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

Sponsor

Women and Infants Hospital of Rhode Island (Other)

Overall Status

Not yet recruiting

CT.gov ID

NCT04455802

Collaborator

National Institute of General Medical Sciences (NIGMS) (NIH)

132

Enrollment

Location

Arms

Anticipated Duration (Months)

2.6

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Neonatal Opioid Withdrawal Syndrome	Drug: Buprenorphine or Placebo Drug: Morphine or Placebo	Phase 3

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.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

132 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Intervention Model Description:

Infants will be randomly assigned to treatment arms of either morphine or buprenorphineInfants will be randomly assigned to treatment arms of either morphine or buprenorphine

Masking:

Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Masking Description:

The study will be a randomized, double-blind, double-dummy, intention-to-treat clinical trial. All clinical providers, research personnel and participants will be blinded to group assignment. Pharmacy personnel will be the only un-blinded individuals. The placebo medication will be identical in appearance and volume to a dose of the medication at the respective dose.

Primary Purpose:

Treatment

Official Title:

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

Anticipated Study Start Date :

Jul 1, 2020

Anticipated Primary Completion Date :

Jun 30, 2022

Anticipated Study Completion Date :

Aug 31, 2024

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Morphine Infants randomized to the morphine arm will start at a dose of 0.06 mg/kg/dose every 4 hours. A buprenorphine placebo will also be given at the same frequency as a faux drug.	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. Drug: 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.
Experimental: Buprenorphine Infants randomized to the buprenorphine arm will be started on a dose of 10 mg/kg/dose every 8 hours. A morphine placebo will also be given at the same frequency as a faux drug. Patients can only be randomized to only one arm.	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. Drug: 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.

Arm

Intervention/Treatment

Active Comparator: Morphine

Infants randomized to the morphine arm will start at a dose of 0.06 mg/kg/dose every 4 hours. A buprenorphine placebo will also be given at the same frequency as a faux drug.

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.

Drug: 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.

Experimental: Buprenorphine

Infants randomized to the buprenorphine arm will be started on a dose of 10 mg/kg/dose every 8 hours. A morphine placebo will also be given at the same frequency as a faux drug. Patients can only be randomized to only one arm.

Drug: Buprenorphine or Placebo

Drug: 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.

Outcome Measures

Primary Outcome Measures

Total amount of opioid medication for treatment of NOWS [Duration of pharmacological treatment with opioid medication while admitted to the hospital up to 30 days]
Total amount of opioid medication given to infant for the duration of their hospitalization

Secondary Outcome Measures

Length of total stay [During hospitalization for NOWS up to 30 days]
Length of hospital stay due to NOWS
Length of stay secondary to NOWS [During hospitalization for NOWS up to 30 days]
Total length of hospital stay secondary to NOWS
Neurobehavioral Profile [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]
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.
Cognitive, Language, and Motor Development From 18 Month Old Bayley Neurodevelopmental Assessment [18 months old]
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.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Infant gestational age greater than or equal 36 weeks
Mother receiving either methadone from a drug treatment program, buprenorphine from a licensed physician, or an opioid prescription for a documented medical need
Mother had at least 2 prenatal appointments.
Infant toleration of oral medication administration
Infant is considered medically stable by the attending physician
Singleton Pregnancy
English Speaking

Exclusion Criteria:

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
The mother has had less than 2 prenatal care visits
The mother reports excessive alcohol use during pregnancy
Mother is less than 18 years of age or is not capable of signing consent
The infant has a gestational age less than or equal to 35 weeks and 6 days
The infant has dysmorphic features including evidence of aneuploidy
The infant is not able to tolerate oral medication administration
Multiple gestation pregnancy
Hypoxic-ischemic encephalopathy
Seizures from etiologies other than NOWS
Non-English Speaking
Infant started on NOWS standard care medication prior to study consent