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

NCT03396588 | Completed Phase 3 Results FDA Drug

• 2 other identifiers: 11-0534-F341R01DA043519-01
• Study Type: interventional
• Target: 120
• Locations: 1 country
• Sites: 1

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.

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

Outcome Measures

Primary Outcomes (7)

• Change in 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.

  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.

• 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 with a range of 55-155 for cognitive and a range of 45-155 for language and motor (lower scores indicating greater impairment). 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 composite 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 with a range of 55-155 for cognitive and a range of 45-155 for language and motor (lower scores indicating greater impairment). 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 composite 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 with a range of 55-155 for cognitive and a range of 45-155 for language and motor (lower scores indicating greater impairment). 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 composite score.

  2 years of life

• Ages and Stages Questionnaire Third Edition (ASQ-3)

  The ASQ-3 is a developmental screening tool to assess developmental progress in children. Children are scored in the areas of communication, gross motor skills, fine motor skills, problem solving, and personal/social skills. The child's parent/guardian answers whether their child already does an activity (yes=10), sometimes does it (sometimes=5), or does not yet do it (not yet=0). The answers are then used to score each category. Each category is then broken down into whether the child falls above the cutoff (child development is on schedule), close to the cutoff (child development is slightly delayed and requires monitoring/intervention), or below the cutoff (delayed development and further assessment required).

  12 months of age

• Ages and Stages Questionnaire Third Edition (ASQ-3)

  The ASQ-3 is a developmental screening tool to assess developmental progress in children. Children are scored in the areas of communication, gross motor skills, fine motor skills, problem solving, and personal/social skills. The child's parent/guardian answers whether their child already does an activity (yes=10), sometimes does it (sometimes=5), or does not yet do it (not yet=0). The answers are then used to score each category. Each category is then broken down into whether the child falls above the cutoff (child development is on schedule), close to the cutoff (child development is slightly delayed and requires monitoring/intervention), or below the cutoff (delayed development and further assessment required).

  24 months

• Childhood Behavior Checklist (CBCL) T-Scores

  The CBCL/1.5-5 is validated for children ages 1.5 to 5 years old. It obtains caregivers' ratings of 113 behavior items. Scores are broken down into internalizing problems (scores range 29-100, normal is below 60), externalizing problems (scores range from 28-100, normal is below 60), and total problems (range is 28-100, normal is below 60). Items are scored on the following syndrome scales: Emotionally Reactive, Anxious/Depressed, Somatic Complaints, Withdrawn, Attention Problems, Aggressive Behavior, and Sleep Problems. Items are also scored on the following DSM-oriented scales: Affective Problems, Anxiety Problems, Pervasive Developmental Problems, Attention Deficit/Hyperactivity Problems, Stress Problems, Autism Spectrum Problems, and Oppositional Defiant Problems. The CBCL consists of 113 items, scored on a three-point Likert scale (0=absent, 1= occurs sometimes, 2=occurs often)

  Once post discharge (between 18 months up to 24 months of age)

Secondary Outcomes (2)

• Duration of Treatment

  60 days

• Childhood Behavior Checklist 1.5-5 T-Scores

  Once post discharge (between 18 months up to 24 months of age)

Study Arms (2)

Clonidine

ACTIVE COMPARATOR

Babies randomized to clonidine will receive 1mcg/kg/dose (with a dosing interval of 3 or 4 hours).

Drug: Clonidine

Morphine

ACTIVE COMPARATOR

Babies randomized to morphine will receive 0.06 mg/kg/dose (with a dosing interval of 3 or 4 hours).

Drug: Morphine

Interventions

Clonidine DRUG

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.

Also known as: clonidine hydrochloride

Clonidine

Morphine DRUG

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.

Also known as: Morphine Sulfate

Morphine

Eligibility Criteria

• Age: 12 Hours - 7 Days
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• 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

You may not qualify if:

• Seizures
• Major congenital malformations
• Blood pressure instability
• Major medical condition in addition to NAS
• Parents unable to understand English

Sponsors & Collaborators

• Henrietta Bada: lead
• National Institute on Drug Abuse (NIDA): collaborator

Study Sites (1)

Kentucky Children's Hospital

Lexington, Kentucky, 40536, United States

Location

Related Publications (2)

• 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.

  PMID: 25624389 BACKGROUND

• 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.

  PMID: 14993525 BACKGROUND

MeSH Terms

Conditions

Neonatal Abstinence Syndrome; Infant, Newborn, Diseases; Substance-Related Disorders; Chemically-Induced Disorders; Mental Disorders

Interventions

Clonidine; Morphine

Condition Hierarchy (Ancestors)

Congenital, Hereditary, and Neonatal Diseases and Abnormalities

Intervention Hierarchy (Ancestors)

Imidazolines; Imidazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Morphine Derivatives; Morphinans; Opiate Alkaloids; Alkaloids; Heterocyclic Compounds, Bridged-Ring; Heterocyclic Compounds, 4 or More Rings; Heterocyclic Compounds, Fused-Ring; Phenanthrenes; Polycyclic Aromatic Hydrocarbons; Polycyclic Compounds

Results Point of Contact

• Title: Dr. Henrietta Bada
• Organization: University of Kentucky

henrietta.bada@uky.edu

8593231019

Study Officials

• Henrietta S Bada, MD MPH

  University of Kentucky

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: The study will mask parents and child caregivers, and NICU nurses giving the drug, other personnel, residents and attending physicians, and research staff. Since initial dose is set using weight based-dosing, a physician's order can be entered in the electronic medical record to give the initial study drug with the infant's weight stated in the order. Increase in dosing will be ordered as to increase by 25% of initial dose or decrease of dose by 10% of maximum dose. During the pilot study, masking of treating personnel was maintained while the hospital pharmacist was the only person aware of which study drug the infant was receiving. The examiners for administration of the NNNS and the research nurse and research case worker will be masked to treatment received. Those seeing the infant in the clinic will also be masked to the treatment assignment. Morphine and clonidine are dispensed in identical appearance, color, smell, and volume.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Professor of Pediatrics

Model Details: 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.

Study Record Dates

• First Submitted: December 13, 2017
• First Posted: January 11, 2018
• Study Start: December 7, 2017
• Primary Completion: April 10, 2024
• Study Completion: April 10, 2024
• Last Updated: May 23, 2025
• Results First Posted: May 23, 2025

Record last verified: 2025-05

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)