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

June 20, 2023 updated by: James Padbury, Women and Infants Hospital of Rhode Island

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

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.

Study Overview

Status

Withdrawn

Conditions

Intervention / 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.

Study Type

Interventional

Phase

  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

  • United States
    • Rhode Island
      • Providence, Rhode Island, United States, 02905
        • Women and Infants Hospital
        • Contact:
        • Principal Investigator:
          • Adam J Czynski, DO

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

16 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Quadruple

Arms and Interventions

Participant Group / 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Total amount of opioid medication for treatment of NOWS
Time Frame: 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
Duration of pharmacological treatment with opioid medication while admitted to the hospital up to 30 days

Secondary Outcome Measures

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

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Women and Infants Hospital of Rhode Island

Collaborators

National Institute of General Medical Sciences (NIGMS)

Investigators

  • Principal Investigator: Adam J Czynski, DO, Women and Infants Hospital

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

October 1, 2020

Primary Completion (Actual)

May 17, 2021

Study Completion (Actual)

May 17, 2021

Study Registration Dates

First Submitted

June 8, 2020

First Submitted That Met QC Criteria

June 30, 2020

First Posted (Actual)

July 2, 2020

Study Record Updates

Last Update Posted (Actual)

June 22, 2023

Last Update Submitted That Met QC Criteria

June 20, 2023

Last Verified

June 1, 2023

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • WIH 19-0042
  • 1P20GM125507-01 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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