Pragmatic, randomized, blinded trial to shorten pharmacologic treatment of newborns with neonatal opioid withdrawal syndrome (NOWS)

The incidence of maternal opioid use in the USA has increased substantially since 2000 [1]. This includes an increase of opioid use during pregnancy including prescription opioids and illicit drugs, as well as a rise in opioid substitution programs for addiction treatment [2]. As a consequence of opioid use during pregnancy, the incidence of neonatal opioid withdrawal syndrome (NOWS) has increased fivefold between 2002 and 2012 [1]. NOWS is a clinical syndrome that reflects signs of withdrawal from opioids in a newborn following in utero exposure. Signs typically occur in the first 5–7 days following birth and reflect dysfunction of the brain, gastrointestinal tract, and autonomic regulation. Simultaneously during this rise in opioid use, the pattern of use has shifted from an inner city, indigent population to a more socioeconomically diverse population. A systematic literature review indicated rural pregnant women have higher rates of polysubstance abuse, as compared to urban pregnant women [3]. The highest incidences of NOWS were reported in the Southeast (i.e., Kentucky, Tennessee, Mississippi, and Alabama) and Northeast (i.e., Maine, New Hampshire, Vermont, Massachusetts, and Rhode Island) United States [4]. This increase in opioid drugs during pregnancy affects neonatal care across the USA. Multiple cross-sectional analyses show that neonatal intensive care unit (NICU) admission rates for NOWS increased from 7 to 27 cases per 1000 admissions and that length of stay increased from 13 to 19 days between 2004 and 2013 [5]. Mean hospital charges for infants discharged with neonatal abstinence syndrome (NAS) increased from $39,400 to $53,400 between 2000 and 2009, and state Medicaid programs bore 78% of these charges [1]. The proportion of neonatal hospital costs due to NAS was estimated to rise from 1.6 to 6.7% between 2004 and 2014 among births covered by Medicaid [6]. Pregnancy complicated by opioid use disorder is associated with high rates of polydrug use, mental health disorders, infectious diseases, poor nutrition, chronic illnesses, and limited social support [7]. Associated risks for newborns beyond NOWS include preterm birth and fetal growth restriction.

Pregnancy represents an opportunity for entry into the healthcare system and initiation of interventions for the mother-infant dyad. However, there are many knowledge gaps in the care of infants with NOWS. The executive summary of a joint workshop by the National Institute of Child Health and Human Development and multiple other partners identified major domains of research priorities on NOWS, including screening and assessment, treatment of NOWS, and transition out of the hospital and follow-up [7].

The ISPCTN and the NRN have undertaken a retrospective chart review to inform the design of clinical trials for infants with NOWS (ACT NOWS current experience: Infant exposure and treatment). Investigators reviewed medical records for infants ≥ 36 weeks gestational age and born between July 1, 2016, through June 30, 2017, and mothers medical records, when available, when there was opioid use, determined by maternal history, maternal/infant toxicology screen, or NOWS scoring. Data were collected from 1808 infants at 23 of 28 ISPCTN sites and two of five NRN sites.

The salient findings from the preliminary data of the ACT NOW Current Experience retrospective chart review were:

Multiple clinical guidelines from IDeA States Pediatric Clinical Trials Network and the Neonatal Research Network were reviewed to understand the extent of variation in weaning strategies for morphine and methadone. Among centers that use morphine, weaning strategies included reduction by a fixed dose (n=2), 10% of the stabilization dose (n=6), or 10–20% of the stabilization dose (n=3). Among centers that use methadone, weaning strategies included reduction by a fixed dose with changes in frequency of dosing (n=2), reductions by 10% of that stabilization dose (n=1), and reductions by greater than 10% of the stabilization dose (n=3). This review supports a wide range of clinical practices for pharmacologic treatment of NOWS.

Seventeen ISPCTN and NRN sites submitted guidelines and protocols they use to treat infants with NOWS (morphine use: 12 sites, methadone use: 5 sites). In eight of the 17 guidelines, there were specific directives that clinical teams should monitor NOWS infants receiving pharmacological therapy in the hospital for at least 48 h after treatment cessation. In the other nine guidelines, there were no comments on the duration of observation after pharmacological treatment cessation.

Primary hypothesis: Among infants receiving an opioid (defined as morphine or methadone) as the primary treatment for NOWS, a rapid-wean intervention will reduce the days of opioid treatment from the first weaning dose to cessation of opioid, compared to a slow-wean intervention.

This will be a superiority trial using a pragmatic, randomized, blinded design 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 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. We 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-h 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.

