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Improving Outcomes in Neonatal Abstinence Syndrome

Sponsor
Tufts Medical Center (Other)
Overall Status
Completed
CT.gov ID
NCT01958476
Collaborator
(none)
117
Enrollment
8
Locations
2
Arms
59.9
Duration (Months)
14.6
Patients Per Site
0.2
Patients Per Site Per Month

Study Details

Study Description

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.

  1. 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.

Condition or Disease Intervention/Treatment Phase
Phase 3

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.

  1. 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 Design

Study Type:
Interventional
Actual Enrollment :
117 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose:
Treatment
Official Title:
Improving Outcomes in Neonatal Abstinence Syndrome
Study Start Date :
Sep 1, 2013
Actual Primary Completion Date :
Mar 5, 2017
Actual Study Completion Date :
Aug 30, 2018

Arms and Interventions

Arm Intervention/Treatment
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.

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 Names:
  • Morphine sulfate

    • 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.
    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.

    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 Names:
  • 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.

    Outcome Measures

    Primary Outcome Measures

    1. Length of Hospital Stay (LOS) [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 Outcome Measures

    1. Length of Hospital Stay (LOS) Due to Neonatal Abstinence Syndrome (NAS) [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) [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 [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) [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 [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 [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 [18 month follow-up visit]

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

    8. Maximum Finnegan Score [Participants monitored for the duration of their hospitalization.]

      Maximum Finnegan score during the hospitalization

    9. Growth Outcome: Length at 18 Months [18 month follow-up visit]

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

    Other Outcome Measures

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

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    N/A and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    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.

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Shands Jacksonville Medical Center Jacksonville Florida United States 32209
    2 Maine Medical Center Portland Maine United States
    3 Tufts Medical Center Boston Massachusetts United States 02111
    4 Boston Medical Center Boston Massachusetts United States 02118
    5 Baystate Medical Center Springfield Massachusetts United States 01199
    6 University of Pittsburgh Medical Center Pittsburgh Pennsylvania United States 15224
    7 Women and Infant's Hospital of Rhode Island Providence Rhode Island United States 02908
    8 Vanderbilt University Nashville Tennessee United States 37232

    Sponsors and Collaborators

    • Tufts Medical Center

    Investigators

    • Principal Investigator: Jonathan Davis, MD, Tufts Medical Center
    • Principal Investigator: Barry Lester, PhD, Women and Infant's Hospital

    Study Documents (Full-Text)

    More Information

    Publications

    Responsible Party:
    Tufts Medical Center
    ClinicalTrials.gov Identifier:
    NCT01958476
    Other Study ID Numbers:
    • 1R01DA032889-01A1
    First Posted:
    Oct 9, 2013
    Last Update Posted:
    Oct 15, 2019
    Last Verified:
    Sep 1, 2019
    Keywords provided by Tufts Medical Center
    Neonatal Abstinence Syndrome
    Opioids
    Additional relevant MeSH terms:
    Neonatal Abstinence Syndrome
    Syndrome
    Morphine
    Methadone
    Phenobarbital
    Pharmaceutical Solutions

