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

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

The objective of this study is to evaluate the efficacy of a rapid wean intervention compared with a slow-wean intervention in reducing the number of days of opioid treatment from the first dose of weaning to cessation of opioid among infants receiving an opioid (defined as morphine or methadone) as the primary treatment for neonatal opioid withdrawal syndrome (NOWS).

Study Overview

• Status: Active, not recruiting
• Conditions: Neonatal Opioid Withdrawal Syndrome
• Intervention / Treatment: Drug: Morphine; Drug: Methadone

Detailed Description

This will be a pragmatic, randomized, blinded trial comparing a rapid-wean intervention (15% decrements from the stabilization dose) to a slow-wean intervention (10% decrements from the stabilization dose) to determine whether rapid weaning will reduce the number of treatment days among infants receiving morphine or methadone orally as the primary treatment for NOWS. Participating hospitals must provide pharmacologic treatment to at least an average of 12 opioid exposed infants each year, use a scoring system to assess for signs of NOWS (original or modified Finnegan Neonatal Abstinence Scoring system, Eat-Sleep or Console), and provide opioid replacement therapy with either morphine or methadone as the primary drug for treating NOWS. Hospitals may change use of these two opioids during the trial period. The investigators will stratify randomization by hospital.

The study protocol will commence after NOWS signs have been controlled with an opioid (stabilization) and weaning of pharmacologic treatment is to be started. At or before each 24-hour interval, clinical team members will evaluate and score infants, per hospital practice, for signs of NOWS to determine if the infant will tolerate weaning of the study drug. After study drug cessation, the clinical team will observe infants in the hospital for at least 48 hours prior to discharge, which is similar to clinical practice. A trained examiner will administer the Neonatal Intensive Care Unit (NICU) Network Neurobehavioral Scale (NNNS) to assess neurobehavioral profiles after infants cease study drug and prior to discharge.

At one month post discharge, primary caregivers will complete the Brief Symptom Inventory (BSI), the Maternal Postnatal Attachment Questionnaire (MPAQ) and a caregiver questionnaire. The site research team will contact the primary caregiver(s) to update contact information and/or complete questionnaires when the infant is 6 months, 12 months, 18 months, and 24 months of age. The questionnaires will assess infant wellness, neurobehavioral functioning and development, postnatal attachment and bonding, and caregiver well-being. At 24 months, the infants will be seen during which a, certified developmental specialists, blinded to the intervention, will administer the Bayley Scales of Infant and Toddler Development, Fourth Edition (Bayley-4) to assess infant neurodevelopment. The BSI and the Brief Infant Toddler Social Emotional Assessment (BITSEA) will also be administered during the 24 month visit along with measures of growth.

• Study Type: Interventional
• Enrollment (Actual): 189
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Birmingham, Alabama, United States, 35249
      • University of Alabama at Birmingham
  • Arizona
    • Tucson, Arizona, United States, 85724
      • University of Arizona
  • Arkansas
    • Little Rock, Arkansas, United States, 72202
      • University of Arkansas Medical Sciences
  • California
    • Loma Linda, California, United States, 92354
      • Loma Linda University Medical Center
    • San Diego, California, United States, 92123
      • Sharp Mary Birch Hospital for Women and Newborns
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • University of Iowa
  • Louisiana
    • Kenner, Louisiana, United States, 70065
      • Ochsner Medical Regional Hospital
    • New Orleans, Louisiana, United States, 70001
      • Tulane University Health Science Center
    • New Orleans, Louisiana, United States, 70115
      • Ochsner Baptist Clinical Trials Unit
  • Maryland
    • Hyattsville, Maryland, United States, 20782
      • MedStar Franklin Square
  • Massachusetts
    • Worcester, Massachusetts, United States, 01605
      • University of Massachusetts Memorial Medical Center-West Campus
  • Michigan
    • Detroit, Michigan, United States, 48201
      • Central Michigan University
  • Missouri
    • Kansas City, Missouri, United States, 64108
      • Children's Mercy Hospital
    • Saint Louis, Missouri, United States, 63110
      • Washington University School of Medicine
  • New Mexico
    • Albuquerque, New Mexico, United States, 87131
      • University of New Mexico
  • North Carolina
    • Durham, North Carolina, United States, 27705
      • RTI International
  • Ohio
    • Cleveland, Ohio, United States, 44109
      • MetroHealth
    • Columbus, Ohio, United States, 43210
      • Ohio State University Hospital
    • Columbus, Ohio, United States, 43205
      • Nationwide Childeren's Hospital
  • Rhode Island
    • Providence, Rhode Island, United States, 02905
      • Women & Infants Hospital of Rhode Island
  • South Dakota
    • Sioux Falls, South Dakota, United States, 57104
      • Sanford Health
  • Tennessee
    • Memphis, Tennessee, United States, 38163
      • The University of Tennessee Health Science Center
    • Memphis, Tennessee, United States, 38119
      • University of Tennessee Health Science Center
  • West Virginia
    • Morgantown, West Virginia, United States, 26506
      • West Virginia University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 2 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Hospital Level

  1. Hospital provides pharmacologic treatment to at least an average of 12 opioid exposed infants each year
  2. Hospital uses a scoring system to assess for signs of NOWS (original or modified Finnegan Neonatal Abstinence Scoring system, Eat-Sleep or Console)
  3. Hospital provides opioid replacement therapy with either morphine or methadone as part of pharmacologic treatment of NOWS

