Non-Opiate Treatment After Prenatal Opiate Exposure to Prevent Postnatal Injury to the Young Brain

Study Overview
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Brief Summary
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The long term goals of our research are to establish the best pharmacological treatment for NAS and determine how pharmacologic treatment of NAS affects long-term developmental outcomes. The objective of this application is to evaluate the effectiveness of clonidine as a treatment for neonates with NAS, in a randomized clinical trial. Our central hypothesis is that clonidine will effectively treat drug withdrawal manifestations in neonates.

Detailed Description
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In this current proposal, the research plan is based on our pilot study, which randomized infants with NAS to receive morphine or clonidine. The treatment groups were similar as to mean birth weight, gestational age, Apgar scores, and postnatal age at treatment. Infants enrolled had no other medical or surgical complications. Treatment was initiated per our NICU standard at the time, and will be continued in this protocol. Total LOS was shorter by about 1 week in the clonidine (mean of 15 days), compared to 21 days in the morphine group. Aims and Objectives: To determine whether the treatment of NAS with a non-opiate medication, clonidine, will be more effective than morphine Compare Clonidine and morphine for the treatment of NAS. Compare the efficacy of each drug which is determined by duration of treatment in number of days, number of dose escalations needed to achieve needed treatment, and the need for second drug treatment. Evaluate the neurobehavioral performance scores (habituation, orientation, self- regulation, motor/reflexes, and stress/ abstinence scales) using the neonatal intensive care (NICU) network neurobehavioral scale (NNNS) in both treatment groups. This exam will take place after treatment begins, and at one month post-natal age (38-44 weeks post menstrual age) or at discharge, whichever comes first. To determine whether treatment of NAS with clonidine will result in better early childhood outcomes than those treated with morphine • Compare the cognitive, motor and behavioral development of children in both treatment groups using the Bayley III Scales of Infant Development at 6 months, one and two years of age. To build population pharmacokinetic/pharmacodynamic models and determine factors that affect exposure and response to morphine and clonidine • Measure blood levels obtained at random times and correlate to Finnegan scores. The pharmacodynamics may help with understanding NAS medications and coping measures in babies.

Official Title
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Non-Opiate Treatment After Prenatal Opiate Exposure to Prevent Postnatal Injury to the Young Brain

Conditions
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Neonatal Abstinence Syndrome

Intervention / Treatment
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* Drug: Clonidine
* Drug: Morphine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Gestational age (GA) > or equal to 35 weeks Known prenatal opiate exposure (by mother admitting use, mom with positive opiate screen during pregnancy, or positive neonatal urine and meconium screening) No known prenatal cocaine exposure No morphine or clonidine dose before enrollment Symptomatic with Finnegan scores (FS): 3 consecutive scores greater than or equal to 8, OR 2 consecutive scores greater than or equal to 12, and/or with attending decision to treat for NAS Less than or equal to 7 days of age Attending physician decides to start pharmacologic treatment and agrees to infant's study participation Exclusion Criteria: Seizures Major congenital malformations Blood pressure instability Major medical condition in addition to NAS Parents unable to understand English

Ages Eligible for Study
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Minimum Age: 12 Hours
Maximum Age: 7 Days

