Randomized Control Trial of Buprenorphine vs. Morphine for the Treatment of Neonatal Opioid Withdrawal Syndrome (NOWS)

Neonatal Opioid Withdrawal Syndrome Clinical Trial

Official title:

Prospective Randomized Blinded Trial to Shorten Pharmacologic Treatment of Newborns With Neonatal Opioid Withdrawal Syndrome (NOWS)

Clinical Trial Details — Status: Withdrawn

Administrative data

• NCT number: NCT04455802
• Other study ID #: WIH 19-0042
• Secondary ID: 1P20GM125507-01
• Status: Withdrawn
• Phase: Phase 3
• Start date: October 1, 2020
• Est. completion date: May 17, 2021

Study information

• Verified date: June 2023
• Source: Women and Infants Hospital of Rhode Island
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This randomized control trial will compare buprenorphine and morphine, two currently used medications for the treatment of neonatal opioid withdrawal syndrome (NOWS), in newborns to determine which medication will reduce the number of days of pharmacological treatment.

Description:

This randomized control trial will compare buprenorphine to morphine, two currently used medications for the treatment of NOWS, to determine whether the use of buprenorphine for NOWS treatment will reduce the number of days of pharmacological treatment. After an infant is born they will be monitored for signs of NOWS. Once an infant reaches treatment thresholds, they will be randomized using a double dummy design to either the buprenorphine or morphine treatment arm. After randomization infants will receive a syringe with either morphine or placebo every 4 hours and every 8 hours infant will receive 1 sublingual application of buprenorphine or placebo. To maintain the blind infants enrolled in the study will receive both interventions. During the study medication doses will be weaned by 10% of the stabilization dose. Study intervention will continue until 20 percent of the maximal dose has been reached. Use of a second line drug will be permissible after randomization and after an infant has had 2 consecutive escalations. Second line drug will be phenobarbital, in addition to the study drug. Infants in both groups will be evaluated and scored for NOWS symptoms to determine if weaning study medication is permissible each day. NOWS scores that do not reach the threshold for escalation will wean in accordance with standard clinical practice. If NOWS symptoms increase during treatment, infants will have the dose of the study drug increased by 10% to the previous day's dose. When stable for 24 hours, the weaning process will continue. The NICU Network Neurobehavioral Scale (NNNS) will be administered prior to starting study medication and once off study medication but prior to discharge to examine proportion of infants in each medication arm for the abnormal NNNS profiles which has been associated with atypical early childhood outcomes including behavior problems and low IQ scores. Development at 18 months of age will also be assessed to examine any differences in both arms of the study.

Recruitment information / eligibility

• Status: Withdrawn
• Enrollment: 0
• Est. completion date: May 17, 2021
• Est. primary completion date: May 17, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

1. Infant gestational age greater than or equal 36 weeks

2. Mother receiving either methadone from a drug treatment program, buprenorphine from a licensed physician, or an opioid prescription for a documented medical need

3. Mother had at least 2 prenatal appointments.

4. Infant toleration of oral medication administration

5. Infant is considered medically stable by the attending physician

6. Singleton Pregnancy

7. English Speaking

Exclusion Criteria:

1. Within 30 days of birth the mother has actively used illicit drugs (excluding THC) or obtaining oral opioids, methadone, or buprenorphine from a non-licensed physician or drug treatment program

2. The mother has had less than 2 prenatal care visits

3. The mother reports excessive alcohol use during pregnancy

4. Mother is less than 18 years of age or is not capable of signing consent

5. The infant has a gestational age less than or equal to 35 weeks and 6 days

6. The infant has dysmorphic features including evidence of aneuploidy

7. The infant is not able to tolerate oral medication administration

8. Multiple gestation pregnancy

9. Hypoxic-ischemic encephalopathy

10. Seizures from etiologies other than NOWS

11. Non-English Speaking

12. Infant started on NOWS standard care medication prior to study consent

Related Conditions & MeSH terms

• Neonatal Opioid Withdrawal Syndrome
• Substance Withdrawal Syndrome
• Syndrome

Intervention

Drug:
• Buprenorphine or Placebo
The double blind, double dummy design necessitates that both drugs be on an identical schedule. The 4-hour dosing allows for this pairing. If a patient is randomized to the buprenorphine arm, medication administration will follow an every 8-hour dosing but medication will be substituted with placebo during the intermediary time point.
• Morphine or Placebo
If a patient is randomized to the morphine arm, morphine will be given every 4 hours. Placebo will also be given at the same frequency as a faux drug.

