Clinical trial NCT00031447: Acyclovir Herpes Simplex Virus (HSV) Skin, Eye, and Mouth
Official title: A Placebo-Controlled Phase III Evaluation of Suppressive Therapy With Oral Acyclovir Suspension Following Neonatal Herpes Simplex Virus Infections Limited to the Skin, Eye, and Mouth
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Herpes Simplex
Keywords: Herpes Simplex, Acyclovir, Infants
Lead sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Sponsor class: NIH
First posted: 2002-03-07
Enrollment: 29
Sex: ALL
Maximum age (years): 28
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to test whether long-term treatment with oral acyclovir improves the outcome for infants with herpes simplex virus (HSV) disease of the skin, eyes, and mouth (SEM). Study participants will include infants in the United States and Canada who have HSV disease of the skin, eyes, and mouth, with no central nervous system disease present. Initially, all subjects will be treated with acyclovir administered through IV access (through the vein) for 14 days while hospitalized. Participants will then be placed in one of two groups, acyclovir given by mouth or a placebo (substance with no medication present). The participant and the study site will not know to which group the subject is assigned. All children will be followed at 6, 12, 24, 36, 48, and 60 months of age. During the follow up visits, physicals, hearing assessments, eye assessments, and neurological assessments will be completed.

Detailed description: Neonatal herpes simplex virus (HSV) disease complicates approximately one in every 3,000 births in the United States. This study will be a placebo-controlled Phase III evaluation of suppressive therapy with oral Acyclovir suspension following neonatal HSV infections limited to the skin, eyes, and mouth (SEM). This study will evaluate the efficacy of long-term suppressive therapy with oral acyclovir in infants with SEM disease. It will determine if suppressive oral acyclovir therapy improves neurological outcome in infants following SEM disease. Only infants with SEM disease will qualify for this study. After qualifying for the study and obtaining informed consent, the infant will complete 14 days of intravenous (IV) Acyclovir (20 mg/kg/dose given every 8 hours). Patients will be randomized to receive suppressive oral Acyclovir versus placebo only if they continue to meet all study inclusion criteria at the completion of the IV therapy. This study will be double-blinded and placebo controlled. At the time of randomization, the patient will be placed in 1 of 2 groups (oral suppressive Acyclovir versus placebo). If a patient in either group has a cutaneous HSV recurrence, open-label oral Acyclovir (80 mg/kg/day divided into 4 doses per day) will be provided for 5 days. During the time of administration of open-label oral Acyclovir, study drug will be withheld. All children will be followed at 6, 12, 24, 36, 48, and 60 months of age. Physical examination, hearing assessment, and retinal examination will be performed at each follow up visit. Standardized neurologic evaluation will be performed at 12, 24, 36, 48, and 60 months of age.

Eligibility criteria: Inclusion Criteria:

* Isolation by viral culture of herpes simplex virus (HSV)-1or HSV-2 from cutaneous lesions, conjunctivae, or oropharynx. Detection of HSV at any of these sites is sufficient, and the presence of skin lesions is not required for study enrollment.
* Normal cerebrospinal fluid (CSF) indices (\<22 white blood cells (WBCs)/mm\^3 and protein \<115 mg/dl for term infants; (\<25 WBCs/mm\^3 and protein \<220 mg/dl for preterm infants both at the time of diagnosis of HSV disease and at the time of study randomization.
* No evidence of HSV central nervous system (CNS) disease by computed tomography (CT) with contrast, magnetic resonance imaging (MRI) with gadolinium, or head ultrasound (HUS) \[NOTE: CT with contrast is the preferred imaging study\].
* Normal electroencephalogram (EEG), if performed \[NOTE: EEG is suggested for the evaluation of infants with HSV disease but is not required for this study\].
* No evidence of visceral dissemination of HSV infection (normal liver function tests, normal chest x-ray, etc.).
* Negative CSF HSV polymerase chain reaction (PCR) results from specimens obtained both within 72 hours of initiation of intravenous acyclovir therapy and 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 skin, eyes, and mouth (SEM) disease.
* Birth weight greater than or equal to equal to 800 grams.