To maintain blinding of study drug dose during the interventions, the volume of the syringe will be constant and equal the volume of the opioid at stabilization. As the clinical team decreases the study drug during the interventions, the pharmacist will add normal saline to keep a constant syringe volume. Only the pharmacy will be aware of the opioid dose. The use of placebo (normal saline without opioid) in the rapid-wean intervention arm will ensure comparable duration of both weaning interventions.

As part of a pragmatic trial, clinical teams will follow hospital practice for other care practices related to NOWS treatment (type of scoring system, threshold to initiate treatment, duration of stabilization, use of second-line and third-line drugs, rooming in, breast milk, etc.). After study drug cessation, the clinical team will observe infants in the hospital for at least 48 h prior to discharge, which is similar to clinical practice. A trained examiner will administer the NNNS to assess neurobehavioral profiles after infants cease study drug and prior to discharge. Some participating sites may need to train their study staff on the NNNS procedure. The NNNS training requires video recordings of infants sent to the training center at Brown University. Only the trainers at the Brown Center or their trainer designee and site trainees will have access to the video. The video will be deleted from the server once it has been reviewed for training purposes, and training on that video is complete. These infants may or may not be otherwise involved in the protocol. Sites may assess infants who will not enroll in the study, infants who will enroll, or both for this training. Because this training activity will not yield study data, a separate consent form will be used for this training.

At 1 month post-discharge, primary caregivers will complete the Parent-Reported Outcome Measure Information System (PROMIS) Measures, 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, 12, 18, 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 PROMIS Measures and the Brief Infant Toddler Social Emotional Assessment (BITSEA) will also be administered during the 24-month visit along with measures of growth.

The study is being conducted in academic medical centers across the USA. A complete reference list of study cites can be obtained at the following website: https://​beta.​clinicaltrials.​gov/​study/​NCT04214834.

Research staff may reach out to, and obtain consent from, pregnant women and postpartum women of eligible or potentially eligible infants at any of the following times: (a) prior to birth, (b) after birth but prior to the determination of the infant’s eligibility, (c) after birth and after infant’s eligibility has been confirmed. The legal guardian or legally authorized representative may be approached when the mother does not have custody.

N/A; we will not collect biological specimens during the conduct of this study.

N/A the information requested for a list of comparators would be redundant to the information provided within the background and rational.

This will be a pragmatic, randomized, blinded trial of opioid weaning to determine whether more rapid weaning, compared to slow wean, will reduce the number of days of opioid treatment in infants receiving morphine or methadone as the primary treatment for NOWS. Figure 1 illustrates when the study interventions will occur during the hospitalization.

Consistent with the pragmatic design, hospitals will use their specific management practices for opioid treatment among NOWS infants after birth and prior to randomization and the start of opioid weaning. This may include the following management practices:

Primary caregiver(s) for infants for whom the protocol study team have obtained informed consent will receive questionnaires via electronic application or via phone interview, if caregiver(s) have limited access to cellular/internet service or prefer this modality of communication. Assessments may also take place in person, if there is a scheduled visit. Caregiver(s) will complete these questionnaires at 1 month after discharge and 6, 12, 18, and 24 months of age. These questionnaires will gather information on infant wellness, and primary caregiver(s) contact information, maternal well-being, infant attachment, and infant behavior. In addition, there will be an in-person follow-up visit with neurodevelopmental assessment at 24 months of age. Study staff will maintain contact in between study assessments at regular intervals. Respondents to these assessments will receive a reimbursement to compensate them for their time.

We will assess maternal well-being with Patient Reported Outcomes Measurement Information System (PROMIS) short forms [32]. Standardized short forms examining mental health, specifically the areas of anxiety (PROMIS Short Form v1.0 - Anxiety - 8a 31May2019), depression (PROMIS_SF_v1.0_-_ED-Depression_8a_5-31-2019), anger (PROMIS Short Form v1.1 - Anger - 5a 27Apr2016), life meaning and purpose (PROMIS Short Form v1.0 - Meaning and Purpose - 8a 18Jul2017), and social support (PROMIS v2.0 - Emotional Support Short Form 4a 23June2016), will be completed by the primary caregiver and will be sent to a central location for review by the protocol study team. The standardized short form for each of the PROMIS Measures consists of between four to eight 5-point Likert scale questions. The PROMIS Depression Short form has been validated in the postpartum period and has been found to be strongly correlated with the Edinburgh Postnatal Depression Scale, the most extensively studied measure of depression in the postpartum period [33, 34]. In addition, the PROMIS anxiety measure has been correlated with the Mood and Anxiety Questionnaire (MASQ) and has been shown to be a valid measurement tool for anxiety in the postpartum period in a sample of parents whose infants were hospitalized in the NICU [34]. Administration takes approximately 10 min and includes a total of 33 questions.

