Prophylactic Phenobarbital After Neonatal Seizures (PROPHENO)

Prophylactic Phenobarbital After Resolution of Neonatal Seizures

The treatment of infants with medications after their seizures have stopped is very variable. No one knows if continuing treatment with phenobarbital for up to several months is helpful or harmful. This clinical trial is designed to help answer that question and provide data that will help determine standard of care for these children.

Study Overview

• Status: Terminated
• Conditions: Neonatal Seizures
• Intervention / Treatment: Drug: phenobarbital; Drug: placebo

Detailed Description

The treatment of infants with antiepileptic medications after the resolution of neonatal seizures is highly variable and controversial. Infants are commonly treated with phenobarbital after their seizures have resolved to prevent recurrence. Data to support this practice are lacking but animal models suggest that the neonatal brain is vulnerable to repeated seizures. Yet exposure of the developing brain to phenobarbital for prolonged periods may have deleterious consequences. We are proposing a multi-center, randomized, clinical trial (RCT) to determine if continued treatment with phenobarbital reduces seizure recurrence without adversely affecting neurodevelopmental outcome or if infants' outcomes are improved if no prophylactic medication is given. We will identify infants with seizures beginning in the first week that resolve within 7 days and randomize them to receive phenobarbital or placebo daily for four months. Via visits and frequent telephone contacts over the first six months, we will determine the rate of seizure recurrence. The primary outcome, neurodevelopmental status, will be assessed at 18-22 months using the Bayley Scales of Infant Development. Additional subgroup analyses are planned to determine the contribution of seizure etiology to outcome and predictive value of initial EEG classification. The trial will be conducted at 18 - 20 sites, chosen for their experience and proven track record for enrollment and retention in this specific population. The trial will be coordinated by the Clinical Trials Coordination Center at the University of Rochester and overseen by a Steering Committee composed of experienced trialists representing neonatology and pediatric neurology, biostatistics, and clinical trial administration.

Extrapolation from the results of an RCT of phenobarbital prophylaxis after febrile seizures in children suggests that phenobarbital may adversely affect brain development and may be ineffective in preventing seizures. Based on this previous RCT that resulted in near universal change in practice (the elimination of prolonged use of phenobarbital after simple febrile seizures), we anticipate that the data we generate may have a similar impact on standard of care for infants with neonatal seizures.

• Study Type: Interventional
• Enrollment (Actual): 13
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • Arkansas
    • Little Rock, Arkansas, United States, 72202
      • University of Arkansas
  • California
    • San Francisco, California, United States, 94143
      • University of California San Francisco
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • Univeristy of Iowa
  • Maryland
    • Baltimore, Maryland, United States, 21224
      • Johns Hopkins University
  • Massachusetts
    • Boston, Massachusetts, United States, 02111
      • Tufts Medical Center
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • University of Michigan
  • New York
    • Buffalo, New York, United States, 14222
      • Women & Children's Hospital of Buffalo
    • Rochester, New York, United States, 14642
      • University of Rochester
  • North Carolina
    • Winston Salem, North Carolina, United States, 27157
      • Forsyth Medical Center
    • Winston Salem, North Carolina, United States, 27157
      • Wake Forest University
  • Ohio
    • Akron, Ohio, United States, 44308
      • Akron Children's Hospital
    • Columbus, Ohio, United States, 43205
      • Nationwide Children's Hospital
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15224
      • Magee Womens Hospital
    • Pittsburgh, Pennsylvania, United States, 15224
      • University of Pittsburgh
  • Rhode Island
    • Providence, Rhode Island, United States, 02905
      • Women & Infants Hospital of Rhode Island
  • Utah
    • Salt Lake City, Utah, United States, 84108
      • University of Utah
    • Salt Lake City, Utah, United States, 84108
      • Primary Children's Medical Center
  • Virginia
    • Charlottesville, Virginia, United States, 22908
      • University of Virginia

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 2 days to 2 weeks (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Birth at > 34 weeks' gestation
• Neonatal seizures (clinical, electrographic or both), with onset in the first 120 hours after birth and resolution within 7 days of onset
• Parental informed consent

Exclusion Criteria:

• Birth at < 34 weeks' gestation
• If the attending neonatologist attributes the seizures solely to a transient abnormality, easily correctable and unlikely to recur (eg, transient electrolyte abnormalities). If the attending neonatologist cannot be contacted, the site PI will be asked to review the available information and judge whether the infant is eligible.
• If the infant has been diagnosed with or there is a strong suspicion of an inborn error of metabolism, significant brain malformation, microcephaly (< 3 %ile), or a chromosomal abnormality which, in the absence of seizures, is known to be independently associated with an increased likelihood of cognitive impairment
• If the infant has been diagnosed with an intrauterine viral infection
• If the infant is not expected to survive to discharge

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Phenobarbital; Phenobarbital, 4-5 mg/kg/day, for 4 months	Drug: phenobarbital; Phenobarbital, 4-5 mg/kg/d, by mouth, for 4 months
Placebo Comparator: Placebo; Placebo in a volume equivalent to active drug for 4 months	Drug: placebo; Matched placebo, same volume as active drug, by mouth daily for 4 months

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mean Bayley Scales of Infant Development (BSID) Score - Cognitive	The Bayley Scales of Infant Development (BSID) measure the mental and motor development and test the behavior of infants from one to 42 months of age. The test is intended to measure a child's level of development in three domains: cognitive, motor, and behavioral. The primary outcome is the Bayley assessment of development at 2 years of age. This is a standardized developmental exam that is normalized to the age of the child in months. The mean adjusted score is 100 with a standard deviation of 15 (higher being better) - very similar to the more familiar IQ score.	18-22 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mean Bayley Scales of Infant Development (BSID) Score - Motor	This part of the BSID assesses the degree of body control, large muscle coordination, finer manipulatory skills of the hands and fingers, dynamic movement, postural imitation, and the ability to recognize objects by sense of touch.	18-22 months
Number of Participants With One or More Seizures	Any clinical or electrographic seizures occurring between study entry and all follow-up examinations and contacts.	18-22 months

Collaborators and Investigators

• Sponsor: University of Rochester
• Investigators: Principal Investigator: Ronnie Guillet, MD, PhD, University of Rochester

Study record dates

Study Major Dates

• Study Start: September 1, 2010
• Primary Completion (Actual): November 1, 2014
• Study Completion (Actual): November 1, 2014

Study Registration Dates

• First Submitted: March 17, 2010
• First Submitted That Met QC Criteria: March 17, 2010
• First Posted (Estimate): March 18, 2010

Study Record Updates

• Last Update Posted (Estimate): February 3, 2016
• Last Update Submitted That Met QC Criteria: January 4, 2016
• Last Verified: January 1, 2016

More Information

Terms related to this study

• Keywords: neonate; seizure; phenobarbital; antiepileptic drugs; neurodevelopmental outcome
• Additional Relevant MeSH Terms: Nervous System Diseases; Neurologic Manifestations; Seizures; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Excitatory Amino Acid Antagonists; Excitatory Amino Acid Agents; Hypnotics and Sedatives; GABA Modulators; GABA Agents; Anticonvulsants; Cytochrome P-450 Enzyme Inducers; Cytochrome P-450 CYP3A Inducers; Cytochrome P-450 CYP2B6 Inducers; Phenobarbital
• Other Study ID Numbers: 28907