• Infant Level

  1. Gestational age ≥ 36 weeks
  2. Receiving scheduled pharmacological therapy with morphine or methadone as the primary drug treatment for NOWS secondary to maternal opioid use
  3. Tolerating enteral feeds and medications by mouth

Exclusion Criteria:

• Hospital Level

  1. Hospitals discharge > 10% of infants from the hospital on opioid replacement therapy on average per year

• Infant Level

  1. Major birth defect (e.g. gastroschisis)
  2. Any major surgery (minor surgery [e.g., circumcision, digit ligation, frenulectomy] is not an exclusion criterion)
  3. Hypoxic-ischemic encephalopathy
  4. Seizures from etiologies other than NOWS
  5. Treatment with opioids for reasons other than NOWS
  6. Respiratory support (nasal cannula or greater) for > 72 hours
  7. Planned discharge from the hospital on opioids
  8. Use of other opioids (e.g., buprenorphine) as primary drugs for treatment of NOWS
  9. Weaning of morphine or methadone as the primary treatment of NOWS has started

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Rapid-wean; 15% decrements from the stabilization dose of morphine/methadone	Drug: Morphine; The dose interval for morphine will be either every 3 or 4 hours, per hospital practice. Clinical teams are asked to wean study drug at least every 24 hours.; Drug: Methadone; The dose interval for methadone will be every 8 or 12 hours, per hospital practice. Clinical teams are asked to wean study drug at least every 24 hours.
Active Comparator: Slow-wean; 10% decrements from the stabilization dose of morphine/methadone	Drug: Morphine; The dose interval for morphine will be either every 3 or 4 hours, per hospital practice. Clinical teams are asked to wean study drug at least every 24 hours.; Drug: Methadone; The dose interval for methadone will be every 8 or 12 hours, per hospital practice. Clinical teams are asked to wean study drug at least every 24 hours.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Days of Opioid Treatment From First Wean to Cessation	The number of days of opioid treatment (used as primary treatment), including escalation, resumption, and spot treatment, from the first weaning dose to cessation of opioid. From the start of opioid study medication until weaning. Infants will exit the study intervention without unblinding (remain in the trial) if they have not weaned off study drug by 35 days (inclusive of the 35th day) form the first weaning dose. Outcome will be truncated at 35 days regardless of the study arm.We note that primary outcome data is missing for 4 participants resulting in total sample of 185 for the primary analysis.	From the start of opioid study medication until weaning. Infants exited the study intervention without unblinding (remained in the trial) by 35 days from the first weaning dose. Outcome truncated at 35 days regardless of the study arm.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Days of Opioid Treatment From First Wean to Cessation Among Infants That Were Not Withdrawn in High Enrolling Centers	The number of days of opioid treatment from first wean to cessation among infants that were not withdrawn in high enrolling centers	From the start of opioid study medication until weaning. Infants exited the study intervention without unblinding (remained in the trial) by 35 days from the first weaning dose. Outcome truncated at 35 days regardless of the study arm.
Days of Opioid Treatment From First Wean to Cessation Among High Enrolling Centers	The number of days of opioid treatment from first wean to cessation among high enrolling centers	From the start of opioid study medication until weaning. Infants exited the study intervention without unblinding (remained in the trial) by 35 days from the first weaning dose. Outcome truncated at 35 days regardless of the study arm.
Days of Opioid Treatment From First Wean to Cessation Among Infants That Were Not Withdrawn	The number of days of opioid treatment from first wean to cessation among infants that were not withdrawn	From the start of opioid study medication until weaning. Infants exited the study intervention without unblinding (remained in the trial) by 35 days from the first weaning dose. Outcome truncated at 35 days regardless of the study arm.

Collaborators and Investigators

• Sponsor: Advancing Clinical Trials in Neonatal Opioid Withdrawal (ACT NOW) Program
• Collaborators: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
• Investigators: Principal Investigator: Abbot Laptook, MD, Women and Infants Hospital of Rhode Island; Principal Investigator: Adam Czynski, DO, Connecticut Children's Medical Center; Principal Investigator: Abhik Das, PhD, RTI International

Study record dates

Study Major Dates

• Study Start (Actual): September 28, 2020
• Primary Completion (Actual): January 31, 2024
• Study Completion (Estimated): June 30, 2026

Study Registration Dates

• First Submitted: December 5, 2019
• First Submitted That Met QC Criteria: December 30, 2019
• First Posted (Actual): January 2, 2020

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: February 25, 2025
• Last Verified: January 1, 2025

More Information

Terms related to this study

• Keywords: NOWS
• Additional Relevant MeSH Terms: Mental Disorders; Pathologic Processes; Disease; Substance-Related Disorders; Chemically-Induced Disorders; Syndrome; Substance Withdrawal Syndrome; Physiological Effects of Drugs; Peripheral Nervous System Agents; Central Nervous System Depressants; Sensory System Agents; Analgesics; Analgesics, Opioid; Narcotics; Respiratory System Agents; Antitussive Agents; Morphine; Methadone
• Other Study ID Numbers: ACTNOW-02

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Data will be made available in NICHD Data and Specimen Hub (DASH).
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No