A Study to Describe the Pharmacokinetics of Acyclovir in Premature Infants (PTN_Acyclo)

This study has been completed.
Sponsor:
Collaborator:
Information provided by (Responsible Party):
Phillip Brian Smith, Duke University Medical Center
ClinicalTrials.gov Identifier:
NCT00942084
First received: July 17, 2009
Last updated: November 19, 2013
Last verified: November 2013
  Purpose

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.


Condition Intervention Phase
Herpes Simplex Virus
Neonatal Sepsis
Drug: Acyclovir
Phase 1

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Pharmacokinetics Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: An Open Label Study to Describe the Pharmacokinetics of Acyclovir in Premature Infants

Resource links provided by NLM:


Further study details as provided by Duke University:

Primary Outcome Measures:
  • Clearance (CL) [ 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 ] [ Designated as safety issue: Yes ]

    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) [ Time Frame: up to 3 days of study drug administration and 10 days of safety monitoring ] [ Designated as safety issue: Yes ]
  • Half-life (T1/2) [ Time Frame: up to 3 days of study drug administration and 10 days of safety monitoring ] [ Designated as safety issue: Yes ]
  • Maximum Steady State Concentration (Cmaxss) [ Time Frame: up to 3 dasy of study drug administration and 10 days of safety monitoring ] [ Designated as safety issue: Yes ]
  • 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 ] [ Designated as safety issue: Yes ]
  • Minimum Steady State Concentration (Cminss) [ Time Frame: up to 3 days of study drug administration and 10 days of safety monitoring ] [ Designated as safety issue: Yes ]

Enrollment: 32
Study Start Date: September 2011
Study Completion Date: June 2012
Primary Completion Date: June 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Protocol V2&up-Grp1-Acyclo10 mg/kg IVq12
Gestational Age 23-29 weeks Postnatal Age < 14 days Dosage 10 mg/kg IV q12 Number of Infants 8
Drug: Acyclovir

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).

Active Comparator: Protocol V2&up-Grp2_Acyclo20 mg/kg IVq12
Gestational Age 23-29 weeks Postnatal Age 14-44 days Dosage 20 mg/kg IV q12 Number of Infants 8
Drug: Acyclovir

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).

Active Comparator: Protocol V2&up-Grp3-Acyclo20 mg/kg IVq8
Gestational Age 30-34 weeks Postnatal Age <45 days Dosage 20 mg/kg IV q8 Number of Infants 4
Drug: Acyclovir

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).

Protocol V1-Grps1-4-Acyclo 500 mg/m2 IVq8h
All patients in protocol V1 were to be dosed with 500 mg/m2 IV q8h. Protocol V1 Group 1: Gestational Age: 23-29 Weeks; PNA: <14 days; Protocol V1 Group 2: Gestational Age: 30-42 Weeks; PNA: <14 days; Protocol V1 Group 3: Gestational Age: 23-29 Weeks; PNA: 14-60 days; Protocol V1 Group 4: Gestational Age: 30-42 Weeks; PNA: 14-60 days
Drug: Acyclovir

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).


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)

  Eligibility

Ages Eligible for Study:   up to 45 Days
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00942084

Locations
United States, Kansas
Wesely Medical Center
Wichita, Kansas, United States, 67214-4976
United States, Louisiana
Tulane School of Medicine
New Orleans, Louisiana, United States, 70112
United States, North Carolina
Duke University
Durham, North Carolina, United States, 27713
Sponsors and Collaborators
Phillip Brian Smith
Investigators
Principal Investigator: Phillip B Smith, M.D. Duke University
  More Information

Publications:

Responsible Party: Phillip Brian Smith, Associate Professor of Pediatrics, Duke University Medical Center
ClinicalTrials.gov Identifier: NCT00942084     History of Changes
Other Study ID Numbers: Pro00028772
Study First Received: July 17, 2009
Results First Received: August 27, 2013
Last Updated: November 19, 2013
Health Authority: United States: Food and Drug Administration

Keywords provided by Duke University:
HSV
Acyclovir
Pharmacokinetics
Neonate
Premature
Sepsis

Additional relevant MeSH terms:
Herpes Simplex
Sepsis
Herpesviridae Infections
DNA Virus Infections
Virus Diseases
Skin Diseases, Viral
Skin Diseases, Infectious
Skin Diseases
Infection
Systemic Inflammatory Response Syndrome
Inflammation
Pathologic Processes
Acyclovir
Antiviral Agents
Anti-Infective Agents
Therapeutic Uses
Pharmacologic Actions

ClinicalTrials.gov processed this record on July 22, 2014