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: The study is intended to treat NAS using a randomized and double-blind study design to compare the use of opiate (morphine) or non-opiate (clonidine). Newborns meeting the study criteria for drug withdrawal and treatment will be randomized to receive one of the drugs (morphine, clonidine). Newborns requiring a second drug to help relieve the symptoms will be treated with phenobarbital for both groups. Randomization, blinding and dispensing will occur in the Investigational Drug Services Unit. Nursing personnel in the NICU will be masked to the treatment administered to each baby.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Clonidine<br>Babies randomized to clonidine will receive 1mcg/kg/dose (with a dosing interval of 3 or 4 hours). | Drug: Clonidine<br>* 1mcg/kg/dose (with a dosing interval of 3 or 4 hours), increases by 25% of initial dose every 12-24 hrs. Decrease by 10% of max dose every 24 hrs.<br>* Other names: clonidine hydrochloride;|
| Active Comparator: Morphine<br>Babies randomized to morphine will receive 0.06 mg/kg/dose (with a dosing interval of 3 or 4 hours). | Drug: Morphine<br>* Starting dose is 0.06 mg/kg/dose (every 3 or 4 hours), increases by 25% of initial dose every 12-24 hrs. Decrease by 10% of max dose every 24 hrs.<br>* Other names: Morphine Sulfate;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Neurobehavioral Performance Summary Scores from the Neonatal Intensive Care Unit Network Neurobehavioral Scale (NNNS) | The summary scores from the Neonatal Intensive Care Unit Network Neurobehavioral Scale (NNNS) give a measure of infant neurobehavior in the following areas (score range): habituation (1-9), regulation (2.20-7.50), attention (1.29-8.4), Handling (0-1), quality of movement (1.20-6.20), Non-optimal reflexes (0-12), Asymmetric reflexes (0-7), arousal (2.43-6.67), hypertonicity (0-8), hypotonicity (0-5.0), excitability (0-11), lethargy (0-11.0), and stress/abstinence (0-0.57). A higher score for each item means a higher level of the construct. For example, a higher score for hypertonicity means the infant is more hypertonic and higher score on hypotonicity means the infant is more hypotonic. No cut-off score published for normal or abnormal behavioral performance. Reference: Lester BM et al. Summary Statistics of Neonatal Intensive Care Unit Network Neurobehavioral Scale Scores From the Maternal Lifestyle Study: A Quasinormative Sample, in Pediatrics 2004; 113,668. | 5-10 days post natal age | 
| Neurobehavioral Performance Summary Scores from the Neonatal Intensive Care Unit Network Neurobehavioral Scale (NNNS) | The summary scores from the Neonatal Intensive Care Unit Network Neurobehavioral Scale (NNNS) give a measure of infant neurobehavior in the following areas (score range): habituation (1-9), regulation (2.20-7.50), attention (1.29-8.4), Handling (0-1), quality of movement (1.20-6.20), Non-optimal reflexes (0-12), Asymmetric reflexes (0-7), arousal (2.43-6.67), hypertonicity (0-8), hypotonicity (0-5.0), excitability (0-11), lethargy (0-11.0), and stress/abstinence (0-0.57). A higher score for each item means a higher level of the construct. For example, a higher score for hypertonicity means the infant is more hypertonic and higher score on hypotonicity means the infant is more hypotonic. No cut-off score published for normal or abnormal behavioral performance. Reference: Lester BM et al. Summary Statistics of Neonatal Intensive Care Unit Network Neurobehavioral Scale Scores From the Maternal Lifestyle Study: A Quasinormative Sample, in Pediatrics 2004; 113,668. | At one month post-natal age (between 4-6 weeks of age), or at discharge, whichever comes first | 
| Bayley Scales of Infant and Toddler Development Third Edition | Scores obtained Bayley Scales of Infant and Toddler Development Third Edition in the developmental domains of motor, cognitive, and language. This tool for measures of motor, cognitive, and language development is a series of standardized measurements and for each domain, the standardized scores have a mean of 100 and standard deviation of 15. Scores below 1 standard deviation (=or less than 84) is considered below normal. Scores above 1 standard deviation (over 115) represent higher than normal functioning in each domain. The score for each domain (motor, cognitive, and language functioning) represents the full-scale score. | 6 months of life | 
| Bayley Scales of Infant and Toddler Development Third Edition | Scores obtained Bayley Scales of Infant and Toddler Development Third Edition in the developmental domains of motor, cognitive, and language. This tool for measures of motor, cognitive, and language development is a series of standardized measurements and for each domain, the standardized scores have a mean of 100 and standard deviation of 15. Scores below 1 standard deviation (=or less than 84) is considered below normal. Scores above 1 standard deviation (over 115) represent higher than normal functioning in each domain. The score for each domain (motor, cognitive, and language functioning) represents the full-scale score. | 1 year of life | 
| Bayley Scales of Infant and Toddler Development Third Edition | Scores obtained Bayley Scales of Infant and Toddler Development Third Edition in the developmental domains of motor, cognitive, and language. This tool for measures of motor, cognitive, and language development is a series of standardized measurements and for each domain, the standardized scores have a mean of 100 and standard deviation of 15. Scores below 1 standard deviation (=or less than 84) is considered below normal. Scores above 1 standard deviation (over 115) represent higher than normal functioning in each domain. The score for each domain (motor, cognitive, and language functioning) represents the full-scale score. | 2 years of life | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of treatment | Total number days of treatment | 60 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Opiate use during pregnancy, Clonidine, Morphine, Prenatal opiate, Neonatal Abstinence Syndrome, Infant, Newborn, Diseases, Substance-Related Disorders, Chemically-Induced Disorders, Opiate Alkaloids, Mental Disorders, Narcotics, Central Nervous System Depressants, Physiological Effects of Drugs, Adrenergic alpha-2 Receptor Agonists, Adrenergic alpha-Agonists, Molecular Mechanisms of Pharmacological Action, Antihypertensive Agents, Analgesics, Peripheral Nervous System Agents, Sympatholytics, Autonomic Agents, Neurotransmitter Agents