Neonatal Opioid Withdrawal SyndromePhase 3NCT04214834

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

A Phase 3 study testing Morphine and Methadone in people with Neonatal Opioid Withdrawal Syndrome, run by Advancing Clinical Trials in Neonatal Opioid Withdrawal (ACT NOW) Program at 24 sites in United States.

Active, not recruiting

Under way, not looking for participants. Everyone needed has enrolled. The study is still running.

Official record

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Trial summary

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… Read more about this study

Who is it for?: Ages 36 weeks and older
Conditions the study is for: Neonatal Opioid Withdrawal Syndrome
What is being tested?: Morphine and Methadone
Could I receive a placebo?: No, everyone receives an active treatment
How many people: 189 participants
Where: 24 sitesUnited States
Study dates: 28 Sep 2020to 30 Jun 2026
Phase: Phase 3
Are there results?: Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

Ages 36 weeks and older
All sexes
No healthy volunteers
Child, Adult, Older adult

Who may be able to join

Hospital Level
Hospital provides pharmacologic treatment to at least an average of 12 opioid exposed infants each year
Hospital uses a scoring system to assess for signs of NOWS (original or modified Finnegan Neonatal Abstinence Scoring system, Eat-Sleep or Console)
Hospital provides opioid replacement therapy with either morphine or methadone as part of pharmacologic treatment of NOWS
Infant Level
Gestational age ≥ 36 weeks
Receiving scheduled pharmacological therapy with morphine or methadone as the primary drug treatment for NOWS secondary to maternal opioid use
Tolerating enteral feeds and medications by mouth

Who cannot join

Hospital Level
1. Hospitals discharge > 10% of infants from the hospital on opioid replacement therapy on average per year
Infant Level
Major birth defect (e.g. gastroschisis)
Any major surgery (minor surgery [e.g., circumcision, digit ligation, frenulectomy] is not an exclusion criterion)
Hypoxic-ischemic encephalopathy

Show all 12Show fewer

Seizures from etiologies other than NOWS
Treatment with opioids for reasons other than NOWS
Respiratory support (nasal cannula or greater) for > 72 hours
Planned discharge from the hospital on opioids
Use of other opioids (e.g., buprenorphine) as primary drugs for treatment of NOWS
Weaning of morphine or methadone as the primary treatment of NOWS has started

Trial locations and contacts

24 sites in 1 country.

City, postcode or hospital

24 sites in 1 country

United States24 sites

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

Other trials in United States

About this study

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

Read the 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.

Conditions: Neonatal Opioid Withdrawal Syndrome
Being tested: Morphine, Methadone
Keywords: NOWS

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

MorphineDrug
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.
MethadoneDrug
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.

Study groups in NCT04214834
Study group	Role	What they receive
Rapid-wean	Active comparator	15% decrements from the stabilization dose of morphine/methadone Receives: Drug: Morphine; Drug: Methadone
Slow-wean	Active comparator	10% decrements from the stabilization dose of morphine/methadone Receives: Drug: Morphine; Drug: Methadone

What is being measured

The primary outcome is the main question the study is designed to answer.

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.
Measured: 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 outcomes (3)

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
Measured: 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
Measured: 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
Measured: 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.

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

28 Sep 202030 Jun 2026

First posted2 Jan 2020
Study start28 Sep 2020
Primary completion31 Jan 2024
Study completion30 Jun 2026 (estimated)

Resources

Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
Publications (2)Papers the sponsor has linked to this study.
Other trials for Neonatal Opioid Withdrawal SyndromeStudies of the same condition, open and under way.
What the trial phases meanHow a treatment moves from first tests in people to approval.

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design

Study type: Interventional
Phase: Phase 3
Primary purpose: Treatment
Allocation: Randomised
Intervention model: Parallel groups
Model description: The study will have two intervention arms (rapid-wean and slow-wean) with 251 morphine/methadone treated infants per intervention arm, for a total of 502 morphine/methadone treated infants.
Masking: Quadruple blind
Who is masked: Participant, Care provider, Investigator, Outcomes assessor
Enrolment: 189 participants (actual)

IDs, dates and publications

ClinicalTrials.gov ID: NCT04214834
Sponsor's protocol ID: ACTNOW-02
Status last verified: Jun 2026
First submitted: 5 Dec 2019
Last updated: 30 Jun 2026
Results posted: Yes, on ClinicalTrials.gov
Data monitoring committee: Yes
FDA-regulated drug: Yes
FDA-regulated device: No
Individual data sharing: Yes: Data will be made available in NICHD Data and Specimen Hub (DASH).

