Herpes Simplex Virus, Neonatal Sepsis
Conditions
Keywords
HSV, Acyclovir, Pharmacokinetics, Neonate, Premature, Sepsis
Brief summary
Acyclovir is a drug used to treat herpes simplex virus (HSV) infections in babies. Appropriate dosing of acyclovir is known for adults and children but acyclovir has not been adequately studied in full-term or premature neonates. HSV is a very serious infection in babies \<6 months of age and often results in death or profound mental retardation. HSV leads to profound mental retardation in young infants because the virus attacks the central nervous system. The investigators hypothesize that the currently recommended dose of acyclovir is inadequate to produce adequate blood levels to combat herpes simplex infection. The investigators propose to study acyclovir levels in the blood of babies who are placed on acyclovir to treat a suspected HSV infection. This will allow them to determine the appropriate dose in premature infants. This is an unmet public health need because it is likely that the drug behaves differently in premature infants than it does in term infants and older children. Premature babies have more body water and less body tissue. Their kidneys are more immature and do not function as well as full term infants. Premature neonates are also at the greatest risk from herpes infection because they have poorly functioning immature immune systems. Early and appropriate treatment with acyclovir has resulted in improved outcome in term infants.
Detailed description
Neonatal herpes infection carries a major risk of death if untreated. Prognosis is related to disease extent and timing of therapy, making early diagnosis crucial. Mortality in the pre-antiviral era was 90% for disseminated disease and 50% for central nervous system (CNS) disease. Institution of high-dose (60 mg/kg/day) antiviral therapy with acyclovir has reduced mortality to 31% for disseminated disease and 6% for CNS disease.1 Although acyclovir has reduced mortality dramatically, morbidity remains high. Study population: Infants \< 45 days postnatal age, suspected to have a systemic infection divided into groups by gestational and postnatal age: Group-1: 23-29 weeks gestational age, \<14 days postnatal age Group-2: 23-29 weeks gestational age, 14-44 days postnatal age Group-3: 30-34 weeks gestational age, \<45 days postnatal age Intravenous acyclovir will be administered for 3 days. Timing of PK sample collection will be with respect to the end of each IV infusion. Timed PK sampling will be drawn at doses 1, and doses 5, 6, 7, 8, or 9. Dose 1: 0-15 minutes after completion of the 1st dose; Within 30 minutes prior to administration of 2nd dose Steady state \[doses 5 or 6 (groups 1 and 2), doses 8 or 9 (group 3)\]: Within 30 minutes prior to dose; 0-15 minutes after completion of the dose; 2-3 hours after completion of the dose; Within 30 minutes prior to administration of the next dose Last dose: 6-7 hours after the last dose (groups 1 and 2)and 10-11 hours after the last dose (group 3)
Interventions
DRUGAcyclovir
Protocol V2 & up: Acyclovir 7mg/ml to be administered IV at 10 mg/kg IV q12 or 20 mg/kg IV q12 or 20 mg/kg IV q8 for a total of 6-9 doses(3 days). Protocol V1: Acyclovir 5 mg/mL to be administered IV at 500 mg/m2 IV q8h for a total of approximately 15 doses (10 days).
Sponsors
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Phillip Brian Smith
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
No minimum to 45 Days
Healthy volunteers
No
Inclusion criteria
The investigator or other study site personnel will document in the source documents (e.g., the hospital chart) that informed consent was obtained. Laboratory tests or non-pharmacologic treatment procedures that were performed as standard of care within 72 hours prior to first dose of study drug may be used for screening procedures and recorded in the CRF. Inclusion Criteria 1. \< 45 days of age at the time of initial study drug administration. 2. Sufficient venous access to permit administration of study medication. 3. Availability and willingness of the parent/legal guardian to provide written informed consent. 4. Suspected HSV sepsis OR At least two (2) of the following * Signs of sepsis AND negative blood cultures for \>24 hours7 * Respiratory distress8 * Lethargy8 * Fever ≥ 38.0°C7 * Skin lesions7,8 * Seizures (clinical OR EEG confirmed)7 * Irritability7 * AST OR ALT \>2 X upper limit of normal7,8 * \>20 WBCs/µL or \>500 RBCs/µL7
Exclusion criteria
1. History of anaphylaxis attributed to acyclovir. 2. Serum creatinine \>1.7 mg/dL. 3. Urine output \<0.5 mL/kg/hour over the previous 12 hours 4. Previous participation in the study. 5. Concomitant condition, which in the opinion of the investigator would preclude a participant's participation in the study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Clearance (CL) | V1:0-5 min,2-4 hrs,6-8 hrs post Doses 1&5-15;prior to doses 5-15; V2:0-15 min post doses 1&5-15; within 30 min prior to doses 2&5-15; 2-3 hrs post doses 5-15; 15-18 hrs post last dose | Timeframe: Version 1:0-5 min,2-4 hrs,6-8 hrs post doses 1 and 5-15; prior to doses 5-15 Version 2:0-15 min post doses 1 and 5-15; within 30 min prior to doses 2 and 5-15; 2-3 hrs post doses 5-15; 15-18 hrs post last dose |
| Volume of Distribution (V) | up to 3 days of study drug administration and 10 days of safety monitoring | — |
| Half-life (T1/2) | up to 3 days of study drug administration and 10 days of safety monitoring | — |
| Maximum Steady State Concentration (Cmaxss) | up to 3 dasy of study drug administration and 10 days of safety monitoring | — |
| Steady State Concentration at 50% of the Dosing Interval (C50ss) | up to 3 days of study drug administration and 10 days of safety monitoring | — |
| Minimum Steady State Concentration (Cminss) | up to 3 days of study drug administration and 10 days of safety monitoring | — |
Countries
United States
Participant flow
Recruitment details
Total enrollment is 32. 32 for safety analysis and 30 in PK population (28 included in final PK analysis).
