleston, South Carolina, 29425, United States
Vanderbilt University
Nashville, Tennessee, 37232-2581, United States
University of Texas Southwestern Medical Center
Dallas, Texas, 75390-9063, United States
Cook Children's Infectious Disease Services
Fort Worth, Texas, 76104, United States
University of Texas Health Science Center San Antonio - Pediatrics - Immunology & Infectious Disease
San Antonio, Texas, 78229, United States
Seattle Children's Hospital - Infectious Diseases
Seattle, Washington, 98105, United States
University of Alberta - Aberhart Centre - Pediatrics
Edmonton, Alberta, T6R 2C2, Canada
Related Publications (1)
Kimberlin DW, Whitley RJ, Wan W, Powell DA, Storch G, Ahmed A, Palmer A, Sanchez PJ, Jacobs RF, Bradley JS, Robinson JL, Shelton M, Dennehy PH, Leach C, Rathore M, Abughali N, Wright P, Frenkel LM, Brady RC, Van Dyke R, Weiner LB, Guzman-Cottrill J, McCarthy CA, Griffin J, Jester P, Parker M, Lakeman FD, Kuo H, Lee CH, Cloud GA; National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group. Oral acyclovir suppression and neurodevelopment after neonatal herpes. N Engl J Med. 2011 Oct 6;365(14):1284-92. doi: 10.1056/NEJMoa1003509.
PMID: 21991950RESULT
MeSH Terms
Conditions
Interventions
Condition Hierarchy (Ancestors)
Intervention Hierarchy (Ancestors)
Results Point of Contact
- Title
- Penelope M. Jester
- Organization
- Collaborative Antiviral Study Group
Publication Agreements
- PI is Sponsor Employee
- No
- Restrictive Agreement
- No
Study Design
- Study Type
- interventional
- Phase
- phase 3
- Allocation
- RANDOMIZED
- Masking
- TRIPLE
- Who Masked
- PARTICIPANT, CARE PROVIDER, INVESTIGATOR
- Purpose
- TREATMENT
- Intervention Model
- PARALLEL
- Sponsor Type
- NIH
- Responsible Party
- SPONSOR
Study Record Dates
First Submitted
March 6, 2002
First Posted
March 7, 2002
Study Start
December 1, 1997
Primary Completion
February 1, 2008
Study Completion
April 1, 2008
Last Updated
May 16, 2012
Results First Posted
April 9, 2010
Record last verified: 2009-10