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NCT Number: NCT01958476

Improving Outcomes in Neonatal Abstinence Syndrome

1: SPECIFIC Aim I: To compare treatment options for neonatal abstinence syndrome (NAS) due to in-utero narcotic exposure. One hundred eighty four full-term infants with a diagnosis of NAS requiring medications will be studied. Infants will be randomized to receive either morphine or methadone. It is hypothesized that morphine treated infants will do better and require fewer days in the hospital compared to methadone treated infants.

2. SPECIFIC Aim II: To evaluate the effects of NAS treatment on long-term neurodevelopmental outcome. Infants will be evaluated with development testing at 18 months of age. It is hypothesized that morphine treated infants will have better neurodevelopmental outcomes. It is also hypothesized that neurobehavioral abnormalities identified at two weeks of age will correlate with neurodevelopmental impairment at 18 months.

3: SPECIFIC Aim III: To determine if common genetic variations in the genes involving narcotic action contribute to the severity of NAS. A DNA sample will be obtained from all infants and analyzed for differences in 3 key genes. This will then be correlated with short-term and long-term outcomes.

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Key information

Conditions

Neonatal Abstinence Syndrome Chemically-Induced Disorders Congenital, Hereditary, and Neonatal Diseases and Abnormalities Infant, Newborn, Diseases Mental Disorders Neonatal Opioid Withdrawal Substance-Related Disorders

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 3

Primary location

Shands Jacksonville Medical Center, Jacksonville, Florida, United States

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About this study

1: SPECIFIC Aim I: To compare the short term efficacy of morphine and methadone for the treatment of NAS. One hundred eighty four term infants with a diagnosis of NAS requiring pharmacotherapy will be studied. Infants born to mothers receiving adequate prenatal care and maintained on opioid agonist medication during pregnancy will be eligible. Infants will be randomized to receive either neonatal morphine solution or methadone in a double blind, double dummy design. It is hypothesized that morphine treated infants will require significantly fewer days in the hospital compared to methadone treated infants. While the primary outcome is the total length of initial hospital stay (LOS), total LOS related to NAS, total duration of medical treatment for NAS, the need for a second drug to control symptoms, and infant growth will also be evaluated as important secondary outcomes by medication group assignment.

  • SPECIFIC Aim II: To evaluate the effects of NAS treatment on long-term neurodevelopmental outcome. Infants in both treatment groups will be evaluated at 18 months of age using the Bayley III Scales of Infant Development. It is hypothesized that morphine treated infants will have better neurodevelopmental outcomes at 18 months compared to methadone treated infants. It is also hypothesized that neurobehavioral abnormalities (from either treatment group) identified at two weeks of age using the Neonatal Intensive Care Unit (NICU) Network Neurobehavioral Scale (NNNS) will correlate with neurodevelopmental impairment detected with the Bayley III. Early identification of infants at highest risk for impaired development will facilitate therapeutic interventions to improve outcome and decrease resource utilization.

3: SPECIFIC Aim III: To determine if single nucleotide polymorphisms (SNPs) in genes controlling opioid pharmacodynamics contribute to the severity of NAS. SNP genotyping from cord blood or buccal swabs will be obtained from all infants and correlated with short term outcomes (Aim 1) and neurodevelopment assessments (Aim 2) to confirm that genetic variation plays a major role in the severity and outcome of infants with NAS.

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

Inclusion criteria

  • Mother receiving methadone or buprenorphine (BPH) from a licensed physician or drug treatment program, or an opioid prescribed by a licensed health care worker for treatment of chronic pain.
  • Need for treatment of NAS by Finnegan Scoring criteria
  • Gestational age >37 weeks at birth defined by best obstetrical estimate
  • Medically stable in the opinion of the Attending Physician
  • Mother receiving "adequate" or "intermediate" prenatal care from a qualified physician or midwife as defined by the Prenatal Care Adequacy Index
  • Singleton pregnancy
  • Mother able to provide informed consent
  • Infant able to take oral medications

Exclusion criteria

  • Gestation <37 weeks at entry defined by best obstetrical estimate
  • Major congenital abnormalities including genetic syndromes
  • Serious medical illness such as sepsis, asphyxia, seizures, or respiratory failure
  • Mother abusing alcohol during pregnancy (average of 3 or more drinks per week in the last 30 days)
  • Multiple gestations
  • Mother received "inadequate" prenatal care as defined by the Prenatal Care Adequacy Index.

Treatment and study plan

Neonatal Morphine Solution

Drug

Infants randomized to this arm will receive neonatal morphine solution (0.2mg/mL) for first line therapy. Infants will be scored using the standardized Finnegan scoring system and will be initiated on treatment if they have 2 consecutive scores greater than or equal to 8 or 1 score greater than 12. Dosing will be weight and symptom based. A "double dummy" design will be used - each infant will be ordered for both a methadone/placebo study drug at 0.4 mg/mL and a morphine/placebo study drug at 0.2 mg/mL. Starting doses will range from 0.3mg/kg/day to 0.9mg/kg/day divided every 4 hours depending on the severity of the Finnegan scores. Doses will be increased to a maximum of 0.9mg/kg/day for continued scores generally >8 caused primarily by worsening NAS. Infants will be weaned by 10% of the maximum dose once every 24 - 48 hours and the medication will be discontinued once at 25% of the maximum dose.

