Neonatal Abstinence SyndromePhase 3NCT01958476
Improving Outcomes in Neonatal Abstinence Syndrome
A Phase 3 study testing Neonatal Morphine Solution, Methadone and Phenobarbital in people with Neonatal Abstinence Syndrome and Neonatal Opioid Withdrawal, run by Tufts Medical Center at 8 sites in United States.
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. Read more about this study
- Who is it for?
- Any age
- Conditions the study is for
- Neonatal Abstinence Syndrome, Neonatal Opioid Withdrawal
- What is being tested?
- Neonatal Morphine Solution, Methadone and Phenobarbital
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 117 participants
- Where
- 8 sitesUnited States
- Study dates
- Sep 2013to 30 Aug 2018
- Phase
- Phase 3
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages Any age
- All sexes
- No healthy volunteers
- Child, Adult, Older adult
Who may be able to join
- 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
Who cannot join
- 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.
Trial locations and contacts
8 sites in 1 country.
8 sites in 1 country
United States8 sites
Tufts Medical Center
Boston, Massachusetts, 02111
Boston Medical Center
Boston, Massachusetts, 02118
Shands Jacksonville Medical Center
Jacksonville, Florida, 32209
Vanderbilt University
Nashville, Tennessee, 37232
University of Pittsburgh Medical Center
Pittsburgh, Pennsylvania, 15224
Maine Medical Center
Portland, Maine
Women and Infant's Hospital of Rhode Island
Providence, Rhode Island, 02908
Baystate Medical Center
Springfield, Massachusetts, 01199
About this study
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.
- 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.
Read the 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.
- 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.
- Being tested
- Neonatal Morphine Solution, Methadone, Phenobarbital
- Keywords
- Neonatal Abstinence Syndrome, Opioids
- Medical subject headings
- Neonatal Abstinence Syndrome
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Neonatal Morphine SolutionDrug
Also called Morphine sulfate
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.
MethadoneDrug
Also called Methadone oral solution
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.
PhenobarbitalDrug
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.
| Study group | Role | What they receive |
|---|---|---|
| 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. Receives: 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. Receives: Drug: Methadone; Drug: Phenobarbital |
What is being measured
The primary outcome is the main question the study is designed to answer.
Length of Hospital Stay (LOS)
Participants were monitored for the duration of their hospitalization, an expected mean of 22 days.
Measured: 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 attributable to NAS only.
Measured: Participants were monitored for the duration of their hospitalization, expected mean 22 days.
Length of Treatment (LOT)
Total number of days infant treated with replacement opioids while admitted to the hospital.
Measured: Participants were monitored for the duration of their hospitalization.
Maximum Daily Dose of Replacement Opioid
Maximum daily dose of neonatal morphine solution or methadone during the hospitalization
Measured: Participants were monitored for the duration of their hospitalization.
Mean Finnegan Score (FS)
Mean Finnegan withdrawal score during the duration of hospitalization.
Measured: Participants were monitored during their entire hospitalization
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).
Measured: Participants were monitored for the duration of their hospitalization, an average of 22 days.
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.
Measured: Birth to 18 month follow-up visit
Growth Outcome: Head Circumference at 18 Months
Average head circumference growth outcome at 18 month follow-up visit.
Measured: 18 month follow-up visit
Maximum Finnegan Score
Maximum Finnegan score during the hospitalization
Measured: Participants monitored for the duration of their hospitalization.
Growth Outcome: Length at 18 Months
Average length (cm) at 18 month follow-up visit.
Measured: 18 month follow-up visit
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted9 Oct 2013 (estimated)
- Study startSep 2013
- Primary completion5 Mar 2017
- Study completion30 Aug 2018
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (10)Papers the sponsor has linked to this study.
- Other trials for Neonatal Abstinence SyndromeStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 117 participants (actual)
Sponsor and investigators
- Lead sponsor
- Tufts Medical Center
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Jonathan Davis, MD, Principal investigator, Tufts Medical CenterBarry Lester, PhD, Principal investigator, Women and Infant's Hospital
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01958476
- Sponsor's protocol ID
- 1R01DA032889-01A1
- Status last verified
- Sep 2019
- First submitted
- 14 Aug 2013
- Last updated
- 15 Oct 2019
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
Publications
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.
PubMed 23632726Sarkar 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.
PubMed 16355103Lainwala 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.
PubMed 16202968Lotsch 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.
PubMed 15530129Jansson LM, Velez M, Harrow C. The opioid-exposed newborn: assessment and pharmacologic management. J Opioid Manag. 2009 Jan-Feb;5(1):47-55.
PubMed 19344048Osborn 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.
PubMed 20927730Jones 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.
PubMed 21142534Zankl 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.
PubMed 34231914Czynski 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.
PubMed 31987653Davis 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.