    Study Results

    Participant Flow

    Recruitment Details Recruitment took place at Tufts Medical Center, Baystate Children's Hospital, Boston Medical Center, Maine Medical Center, Shands Jacksonville Medical Center, University of Pittsburgh Medical Center, Vanderbilt University Medical Center, and Women & Infants Hospital of Rhode Island.
    Pre-assignment Detail If infant was diagnosed with NAS (Finnegan score ≥8 on two consecutive occasions, or ≥12 on single assessment) and research pharmacy staff were unavailable for preparation of trial drug, infant could receive one dose of morphine prior to randomization. Dosing was based on weight and Finnegan scores.
    Arm/Group Title Methadone Neonatal Morphine Solution
    Arm/Group Description First line therapy: 0.4mg/mL oral solution, based on weight and symptoms. Clinical monitoring: Infants scored using standardized Finnegan system; Regimen: Initiated treatment w/ 2 consec. scores ≥8, or 1 score ≥12. Starting doses range 0.3mg/kg/day - 0.9mg/kg/day, divided every 8hrs depending on the severity of Finnegan scores. Doses were increased to max of 0.9mg/kg/day for contd. scores generally >8 caused primarily by worsening NAS, as needed. Weaned by 10% of max dose every 24-48 hours; Medication discontinued once at 25% of max dose. Second Line Therapy: Phenobarbital (20mg/kg) was added once infant reached max methadone doses for contd. scores generally >8. Option to re-load w/ 10mg/kg q8-12 hours for 2 more doses if needed for contd. high scores. Maintenance therapy of 5mg/kg/day was initiated 12 - 24hrs after last loading dose. Phenobarbital trough levels monitored, w/ goal levels 20 - 30 mcg/mL. Weaning procedure outlined in protocol. First line therapy: 0.2mg/mL solution, based on weight and symptoms. Clinical monitoring: Infants scored using standardized Finnegan system; Regimen: Initiated treatment w/ 2 consec. scores ≥8, or 1 score ≥12. Starting doses range 0.3mg/kg/day - 0.9mg/kg/day, divided every 4hrs depending on the severity of Finnegan scores. Doses were increased to max of 0.9mg/kg/day for contd. scores generally >8 caused primarily by worsening NAS, as needed. Weaned by 10% of max dose every 24 - 48 hours; Medication discontinued once at 25% of max dose. Second Line Therapy: Phenobarbital (20mg/kg) was added once infant reached max morphine doses for contd. scores generally >8. Option to re-load w/ 10mg/kg q8-12 hours for 2 more doses if needed for contd. high scores. Maintenance therapy of 5mg/kg/day was initiated 12 - 24hrs after last loading dose. Phenobarbital trough levels monitored, w/ goal levels 20 - 30 mcg/mL. Weaning procedure outlined in protocol.
    Period Title: Overall Study
    STARTED 59 58
    COMPLETED 58 58
    NOT COMPLETED 1 0

