Acyclovir Herpes Simplex Virus (HSV) Skin, Eye, and Mouth

Herpes Simplex Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00031447
• Other study ID #: 97-006
• Secondary ID: CASG 104N01AI300
• Status: Completed
• Phase: Phase 3
• First received: March 6, 2002
• Last updated: May 10, 2012
• Start date: August 1999
• Est. completion date: April 2008

Study information

• Verified date: November 2009
• Source: National Institute of Allergy and Infectious Diseases (NIAID)
• Contact: n/a
• Is FDA regulated: No
• Health authority: Canada: Ethics Review CommitteeUnited States: Institutional Review BoardUnited States: Federal GovernmentUnited States: Food and Drug Administration
• Study type: Interventional

Clinical Trial 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.

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.

Other known NCT identifiers

• NCT00001099

Recruitment information / eligibility

• Status: Completed
• Enrollment: 29
• Est. completion date: April 2008
• Est. primary completion date: February 2008
• Accepts healthy volunteers: No
• Gender: Both
• Age group: N/A to 28 Days

Eligibility

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.

Study Design

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Herpes Simplex

Intervention

Drug:
• Acyclovir
Oral suspension 300 mg/m^2/dose, 3 times per day (TID), for 6 months.
• Placebo
Placebo identical to oral acyclovir suspension in appearance and taste.

Locations

Country	Name	City	State
Canada	University of Alberta - Aberhart Centre - Pediatrics	Edmonton	Alberta
United States	Johns Hopkins Hospital	Baltimore	Maryland
United States	University of Alabama at Birmingham	Birmingham	Alabama
United States	Medical University of South Carolina	Charleston	South Carolina
United States	Carolinas Medical Center	Charlotte	North Carolina
United States	The University of Chicago - Comer Children's Hospital - Infectious Diseases	Chicago	Illinois
United States	Cincinnati Children's Hospital Medical Center	Cincinnati	Ohio
United States	MetroHealth Medical Center - Pediatric Infectious Disease	Cleveland	Ohio
United States	Nationwide Children's Hospital - Infectious Diseases	Columbus	Ohio
United States	University of Texas Southwestern Medical Center	Dallas	Texas
United States	Children's Hospital of Michigan - Pediatric Infectious Diseases	Detroit	Michigan
United States	Cook Children's Infectious Disease Services	Fort Worth	Texas
United States	University of Mississippi	Jackson	Mississippi
United States	University of Florida - College of Medicine - Jacksonville	Jacksonville	Florida
United States	Arkansas Children's Hospital, Department of Infectious Diseases	Little Rock	Arkansas
United States	Kosair Children's Hospital	Louisville	Kentucky
United States	Vanderbilt University	Nashville	Tennessee
United States	Tulane University - Tulane Medical Center - Department of Pediatrics	New Orleans	Louisiana
United States	Mount Sinai Hospital	New York	New York
United States	Maine Medical Center - Department of Pediatric Specialty Care - Infectious Disease	Portland	Maine
United States	Oregon Health and Science University	Portland	Oregon
United States	Rhode Island Hospital	Providence	Rhode Island
United States	University of Texas Health Science Center San Antonio - Pediatrics - Immunology & Infectious Disease	San Antonio	Texas
United States	Rady Children's Hospital San Diego	San Diego	California
United States	Seattle Children's Hospital - Infectious Diseases	Seattle	Washington
United States	Washington University School of Medicine in St. Louis - Center for Clinical Studies	St. Louis	Missouri
United States	Stanford University School of Medicine	Stanford	California
United States	UNY Upstate Medical University Hospital - Pediatrics	Syracuse	New York

Sponsors (1)

Lead Sponsor	Collaborator
National Institute of Allergy and Infectious Diseases (NIAID)

Countries where clinical trial is conducted

United States,  Canada, 

References & Publications (1)

Kimberlin DW, Whitley RJ, Wan W, Powell DA, Storch G, Ahmed A, Palmer A, Sánchez 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, McCar — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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.	No
Primary	Participants With Neurologic Impairment at 12 Months as Measured by a Bayley's Neuro-developmental Assessment.(Mental Scores)	Mental 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: less 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.	No
Secondary	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.	Number of participants with positive herpes simplex virus (HSV) DNA by polymerase cahin reaction (PCR) in the cerebrospinal fluid of subjects assessed during the initial 12 months of life.	post randomization at 12 months	No
Secondary	Two or Fewer Episodes of Cutaneous Recurrence of HSV Disease Post-randomization During the Initial 12 Months of Life.	Number of participants experiencing 2 or fewer HSV recurrences during the first 12 months of life as measured by assessments and reports at study visits.	post randomization - 12 months	No