- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT01958476
Improving Outcomes in Neonatal Abstinence Syndrome
1: SPECIFIC Aim I: To compare treatment options for neonatal abstinence syndrome (NAS) due to in-utero narcotic exposure. One hundred eighty four full-term infants with a diagnosis of NAS requiring medications will be studied. Infants will be randomized to receive either morphine or methadone. It is hypothesized that morphine treated infants will do better and require fewer days in the hospital compared to methadone treated infants.
2. SPECIFIC Aim II: To evaluate the effects of NAS treatment on long-term neurodevelopmental outcome. Infants will be evaluated with development testing at 18 months of age. It is hypothesized that morphine treated infants will have better neurodevelopmental outcomes. It is also hypothesized that neurobehavioral abnormalities identified at two weeks of age will correlate with neurodevelopmental impairment at 18 months.
3: SPECIFIC Aim III: To determine if common genetic variations in the genes involving narcotic action contribute to the severity of NAS. A DNA sample will be obtained from all infants and analyzed for differences in 3 key genes. This will then be correlated with short-term and long-term outcomes.
Study Overview
Status
Intervention / Treatment
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
Enrollment (Actual)
Phase
- Phase 3
Contacts and Locations
Study Locations
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Florida
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Jacksonville, Florida, United States, 32209
- Shands Jacksonville Medical Center
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Maine
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Portland, Maine, United States
- Maine Medical Center
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Massachusetts
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Boston, Massachusetts, United States, 02111
- Tufts Medical Center
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Boston, Massachusetts, United States, 02118
- Boston Medical Center
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Springfield, Massachusetts, United States, 01199
- Baystate Medical Center
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Pennsylvania
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Pittsburgh, Pennsylvania, United States, 15224
- University of Pittsburgh Medical Center
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Rhode Island
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Providence, Rhode Island, United States, 02908
- Women and Infant's Hospital of Rhode Island
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Tennessee
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Nashville, Tennessee, United States, 37232
- Vanderbilt University
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Participation Criteria
Eligibility Criteria
Ages Eligible for Study
- Child
- Adult
- Older Adult
Accepts Healthy Volunteers
Genders Eligible for Study
Description
Inclusion criteria:
- Mother receiving methadone or buprenorphine (BPH) from a licensed physician or drug treatment program, or an opioid prescribed by a licensed health care worker for treatment of chronic pain.
- Need for treatment of NAS by Finnegan Scoring criteria
- Gestational age >37 weeks at birth defined by best obstetrical estimate
- Medically stable in the opinion of the Attending Physician
- Mother receiving "adequate" or "intermediate" prenatal care from a qualified physician or midwife as defined by the Prenatal Care Adequacy Index
- Singleton pregnancy
- Mother able to provide informed consent
- Infant able to take oral medications
Exclusion criteria:
- Gestation <37 weeks at entry defined by best obstetrical estimate
- Major congenital abnormalities including genetic syndromes
- Serious medical illness such as sepsis, asphyxia, seizures, or respiratory failure
- Mother abusing alcohol during pregnancy (average of 3 or more drinks per week in the last 30 days)
- Multiple gestations
- Mother received "inadequate" prenatal care as defined by the Prenatal Care Adequacy Index.
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: Randomized
- Interventional Model: Parallel Assignment
- Masking: Quadruple
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
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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.
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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:
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.
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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.
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:
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What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
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Length of Hospital Stay (LOS)
Time Frame: Participants will be monitored during their entire hospitalization, expected mean 22 days.
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Participants were monitored for the duration of their hospitalization, an expected mean of 22 days.
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Participants will be monitored during their entire hospitalization, expected mean 22 days.
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Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
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.
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Participants were monitored for the duration of their hospitalization attributable to NAS only.
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Participants were monitored for the duration of their hospitalization, expected mean 22 days.
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Length of Treatment (LOT)
Time Frame: Participants were monitored for the duration of their hospitalization.
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Total number of days infant treated with replacement opioids while admitted to the hospital.
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Participants were monitored for the duration of their hospitalization.
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Maximum Daily Dose of Replacement Opioid
Time Frame: Participants were monitored for the duration of their hospitalization.
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Maximum daily dose of neonatal morphine solution or methadone during the hospitalization
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Participants were monitored for the duration of their hospitalization.
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Mean Finnegan Score (FS)
Time Frame: Participants were monitored during their entire hospitalization
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Mean Finnegan withdrawal score during the duration of hospitalization.
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Participants were monitored during their entire hospitalization
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Number of Infants Needing a Second NAS Medication
Time Frame: Participants were monitored for the duration of their hospitalization, an average of 22 days.
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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).
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Participants were monitored for the duration of their hospitalization, an average of 22 days.
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Growth Outcome: Weight Change From Birth to 18 Months
Time Frame: Birth to 18 month follow-up visit
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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.
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Birth to 18 month follow-up visit
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Growth Outcome: Head Circumference at 18 Months
Time Frame: 18 month follow-up visit
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Average head circumference growth outcome at 18 month follow-up visit.
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18 month follow-up visit
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Maximum Finnegan Score
Time Frame: Participants monitored for the duration of their hospitalization.
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Maximum Finnegan score during the hospitalization
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Participants monitored for the duration of their hospitalization.
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Growth Outcome: Length at 18 Months
Time Frame: 18 month follow-up visit
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Average length (cm) at 18 month follow-up visit.
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18 month follow-up visit
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Other Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Cognitive, Language, and Motor Development From 18 Month Bayley III Neurodevelopmental Assessment
Time Frame: Assessment at 18 month follow-up visit
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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.
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Assessment at 18 month follow-up visit
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Collaborators and Investigators
Sponsor
Investigators
- Principal Investigator: Barry Lester, PhD, Women and Infant's Hospital
Publications and helpful links
General Publications
- Jones HE, Kaltenbach K, Heil SH, Stine SM, Coyle MG, Arria AM, O'Grady KE, Selby P, Martin PR, Fischer G. Neonatal abstinence syndrome after methadone or buprenorphine exposure. N Engl J Med. 2010 Dec 9;363(24):2320-31. doi: 10.1056/NEJMoa1005359.
- Wachman EM, Hayes MJ, Brown MS, Paul J, Harvey-Wilkes K, Terrin N, Huggins GS, Aranda JV, Davis JM. Association of OPRM1 and COMT single-nucleotide polymorphisms with hospital length of stay and treatment of neonatal abstinence syndrome. JAMA. 2013 May 1;309(17):1821-7. doi: 10.1001/jama.2013.3411.
- Sarkar S, Donn SM. Management of neonatal abstinence syndrome in neonatal intensive care units: a national survey. J Perinatol. 2006 Jan 1;26(1):15-7. doi: 10.1038/sj.jp.7211427.
- Lainwala S, Brown ER, Weinschenk NP, Blackwell MT, Hagadorn JI. A retrospective study of length of hospital stay in infants treated for neonatal abstinence syndrome with methadone versus oral morphine preparations. Adv Neonatal Care. 2005 Oct;5(5):265-72. doi: 10.1016/j.adnc.2005.06.003.
- Lotsch J, Skarke C, Liefhold J, Geisslinger G. Genetic predictors of the clinical response to opioid analgesics: clinical utility and future perspectives. Clin Pharmacokinet. 2004;43(14):983-1013. doi: 10.2165/00003088-200443140-00003.
- Jansson LM, Velez M, Harrow C. The opioid-exposed newborn: assessment and pharmacologic management. J Opioid Manag. 2009 Jan-Feb;5(1):47-55.
- Osborn DA, Jeffery HE, Cole MJ. Opiate treatment for opiate withdrawal in newborn infants. Cochrane Database Syst Rev. 2010 Oct 6;(10):CD002059. doi: 10.1002/14651858.CD002059.pub3.
- Zankl A, Martin J, Davey JG, Osborn DA. Opioid treatment for opioid withdrawal in newborn infants. Cochrane Database Syst Rev. 2021 Jul 7;7(7):CD002059. doi: 10.1002/14651858.CD002059.pub4.
- Czynski AJ, Davis JM, Dansereau LM, Engelhardt B, Marro P, Bogen DL, Hudak ML, Shenberger J, Wachman EM, Oliveira EL, Lester BM. Neurodevelopmental Outcomes of Neonates Randomized to Morphine or Methadone for Treatment of Neonatal Abstinence Syndrome. J Pediatr. 2020 Apr;219:146-151.e1. doi: 10.1016/j.jpeds.2019.12.018. Epub 2020 Jan 24.
- Davis JM, Shenberger J, Terrin N, Breeze JL, Hudak M, Wachman EM, Marro P, Oliveira EL, Harvey-Wilkes K, Czynski A, Engelhardt B, D'Apolito K, Bogen D, Lester B. Comparison of Safety and Efficacy of Methadone vs Morphine for Treatment of Neonatal Abstinence Syndrome: A Randomized Clinical Trial. JAMA Pediatr. 2018 Aug 1;172(8):741-748. doi: 10.1001/jamapediatrics.2018.1307.
Study record dates
Study Major Dates
Study Start
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Estimate)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Keywords
Additional Relevant MeSH Terms
- Mental Disorders
- Chemically-Induced Disorders
- Pathologic Processes
- Substance-Related Disorders
- Disease
- Infant, Newborn, Diseases
- Syndrome
- Neonatal Abstinence Syndrome
- Physiological Effects of Drugs
- Neurotransmitter Agents
- Molecular Mechanisms of Pharmacological Action
- Central Nervous System Depressants
- Peripheral Nervous System Agents
- Analgesics
- Sensory System Agents
- Excitatory Amino Acid Antagonists
- Excitatory Amino Acid Agents
- Analgesics, Opioid
- Narcotics
- Hypnotics and Sedatives
- GABA Modulators
- GABA Agents
- Anticonvulsants
- Respiratory System Agents
- Cytochrome P-450 Enzyme Inducers
- Cytochrome P-450 CYP3A Inducers
- Antitussive Agents
- Cytochrome P-450 CYP2B6 Inducers
- Pharmaceutical Solutions
- Morphine
- Methadone
- Phenobarbital
Other Study ID Numbers
- 1R01DA032889-01A1 (U.S. NIH Grant/Contract)
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