    Baseline Characteristics

    Arm/Group Title Randomized: Methadone Randomized: Neonatal Morphine Solution Total
    Arm/Group Description First line therapy: 0.4mg/mL oral solution, based on weight and symptoms. Clinical monitoring: Infants scored using standardized Finnegan system; Regimen: Initiated treatment w/ 2 consec. scores ≥8, or 1 score ≥12. Starting doses range 0.3mg/kg/day - 0.9mg/kg/day, divided every 8hrs depending on the severity of Finnegan scores. Doses were increased to max of 0.9mg/kg/day for contd. scores generally >8 caused primarily by worsening NAS, as needed. Weaned by 10% of max dose every 24-48 hours; Medication discontinued once at 25% of max dose. Second Line Therapy: Phenobarbital (20mg/kg) was added once infant reached max methadone doses for contd. scores generally >8. Option to re-load w/ 10mg/kg q8-12 hours for 2 more doses if needed for contd. high scores. Maintenance therapy of 5mg/kg/day was initiated 12 - 24hrs after last loading dose. Phenobarbital trough levels monitored, w/ goal levels 20 - 30 mcg/mL. Weaning procedure outlined in protocol. First line therapy: 0.2mg/mL solution, based on weight and symptoms. Clinical monitoring: Infants scored using standardized Finnegan system; Regimen: Initiated treatment w/ 2 consec. scores ≥8, or 1 score ≥12. Starting doses range 0.3mg/kg/day - 0.9mg/kg/day, divided every 4hrs depending on the severity of Finnegan scores. Doses were increased to max of 0.9mg/kg/day for contd. scores generally >8 caused primarily by worsening NAS, as needed. Weaned by 10% of max dose every 24 - 48 hours; Medication discontinued once at 25% of max dose. Second Line Therapy: Phenobarbital (20mg/kg) was added once infant reached max morphine doses for contd. scores generally >8. Option to re-load w/ 10mg/kg q8-12 hours for 2 more doses if needed for contd. high scores. Maintenance therapy of 5mg/kg/day was initiated 12 - 24hrs after last loading dose. Phenobarbital trough levels monitored, w/ goal levels 20 - 30 mcg/mL. Weaning procedure outlined in protocol. Total of all reporting groups
    Overall Participants 58 58 116
    Age, Customized (days) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [days]
    3.2
    (1.3)
    3.5
    (1.6)
    3.4
    (1.6)
    Sex: Female, Male (Count of Participants)
    Female
    29
    50%
    29
    50%
    58
    50%
    Male
    29
    50%
    29
    50%
    58
    50%
    Race/Ethnicity, Customized (Count of Participants)
    White
    46
    79.3%
    42
    72.4%
    88
    75.9%
    Hispanic
    6
    10.3%
    6
    10.3%
    12
    10.3%
    Other
    6
    10.3%
    10
    17.2%
    16
    13.8%
    Maternal opioid use (Count of Participants)
    Buprenorphine
    20
    34.5%
    19
    32.8%
    39
    33.6%
    Methadone
    38
    65.5%
    35
    60.3%
    73
    62.9%
    Prescription opioids for pain
    0
    0%
    4
    6.9%
    4
    3.4%
    Maternal Smoking Frequency during Pregnancy (Count of Participants)
    Smoked >5 cigarettes per day
    33
    56.9%
    15
    25.9%
    48
    41.4%
    Unknown/Data Missing
    25
    43.1%
    43
    74.1%
    68
    58.6%
    Maternal urine toxicology (Count of Participants)
    Positive urine toxicology
    13
    22.4%
    16
    27.6%
    29
    25%
    Negative urine toxicology
    41
    70.7%
    33
    56.9%
    74
    63.8%
    Data Missing
    4
    6.9%
    9
    15.5%
    13
    11.2%
    Maternal psychiatric diagnoses (Count of Participants)
    Psychiatric diagnoses
    42
    72.4%
    37
    63.8%
    79
    68.1%
    No psychiatric diagnoses/Unknown
    16
    27.6%
    21
    36.2%
    37
    31.9%
    Maternal psychiatric medication during pregnancy (Count of Participants)
    Psychiatric medication during pregnancy
    20
    34.5%
    16
    27.6%
    36
    31%
    No psychiatric medication during pregnancy/Unknown
    38
    65.5%
    42
    72.4%
    80
    69%
    Infant mean gestational age (weeks) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [weeks]
    39.2
    (1.2)
    39.1
    (1.1)
    39.2
    (1.2)
    Infant birth weight (grams) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [grams]
    3186
    (488)
    3128
    (487)
    3146
    (486)
    Infant APGAR score at 1 minute (Count of Participants)
    Score ≥7
    54
    93.1%
    53
    91.4%
    107
    92.2%
    Score <7/Data missing
    4
    6.9%
    5
    8.6%
    9
    7.8%
    Infant mean head circumference (cm) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [cm]
    33.9
    (1.7)
    33.7
    (1.8)
    33.8
    (1.7)
    Infant urine toxicology (Count of Participants)
    Positive
    41
    70.7%
    42
    72.4%
    83
    71.6%
    Negative
    14
    24.1%
    14
    24.1%
    28
    24.1%
    Missing
    3
    5.2%
    2
    3.4%
    5
    4.3%
    Site of initial care before treatment (Count of Participants)
    NICU
    3
    5.2%
    10
    17.2%
    13
    11.2%
    Newborn Nursery
    55
    94.8%
    48
    82.8%
    103
    88.8%
    Other
    0
    0%
    0
    0%
    0
    0%
    Single dose of morphine prior to randomization (Count of Participants)
    Single dose of morphine prior to randomization
    23
    39.7%
    17
    29.3%
    40
    34.5%
    No dose of morphine prior to randomization
    35
    60.3%
    41
    70.7%
    76
    65.5%
    Initial site of NAS care (Count of Participants)
    NICU
    17
    29.3%
    17
    29.3%
    34
    29.3%
    Special Care Nursery
    9
    15.5%
    7
    12.1%
    16
    13.8%
    General Pediatric Unit
    16
    27.6%
    18
    31%
    34
    29.3%
    Newborn Unit
    16
    27.6%
    16
    27.6%
    32
    27.6%
    Starting dose of study drug (Count of Participants)
    Level I: 0.3 mg/kg/day
    26
    44.8%
    32
    55.2%
    58
    50%
    Level II: 0.5 mg/kg/day
    25
    43.1%
    21
    36.2%
    46
    39.7%
    Level I: 0.7 mg/kg/day
    7
    12.1%
    5
    8.6%
    12
    10.3%
    Maximum Finnegan score prior to starting treatment (units on a scale) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [units on a scale]
    12.9
    (2.9)
    12.6
    (2.8)
    NA
    (NA)
    Primary feeding during hospitalization (Count of Participants)
    Formula only
    22
    37.9%
    32
    55.2%
    54
    46.6%
    Breast milk (exclusive or with formula supplement)
    36
    62.1%
    26
    44.8%
    62
    53.4%
    Maternal Smoking Status during Pregnancy (Count of Participants)
    Smoked during pregnancy
    49
    84.5%
    44
    75.9%
    93
    80.2%
    Did not smoke during pregancy/Data missing
    9
    15.5%
    14
    24.1%
    23
    19.8%
    Infant APGAR Score at 5 minutes (Count of Participants)
    Score ≥7
    57
    98.3%
    57
    98.3%
    114
    98.3%
    Score <7/Data missing
    1
    1.7%
    1
    1.7%
    2
    1.7%

