Trial design {8}
breast milk
BROWN
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.If the infant can tolerate weaning and is in the rapid-wean intervention arm, the clinical team will reduce the study drug by 15% of the stabilization dose. The clinical team will terminate the study drug when the infant can tolerate 25% of the stabilization dose without NOWS signs.If the infant can tolerate weaning and is in the slow-wean intervention arm, the clinical team will reduce the study drug by 10% of the stabilization dose. The clinical team will terminate the study drug when the infant can tolerate 20% of the stabilization dose without NOWS signs.If infants cannot tolerate weaning in either intervention arm, infants will enter a 12-h period of study protocol guideline that will mandate either weaning or escalating the study drug by the end of the 12-h interval. If the clinical team escalates the study drug, infants will receive opioid using the prior step of the assigned intervention arm.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.