Clinical trial NCT03396588: Non-Opiate Treatment After Prenatal Opiate Exposure to Prevent Postnatal Injury to the Young Brain
Official title: Non-Opiate Treatment After Prenatal Opiate Exposure to Prevent Postnatal Injury to the Young Brain
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Neonatal Abstinence Syndrome
Keywords: 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
Lead sponsor: University of Kentucky
Sponsor class: OTHER
Collaborators: name: National Institute on Drug Abuse (NIDA)
First posted: 2018-01-11
Enrollment: 120
Sex: ALL
Minimum age (years): 12
Maximum age (years): 7
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention 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.
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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

Primary outcomes:
measure: Change in Neurobehavioral Performance Summary Scores From the Neonatal Intensive Care Unit Network Neurobehavioral Scale (NNNS)
timeFrame: Baseline (5-10 days post natal age) and one-month post-natal age (between 4-6 weeks of age), or at discharge, whichever comes first.
measure: Bayley Scales of Infant and Toddler Development Third Edition
timeFrame: 6 months of life
measure: Bayley Scales of Infant and Toddler Development Third Edition
timeFrame: 1 year of life
measure: Bayley Scales of Infant and Toddler Development Third Edition
timeFrame: 2 years of life
measure: Ages and Stages Questionnaire Third Edition (ASQ-3)
timeFrame: 12 months of age
measure: Ages and Stages Questionnaire Third Edition (ASQ-3)
timeFrame: 24 months
measure: Childhood Behavior Checklist (CBCL) T-Scores
timeFrame: Once post discharge (between 18 months up to 24 months of age)
Secondary outcomes:
measure: Duration of Treatment
timeFrame: 60 days
measure: Childhood Behavior Checklist 1.5-5 T-Scores
timeFrame: Once post discharge (between 18 months up to 24 months of age)
Other outcomes:
Locations:
city: Lexington
country: United States
facility: Kentucky Children's Hospital
state: Kentucky
Study officials:
affiliation: University of Kentucky
name: Henrietta S Bada, MD MPH
role: PRINCIPAL_INVESTIGATOR
References:
citation: Bada HS, Sithisarn T, Gibson J, Garlitz K, Caldwell R, Capilouto G, Li Y, Leggas M, Breheny P. Morphine versus clonidine for neonatal abstinence syndrome. Pediatrics. 2015 Feb;135(2):e383-91. doi: 10.1542/peds.2014-2377.
citation: Lester BM, Tronick EZ, LaGasse L, Seifer R, Bauer CR, Shankaran S, Bada HS, Wright LL, Smeriglio VL, Lu J. Summary statistics of neonatal intensive care unit network neurobehavioral scale scores from the maternal lifestyle study: a quasinormative sample. Pediatrics. 2004 Mar;113(3 Pt 2):668-75.