No-POPPY: Non-Opiate Treatment After Prenatal Opiate Exposure to Prevent Postnatal Injury to the Young Brain

Sponsor

Henrietta Bada (Other)

Overall Status

Recruiting

CT.gov ID

NCT03396588

Collaborator

National Institute on Drug Abuse (NIDA) (NIH)

200

Enrollment

Location

Arms

62.7

Anticipated Duration (Months)

3.2

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Neonatal Abstinence Syndrome	Drug: Clonidine Drug: Morphine	Phase 3

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.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

200 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

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.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 (Participant, Care Provider, Investigator, Outcomes Assessor)

Masking Description:

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.

Primary Purpose:

Treatment

Official Title:

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

Actual Study Start Date :

Dec 7, 2017

Anticipated Primary Completion Date :

Feb 28, 2023

Anticipated Study Completion Date :

Feb 28, 2023

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Clonidine Babies randomized to clonidine will receive 1mcg/kg/dose (with a dosing interval of 3 or 4 hours).	Drug: Clonidine 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. Other Names: clonidine hydrochloride
Active Comparator: Morphine Babies randomized to morphine will receive 0.06 mg/kg/dose (with a dosing interval of 3 or 4 hours).	Drug: Morphine 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. Other Names: Morphine Sulfate

Arm

Intervention/Treatment

Active Comparator: Clonidine

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

Drug: Clonidine

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.

Other Names:

clonidine hydrochloride

Active Comparator: Morphine

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

Drug: Morphine

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.

Other Names:

Morphine Sulfate

Outcome Measures

Primary Outcome Measures

Neurobehavioral Performance Summary Scores from the Neonatal Intensive Care Unit Network Neurobehavioral Scale (NNNS) [5-10 days post natal age]
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.
Neurobehavioral Performance Summary Scores from the Neonatal Intensive Care Unit Network Neurobehavioral Scale (NNNS) [At one month post-natal age (between 4-6 weeks of age), or at discharge, whichever comes first]
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.
Bayley Scales of Infant and Toddler Development Third Edition [6 months of life]
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.
Bayley Scales of Infant and Toddler Development Third Edition [1 year of life]
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.
Bayley Scales of Infant and Toddler Development Third Edition [2 years of life]
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.

Secondary Outcome Measures

Duration of treatment [60 days]
Total number days of treatment

Eligibility Criteria

Criteria

Ages Eligible for Study:

12 Hours to 7 Days

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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