The PROMIS Measures will be administered at 1-month after discharge and again at 24 months of age.

We will briefly assess mother-infant attachment with the Maternal Postnatal Attachment Questionnaire (MPAQ; [35]), a 19-item questionnaire that assesses quality of bonding, absence of hostility, and pleasure in interaction. Higher MPAQ scores reflect higher levels of mother-infant bonding. The MPAQ requires approximately 5 min to complete, and researchers have validated the MPAQ among postpartum women with substance abuse problems [36]. The MPAQ will be administered at 1 month after discharge.

Caregiver(s) will complete the caregiver questionnaire (CQ) to assess enteral feeding, number of emergency room (ER) visits and/or acute/urgent care visits, and hospital readmissions.

We will assess infant neurobehavioral functioning at 24 months of age using the Brief Infant-Toddler Social and Emotional Assessment (BITSEA). The BITSEA is 42-item parent report screener used to indicate social-emotional/behavioral problems in children 12–36 months [37]. It will be administered at the 24-month in-person visit. We chose this measure because it is brief, easy to administer, and has good reliability and validity [38, 39].

We will assess infant development with the Bayley Scales of Infant and Toddler Development, Fourth Edition (Bayley-4): Cognitive, Language, Motor at 24 months of age. The Bayley-4 is recognized internationally as one of the most comprehensive tools to assess developmental outcomes in children. With the Bayley-4, it is possible to obtain detailed information even from non-verbal children as to their functioning. Children are assessed in the 3 key developmental domains of cognition, language, and motor. Reliability and validity of the previous version of the instrument have been well established [40].

Strategies to improve or monitor adherence to the study protocol will include the following:

Similar to clinical practice, the clinical team should monitor participants who have weaned off study drug for 48–72 h prior to discharge to ensure that recurrence of NOWS signs do not occur. If there is a recurrence of NOWS signs during the 48–72 h post-intervention period, and if that recurrence merits pharmacologic therapy per the institution’s guideline, study drug will be restarted at the prior dose of the rapid wean (25% of stabilization dose) or the slow wean (20% of the stabilization dose) interventions. Tolerance for weaning will then be re-evaluated after 24 h of study drug administration. When the infant has been off the opioid and prior to discharge, a trained examiner will administer the NNNS. The assessment takes approximately 20–25 min to complete. We will not administer the NNNS at the same time relative to the last opioid exposure due to the unpredictable number and timing of opioid escalations in each weaning intervention and to avoid potential unblinding of the intervention.

See Additional file 1 for schedule of activities.

There are 3 major components to a successful recruitment plan as follows:

The first two of these components are part of a system-level recruitment initiative while the third component is patient specific. The single most important element of the recruitment strategy is the prenatal consultation. If prenatal consultation is not feasible, effective antenatal dissemination of information regarding the clinical trial will be exceptionally important when approaching mothers after delivery.

Because the randomization will occur through a central web-based application, site Principal Investigator (PI), research team, and clinical team will not be able to access the allocation sequence. To further add concealment, the act of randomizing is performed by the pharmacy team, which is the only unblinded service at each site. The act of randomization will be performed by the pharmacy team.

The NRN DCC will develop an allocation sequence with randomly varying block sizes, and they will implement this sequence through a central process that will be available 24 h each day. The NRN DCC will independently randomize multiple births. Pharmacy personnel of each participating hospital will be the only staff with access to group assignment.

All site research personnel (site PI, research coordinator, research nurses), the clinical team (physicians, nurse practitioners, physician assistants, house-staff, medical students), family members, care givers legally responsible for the infant, hospital personnel (nurses, nursing assistants, clinical nurse managers, respiratory therapists, etc.), and any other personnel working in the area of the hospital where the infants is cared for will be blinded to the treatment intervention (rate of weaning). Only pharmacy personnel will not be blinded. All site research personnel responsible for administering questionnaires after discharge or performing evaluations at 2 years of age will be blinded. Participating hospitals will be responsible for in-services of all involved staff regarding blinding.