Other names: Morphine sulfate

Methadone

Drug

Infants randomized to this group will receive methadone oral solution (0.4mg/mL) for first line therapy. Infants will be scored using the standardized Finnegan scoring system and will be initiated on treatment if they have 2 consecutive scores greater than or equal to 8 or 1 score greater than or equal to 12. Dosing will be weight and symptom based. Starting doses will range from 0.3mg/kg/day to 0.9mg/kg/day divided every 8 hours depending on the severity of the Finnegan scores. To maintain blinding of the two study arms, a "double dummy" design will be used - each infant will receive both methadone/placebo study drug at 0.4 mg/mL and a morphine/placebo study drug at 0.2 mg/mL. Doses will be increased to a maximum of 0.9mg/kg/day for continued scores generally >8 caused primarily by worsening NAS as needed. Infants will be weaned by 10% of the maximum dose once every 24-48 hours and the medication will be discontinued once at 25% of the maximum dose.

Other names: Methadone oral solution

Phenobarbital

Drug

A second line medication will be added once the infant reaches maximum doses of the study drug (morphine or methadone) for continued scores generally >8. Infants will be loaded with 20mg/kg of phenobarbital with the option to re-load with 10mg/kg q8-12 hours for 2 more doses if needed for continued high scores. Maintenance therapy of 5mg/kg/day will be initiated 12 - 24 hours after the last loading dose. Phenobarbital trough levels will be monitored with goal levels of 20 - 30 mcg/mL.

Phenobarbital will be weaned only after the infant has been weaned off of the study drug. Weaning will begin 48 hours after the study drug has been stopped by 20% of the maximum total daily dose every 3 days for scores <8. An infant may be discharged home 48 - 72 hours after the first wean. The remaining wean will be outlined in the discharge prescription, and followed up on by study staff with the goal of the phenobarbital discontinuation within a 2 week period.

Primary outcomes

  1. Length of Hospital Stay (LOS)

    Time frame: Participants will be monitored during their entire hospitalization, expected mean 22 days.

    Participants were monitored for the duration of their hospitalization, an expected mean of 22 days.

Secondary outcomes

  1. Length of Hospital Stay (LOS) Due to Neonatal Abstinence Syndrome (NAS)

    Time frame: Participants were monitored for the duration of their hospitalization, expected mean 22 days.

    Participants were monitored for the duration of their hospitalization attributable to NAS only.

  2. Length of Treatment (LOT)

    Time frame: Participants were monitored for the duration of their hospitalization.

    Total number of days infant treated with replacement opioids while admitted to the hospital.

  3. Maximum Daily Dose of Replacement Opioid

    Time frame: Participants were monitored for the duration of their hospitalization.

    Maximum daily dose of neonatal morphine solution or methadone during the hospitalization

  4. Mean Finnegan Score (FS)

    Time frame: Participants were monitored during their entire hospitalization

    Mean Finnegan withdrawal score during the duration of hospitalization.

  5. Number of Infants Needing a Second NAS Medication

    Time frame: Participants were monitored for the duration of their hospitalization, an average of 22 days.

    Number of infants treated with a second medication following protocol, phenobarbital. If the Finnegan Score remained elevated (still scored ≥8 two times consecutively, or still scored once ≥12) despite increasing to a predetermined maximal opioid dose (methadone or morphine), phenobarbital was administered (20-mg/kg loading dose followed by 4-5 mg/kg daily).

  6. Growth Outcome: Weight Change From Birth to 18 Months

    Time frame: Birth to 18 month follow-up visit

    Growth outcome weight (lbs) depicted as difference in averaged weights from birth to 18 month follow-up visit. Standard deviations were averaged between birth and 18 mo time points.

  7. Growth Outcome: Head Circumference at 18 Months

    Time frame: 18 month follow-up visit

    Average head circumference growth outcome at 18 month follow-up visit.

  8. Maximum Finnegan Score

    Time frame: Participants monitored for the duration of their hospitalization.

    Maximum Finnegan score during the hospitalization

  9. Growth Outcome: Length at 18 Months

    Time frame: 18 month follow-up visit

    Average length (cm) at 18 month follow-up visit.

Other outcomes

  1. Cognitive, Language, and Motor Development From 18 Month Bayley III Neurodevelopmental Assessment

    Time frame: Assessment at 18 month follow-up visit

    The Bayley Scales of Infant and Toddler Development (BSID-III) assesses the development of infants and children (1-42 months) through a series of developmental play tasks, identifying children with developmental delay. Raw scores of completed items are summarized within three distinct scale scores (Cognitive Scale, Language Scale, Motor Scale). Scale scores are each converted to composite scores to determine the child's performance compared with scores of age-matched children of typical development (percentile rank). A higher composite score indicates more ideal developmental outcome (range 40-160). At 18 month follow-up visit, participants were assessed using the BSID-III for cognitive, language and motor scale composite score outcomes.

Sponsors and collaborators

Lead sponsor

Tufts Medical Center

Other

Registry information

Important dates

Study start
2013
Primary completion
2017
Study completion
2018
First posted
Oct 9, 2013
Registry last updated
Oct 15, 2019

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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