Improving Outcomes in Neonatal Abstinence Syndrome

Neonatal Abstinence Syndrome Clinical Trial

Official title:

Improving Outcomes in Neonatal Abstinence Syndrome

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01958476
• Other study ID #: 1R01DA032889-01A1
• Status: Completed
• Phase: Phase 3
• Start date: September 2013
• Est. completion date: August 30, 2018

Study information

• Verified date: September 2019
• Source: Tufts Medical Center
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 117
• Est. completion date: August 30, 2018
• Est. primary completion date: March 5, 2017
• Accepts healthy volunteers: No
• Gender: All
• Age group: N/A and older

Eligibility

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.

Related Conditions & MeSH terms

• Neonatal Abstinence Syndrome
• Neonatal Opioid Withdrawal
• Syndrome

Intervention

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.
• 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.
• 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.

Locations

Country	Name	City	State
United States	Boston Medical Center	Boston	Massachusetts
United States	Tufts Medical Center	Boston	Massachusetts
United States	Shands Jacksonville Medical Center	Jacksonville	Florida
United States	Vanderbilt University	Nashville	Tennessee
United States	University of Pittsburgh Medical Center	Pittsburgh	Pennsylvania
United States	Maine Medical Center	Portland	Maine
United States	Women and Infant's Hospital of Rhode Island	Providence	Rhode Island
United States	Baystate Medical Center	Springfield	Massachusetts

Sponsors (1)

Lead Sponsor	Collaborator
Tufts Medical Center

Country where clinical trial is conducted

United States, 

References & Publications (7)

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

Lötsch 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. Review. — View 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. Review. — View 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. — View 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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Cognitive, Language, and Motor Development From 18 Month Bayley III Neurodevelopmental Assessment	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.	Assessment at 18 month follow-up visit
Primary	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	Length of Hospital Stay (LOS) Due to Neonatal Abstinence Syndrome (NAS)	Participants were monitored for the duration of their hospitalization attributable to NAS only.	Participants were monitored for the duration of their hospitalization, expected mean 22 days.
Secondary	Length of Treatment (LOT)	Total number of days infant treated with replacement opioids while admitted to the hospital.	Participants were monitored for the duration of their hospitalization.
Secondary	Maximum Daily Dose of Replacement Opioid	Maximum daily dose of neonatal morphine solution or methadone during the hospitalization	Participants were monitored for the duration of their hospitalization.
Secondary	Mean Finnegan Score (FS)	Mean Finnegan withdrawal score during the duration of hospitalization.	Participants were monitored during their entire hospitalization
Secondary	Number of Infants Needing a Second NAS Medication	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).	Participants were monitored for the duration of their hospitalization, an average of 22 days.
Secondary	Growth Outcome: Weight Change From Birth to 18 Months	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.	Birth to 18 month follow-up visit
Secondary	Growth Outcome: Head Circumference at 18 Months	Average head circumference growth outcome at 18 month follow-up visit.	18 month follow-up visit
Secondary	Maximum Finnegan Score	Maximum Finnegan score during the hospitalization	Participants monitored for the duration of their hospitalization.
Secondary	Growth Outcome: Length at 18 Months	Average length (cm) at 18 month follow-up visit.	18 month follow-up visit