To maintain treatment blind, the volume of opioid will remain constant throughout the intervention for the rapid-wean and slow-wean intervention arms. At the time of opioid dosing, infants will receive one syringe with study drug at a volume equivalent to the volume of the stabilization dose, or a volume greater than the stabilization to facilitate maintaining a set volume (e.g., a stabilization dose of 0.28 ml may be set at 0.5 ml for ease of drawing up medication with saline during weaning). As infants progress through the dose levels, the research pharmacist will reduce the opioid volume and the pharmacist will make up the difference by normal saline so that the volume of the syringe is constant throughout all dose levels. To ensure that infants in the rapid-wean intervention arm have an equal number of study steps as infants in the slow-wean intervention arm, the pharmacy will use a placebo (normal saline without opioid) for three dose levels. Depending on the timing of escalations, the three placebo dose levels do not need to occur consecutively. We will label the study drugs as either morphine/study drug and the respective volume or methadone/study drug and the respective volume.

Infants will exit the study intervention without unblinding (but remain in the trial) if they have not weaned off study drug by 35 days from the first weaning dose. This represents more than twice the median and mean length of treatment for the morphine arm in the Davis et al. trial. This will avoid prolongation of treatment and length of hospital stay due to inability to tolerate the intervention guideline. To exit the Intervention one of the following criteria would need to be meet:

If an infant meets one of the above criteria for exiting the intervention without unmasking, the following actions should be taken:

The clinical team responsible for the daily management of the infant will consult with the site research team. The site research team will verify that the circumstance for exiting the study intervention is appropriate by checking the Manual of Operations. Once verified, the site research team will communicate with the clinical team and the pharmacy that the infant will exit the study intervention. The pharmacy will provide the clinical team of what the opioid dose would have been in each arm of the trial.

The clinical team will assume the management of the opioid medication using the clinical standards of the hospital. The treatment assignment will not be unmasked, and the infant continues as a study participant.

The actual dose that the infant is receiving will only be divulged to the clinical team if the physician caring for the infant feels that this information is essential for clinical management of the infant.

Study Objectives and Endpoints

To support retention of study participants after discharge, sites are instructed to use any retention resources at their institution including follow-up clinics and other similar resources. Sites should update contact information at every study follow-up timepoint. Participants will receive $50 compensation for each follow-up timepoint (1 month post-discharge, 6, 12, and 18 months) except 24 months, at which they will receive $100. Each site should use the appropriate type of participant reimbursement at their hospital. It is critical to keep participants informed and engaged during their participation in the study. Make sure that all of the contact timepoints are clearly communicated with each participant. After a participant enters the study, the site can follow up with a thank you note. Sites may also use text messaging to keep in contact with participants to update contact information and send reminders. Sites should check hospital records for updated contact information if they are unable to reach the participant by text, email, phone, or letter. Sites should document every attempt to contact a participant. More frequent contacts with the care giver (phone, text, email, etc.) in between study follow-up time points is encouraged but left to the discretion of the participating hospital. To maximize success rate in follow-up, it is recommended that participants are contacted/seen as early as possible in the following time windows:

Follow-up personnel/coordinators should anticipate that it will take multiple attempts to reach the caregiver. Attempts to contact a participant should be made on different days/times for a particular follow-up timepoint. If a family is unable to be contacted during one of the designated follow-up periods, they should be contacted again during the next follow-up period. If contact is made via telephone, and the family has limited time available for questionnaires, questionnaires should be administered in the following order:

Follow-up programs should anticipate that multiple attempts to establish contact will be necessary. If the site research team is having difficulty contacting a participant, the number of continued attempts should be discussed with the participating site/hospital PI. Regular meetings of the site/hospital research team and those involved in follow-up may be of benefit to devise strategies to maximize retention.

Critical to maintaining compliance for follow-up visits is the contact form collected during the recruitment period. The contact form incorporates information including the address and phone contacts of the parent/caregiver, as well as any other person listed as additional contacts. At the initial visit with the parent/caregiver and on all subsequent visits, contact information should be reviewed and updated. Two-way communication with the family needs to be implemented at each site through the parent’s preferred method of communication(s) including, telephone calls, text messages, emails, and face-to-face interactions. Seasonal/birthday cards, mailings, and/or newsletters are encouraged because it keeps participants engaged, as well as provides address verification. Returned mailings should be updated in the tracking system. The use of private messages, similar to email, may be allowed and an effective tracking tool when other contact information is no longer in use.

Before hospital discharge, the study team should obtain information from the mother or other caregivers so that other relatives or friends could be contacted to find the family’s new address if they had moved. It is important that families and caregivers be made aware that any information regarding address or phone number remain strictly confidential and will not be shared with anyone for any other purpose but making appointments for the infants’ benefit.

