Improving Outcomes in Neonatal Abstinence Syndrome

This study is currently recruiting participants. (see Contacts and Locations)
Verified April 2014 by Tufts Medical Center
Sponsor:
Information provided by (Responsible Party):
Tufts Medical Center
ClinicalTrials.gov Identifier:
NCT01958476
First received: August 14, 2013
Last updated: April 21, 2014
Last verified: April 2014
  Purpose

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.


Condition Intervention Phase
Neonatal Abstinence Syndrome
Neonatal Opioid Withdrawal
Drug: Neonatal Morphine Solution
Drug: Methadone
Drug: Phenobarbital
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Factorial Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Improving Outcomes in Neonatal Abstinence Syndrome

Resource links provided by NLM:


Further study details as provided by Tufts Medical Center:

Primary Outcome Measures:
  • Length of hospital stay [ Time Frame: Participants will be monitored for the duration of their hospitalization, which is an expected mean of 22 days ] [ Designated as safety issue: No ]
    Participants will be monitored for the duration of their hospitalization for neonatal abstinence syndrome, which is an expected mean of 22 days


Secondary Outcome Measures:
  • Total opioid days [ Time Frame: Participants will be monitored for the duration of their hospitalization, expected mean 22 days ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    Need for a second medication to control opioid withdrawal


Other Outcome Measures:
  • 4 Domains of the NICU Network Neurobehavioral Scale (NNNS) [ Time Frame: At the end of the hospitalization ] [ Designated as safety issue: No ]

    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 ] [ Designated as safety issue: No ]
    Mental and Physical Disability Indexes from the Bayleys III Neurodevelopmental Assessment


Estimated Enrollment: 184
Study Start Date: September 2013
Estimated Study Completion Date: December 2016
Estimated Primary Completion Date: September 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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 >8. 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 >8. 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: Phenobarbital

A second line medication will be added once the infant reaches maximum doses of the study drug (morphine or methadone) for continued scores >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 >8 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 >8 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 >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.


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 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.

  Eligibility

Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01958476

Contacts
Contact: Jonathan Davis, MD 617-636-5322 jdavis@tuftsmedicalcenter.org

Locations
United States, Maine
Maine Medical Center Recruiting
Portland, Maine, United States
Contact: Peter Marro, MD       MARROP@mmc.org   
Principal Investigator: Peter Marro, MD         
United States, Massachusetts
Tufts Medical Center Recruiting
Boston, Massachusetts, United States, 02111
Contact: Jonathan Davis, MD    617-636-5322    jdavis@tuftsmedicalcenter.org   
Principal Investigator: Jonathan Davis, MD         
Boston Medical Center Recruiting
Boston, Massachusetts, United States, 02118
Contact: Elisha Wachman, MD    617-414-3690    Elisha.Wachman@bmc.org   
Principal Investigator: Michael Silverstein, MD         
Sub-Investigator: Elisha Wachman, MD         
United States, Rhode Island
Women and Infant's Hospital of Rhode Island Recruiting
Providence, Rhode Island, United States, 02908
Contact: Barry Lester, PhD    401-453-7640    BLester@WIHRI.org   
Principal Investigator: Barry Lester, PhD         
United States, Tennessee
Vanderbilt University Recruiting
Nashville, Tennessee, United States, 37232
Contact: Barbara Engelhardt, MD    615-322-3475    Barbara.Engerhardt@vanderbilt.edu   
Principal Investigator: Barbara Engelhardt, MD         
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
  More Information

Publications:

Responsible Party: Tufts Medical Center
ClinicalTrials.gov Identifier: NCT01958476     History of Changes
Other Study ID Numbers: 1R01DA032889-01A1
Study First Received: August 14, 2013
Last Updated: April 21, 2014
Health Authority: United States: Data and Safety Monitoring Board
United States: Food and Drug Administration
United States: Institutional Review Board

Keywords provided by Tufts Medical Center:
Neonatal Abstinence Syndrome
Opioids

Additional relevant MeSH terms:
Methadone
Syndrome
Neonatal Abstinence Syndrome
Disease
Pathologic Processes
Infant, Newborn, Diseases
Substance-Related Disorders
Chemically-Induced Disorders
Mental Disorders
Pharmaceutical Solutions
Morphine
Phenobarbital
Therapeutic Uses
Pharmacologic Actions
Analgesics, Opioid
Narcotics
Central Nervous System Depressants
Physiological Effects of Drugs
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Central Nervous System Agents
Antitussive Agents
Respiratory System Agents
Anticonvulsants
Hypnotics and Sedatives
Excitatory Amino Acid Antagonists
Excitatory Amino Acid Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on September 18, 2014