Participants by arm
| Arm | Count |
|---|---|
| Acyclovir Study Design Two open-label PK studies contributed the data for this report. Version 1 was single-center and Version \>=2 was multi-center. Acyclovir was administered intravenously as a 1-hour infusion for up to 3 days. Dosing in Study 1 was 500 mg/m2 every 8 hours. Dosing in Study 2 was determined by GA and PNA: 10 mg/kg every 12 hours (23-29 weeks GA and \<14 days PNA); 20 mg/kg every 12 hours (23-29 weeks GA and 14-44 days PNA); and 20 mg/kg every 8 hours (30-34 weeks GA and \<45 days PNA). | 32 |
| Total | 32 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Death | 2 |
Baseline characteristics
| Characteristic | Acyclovir Study Design |
|---|---|
| Age, Continuous Gestational Age (weeks) | 30.5 weeks |
| Age, Continuous Postnatal Age (days) | 3.0 days |
| Birthweight | 1295 grams |
| Ethnicity (NIH/OMB) Hispanic or Latino | 4 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 28 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants |
| Race (NIH/OMB) Black or African American | 11 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 20 Participants |
| Region of Enrollment United States | 32 participants |
| Sex: Female, Male Female | 17 Participants |
| Sex: Female, Male Male | 15 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 21 / 32 |
| serious Total, serious adverse events | 4 / 32 |
Outcome results
Primary
Clearance (CL)
Timeframe: Version 1:0-5 min,2-4 hrs,6-8 hrs post doses 1 and 5-15; prior to doses 5-15 Version 2:0-15 min post doses 1 and 5-15; within 30 min prior to doses 2 and 5-15; 2-3 hrs post doses 5-15; 15-18 hrs post last dose
Time frame: V1:0-5 min,2-4 hrs,6-8 hrs post Doses 1&5-15;prior to doses 5-15; V2:0-15 min post doses 1&5-15; within 30 min prior to doses 2&5-15; 2-3 hrs post doses 5-15; 15-18 hrs post last dose
Population: 32 infants enrolled. 2 infants died. 2 infants did not contribute PK samples to the analysis. 28 contributed PK samples to the final analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Acyclovir Study Design | Clearance (CL) | 0.278 L/h/kg |
Primary
Half-life (T1/2)
Time frame: up to 3 days of study drug administration and 10 days of safety monitoring
Population: 32 infants enrolled. 2 infants died. 2 infants did not contribute PK samples to the analysis. 28 contributed PK samples to the final analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Acyclovir Study Design | Half-life (T1/2) | 7.07 h |
Primary
Maximum Steady State Concentration (Cmaxss)
Time frame: up to 3 dasy of study drug administration and 10 days of safety monitoring
Population: 32 infants enrolled. 2 infants died. 2 infants did not contribute PK samples to the analysis. 28 contributed PK samples to the final analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Acyclovir Study Design | Maximum Steady State Concentration (Cmaxss) | 11.1 mg/L |
Primary
Minimum Steady State Concentration (Cminss)
Time frame: up to 3 days of study drug administration and 10 days of safety monitoring
Population: 32 infants enrolled. 2 infants died. 2 infants did not contribute PK samples to the analysis. 28 contributed PK samples to the final analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Acyclovir Study Design | Minimum Steady State Concentration (Cminss) | 4.15 mg/L |
Primary
Steady State Concentration at 50% of the Dosing Interval (C50ss)
Time frame: up to 3 days of study drug administration and 10 days of safety monitoring
Population: 32 infants enrolled. 2 infants died. 2 infants did not contribute PK samples to the analysis. 28 contributed PK samples to the final analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Acyclovir Study Design | Steady State Concentration at 50% of the Dosing Interval (C50ss) | 6.33 mg/L |
Primary
Volume of Distribution (V)
Time frame: up to 3 days of study drug administration and 10 days of safety monitoring
Population: 32 infants enrolled. 2 infants died. 2 infants did not contribute PK samples to the analysis. 28 contributed PK samples to the final analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Acyclovir Study Design | Volume of Distribution (V) | 3.34 L/kg |