Study identifiers will be strictly protected in this study. Subjects are assigned a unique study identification number, which is used on all electronic data files and study forms with the exception of the screening log. Identifying information such as name, date/time of birth, and medical record number (MRN) will be used on screening log for documentation and tracking purposes. Name and MRN will not be entered into the online study databases RAVE and REDCap. The password-protected screening log will be securely stored on hospital password-protected computers only. The log will be destroyed at the end of the study. Confidentiality will be protected by removing any information that can be associated with date/time of birth and other dates/time data points. The link between the identifying numbers and names will be securely locked and accessible only to personnel of the Weaning Trial including study coordinator and PI. Data for the in-hospital weaning data collection forms will be entered into the Medidata RAVE Electronic Data Capture (EDC) system. Medidata RAVE is a CFR 21 Part 11 compliant Electronic Data Capture System with ISO 27018 privacy protection certification. The RAVE system is an interface for data capture, queries, data cleaning, and site monitoring and reporting.

In-hospital weaning data abstraction and collection forms will be entered into the web-based online EDC system RAVE database electronically, verified and stored without identifying information. REDCap EDC will be used for the post-hospital discharge questionnaires and follow-up data. Participants can complete study questionnaire electronically via REDCAP. These electronic data files are linked to the participant by the unique participant identification number only.

Not applicable; we will not collect biological specimens during the conduct of this study.

Analysis will be completed on the intention to treat principle, so data will be analyzed as randomized. No imputation for missing outcome data is planned, so the analysis will be on the Full Analysis Set [43].

This study will comply with the NIH Public Access Policy, which ensures that the public has access to the published results of NIH-funded research. The study will also comply with the NIH Data Sharing Policy and Policy on the Dissemination of NIH-Funded Clinical Trial Information and the Clinical Trials Registration and Results Information Submission rule.

As such, this study will:

NIH Program Officers at NICHD and ISPCTN-ECHO (in the NIH the Office of the Director (OD)) will be responsible for:

• Providing oversight for the trial.

• Facilitating and participating in all study-related committees.

• Funding the study, administering the Protocol Review Committee (PRC) which meets at a minimum twice a month.

• Administering the Data Safety and Monitoring Committee (DSMC) which meets on a quarterly basis.

• The NIH Program Officers at each of these institutions will have final authority on the commencement and continuation of the protocols.

Three coordinating centers will collaborate to perform all coordination activities for the ACT NOW collaborative:

The three coordinating centers will be jointly responsible for working with the Clinical Sites on study implementation. Activities include training, data management and biostatistical management. Responsibilities for each organization are outlined in the subsections below.

The CC, DCRI, will:

The independent DSMC will have overall responsibility for interim data monitoring and operate based on the Institutional Development Award (IDeA) States Pediatric Clinical Trials Network (ISPCTN) and NRN charter for the DSMC. The DSMC meets regularly to review the ongoing ACT NOW Weaning protocol with respect to ethical and safety standards. It monitors the safety of the clinical trials and advises the on continued study conduct. The DSMC provides recommendations to the Directors of NICHD and ECHO about starting, continuing, and stopping the ACT NOW Weaning clinical trial. All data distributed to the DSMC and deliberations of the DSMC are strictly confidential. Decisions to alter or halt studies are the responsibility of the Directors of NICHD and ECHO. The DSMC may recommend protocol modifications based on concerns for patient welfare or scientific integrity. The committee has confidential access to statistical data and adverse events that it may require for its deliberations. It reviews interim reports of patient accrual and outcome measures provided by the Data Coordinating Center.

Proposed protocol and patient-facing material modifications are communicated to the Data Coordinating and Operations Center (DCOC) at University of Arkansas for Medical Sciences (UAMS) for submission to the cIRB at UAMS. Upon cIRB approval of the modification, the DCOC will send the amendment with an accompanying approval letter to sites via email, using a study-wide contact list. For changes to non-patient-facing material, the RTI DCC will update the study documents and send updated materials with an accompanying technical memo to sites via email, using a study-wide contact list. All final, updated documents will be posted to the study website hosted by the ISPCTN

The protocol study team will make every attempt to publish results in peer-reviewed journals. The team will submit all final peer-reviewed journal manuscripts from this study to the digital archive PubMed Central upon acceptance for publication.

Deposit data for data sharing with other researchers. Within the bounds of relevant IRB approvals and guidelines for protection of personally identifiable data, the protocol study team will deposit de-identified data from this study in an appropriate, NIH-approved data repository.