    Outcome Measures

    1. Primary Outcome
    Title Length of Hospital Stay (LOS)
    Description Participants were monitored for the duration of their hospitalization, an expected mean of 22 days.
    Time Frame Participants will be monitored during their entire hospitalization, expected mean 22 days.

    Outcome Measure Data

    Analysis Population Description
    Includes infants requiring treatment for NAS who were randomized to either methadone or morphine study intervention. Analysis does not include Standard Clinical Care cohort.
    Arm/Group Title Methadone Neonatal Morphine Solution
    Arm/Group Description 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. 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.
    Measure Participants 58 58
    Mean (Standard Deviation) [days]
    21.8
    (15)
    23.2
    (8.8)
    2. Secondary Outcome
    Title Length of Hospital Stay (LOS) Due to Neonatal Abstinence Syndrome (NAS)
    Description Participants were monitored for the duration of their hospitalization attributable to NAS only.
    Time Frame Participants were monitored for the duration of their hospitalization, expected mean 22 days.

    Outcome Measure Data

    Analysis Population Description
    Includes infants requiring treatment for NAS who were randomized to either methadone or morphine study intervention. Analysis does not include Standard Clinical Care cohort.
    Arm/Group Title Methadone Neonatal Morphine Solution
    Arm/Group Description 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. 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.
    Measure Participants 58 58
    Mean (Standard Deviation) [days]
    18.9
    (7.9)
    21.1
    (6.9)
    3. Secondary Outcome
    Title Length of Treatment (LOT)
    Description Total number of days infant treated with replacement opioids while admitted to the hospital.
    Time Frame Participants were monitored for the duration of their hospitalization.

    Outcome Measure Data

    Analysis Population Description
    Includes infants requiring treatment for NAS who were randomized to either methadone or morphine study intervention. Analysis does not include Standard Clinical Care cohort.
    Arm/Group Title Methadone Neonatal Morphine Solution
    Arm/Group Description 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. 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.
    Measure Participants 58 58
    Mean (Standard Deviation) [days]
    14.7
    (8.0)
    16.6
    (6.9)
    4. Secondary Outcome
    Title Maximum Daily Dose of Replacement Opioid
    Description Maximum daily dose of neonatal morphine solution or methadone during the hospitalization
    Time Frame Participants were monitored for the duration of their hospitalization.

    Outcome Measure Data

    Analysis Population Description
    Data were not collected due to insufficient funding to carry out data collection.
    Arm/Group Title Methadone Neonatal Morphine Solution
    Arm/Group Description 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. 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.
    Measure Participants 0 0
    5. Secondary Outcome
    Title Mean Finnegan Score (FS)
    Description Mean Finnegan withdrawal score during the duration of hospitalization.
    Time Frame Participants were monitored during their entire hospitalization

    Outcome Measure Data

    Analysis Population Description
    Data were not collected due to insufficient funding to carry out data collection.
    Arm/Group Title Methadone Neonatal Morphine Solution
    Arm/Group Description 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. 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.
    Measure Participants 0 0
    6. Secondary Outcome
    Title Number of Infants Needing a Second NAS Medication
    Description 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).
    Time Frame Participants were monitored for the duration of their hospitalization, an average of 22 days.

    Outcome Measure Data

    Analysis Population Description
    Includes infants requiring treatment for NAS who were randomized to either methadone or morphine study intervention. Analysis does not include Standard Clinical Care cohort.
    Arm/Group Title Methadone Neonatal Morphine Solution
    Arm/Group Description 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. 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.
    Measure Participants 58 58
    Count of Participants [Participants]
    10
    17.2%
    17
    29.3%
    7. Secondary Outcome
    Title Growth Outcome: Weight Change From Birth to 18 Months
    Description 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.
    Time Frame Birth to 18 month follow-up visit

    Outcome Measure Data

    Analysis Population Description
    Participants who were continuously enrolled and attended the 18 month follow-up visit for developmental and growth measures.
    Arm/Group Title Methadone Neonatal Morphine Solution
    Arm/Group Description 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. 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.
    Measure Participants 46 36
    Mean (Standard Deviation) [lbs]
    19.1
    (2.5)
    18.7
    (2.8)
    8. Secondary Outcome
    Title Growth Outcome: Head Circumference at 18 Months
    Description Average head circumference growth outcome at 18 month follow-up visit.
    Time Frame 18 month follow-up visit

    Outcome Measure Data

    Analysis Population Description
    Participants who were continuously enrolled and attended the 18 month follow-up visit for developmental and growth measures.
    Arm/Group Title Methadone Neonatal Morphine Solution
    Arm/Group Description 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. 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.
    Measure Participants 46 36
    Mean (Standard Deviation) [cm]
    47.8
    (2.4)
    48.2
    (2.3)
    9. Secondary Outcome
    Title Maximum Finnegan Score
    Description Maximum Finnegan score during the hospitalization
    Time Frame Participants monitored for the duration of their hospitalization.

    Outcome Measure Data

    Analysis Population Description
    Data were not collected due to insufficient funding to carry out data collection.
    Arm/Group Title Methadone Neonatal Morphine Solution
    Arm/Group Description 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. 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.
    Measure Participants 0 0
    10. Secondary Outcome
    Title Growth Outcome: Length at 18 Months
    Description Average length (cm) at 18 month follow-up visit.
    Time Frame 18 month follow-up visit

    Outcome Measure Data

    Analysis Population Description
    Participants who were continuously enrolled and attended the 18 month follow-up visit for developmental and growth measures.
    Arm/Group Title Methadone Neonatal Morphine Solution
    Arm/Group Description 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. 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.
    Measure Participants 46 36
    Mean (Standard Deviation) [cm]
    82.1
    (4.6)
    81.7
    (5.2)
    11. Other Pre-specified Outcome
    Title Cognitive, Language, and Motor Development From 18 Month Bayley III Neurodevelopmental Assessment
    Description 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.
    Time Frame Assessment at 18 month follow-up visit

    Outcome Measure Data

    Analysis Population Description
    Includes subjects who were randomized and remained enrolled at 18 month follow-up visit.
    Arm/Group Title Methadone Neonatal Morphine Solution
    Arm/Group Description 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. 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.
    Measure Participants 46 36
    Cognitive Composite
    100.1
    (21.6)
    98.1
    (17.2)
    Language Composite
    96.0
    (17.1)
    94.2
    (18.2)
    Motor Composite
    103.6
    (17.3)
    99.1
    (17.2)
    12. Post-Hoc Outcome
    Title Number of Infants Needing a Dose Increase
    Description One Finnegan score ≥12, or two consecutive scores ≥8 affirms the requirement for pharmacological treatment or increasing treatment dosage. If the infant continued to have two consecutive Finnegan Scores ≥8 two times consecutively, or one ≥12, the dose was increased to the next level. (Level I: 0.3 mg/kg/day) (Level II: 0.5 mg/kg/day) (Level III: 0.7 mg/kg/day) A higher Finnegan score indicates greater severity of NAS (min 0, max 50).
    Time Frame Participants were monitored for the duration of their hospitalization, an average of 22 days.

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Methadone Neonatal Morphine Solution
    Arm/Group Description 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. 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.
    Measure Participants 58 58
    Count of Participants [Participants]
    22
    37.9%
    28
    48.3%

    Adverse Events

    Time Frame Participants were monitored for the duration of their hospitalization, an average of 22 days.
    Adverse Event Reporting Description Adverse Events and Serious Adverse Events were reported according to standard definitions.
    Arm/Group Title Methadone Neonatal Morphine Solution
    Arm/Group Description Methadone oral solution (0.4mg/mL) for first line therapy. Infants were scored using the standardized Finnegan Scoring Tool and were initiated on treatment with 2 consecutive scores ≥8 or 1 score ≥12. Dosing was weight and symptom based. Starting doses range from 0.3mg/kg/day - 0.9mg/kg/day divided every 8 hours, depending on the severity of the Finnegan scores. To maintain blinding, a "double dummy" design was used - each infant received both methadone/placebo study drug at 0.4 mg/mL and a morphine/placebo study drug at 0.2 mg/mL. Doses were increased to a maximum of 0.9mg/kg/day for continued scores generally >8 caused primarily by worsening NAS, as needed. Infants were weaned by 10% of the maximum dose every 24-48 hours and the medication was discontinued once at 25% of the maximum dose. Neonatal morphine solution (0.2mg/mL) for first line therapy. Infants were scored using the standardized Finnegan Scoring Tool and were initiated on treatment with 2 consecutive scores ≥8 or 1 score ≥12. Dosing was weight and symptom based. Starting doses range from 0.3mg/kg/day - 0.9mg/kg/day divided every 4 hrs, depending on the severity of the Finnegan scores. To maintain blinding, a "double dummy" design was used - each infant received both methadone/placebo study drug at 0.4 mg/mL and a morphine/placebo study drug at 0.2 mg/mL. Doses were increased to a maximum of 0.9mg/kg/day for continued scores generally >8 caused primarily by worsening NAS, as needed. Infants were weaned by 10% of the maximum dose every 24-48 hours and the medication was discontinued once at 25% of the maximum dose.
    All Cause Mortality
    Methadone Neonatal Morphine Solution
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 0/58 (0%) 0/58 (0%)
    Serious Adverse Events
    Methadone Neonatal Morphine Solution
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 5/58 (8.6%) 3/58 (5.2%)
    General disorders
    Hypothermia, apnea and lethargy 1/58 (1.7%) 1 0/58 (0%) 0
    Surgical and medical procedures
    Medication Administration Error 4/58 (6.9%) 6 3/58 (5.2%) 3
    Other (Not Including Serious) Adverse Events
    Methadone Neonatal Morphine Solution
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 8/58 (13.8%) 6/58 (10.3%)
    Cardiac disorders
    Bradychardia 3/58 (5.2%) 3 1/58 (1.7%) 1
    Gastrointestinal disorders
    Emesis 0/58 (0%) 0 1/58 (1.7%) 1
    Investigations
    Excessive sleepiness/somnolence 4/58 (6.9%) 4 2/58 (3.4%) 2
    Lethargy 0/58 (0%) 0 1/58 (1.7%) 1
    Hypothermia 2/58 (3.4%) 2 0/58 (0%) 0
    Poor feeding 0/58 (0%) 0 1/58 (1.7%) 1
    Respiratory, thoracic and mediastinal disorders
    Apnea and shallow breathing episodes 1/58 (1.7%) 1 0/58 (0%) 0
    Stridor/desaturation/shalllow breathing 2/58 (3.4%) 2 0/58 (0%) 0

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

    Principal Investigators are NOT employed by the organization sponsoring the study.

    There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

    Results Point of Contact

    Name/Title Jonathan M. Davis, MD
    Organization Tufts Medical Center Floating Hospital for Children
    Phone (617) 636-5322
    Email jdavis@tuftsmedicalcenter.org
    Responsible Party:
    Tufts Medical Center
    ClinicalTrials.gov Identifier:
    NCT01958476
    Other Study ID Numbers:
    • 1R01DA032889-01A1
    First Posted:
    Oct 9, 2013
    Last Update Posted:
    Oct 15, 2019
    Last Verified:
    Sep 1, 2019