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Trial record 1 of 1 for:    NCT01958476
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Improving Outcomes in Neonatal Abstinence Syndrome

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ClinicalTrials.gov Identifier: NCT01958476
Recruitment Status : Completed
First Posted : October 9, 2013
Results First Posted : October 15, 2019
Last Update Posted : October 15, 2019
Sponsor:
Information provided by (Responsible Party):
Tufts Medical Center

Tracking Information
First Submitted Date  ICMJE August 14, 2013
First Posted Date  ICMJE October 9, 2013
Results First Submitted Date  ICMJE July 1, 2019
Results First Posted Date  ICMJE October 15, 2019
Last Update Posted Date October 15, 2019
Study Start Date  ICMJE September 2013
Actual Primary Completion Date March 5, 2017   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: September 27, 2019)
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.
Original Primary Outcome Measures  ICMJE
 (submitted: October 8, 2013)
Length of hospital stay [ Time Frame: Participants will be monitored for the duration of their hospitalization, which is an expected mean of 22 days ]
Participants will be monitored for the duration of their hospitalization for neonatal abstinence syndrome, which is an expected mean of 22 days
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: September 27, 2019)
  • 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.
  • 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.
  • 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
  • Mean Finnegan Score (FS) [ Time Frame: Participants were monitored during their entire hospitalization ]
    Mean Finnegan withdrawal score during the duration of hospitalization.
  • 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).
  • 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.
  • 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.
  • Maximum Finnegan Score [ Time Frame: Participants monitored for the duration of their hospitalization. ]
    Maximum Finnegan score during the hospitalization
  • Growth Outcome: Length at 18 Months [ Time Frame: 18 month follow-up visit ]
    Average length (cm) at 18 month follow-up visit.
Original Secondary Outcome Measures  ICMJE
 (submitted: October 8, 2013)
  • Total opioid days [ Time Frame: Participants will be monitored for the duration of their hospitalization, expected mean 22 days ]
    Total number of days infant treated with replacement opioids while in the hospital
  • Maximum Daily Dose of Replacement Opioid [ Time Frame: Participants will be monitored until the end of their hospitalization, expected mean 22 days ]
    Maximum daily dose of neonatal morphine solution or methadone during the hospitalization
  • Mean Finnegan Score [ Time Frame: Participants will be monitored during their entire hospitalization, expected mean 22 days ]
    Mean Finnegan withdrawal score during the hospitalization
  • Need for a second NAS medication [ Time Frame: Participants will be monitored during their entire hospitalization, expected mean 22 days ]
    Need for a second medication to control opioid withdrawal
Current Other Pre-specified Outcome Measures
 (submitted: September 27, 2019)
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.
Original Other Pre-specified Outcome Measures
 (submitted: October 8, 2013)
  • 4 Domains of the NICU Network Neurobehavioral Scale (NNNS) [ Time Frame: At the end of the hospitalization ]
    4 domains of the NNNS:
    1. Quality of movement
    2. Arousal
    3. Hypertonicity
    4. Stress / Abstinence
  • Mental Disability Index (MDI) and Physical Disbaility Index (PDI) from 18 month Bayleys III Neurodevelopmental Assessment [ Time Frame: 18 month follow-up visit ]
    Mental and Physical Disability Indexes from the Bayleys III Neurodevelopmental Assessment
 
Descriptive Information
Brief Title  ICMJE Improving Outcomes in Neonatal Abstinence Syndrome
Official Title  ICMJE Improving Outcomes in Neonatal Abstinence Syndrome
Brief Summary

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.

Detailed Description

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.

2. 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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE
  • Neonatal Abstinence Syndrome
  • Neonatal Opioid Withdrawal
Intervention  ICMJE
  • Drug: Neonatal Morphine Solution
    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 Name: Morphine sulfate
  • Drug: Methadone
    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 Name: Methadone oral solution
  • Drug: Phenobarbital

    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.

Study Arms  ICMJE
  • Active Comparator: Neonatal Morphine Solution
    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 or equal to 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.
    Interventions:
    • Drug: Neonatal Morphine Solution
    • Drug: Phenobarbital
  • Active Comparator: Methadone
    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.
    Interventions:
    • Drug: Methadone
    • Drug: Phenobarbital
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: September 27, 2019)
117
Original Estimated Enrollment  ICMJE
 (submitted: October 8, 2013)
184
Actual Study Completion Date  ICMJE August 30, 2018
Actual Primary Completion Date March 5, 2017   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion criteria:

  1. 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.
  2. Need for treatment of NAS by Finnegan Scoring criteria
  3. Gestational age >37 weeks at birth defined by best obstetrical estimate
  4. Medically stable in the opinion of the Attending Physician
  5. Mother receiving "adequate" or "intermediate" prenatal care from a qualified physician or midwife as defined by the Prenatal Care Adequacy Index
  6. Singleton pregnancy
  7. Mother able to provide informed consent
  8. Infant able to take oral medications

Exclusion criteria:

  1. Gestation <37 weeks at entry defined by best obstetrical estimate
  2. Major congenital abnormalities including genetic syndromes
  3. Serious medical illness such as sepsis, asphyxia, seizures, or respiratory failure
  4. Mother abusing alcohol during pregnancy (average of 3 or more drinks per week in the last 30 days)
  5. Multiple gestations
  6. Mother received "inadequate" prenatal care as defined by the Prenatal Care Adequacy Index.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE Child, Adult, Older Adult
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01958476
Other Study ID Numbers  ICMJE 1R01DA032889-01A1( U.S. NIH Grant/Contract )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Tufts Medical Center
Study Sponsor  ICMJE Tufts Medical Center
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Jonathan Davis, MD Tufts Medical Center
Principal Investigator: Barry Lester, PhD Women and Infant's Hospital
PRS Account Tufts Medical Center
Verification Date September 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP