Clinical trial NCT01958476: Improving Outcomes in Neonatal Abstinence Syndrome
Official title: Improving Outcomes in Neonatal Abstinence Syndrome
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Neonatal Abstinence Syndrome
Neonatal Opioid Withdrawal
Keywords: Neonatal Abstinence Syndrome
Opioids
Lead sponsor: Tufts Medical Center
Sponsor class: OTHER
First posted: 2013-10-09
Enrollment: 117
Sex: ALL
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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

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

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

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

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

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

Eligibility 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.

Primary outcomes:
measure: Length of Hospital Stay (LOS)
timeFrame: Participants will be monitored during their entire hospitalization, expected mean 22 days.
Secondary outcomes:
measure: Length of Hospital Stay (LOS) Due to Neonatal Abstinence Syndrome (NAS)
timeFrame: Participants were monitored for the duration of their hospitalization, expected mean 22 days.
measure: Length of Treatment (LOT)
timeFrame: Participants were monitored for the duration of their hospitalization.
measure: Maximum Daily Dose of Replacement Opioid
timeFrame: Participants were monitored for the duration of their hospitalization.
measure: Mean Finnegan Score (FS)
timeFrame: Participants were monitored during their entire hospitalization
measure: Number of Infants Needing a Second NAS Medication
timeFrame: Participants were monitored for the duration of their hospitalization, an average of 22 days.
measure: Growth Outcome: Weight Change From Birth to 18 Months
timeFrame: Birth to 18 month follow-up visit
measure: Growth Outcome: Head Circumference at 18 Months
timeFrame: 18 month follow-up visit
measure: Maximum Finnegan Score
timeFrame: Participants monitored for the duration of their hospitalization.
measure: Growth Outcome: Length at 18 Months
timeFrame: 18 month follow-up visit
Other outcomes:
measure: Cognitive, Language, and Motor Development From 18 Month Bayley III Neurodevelopmental Assessment
timeFrame: Assessment at 18 month follow-up visit
Locations:
city: Jacksonville
country: United States
facility: Shands Jacksonville Medical Center
state: Florida
city: Portland
country: United States
facility: Maine Medical Center
state: Maine
city: Boston
country: United States
facility: Tufts Medical Center
state: Massachusetts
city: Boston
country: United States
facility: Boston Medical Center
state: Massachusetts
city: Springfield
country: United States
facility: Baystate Medical Center
state: Massachusetts
city: Pittsburgh
country: United States
facility: University of Pittsburgh Medical Center
state: Pennsylvania
city: Providence
country: United States
facility: Women and Infant's Hospital of Rhode Island
state: Rhode Island
city: Nashville
country: United States
facility: Vanderbilt University
state: Tennessee
Study officials:
affiliation: Tufts Medical Center
name: Jonathan Davis, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Women and Infant's Hospital
name: Barry Lester, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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.
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citation: Jansson LM, Velez M, Harrow C. The opioid-exposed newborn: assessment and pharmacologic management. J Opioid Manag. 2009 Jan-Feb;5(1):47-55.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.