Publications

Laptook AR, Czynski A, Chahine R, Greenberg RG, Smith PB, Oliveira E, Gabrio J, Eggleston B, Das A, Lee J, Lester B, Clark D, Walsh M, Ko H, Asher CC, Friedman H, Gentle S, Rao K, Katheria A, Benninger K, Jani S, Smith MC, Khan A, Talati A, Lodhi S, Mena F, England A, Parimi P, Kylat R, Harmon H, Mannan J, Howell MP, Wright T, Snowden J; ACT NOW Collaborative. Accelerated Weaning of Opioids to Reduce Pharmacologic Exposure for Neonatal Opioid Withdrawal Syndrome: A Randomized Clinical Trial. J Pediatr. 2026 May;292:114992. doi: 10.1016/j.jpeds.2026.114992. Epub 2026 Jan 17.
PubMed 41554434
Czynski A, Laptook A, Das A, Smith B, Simon A, Greenberg R, Annett R, Lee J, Snowden J, Pedroza C, Lester B, Eggleston B, Bremer D, McGowan E. Pragmatic, randomized, blinded trial to shorten pharmacologic treatment of newborns with neonatal opioid withdrawal syndrome (NOWS). Trials. 2023 Jul 21;24(1):466. doi: 10.1186/s13063-023-07378-x.
PubMed 37480087

Want to know more?

The sponsor has not listed a contact. The official record may have more details.

Talk to your doctor first and take this page with you. Only the study team can confirm whether you can join.

Questions to ask the study team

What is the study trying to find out?
What would I need to do, and how often would I visit?
Could I receive a placebo instead of the treatment?
What are the possible risks and benefits for me?
Will it cost me anything? Are travel or time paid for?
Can I keep seeing my own doctor during the study?
What happens when the study ends?

See locations

Not yet recruiting
Recorded Parent/Caregiver Voice for Infants With Neonatal Opioid Withdrawal Syndrome
Neonatal Opioid Withdrawal Syndrome, Prenatal Opioid Exposure
Not yet recruitingPhase 2/3
Dexmedetomidine for Invasive Ventilation In the NEOnate
Invasive Ventilation, Infant Pain
Recruiting
Cerebral Physiology of NOWS
Neonatal Opioid Withdrawal, Neonatal Opioid Withdrawal Syndrome
Active, not recruiting
Neurostimulation to Improve NOWS Outcomes
Neonatal Opioid Withdrawal Syndrome, Neonatal Abstinence Syndrome
RecruitingObservational study
Target Trial Emulation for Pharmacologic Treatment of Neonatal Opioid Withdrawal Syndrome
Neonatal Opioid Withdrawal Syndrome

All Neonatal Opioid Withdrawal Syndrome trials

Study at a glance

From the registry record, last updated by the sponsor on 30 Jun 2026. Recruitment status is as the sponsor reported it: confirm with the study team.

Official title: Pragmatic, Randomized, Blinded Trial to Shorten Pharmacologic Treatment of Newborns With Neonatal Opioid Withdrawal Syndrome (NOWS)
ClinicalTrials.gov ID: NCT04214834
Acronym / sponsor ID: ACTNOW-02
Conditions: Neonatal Opioid Withdrawal Syndrome
Keywords: NOWS
Phase: Phase 3
Study type: Interventional
Recruitment status: Active, not recruiting
Enrolment: 189 participants (actual)
Lead sponsor: Advancing Clinical Trials in Neonatal Opioid Withdrawal (ACT NOW) ProgramResearch network
Collaborators: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Study start: 28 Sep 2020 (actual)
Primary completion: 31 Jan 2024 (actual)
Study completion: 30 Jun 2026 (estimated)
First posted: 2 Jan 2020 (actual)
Results: Posted 13 Mar 2025

Clinical summary

The research question as the sponsor registered it. This describes what the study plans to test, not what it found.

Detailed description

Study design

Primary purpose: Treatment
Allocation: Randomised
Intervention model: Parallel groups
Masking: Quadruple blind (participant, care provider, investigator, outcomes assessor)
Number of arms: 2
Model description: The study will have two intervention arms (rapid-wean and slow-wean) with 251 morphine/methadone treated infants per intervention arm, for a total of 502 morphine/methadone treated infants.

Arm	Type	Receives
Rapid-wean	Active comparator	Drug: Morphine, Drug: Methadone15% decrements from the stabilization dose of morphine/methadone
Slow-wean	Active comparator	Drug: Morphine, Drug: Methadone10% decrements from the stabilization dose of morphine/methadone

Who may qualify

Ages: 36 weeks and older
Sex: All
Healthy volunteers: Not accepted
Age groups: Child, Adult, Older adult

Key inclusion criteria (8 listed)

Hospital Level
Infant Level

Key exclusion criteria (12 listed)

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

Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.