Exclusion Criteria:

* Infants with either grade 3 or grade 4 intraventricular hemorrhage (IVH) prior to study enrollment.
* Breast feeding infants whose mothers are taking acyclovir, valacyclovir, or famciclovir for \>120 hours (\>5 days). If at any point following enrollment the mother takes these antiviral drugs for \>120 hours (\>5 days), she will be asked to refrain from breast feeding while taking the drug.
* 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 for acquiring HIV, which would alter their immune response to other infections, including HSV infection. Additionally, they may be receiving antiretroviral and/or antiviral drugs during the time in which the study of suppressive oral acyclovir 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, he/she will be continued on the study protocol.
* Infants with either central nervous system (CNS) or disseminated HSV infection. Patients with CNS 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 involving the CNS.
* Infants with creatinine \>1.5mg/dl at time of study enrollment.
* Infants receiving acyclovir expectantly do not qualify for this study because they never developed HSV disease. Expectant therapy describes infants who are cultured at approximately 24 hours of life because of a risk of HSV infection (i.e. they are born to women with active genital lesions). Oftentimes, if these cultures are positive, the infant will receive a course of intravenous acyclovir to prevent the development of HSV disease. However, since they never actually had HSV disease, their potential outcome cannot be compared with infants with typical skin, eyes, and mouth (SEM) disease, and so they are not included in this study.

Primary outcomes:
measure: Participants With Neurologic Impairment at 12 Months as Measured by a Bayley's Neuro-developmental Assessment.(Motor Scores)
timeFrame: At 12 months of life.
measure: Participants With Neurologic Impairment at 12 Months as Measured by a Bayley's Neuro-developmental Assessment.(Mental Scores)
timeFrame: At 12 months of life.
Secondary outcomes:
measure: Detection of Herpes Simplex Virus (HSV) DNA in the Cerebrospinal Fluid (CSF) by Polymerase Chain Reaction (PCR) at Anytime During the Initial 12 Months of Life.
timeFrame: post randomization at 12 months
measure: Two or Fewer Episodes of Cutaneous Recurrence of HSV Disease Post-randomization During the Initial 12 Months of Life.
timeFrame: post randomization - 12 months
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama at Birmingham
state: Alabama
city: Little Rock
country: United States
facility: Arkansas Children's Hospital, Department of Infectious Diseases
state: Arkansas
city: San Diego
country: United States
facility: Rady Children's Hospital San Diego
state: California
city: Stanford
country: United States
facility: Stanford University School of Medicine
state: California
city: Jacksonville
country: United States
facility: University of Florida - College of Medicine - Jacksonville
state: Florida
city: Chicago
country: United States
facility: The University of Chicago - Comer Children's Hospital - Infectious Diseases
state: Illinois
city: Louisville
country: United States
facility: Kosair Children's Hospital
state: Kentucky
city: New Orleans
country: United States
facility: Tulane University - Tulane Medical Center - Department of Pediatrics
state: Louisiana
city: Portland
country: United States
facility: Maine Medical Center - Department of Pediatric Specialty Care - Infectious Disease
state: Maine
city: Baltimore
country: United States
facility: Johns Hopkins Hospital
state: Maryland
city: Detroit
country: United States
facility: Children's Hospital of Michigan - Pediatric Infectious Diseases
state: Michigan
city: Jackson
country: United States
facility: University of Mississippi
state: Mississippi
city: St. Louis
country: United States
facility: Washington University School of Medicine in St. Louis - Center for Clinical Studies
state: Missouri
city: New York
country: United States
facility: Mount Sinai Hospital
state: New York
city: Syracuse
country: United States
facility: UNY Upstate Medical University Hospital - Pediatrics
state: New York
city: Charlotte
country: United States
facility: Carolinas Medical Center
state: North Carolina
city: Cincinnati
country: United States
facility: Cincinnati Children's Hospital Medical Center
state: Ohio
city: Cleveland
country: United States
facility: MetroHealth Medical Center - Pediatric Infectious Disease
state: Ohio
city: Columbus
country: United States
facility: Nationwide Children's Hospital - Infectious Diseases
state: Ohio
city: Portland
country: United States
facility: Oregon Health and Science University
state: Oregon
city: Providence
country: United States
facility: Rhode Island Hospital
state: Rhode Island
city: Charleston
country: United States
facility: Medical University of South Carolina
state: South Carolina
city: Nashville
country: United States
facility: Vanderbilt University
state: Tennessee
city: Dallas
country: United States
facility: University of Texas Southwestern Medical Center
state: Texas
city: Fort Worth
country: United States
facility: Cook Children's Infectious Disease Services
state: Texas
city: San Antonio
country: United States
facility: University of Texas Health Science Center San Antonio - Pediatrics - Immunology & Infectious Disease
state: Texas
city: Seattle
country: United States
facility: Seattle Children's Hospital - Infectious Diseases
state: Washington
city: Edmonton
country: Canada
facility: University of Alberta - Aberhart Centre - Pediatrics
state: Alberta
Study officials:
References:
citation: 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.