Clinical trial NCT04455802: Randomized Control Trial of Buprenorphine vs. Morphine for the Treatment of Neonatal Opioid Withdrawal Syndrome (NOWS)
Official title: Prospective Randomized Blinded Trial to Shorten Pharmacologic Treatment of Newborns With Neonatal Opioid Withdrawal Syndrome (NOWS)
Study type: INTERVENTIONAL
Overall status: WITHDRAWN
Phase: PHASE3
Conditions: Neonatal Opioid Withdrawal Syndrome
Keywords: Neonatal Opioid Withdrawal Syndrome
Neonatal Abstinence Syndrome
Lead sponsor: Women and Infants Hospital of Rhode Island
Sponsor class: OTHER
Collaborators: name: National Institute of General Medical Sciences (NIGMS)
First posted: 2020-07-02
Enrollment: 0
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Infants will be randomly assigned to treatment arms of either morphine or buprenorphine
Primary purpose: TREATMENT

Brief 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.

Detailed 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.

Eligibility criteria: 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

Primary outcomes:
measure: Total amount of opioid medication for treatment of NOWS
timeFrame: Duration of pharmacological treatment with opioid medication while admitted to the hospital up to 30 days
Secondary outcomes:
measure: Length of total stay
timeFrame: During hospitalization for NOWS up to 30 days
measure: Length of stay secondary to NOWS
timeFrame: During hospitalization for NOWS up to 30 days
measure: Neurobehavioral Profile
timeFrame: 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
measure: Cognitive, Language, and Motor Development From 18 Month Old Bayley Neurodevelopmental Assessment
timeFrame: 18 months old
Other outcomes:
Locations:
city: Providence
country: United States
facility: Women and Infants Hospital
state: Rhode Island
Study officials:
affiliation: Women and Infants Hospital
name: Adam J Czynski, DO
role: PRINCIPAL_INVESTIGATOR
References:
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.
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.
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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.
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.
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.
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