PubMed 29913015
Study at a glance
From the registry record, last updated by the sponsor on 15 Oct 2019. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Improving Outcomes in Neonatal Abstinence Syndrome
- ClinicalTrials.gov ID
- NCT01958476
- Acronym / sponsor ID
- 1R01DA032889-01A1
- Keywords
- Neonatal Abstinence Syndrome, Opioids
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 117 participants (actual)
- Lead sponsor
- Tufts Medical CenterUniversity, hospital or other
- Study start
- Sep 2013
- Primary completion
- 5 Mar 2017 (actual)
- Study completion
- 30 Aug 2018 (actual)
- First posted
- 9 Oct 2013 (estimated)
- Results
- Posted 15 Oct 2019
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
- 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.
- 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 design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Neonatal Morphine Solution | Active comparator | Drug: Neonatal Morphine Solution, Drug: PhenobarbitalInfants 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. |
| Methadone | Active comparator | Drug: Methadone, Drug: PhenobarbitalInfants 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. |
Who may qualify
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult, Older adult
Key inclusion criteria (8 listed)
- 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
Key exclusion criteria (6 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Neonatal Morphine SolutionAlso: Morphine sulfateInfants 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. | Drug | Neonatal Morphine Solution |
| MethadoneAlso: Methadone oral solutionInfants 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 |
| PhenobarbitalA 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. | Drug | Methadone, Neonatal Morphine Solution |
Primary outcome
Length of Hospital Stay (LOS)
Time frame: Participants will be monitored during their entire hospitalization, expected mean 22 days.
Participants were monitored for the duration of their hospitalization, an expected mean of 22 days.
9 secondary outcomes
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.
Length of Treatment (LOT)
Time frame: Participants were monitored for the duration of their hospitalization.
Maximum Daily Dose of Replacement Opioid
Time frame: Participants were monitored for the duration of their hospitalization.
Mean Finnegan Score (FS)
Time frame: Participants were monitored during their entire hospitalization
Number of Infants Needing a Second NAS Medication
Time frame: Participants were monitored for the duration of their hospitalization, an average of 22 days.
Growth Outcome: Weight Change From Birth to 18 Months
Time frame: Birth to 18 month follow-up visit
Growth Outcome: Head Circumference at 18 Months
Time frame: 18 month follow-up visit
Maximum Finnegan Score
Time frame: Participants monitored for the duration of their hospitalization.
Growth Outcome: Length at 18 Months
Time frame: 18 month follow-up visit
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 15 Oct 2019.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Background: PubMed 23632726Wachman 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.
- Background: PubMed 16355103Sarkar 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.
- Background: PubMed 16202968Lainwala 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.
- Background: PubMed 15530129Lotsch 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.
- Background: PubMed 19344048Jansson LM, Velez M, Harrow C. The opioid-exposed newborn: assessment and pharmacologic management. J Opioid Manag. 2009 Jan-Feb;5(1):47-55.
- Background: PubMed 20927730Osborn 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.
- Background: PubMed 21142534Jones 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.
- Derived from this study: PubMed 34231914Zankl 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.
- Derived from this study: PubMed 31987653Czynski 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.
- Derived from this study: PubMed 29913015Davis 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.
Related trials for Neonatal Abstinence Syndrome
Active, not recruiting
Effective Caregiving for Neonatal Abstinence Syndrome: Testing an Instructional Mobile Technology Platform for High-Risk Pregnant Women
Neonatal Abstinence Syndrome, Opioid-use Disorder
Not yet recruiting
Recorded Parent/Caregiver Voice for Infants With Neonatal Opioid Withdrawal Syndrome
Neonatal Opioid Withdrawal Syndrome, Prenatal Opioid Exposure
Recruiting
Effect of Music Therapy on Infants With Neonatal Abstinence Syndrome
NAS
Recruiting
An Intervention Mapping Approach to Closing the Gap in Maternal OUD and Infant NAS Care (SUPPORT)
Opioid Use Disorder, Neonatal Abstinence Syndrome
Active, not recruiting
Neurostimulation to Improve NOWS Outcomes
Neonatal Opioid Withdrawal Syndrome, Neonatal Abstinence Syndrome
Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Jonathan Davis, MD principal investigator
Tufts Medical Center
Barry Lester, PhD principal investigator
Women and Infant's Hospital
8 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing Neonatal Morphine Solution, Methadone and Phenobarbital in people with Neonatal Abstinence Syndrome and Neonatal Opioid Withdrawal, run by Tufts Medical Center at 8 sites in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 8 inclusion and 6 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 15 Oct 2019. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 8 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 15 Oct 2019). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Length of Hospital Stay (LOS) (time frame: Participants will be monitored during their entire hospitalization, expected mean 22 days.). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT01958476, which also lists 10 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 15 Oct 2019.