Neonatal Opioid Withdrawal Syndrome
Conditions
Keywords
NOWS
Brief 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 treatment for neonatal opioid withdrawal syndrome (NOWS).
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.
Interventions
DRUGMorphine
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.
DRUGMethadone
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.
Sponsors
Advancing Clinical Trials in Neonatal Opioid Withdrawal (ACT NOW) Program
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
The pharmacy will track dose levels to know where an infant is within a rapid- or slow-wean intervention arm. The clinical team will be blinded to the dose level and will only be aware of the study steps. Both the rapid- and slow-wean intervention arms are depicted to indicate that if each intervention arm has the same number of escalations, the study steps will be identical. This is critical to maintaining the clinical team blinding.
Intervention 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.
Eligibility
Sex/Gender
ALL
Age
36 Weeks to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Days of Opioid Treatment From First Wean to Cessation | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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. | The number of days of opioid treatment from first wean to cessation among infants that were not withdrawn in high enrolling centers |
| 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. | The number of days of opioid treatment from first wean to cessation among high enrolling centers |
| 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. | The number of days of opioid treatment from first wean to cessation among infants that were not withdrawn |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORAbhik Das, PhD
RTI International
PRINCIPAL_INVESTIGATORAbbot Laptook, MD
Women and Infants Hospital of Rhode Island
PRINCIPAL_INVESTIGATORAdam Czynski, DO
Connecticut Children's Medical Center
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Rapid Wean Rapid Wean: 15% decrements from the stabilization dose of morphine/methadone | 98 |
| Slow Wean Slow Wean: 10% decrements from the stabilization dose of morphine/methadone | 91 |
| Total | 189 |
Baseline characteristics
| Characteristic | Slow Wean | Total | Rapid Wean |
|---|---|---|---|
| Age, Continuous | 38.8 weeks STANDARD_DEVIATION 1.3 | 38.8 weeks STANDARD_DEVIATION 1.2 | 38.8 weeks STANDARD_DEVIATION 1.2 |
| Infant feed Bottle | 80 Participants | 156 Participants | 76 Participants |
| Infant feed Breast | 8 Participants | 23 Participants | 15 Participants |
| Infant feed unknown | 3 Participants | 10 Participants | 7 Participants |
| Mothers opioid treatment Buprenorphine w/wo naloxone | 30 Participants | 70 Participants | 40 Participants |
| Mothers opioid treatment Methadone | 38 Participants | 70 Participants | 32 Participants |
| Mothers opioid treatment Missing | 1 Participants | 2 Participants | 1 Participants |
| Mothers opioid treatment None/Other | 22 Participants | 47 Participants | 25 Participants |
| Race/Ethnicity, Customized American Indian or AlaskaNative | 1 Participants | 4 Participants | 3 Participants |
| Race/Ethnicity, Customized Black or African American | 10 Participants | 26 Participants | 16 Participants |
| Race/Ethnicity, Customized Hispanic or Latino | 18 Participants | 35 Participants | 17 Participants |
| Race/Ethnicity, Customized Missing | 1 Participants | 2 Participants | 1 Participants |
| Race/Ethnicity, Customized More than one race | 1 Participants | 1 Participants | 0 Participants |
| Race/Ethnicity, Customized Not Hispanic or Latino | 66 Participants | 143 Participants | 77 Participants |
| Race/Ethnicity, Customized Unknown | 6 Participants | 9 Participants | 3 Participants |
| Race/Ethnicity, Customized White | 74 Participants | 148 Participants | 74 Participants |
| Sex/Gender, Customized Female | 35 Participants | 74 Participants | 39 Participants |
| Sex/Gender, Customized Male | 56 Participants | 114 Participants | 58 Participants |
| Sex/Gender, Customized Missing | 0 Participants | 1 Participants | 1 Participants |
| Stabilization dose: Methadone | 0.33 mg | 0.31 mg | 0.28 mg |
| Stabilization dose: Morphine | 0.25 mg | 0.23 mg | 0.22 mg |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 98 | 0 / 91 |
| other Total, other adverse events | 3 / 98 | 4 / 91 |
| serious Total, serious adverse events | 1 / 98 | 1 / 91 |
Outcome results
Primary
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.
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.
Population: An intent-to-treat (ITT) analysis which included all infants participants who were randomized and who provided outcome data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Rapid Wean | Days of Opioid Treatment From First Wean to Cessation | 9.3 days | Standard Deviation 6.3 |
| Slow Wean | Days of Opioid Treatment From First Wean to Cessation | 11.7 days | Standard Deviation 6.1 |
Comparison: A logarithmic transformation was applied to the outcome, centers were added as random effects to account for variation between them.p-value: <0.00195% CI: [1.7, 4.29]Mixed Models Analysis
Secondary
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
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.
Population: An intent-to-treat (ITT) analysis which included all infants participants who were randomized and who provided outcome data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Rapid Wean | Days of Opioid Treatment From First Wean to Cessation Among High Enrolling Centers | 9 days | Standard Deviation 5.9 |
| Slow Wean | Days of Opioid Treatment From First Wean to Cessation Among High Enrolling Centers | 11.3 days | Standard Deviation 5.7 |
Secondary
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
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.
Population: An intent-to-treat (ITT) analysis which included all infants participants who were randomized and who provided outcome data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Rapid Wean | Days of Opioid Treatment From First Wean to Cessation Among Infants That Were Not Withdrawn | 8 days | Standard Deviation 4.8 |
| Slow Wean | Days of Opioid Treatment From First Wean to Cessation Among Infants That Were Not Withdrawn | 10.7 days | Standard Deviation 4.1 |
Secondary
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
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.
Population: An intent-to-treat (ITT) analysis which included all infants participants who were randomized and who provided outcome data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Rapid Wean | Days of Opioid Treatment From First Wean to Cessation Among Infants That Were Not Withdrawn in High Enrolling Centers | 8.1 days | Standard Deviation 4.9 |
| Slow Wean | Days of Opioid Treatment From First Wean to Cessation Among Infants That Were Not Withdrawn in High Enrolling Centers | 10.5 days | Standard Deviation 4.2 |