Valacyclovir in Neonatal Herpes Simplex Virus Disease

Study Overview
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Brief Summary
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This is an open-label, single center, pharmacokinetic (PK) study to assess valacyclovir pharmacokinetics and pharmacodynamics in neonates and compare to the pharmacokinetics and pharmacodynamics of the standard of care treatment dose of intravenous acyclovir. 6 (up to 10 infants) with virologically confirmed neonatal herpes simplex virus (HSV) disease who meet all inclusion/exclusion criteria will be enrolled in the study. Study duration is 5 years. Primary objective is to define the pharmacokinetics of valacyclovir and assess its safety in neonates 2-12 weeks of age who are ≥ 34 weeks gestation.

Detailed Description
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This is an open-label, single center, PK study to assess valacyclovir pharmacokinetics and pharmacodynamics in neonates and compare to the pharmacokinetics and pharmacodynamics of the standard of care treatment dose of intravenous acyclovir. Only those babies with virologically confirmed neonatal HSV disease will be enrolled in the study. The decision to initiate valacyclovir for 2 (up to 7) days will be made by a physician based on inclusion/exclusion criteria, and those who meet entry criteria will be eligible for the study. Those enrolled in the study will have daily random parenteral acyclovir PK levels drawn during the first week of treatment (drawn only at times of other lab draws). These infants will also have a pharmacokinetic sampling profile obtained on or after dose 22 and before dose 42 of intravenous acyclovir. The PK samples for the sampling profile will be collected just prior to the next dose of intravenous acyclovir (within 30 minutes prior to the start of the infusion), within 15 minutes of completion of the infusion, and 3-4 hours after infusion. Upon completion of the recommended treatment course duration with intravenous acyclovir determined by disease classification (skin, eye, and mouth; central nervous system; or disseminated disease), the infant will be started on enteral valacyclovir 20 mg/kg every 8 hours. On day 2 and no more than day 7 of valacyclovir 20 mg/kg every 8 hours, a pharmacokinetic sampling profile will be obtained. The PK samples will be collected just prior to the enteral dose of valacyclovir (hour 0; 8 hours after previous dose and immediately before next dose), 1-2 hours after dose, and 3-5 hours after dose. Primary objective is to define the pharmacokinetics of valacyclovir and assess its safety in neonates 2-12 weeks of age who are ≥ 34 weeks gestation. Secondary objectives are to: 1) assess the pharmacokinetics of high-dose parenteral acyclovir in neonates ≥ 34 weeks gestation with virologically confirmed neonatal HSV disease who are receiving acyclovir as standard of care, 2) compare the pharmacokinetics of high-dose parenteral acyclovir to the pharmacokinetics of the proposed study dose of valacyclovir (20 mg/kg every 8 hours).

Official Title
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Evaluation of the Pharmacokinetics and Pharmacodynamics of Valacyclovir in Neonates With Neonatal Herpes Simplex Virus Disease Who Have Completed Standard of Care Treatment With Acyclovir

Conditions
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Neonatal Herpes Simplex Infection

Intervention / Treatment
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* Drug: Valacyclovir


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Signed informed consent from parent(s) or legal guardian(s) Confirmation of HSV infection from surface culture/PCR, skin lesion culture/PCR, blood PCR, or CSF PCR (performed at UAB Virology lab) ≥34 weeks gestational age at birth Weight at study enrollment is ≥ 2000 grams Receiving intravenous acyclovir, prescribed by the patient's physician for ≤ 14 days ≤ 42 days of age at initiation of parenteral acyclovir Creatinine ≤ 1.2 Exclusion Criteria: Imminent demise Current receipt of other investigational drugs Major congenital anomaly that in the site investigator's opinion may impact drug metabolism or the patient's volume of distribution Creatinine of > 1.2 prior to initiation of valacyclovir Evidence of immunosuppression (HIV infected, immune deficiencies, etc.) Any condition that, in the opinion of the investigator, would place the subject at an unacceptable injury risk or that may interfere with successful study completion > 42 days of age at initiation of parenteral acyclovir Concern for parental/guardian compliance

Ages Eligible for Study
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Minimum Age: 2 Weeks
Maximum Age: 12 Weeks

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Neonatal HSV disease requiring suppressive therapy<br>All subjects enrolled in the study will receive 2 (up to 7) days of valacyclovir 20 mg/kg every 8 hours after completion of standard of care treatment course with acyclovir. | Drug: Valacyclovir<br>* Upon completion of standard of care acyclovir for treatment of neonatal HSV disease, valacyclovir oral suspension (per ASHP recipe), 20 mg/kg every 8 hours, to be given for 2 (up to 7) days<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area under the curve following administration of oral valacyclovir suspension 20 mg/kg every 8 hours | To determine the concentration of the active metabolite acyclovir after administration of valacyclovir at specified time intervals in order to calculate the area under the curve | Between Day 2 and Day 7 of valacyclovir administration: 0, 1-2, 3-5 hours. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area under the curve following administration of parenteral acyclovir 20 mg/kg every 8 hours | To determine the concentration of the active metabolite acyclovir after administration of parenteral acyclovir at specified time intervals in order to calculate the area under the curve | One PK level drawn randomly on days 1-7; in addition, on one day between day 8 -14 of parenteral acyclovir, 3 PK levels to be drawn (drawn 30 minutes prior to infusion, 15 minutes after completion of infusion, and 3-4 hours after infusion) | 
| Comparison of the Area under the curve of 20 mg/kg IV acyclovir to the area under the curve of 20 mg/kg PO valacyclovir | to determine if the concentration of the active metabolite acyclovir after administration of acyclovir and valacyclovir at specified time intervals produces the same area under the curve | Random PK levels on days 1-7 of acyclovir administration, PK levels obtained on one day between day 8-14 at specified time intervals, and PK levels obtained one day while on valacyclovir (see outcome 1 and outcome 3 for time intervals) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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valacyclovir