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 (CASG 104)”

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 disease). Study participants will include infants in the US 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.

Study Type: Interventional

Study Design: Treatment, Randomized, Double Blind (Subject, Investigator), Placebo Control, Parallel Assignment, Efficacy Study

Study Primary Completion Date: April 2008

Herpes Simples Virus (HSV) complicates 1 out of 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.

Intervention(s) in this Clinical Trial

• Drug: Acyclovir
  • Oral suspension 300 mg/m^2/dose TID for 6 months.
• Drug: Placebo
  • Placebo identical to oral acyclovir suspension in appearance and taste.

Arms, Groups and Cohorts in this Clinical Trial

• Placebo Comparator: Placebo
• Experimental: Acyclovir

Primary Measures

• Neurologic Impairment.
  • Time Frame: At 12 months of life.
    Safety Issue?: No

Secondary Measures

• Two or fewer episodes post-randomization of cutaneous recurrence of herpes simplex virus (HSV) disease.
  • Time Frame: During the initial 12 months of life.
    Safety Issue?: No
• Post-randomization detection of HSV DNA in the cerebral spinal fluid (CSF).
  • Time Frame: At any time during the initail 12 months of life.
    Safety Issue?: No

Inclusion Criteria:

• Isolation by viral culture of Herpes Simplex Virus-1 (HSV-1) or Herpes Simplex Virus-2 (HSV-2) from cutaneous lesions, conjunctivae, or oropharynx.
• Detection of Herpes Simplex Virus (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; (<25WBCs/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 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 herpes simplex virus (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.

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: N/A

Maximum Age for this Clinical Trial: 28 Days

Are Healthy Volunteers Accepted for this Clinical Trial?: No

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

Information obtained from ClinicalTrials.gov on July 02, 2009

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00031447

Study ID Number: 97-006

ClinicalTrials.gov Identifier: NCT00031447

Health Authority: United States: Food and Drug Administration