Locations

Country	Name	City	State
United States	Women and Infants Hospital	Providence	Rhode Island

Sponsors (2)

Lead Sponsor	Collaborator
Women and Infants Hospital of Rhode Island	National Institute of General Medical Sciences (NIGMS)

Country where clinical trial is conducted

United States, 

References & Publications (10)

Anagnostis EA, Sadaka RE, Sailor LA, Moody DE, Dysart KC, Kraft WK. Formulation of buprenorphine for sublingual use in neonates. J Pediatr Pharmacol Ther. 2011 Oct;16(4):281-4. doi: 10.5863/1551-6776-16.4.281. — View Citation

Asti L, Magers JS, Keels E, Wispe J, McClead RE Jr. A quality improvement project to reduce length of stay for neonatal abstinence syndrome. Pediatrics. 2015 Jun;135(6):e1494-500. doi: 10.1542/peds.2014-1269. Epub 2015 May 4. — View Citation

Brown MS, Hayes MJ, Thornton LM. Methadone versus morphine for treatment of neonatal abstinence syndrome: a prospective randomized clinical trial. J Perinatol. 2015 Apr;35(4):278-83. doi: 10.1038/jp.2014.194. Epub 2014 Oct 30. — View 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. — View Citation

Devlin LA, Lau T, Radmacher PG. Decreasing Total Medication Exposure and Length of Stay While Completing Withdrawal for Neonatal Abstinence Syndrome during the Neonatal Hospital Stay. Front Pediatr. 2017 Oct 10;5:216. doi: 10.3389/fped.2017.00216. eCollection 2017. — View Citation

Hall ES, Rice WR, Folger AT, Wexelblatt SL. Comparison of Neonatal Abstinence Syndrome Treatment with Sublingual Buprenorphine versus Conventional Opioids. Am J Perinatol. 2018 Mar;35(4):405-412. doi: 10.1055/s-0037-1608634. Epub 2017 Nov 7. — View Citation

Kraft WK, Adeniyi-Jones SC, Ehrlich ME. Buprenorphine for the Neonatal Abstinence Syndrome. N Engl J Med. 2017 Sep 7;377(10):997-998. doi: 10.1056/NEJMc1709121. No abstract available. — View Citation

Kraft WK, Dysart K, Greenspan JS, Gibson E, Kaltenbach K, Ehrlich ME. Revised dose schema of sublingual buprenorphine in the treatment of the neonatal opioid abstinence syndrome. Addiction. 2011 Mar;106(3):574-80. doi: 10.1111/j.1360-0443.2010.03170.x. Epub 2010 Oct 6. — View Citation

Lester BM, Tronick EZ, Brazelton TB. The Neonatal Intensive Care Unit Network Neurobehavioral Scale procedures. Pediatrics. 2004 Mar;113(3 Pt 2):641-67. — View Citation

Moore JN, Gastonguay MR, Ng CM, Adeniyi-Jones SC, Moody DE, Fang WB, Ehrlich ME, Kraft WK. The Pharmacokinetics and Pharmacodynamics of Buprenorphine in Neonatal Abstinence Syndrome. Clin Pharmacol Ther. 2018 Jun;103(6):1029-1037. doi: 10.1002/cpt.1064. Epub 2018 Apr 28. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Total amount of opioid medication for treatment of NOWS	Total amount of opioid medication given to infant for the duration of their hospitalization	Duration of pharmacological treatment with opioid medication while admitted to the hospital up to 30 days
Secondary	Length of total stay	Length of hospital stay due to NOWS	During hospitalization for NOWS up to 30 days
Secondary	Length of stay secondary to NOWS	Total length of hospital stay secondary to NOWS	During hospitalization for NOWS up to 30 days
Secondary	Neurobehavioral Profile	Neurobehavior will be assessed with Neonatal Intensive Care Unit (NICU) Network Neurobehavioral Scale (NNNS). The NNNS is a comprehensive evaluation of neurologic and behavioral functioning as well as signs of stress. Profile 5 is the most atypical, and is characterized by exaggerated scores for arousal, excitability, hypertonicity, quality of movement, and stress abstinence. The atypical profile as been associated with atypical early childhood outcomes, including more behavior problems and lower IQ scores. Researchers will compare the proportion of atypical neurobehavioral profiles for infants in each intervention arm.	At birth before randomization to NOWS treatment arm around 18-24 hours of life and prior to hospital discharge up to 30 days of life
Secondary	Cognitive, Language, and Motor Development From 18 Month Old Bayley 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 composite score outcomes.	18 months old