Interventions

Intervention	Type	Arms
MorphineThe 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	Rapid-wean, Slow-wean
MethadoneThe 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.	Drug	Rapid-wean, Slow-wean

Primary outcome

Days of Opioid Treatment From First Wean to Cessation
Time frame: 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.
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.

3 secondary outcomes

Days of Opioid Treatment From First Wean to Cessation Among Infants That Were Not Withdrawn in High Enrolling Centers
Time frame: 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
Time frame: 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
Time frame: 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.

Results and safety

Results posted to the registry on 13 Mar 2025, as reported by the sponsor. Figures are copied from the record, not re-analysed. Full results on ClinicalTrials.gov.

Participant flow

Group	Started	Completed
Rapid Wean	98	94
Slow Wean	91	91

Primary outcome: Days of Opioid Treatment From First Wean to Cessation

Time frame: 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.. Mean (Standard Deviation). Unit: days

Measure	Rapid Wean n = 94	Slow Wean n = 91
Value	9.3 (6.3)	11.7 (6.1)

Rapid Wean vs Slow Wean: Mean Difference (Final Values): 2.96 (95% CI 1.70 to 4.29), p <0.001, Mixed Models Analysis

Population analysed: An intent-to-treat (ITT) analysis which included all infants participants who were randomized and who provided outcome data.

3 secondary outcomes are reported in the full results.

Adverse events

Time frame: Randomization through 8-weeks post discharge. Other adverse events reported at 0.00% frequency or more

Group	Serious adverse events	Other adverse events	Deaths
Rapid Wean	1 of 98 (1%)	3 of 98 (3.1%)	0 of 98
Slow Wean	1 of 91 (1.1%)	4 of 91 (4.4%)	0 of 91

Loading the posted results from ClinicalTrials.gov…

Research links

Official record on ClinicalTrials.govLast updated by the sponsor 30 Jun 2026.
Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
Derived from this study: PubMed 41554434Laptook AR, Czynski A, Chahine R, Greenberg RG, Smith PB, Oliveira E, Gabrio J, Eggleston B, Das A, Lee J, Lester B, Clark D, Walsh M, Ko H, Asher CC, Friedman H, Gentle S, Rao K, Katheria A, Benninger K, Jani S, Smith MC, Khan A, Talati A, Lodhi S, Mena F, England A, Parimi P, Kylat R, Harmon H, Mannan J, Howell MP, Wright T, Snowden J; ACT NOW Collaborative. Accelerated Weaning of Opioids to Reduce Pharmacologic Exposure for Neonatal Opioid Withdrawal Syndrome: A Randomized Clinical Trial. J Pediatr. 2026 May;292:114992. doi: 10.1016/j.jpeds.2026.114992. Epub 2026 Jan 17.
Derived from this study: PubMed 37480087Czynski A, Laptook A, Das A, Smith B, Simon A, Greenberg R, Annett R, Lee J, Snowden J, Pedroza C, Lester B, Eggleston B, Bremer D, McGowan E. Pragmatic, randomized, blinded trial to shorten pharmacologic treatment of newborns with neonatal opioid withdrawal syndrome (NOWS). Trials. 2023 Jul 21;24(1):466. doi: 10.1186/s13063-023-07378-x.
Individual participant dataSharing planned: Yes. Data will be made available in NICHD Data and Specimen Hub (DASH).

Related trials for Neonatal Opioid Withdrawal Syndrome

Not yet recruiting
Recorded Parent/Caregiver Voice for Infants With Neonatal Opioid Withdrawal Syndrome
Neonatal Opioid Withdrawal Syndrome, Prenatal Opioid Exposure
Not yet recruitingPhase 2/3
Dexmedetomidine for Invasive Ventilation In the NEOnate
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Recruiting
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Neurostimulation to Improve NOWS Outcomes
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RecruitingObservational study
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Referral and contact

AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.

Abhik Das, PhD principal investigator

RTI International

Abbot Laptook, MD principal investigator

Women and Infants Hospital of Rhode Island

Adam Czynski, DO principal investigator

Connecticut Children's Medical Center

24 sites in 1 country: see every site and its status.

Questions about this trial

What is this clinical trial studying?

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 8 inclusion and 12 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: under way, not looking for participants, as of the sponsor's last update on 30 Jun 2026. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 24 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 13 Mar 2025). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Days of Opioid Treatment From First Wean to Cessation (time frame: 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.). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT04214834, which also lists 2 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 30 Jun 2026.