Improving Outcomes in Neonatal Abstinence Syndrome

NCT01958476 | Completed Phase 3 Results DMC

• 1 other identifier: 1R01DA032889-01A1
• Study Type: interventional
• Target: 117
• Locations: 1 country
• Sites: 8

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.

Conditions

Neonatal Abstinence Syndrome; Neonatal Opioid Withdrawal

Keywords

Neonatal Abstinence Syndrome; Opioids

Outcome Measures

Primary Outcomes (1)

• Length of Hospital Stay (LOS)

  Participants were monitored for the duration of their hospitalization, an expected mean of 22 days.

  Participants will be monitored during their entire hospitalization, expected mean 22 days.

Secondary Outcomes (9)

• Length of Hospital Stay (LOS) Due to Neonatal Abstinence Syndrome (NAS)

  Participants were monitored for the duration of their hospitalization, expected mean 22 days.

• Length of Treatment (LOT)

  Participants were monitored for the duration of their hospitalization.

• Maximum Daily Dose of Replacement Opioid

  Participants were monitored for the duration of their hospitalization.

• Mean Finnegan Score (FS)

  Participants were monitored during their entire hospitalization

• Number of Infants Needing a Second NAS Medication

  Participants were monitored for the duration of their hospitalization, an average of 22 days.

Other Outcomes (1)

• Cognitive, Language, and Motor Development From 18 Month Bayley III Neurodevelopmental Assessment

  Assessment at 18 month follow-up visit

Study Arms (2)

Neonatal Morphine Solution

ACTIVE COMPARATOR

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; Drug: Phenobarbital

Methadone

ACTIVE COMPARATOR

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; Drug: Phenobarbital

Interventions

Neonatal Morphine Solution DRUG

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.

Also known as: Morphine sulfate

Neonatal Morphine Solution

Methadone DRUG

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.

Also known as: Methadone oral solution

Methadone

Phenobarbital DRUG

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.

Methadone; Neonatal Morphine Solution

Eligibility Criteria

• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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.

Sponsors & Collaborators

• Tufts Medical Center: lead

Study Sites (8)

Shands Jacksonville Medical Center

Jacksonville, Florida, 32209, United States

Location

Maine Medical Center

Portland, Maine, United States

Location

Tufts Medical Center

Boston, Massachusetts, 02111, United States

Location

Boston Medical Center

Boston, Massachusetts, 02118, United States

Location

Baystate Medical Center

Springfield, Massachusetts, 01199, United States

Location

University of Pittsburgh Medical Center

Pittsburgh, Pennsylvania, 15224, United States

Location

Women and Infant's Hospital of Rhode Island

Providence, Rhode Island, 02908, United States

Location

Vanderbilt University

Nashville, Tennessee, 37232, United States

Location

Related Publications (10)

• 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.

  PMID: 23632726 BACKGROUND

• 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.

  PMID: 16355103 BACKGROUND

• 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.

  PMID: 16202968 BACKGROUND

• 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.

  PMID: 15530129 BACKGROUND

• Jansson LM, Velez M, Harrow C. The opioid-exposed newborn: assessment and pharmacologic management. J Opioid Manag. 2009 Jan-Feb;5(1):47-55.

  PMID: 19344048 BACKGROUND

• 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.

  PMID: 20927730 BACKGROUND

• 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.

  PMID: 21142534 BACKGROUND

• 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.

  PMID: 34231914 DERIVED

• 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.

  PMID: 31987653 DERIVED

• 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.

  PMID: 29913015 DERIVED

MeSH Terms

Conditions

Neonatal Abstinence Syndrome

Interventions

Morphine; Methadone; Phenobarbital

Condition Hierarchy (Ancestors)

Infant, Newborn, Diseases; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Substance-Related Disorders; Chemically-Induced Disorders; Mental Disorders

Intervention Hierarchy (Ancestors)

Morphine Derivatives; Morphinans; Opiate Alkaloids; Alkaloids; Heterocyclic Compounds; Heterocyclic Compounds, Bridged-Ring; Heterocyclic Compounds, 4 or More Rings; Heterocyclic Compounds, Fused-Ring; Phenanthrenes; Polycyclic Aromatic Hydrocarbons; Polycyclic Compounds; Ketones; Organic Chemicals; Barbiturates; Pyrimidinones; Pyrimidines; Heterocyclic Compounds, 1-Ring

Results Point of Contact

• Title: Jonathan M. Davis, MD
• Organization: Tufts Medical Center Floating Hospital for Children

jdavis@tuftsmedicalcenter.org

(617) 636-5322

Study Officials

• Jonathan Davis, MD

  Tufts Medical Center

  PRINCIPAL INVESTIGATOR

• Barry Lester, PhD

  Women and Infant's Hospital

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 14, 2013
• First Posted: October 9, 2013
• Study Start: September 1, 2013
• Primary Completion: March 5, 2017
• Study Completion: August 30, 2018
• Last Updated: October 15, 2019
• Results First Posted: October 15, 2019

Record last verified: 2019-09

Locations

US (8)